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Psorilax:Dove si compra |crema corpo proxera psomed 20 per curare la psoriasi

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Psorilax: prezzo, funziona, recensioni, opinioni, come si usa

Number: 0658

Commercial CPB | Medicare CPB

Least Cost Medically Necessary Brands

Moderate to severe plaque psoriasis

Avsola (infliximab-axxq), Cosentyx (secukinumab), Enbrel (etanercept), Inflectra (infliximab-dyyb), Renflexis (infliximab-abda), and Siliq (brodalumab) brands are more costly to Aetna than other brands of targeted immune modulators (“least cost brands of targeted immune modulators”) for moderate to severe plaque psoriasis. There is a lack of reliable evidence that these brands are superior to the least cost brands of targeted immune modulators Humira, Ilumya, Otezla, Remicade, Skyrizi, Stelara (SQ), Taltz, and Tremfya for plaque psoriasis. Therefore, Aetna considers Avsola, Cosentyx, Enbrel, Inflectra, Renflexis, and Siliq to be medically necessary for members who have a contraindication, intolerance or ineffective response to the least cost brands of targeted immune modulators per criteria below:

  • For the subcutaneously administered targeted immune modulators Cosentyx, Enbrel, and Siliq, member has a contraindication, intolerance or ineffective response to all of the following subcutaneously and orally administered least cost brands (one-month trial): Humira, Ilumya, Otezla, Skyrizi, Stelara (SQ), Taltz, and Tremfya.

  • For the intravenously administered targeted immune modulators Avsola, Inflectra, and Renflexis member has a contraindication, intolerance or ineffective response to all of the following least cost brands (one-month trial): Humira, Ilumya, Otezla, Remicade, Skyrizi, Stelara (SQ), Taltz, and Tremfya.

Active psoriatic arthritis (PsA)

Avsola (infliximab-axxq), Inflectra (infliximab-dyyb), Orencia (abatacept), Renflexis (infliximab-abda), Simponi (golimumab for subcutaneous injection), Stelara (ustekinumab for subcutaneous injection), Taltz (ixekizumab), Xeljanz (tofacitinib), and Xeljanz XR (tofacitinib extended-release) brands are more costly to Aetna than other brands of targeted immune modulators (“least cost brands of targeted immune modulators”) for active psoriatic arthritis. There is a lack of reliable evidence that these brands are superior to the least cost brands of targeted immune modulators Cosentyx, Enbrel, Humira, Otezla, Remicade, and Simponi Aria for active psoriatic arthritis. Therefore, Aetna considers Avsola, Inflectra, Orencia, Renflexis, Simponi, Stelara (SQ), Taltz, Xeljanz and Xeljanz XR to be medically necessary for members who have a contraindication, intolerance or ineffective response to the least cost brands of targeted immune modulators per criteria below:

  • For the subcutaneously and orally administered targeted immune modulators Orencia (SQ), Simponi (SQ), Stelara (SQ), Taltz, Xelajanz and Xeljanz XR, member has a contraindication, intolerance or ineffective response to all of the following subcutaneously and orally administered least cost brands (one-month trial each): Cosentyx, Enbrel, Humira, and Otezla.

  • For the intravenously administered targeted immune modulators Avsola, Inflectra, Renflexis, and Orencia (IV) member has a contraindication, intolerance or ineffective response to all of the following least cost brands (one-month trial each): Cosentyx, Enbrel, Humira, Otezla, Remicade, and Simponi Aria.

Policy

Note: REQUIRES PRECERTIFICATION.

Precertification of targeted immune modulators for psoriasis and psoriatic arthritis is required of all Aetna participating providers and members in applicable plan designs.  For precertification of these agents, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies. For information on site of service for infliximab products (Remicade, Avsola, Inflectra, and Renflexis), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

  1. Moderate to severe plaque psoriasis (PsO)

    Aetna considers targeted immune modulators adalimumab (Humira), apremilast (Otezla), brodalumab (Siliq), certolizumab (Cimzia), etanercept (Enbrel), guselkumab (Tremfya)  infliximab (Remicade, Avsola, Inflectra, Renflexis), ixekizumab (Taltz), risankizumab-rzaa (Skyrizi), secukinumab (Cosentyx), tildrakizumab-asmn (Ilumya), and ustekinumab (Stelara) medically necessary for the treatment of moderate-to-severe plaque psoriasis who meet the following:

    1. For members who have previously received apremilast (Otezla) or a biologic indicated for the treatment of moderate-to-severe plaque psoriasis; or
    2. For treatment of moderate-to-severe plaque psoriasis when any of the following criteria are met:
      1. Crucial body areas (e.g., hands, feet, face, neck, scalp, genitals/groin, intertriginous areas) are affected; or
      2. At least 10% of the body surface area (BSA) is affected; or
      3. At least 3% of the BSA is affected and the member meets any of the following criteria:
        1. Member has had an inadequate response or intolerance to either phototherapy (e.g., UVB, PUVA) or pharmacologic treatment with methotrexate, cyclosporine, or acitretin; or
        2. Member has a clinical reason to avoid pharmacologic treatment with methotrexate, cyclosporine, and acitretin (see Appendix).
  2. Active psoriatic arthritis (PsA)

    Aetna considers targeted immune modulators abatacept (Orencia), adalimumab (Humira), apremilast (Otezla), certolizumab (Cimzia), etanercept (Enbrel), infliximab (Remicade, Avsola, Inflectra, Renflexis), ixekizumab (Taltz), golimumab (Simponi and Simponi Aria), secukinumab (Cosentyx), and ustekinumab (Stelara) medically necessary for the treatment of active psoriatic arthritis (PsA).

    Aetna considers targeted immune modulator tofacitinib (Xeljanz and Xeljanz XR) medically necessary when used in combination with a nonbiologic DMARD for the treatment of active PsA; see CPB 0839 – Tofacitinib (Xeljanz).

  3. TB testing for all indications

    Except for apremilast (Otezla), member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray) within 6 months of initiating therapy for persons who are naive to biologics, and repeated yearly for members with risk factors for TB that are continuing therapy with biologics.

  4. Continuation of therapy

    Aetna considers continuation of targeted immune modulators medically necessary for all members (including new members) who are using a targeted immune modulator for an indication outlined above and who achieve or maintain positive clinical response as evidenced by low disease activity or improvement in signs and symptoms of the condition. Note: for brodalumab (Siliq) only, further treatment is contraindicated and considered not medically necessary in persons who develop Crohn’s disease during treatment.

  5. Experimental and Investigational

    Aetna considers the use of targeted immune modulators in combination with other targeted immune modulators for plaque psoriasis (e.g., adalimumab (Humira), apremilast (Otezla), brodalumab (Siliq), certolizumab (Cimzia), etanercept (Enbrel), guselkumab (Tremfya) infliximab (Remicade, Avsola, Inflectra, Renflexis), ixekizumab (Taltz), risankizumab-rzaa (Skyrizi), secukinumab (Cosentyx), tildrakizumab-asmn (Ilumya), and ustekinumab (Stelara)) experimental and investigational because of insufficient evidence of effectiveness.

    Aetna considers combination use of two or more targeted immune modulators for psoriatic arthritis experimental and investigational because of insufficient evidence of effectiveness.

Notes:

As of June 8, 2009, efalizumab (Raptiva) is no longer available in the U.S. market (FDA, 2009).

As of November 16, 2011, alefacept (Amevive) is no longer available in the U.S. market.

For ustekinumab for Crohn’s disease, see CPB 0912 – Ustekinumab (Stelara) or CPB 0912m – Ustekinumab (Stelara) (Medicare).

Dosing Recommendations

Abatacept (Orencia) (BMS, 2019)

Available as:

Adalimumab (Humira) (AbbVie, 2019)

  • Available as a subcutaneous injection
    • Injection: 40 mg/0.8 mL in a single‐use prefilled pen (Humira Pen)
    • Injection: 40 mg/0.8 mL in a single‐use prefilled glass syringe
    • Injection: 40 mg/0.4 mL in a single‐use prefilled glass syringe
    • Injection: 20 mg/0.4 mL in a single‐use prefilled glass syringe
    • Injection: 10 mg/0.2 mL in a single‐use prefilled glass syringe
    • Injection: 40 mg/0.8 mL in a single‐use glass vial for institutional use only
  • Psoriatic Arthritis (PsA): The recommended dose of Humira for adults with PsA is 40 mg administered every other week. Methotrexate (MTX), other non-biologic DMARDS, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Humira.
  • Plaque Psoriasis: The recommended dose of Humira for adults with plaque psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. The use of Humira in moderate to severe chronic plaque psoriasis beyond one year has not been evaluated in controlled clinical studies.

Apremilast (Otezla) (Celgene, 2019)

Brodulumab (Siliq) (Valeant, 2017)

Certolizumab (Cimzia) (UCB, 2019)

  • Available as 200 mg lyophylized powder for reconstitution in a single‐use vial and 200 mg/mL in a single‐use prefilled glass syringe for subcutaneous administration.
  • Plaque Psoriasis: The recommended dose of Cimzia for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy is 400 mg (given as two subcutaneous injections of 200 mg each) every other week. For some persons (with body weight less than or equal to 90 kg), a dose of 400 mg (given as two subcutaneous injections of 200 mg each) initially and at Weeks 2 and 4, followed by 200 mg every other week may be considered.
  • Psoriatic Arthritis: The recommended dose of Cimzia for adults with psoriatic arthritis is 400 mg (given as two subcutaneous injections of 200 mg) initially and at Weeks 2 and 4, followed by 200 mg every other week. For maintenance dosing, Cimzia 400 mg every 4 weeks can be considered.

Etanercept (Enbrel) (Amgen, 2019)

  • Available as subcutaneous injection
    • Injection: 25 mg/0.5 mL and 50 mg/mL solution in a single-dose prefilled syringe
    • Injection: 50 mg/mL solution in single-dose prefilled SureClick Autoinjector
    • Injection: 25 mg lyophilized powder in a multiple-dose vial for reconstitution
    • Injection: 50 mg/mL solution in Enbrel Mini® single-dose prefilled cartridge for use with the AutoTouch® reusable autoinjector only
  • Plaque Psoriasis in persons 4 years or older:
    • Adults: 50 mg twice weekly for 3 months, followed by 50 mg once weekly
    • Pediatric: 0.8 mg/kg weekly, with a maximum of 50 mg per week
  • Psoriatic Arthritis: 50 mg once weekly with or without methotrexate (MTX)

Golimumab (Simponi and Simponi Aria) (Janssen Biotech, 2018)

  • Simponi is available as subcutaneous (SC) injection:
    • 50 mg/0.5 mL in a single-dose prefilled syringe or single-dose prefilled SmartJect autoinjector
    • 100 mg/mL in a single-dose prefilled syringe or single-dose prefilled SmartJect autoinjector
  • Psoriatic Arthritis: The Simponi dose regimen is 50 mg administered by SC injection once a month. Simponi may be given with or without methotrexate or other nonbiologic Disease-Modifying Antirheumatic Drugs (DMARDs). Corticosteroids, non-biologic DMARDs, and/or NSAIDs may be continued during treatment with Simponi.
  • Simponi Aria is available as intravenous (IV) infusion:
    • Injection: 50 mg/4 mL (12.5 mg/mL) solution in a single-dose vial
  • Psoriatic Arthritis: The Simponi Aria dose regimen is 2 mg / kg given as an IV infusion over 30 minutes at weeks 0 and 4, then every 8 weeks thereafter. May be given with or without methotrexate or other non-biologic DMARDs. Corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be continued during treatment with Simponi Aria.
  • The efficacy and safety of switching between IV and SC formulations and routes of administration have not been established.

Guselkumab (Tremfya) (Janssen Biotech, 2019)

  • Available as subcutaneous injection: 100 mg/mL in a single-dose prefilled syringe or single-dose One-Press person-controlled injector
  • Plaque Psoriasis: The recommended dose is 100 mg at Week 0, Week 4, and every 8 weeks thereafter.

Infliximab (Avsola, Remicade, Renflexis, Inflectra) (Amgen, 2019; Janssen Biotech, 2018; Merck, 2019; Pfizer, 2019)

  • Infliximab products (Avsola, Remicade, Renflexis, and Inflectra) are available for injection using 100 mg of lyophilized infliximab, or its biosimilar, in a 20 mL vial for intravenous infusion.
  • Plaque Psoriasis: Induction: 5 mg/kg at weeks 0, 2, and 6; and maintenance: 5 mg/kg IV every 8 weeks
  • Psoriasis Arthritis: Induction: 5 mg/kg at weeks 0, 2, and 6; and maintenance: 5 mg/kg IV every 8 weeks

Ixekizumab (Taltz) (Eli Lilly, 2020)

  • Available as subcutaneous injection: 80 mg/mL solution in a single-dose prefilled syringe, and 80 mg/mL solution in a single-dose prefilled autoinjector.
  • Plaque Psoriasis:
    • Adults: Recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks.
    • Pediatrics: The recommended dose is administered every 4 weeks by subcutaneous injection based on body weight for persons 6 to 17 years of age.
      Table: Recommended Dosing and Administration for Pediatrics
      Pediatric Body Weight Starting Dose (Week 0) Dose every 4 weeks Thereafter
      Greater than 50 kg 160 mg (two 80 mg injections) 80 mg
      25 to 50 kg 80 mg 40 mg
      Less than 25 kg 40 mg 20 mg
  • Psoriatic Arthritis:

    • Recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at Week 0, followed by 80 mg every 4 weeks
    • For persons with psoriatic arthritis who have coexistent moderate-to-severe plaque psoriasis, use the dosing regimen for adult plaque psoriasis
    • Talz may be administered alone or in combination with a conventional DMARD (e.g., methotrexate)

Risankizumab-rzaa (Skyrizi) (AbbVie, 2019b)

  • Available as subcutaneous injection: 75 mg/0.83 mL in a single-dose prefilled syringe
  • Plaque Psoriasis: The recommended dose is 150 mg (two 75 mg injections) administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

Secukinumab (Cosentyx) (Novartis, 2018)

  • Available as subcutaneous injection:
    • Injection: 150 mg/mL solution in a single-use Sensoready pen
    • Injection: 150 mg/mL solution in a single-use prefilled syringe
    • For Injection: 150 mg, lyophilized powder in a single-use vial for reconstitution for healthcare professional use only
  • Plaque Psoriasis: The recommended dose is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks. Each 300 mg dosage is given as 2 subcutaneous injections of 150 mg. For some individuals, a dosage of 150 mg may be acceptable.
  • Psoriatic Arthritis:
    • For persons with PsA and coexistent moderate to severe plaque psoriasis (PsO), use the dosing and administration recommendations for PsO
    • For other individuals with PsA, administer Cosentyx with or without a loading dosage by subcutaneous injection. The recommended dosage:
      • With a loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter
      • Without a loading dosage is 150 mg every 4 weeks
      • If a person continues to have active psoriatic arthritis, consider a dosage of 300 mg.
  • Cosentyx may be administered with or without methotrexate.

Tildrakizumab-asmn (Ilumya) (Merck, 2018)

  • Available as subcutaneous injection: 100 mg/mL solution in a single-dose prefilled syringe.
  • Plaque Psoriasis: The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter. Each syringe contains 1 mL of 100 mg/mL tildrakizumab-asmn.

Tofacitinib (Xeljanz and Xeljanz XR) (Pfizer, 2019)

  • Xeljanz is available as 5 mg, 10 mg tablets
  • Xeljanz XR is available as 11 mg tablets
  • Psoriatic Arthritis (in combination with nonbiologic DMARDs): Xeljanz 5 mg twice-daily or Xeljanz XR 11 mg once-daily. Decrease dose to 5 mg once-daily in persons with moderate and severe renal impairment or moderate hepatic impairment.
  • Discontinue dosing for persons with lymphocyte count less than 500 cells/mm3, confirmed by repeat testing, and persons with ANC less than 500 cells/mm3.

Ustekinumab (Stelara) (Janssen Biotech, 2018)

  • Available as:
  • Plaque Psoriasis:
    • Adult dosing:
      • Weight less than or equal to 100 kg, the recommended dose is 45 mg administered subcutaneously (SC) initially and 4 weeks later, followed by 45 mg SC every 12 weeks
      • Weight greater than 100 kg, the recommended dose is 90 mg administered SC initially and 4 week later, followed by 90 mg SC every 12 weeks
    • Adolescent (12 years and older):

      Weight based dosing is recommended at the initial dose administered SC, 4 weeks later, then every 12 weeks thereafter

  • Psoriatic Arthritis: (adults) The recommended dosage is 45 mg administered SC initially and 4 weeks later, followed by 45 mg SC every 12 weeks. For persons with co-existent moderate-to-severe plaque psoriasis weighing greater than 100 kg, the recommended dosage is 90 mg administered SC initially and 4 weeks later, followed by 90 mg administered SC every 12 weeks.

Background

Psoriasis is a common chronic skin disease characterized by cutaneous inflammation and epidermal hyperproliferation.  Lesions appear on any part of the skin, but particularly the scalp, sacral area, and over the extensor aspect of the knees and elbows.

Ultraviolet light in conjunction with systemic psoralens (PUVA) is the phototherapy treatment of first choice for psoriasis other than localized psoriasis.  PUVA is a form of photochemotherapy that combines the use of a psoralens (e.g., methoxsalen) with ultraviolet A phototherapy in the range of 320 to 400 nm.  PUVA is highly effective in the treatment of psoriasis with resolution of skin lesions in over 85 % of patients after 20 to 30 treatments combining drug use and ultraviolet A irradiation.  UVB may be given alone or in combination with tar or dithranol.

Other systemic treatments for psoriasis include methotrexate or cyclosporine.  Both are contraindicated in pregnancy and require close monitoring.

Sbidian et al (2017) stated psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. There have been several randomized controlled trials (RCTs) comparing the efficacy of different systemic treatments; however, due to lack of head-to-head comparison, the benefit of these treatments remains unclear. Sbidian and colleagues conducted a network meta-analysis to compare the efficacy and safety of conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and ranked the treatments according to their efficacy and safety. The authors conducted a search of multiple databases which included CENTRAL, MEDLINE, Embase, and LILACS. An additional search of trial registers and the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports were used, to name a few. The selection criteria included RCTs of systemic and biological treatments in adults with moderate to severe plaque psoriasis or psoriatic arthritis at any stage of treatment, in comparison to placebo or another active agent. The data was ranked according to their effectiveness (as measured by the Psoriasis Area and Severity Index score (PASI) 90) and acceptability (the inverse of serious adverse effects). The authors included 109 studies, of which 39,882 participants were randomized. The authors found that most of the studies were placebo controlled (67%), 23% were head-to-head, and 10% were multi-armed with both an active comparator and placebo. In all, 86 trials were multicentric trials. All of the trials were limited to the induction phase (assessment at less than 24 weeks after randomization). All trials included in the network meta-analysis were measured between 12 and 16 weeks after randomization. The authors assessed the majority of studies (48/109) as being at high risk of bias; 38 were assessed as at an unclear risk, and 23, low risk. Network meta-analysis showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90; however, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents. At drug level, in terms of reaching PASI 90, all of the anti-IL17 agents and guselkumab (an anti-IL23 drug) were significantly more effective than the anti-TNF alpha agents infliximab, adalimumab, and etanercept, but not certolizumab. Ustekinumab was superior to etanercept. No clear difference was shown between infliximab, adalimumab, and etanercept. Only one trial assessed the efficacy of infliximab in this network; thus, these results have to be interpreted with caution. Tofacitinib was significantly superior to methotrexate, and no clear difference was shown between any of the other small molecules versus conventional treatments. Network meta-analysis also showed that ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab outperformed other drugs when compared to placebo in terms of reaching PASI 90: the most effective drug was ixekizumab, followed by secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab. The authors found no significant difference between all of the interventions and the placebo regarding the risk of serious adverse effects (SAEs): the relative ranking strongly suggested that methotrexate was associated with the best safety profile regarding all of the SAEs, followed by ciclosporin, certolizumab, infliximab, alefacept, and fumaric acid esters. Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability. Regarding the other efficacy outcomes, PASI 75 and Physician Global Assessment (PGA) 0/1, the results were very similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for a third of the interventions. The authors concluded that compared to placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis on the basis of moderate- to high-certainty evidence. At class level, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Study limitations include induction therapy outcomes were measured between 12 to 16 weeks after randomization and is not sufficiently relevant for a chronic disease, low numbers of studies were found for some of the interventions, and younger ages and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice. The authors note that short-term trials provide scanty and sometimes poorly reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. For this study, the authors found no significant difference in the assessed interventions and placebo in terms of SAEs, with methotrexate appearing to have the best safety profile. The authors state that long-term information on the safety of the treatments should also be evaluated in non-randomized studies and post-marketing reports released from regulatory agencies. The authors suggest that future research include randomized trials comparing directly active agents once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents. In addition, trials should include systematic subgroup analyses (e.g. assessing biological-naïve patients, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, in future psoriasis trials, researchers should look at the medium- and long-term benefit and safety of the interventions, as well as the comparative safety of different agents.

The NICE guidance for the assessment and management of Psoriasis (2017) stated that topical therapy was first-line treatment, followed by second- or third-line treatment options (phototherapy or systemic therapy) which could be added on when topical therapy alone is unlikely to adequately control psoriasis, such as for extensive disease (e.g. more than 10% of body surface area affected), or at least ‘moderate’ on the static Physician’s Global Assessment, or where topical therapy is ineffective, such as nail disease).

Psoriasis guidelines from the Academy of Dermatology (2011) stated that for mild disease, topical therapies are the mainstay as either monotherapy or in combination. For moderate to severe disease, topical therapies are commonly used in conjunction with phototherapy, traditional systemic agents, or biologic agents. Phototherapy, photochemotherapy, and traditional systemic agents are generally used for individuals with moderate or severe disease and in situations in which topical therapy is ineffective or otherwise contraindicated.

Guidelines on psoriasis from the British Association of Dermatologists (2017) state biologic therapy should be offered to people with psoriasis who require systemic therapy if:

  1. methotrexate and ciclosporin have failed, are not tolerated or are contraindicated (see NICE guidelines CG153) and
  2. the psoriasis has a large impact on physical, psychological or social functioning (e.g. Dermatology Life Quality Index (DLQI) or Children’s DLQI > 10 or clinically relevant depressive or anxiety symptoms) and

one or more of the following disease severity criteria apply:

  1. the psoriasis is extensive (defined as body surface area (BSA) > 10% or Psoriasis Area and Severity Index (PASI) ≥ 10)
  2. the psoriasis is severe at localized sites and associated with significant functional impairment and/or high levels of distress (e.g. nail disease or involvement of high-impact and difficult-to-treat sites such as the face, scalp, palms, soles, flexures and genitals).

Consider biologic therapy earlier in the treatment pathway in people with psoriasis who fulfill the disease severity criteria and who also have active psoriatic arthritis or who have psoriasis that is persistent, i.e. that relapses rapidly (defined as >50% baseline disease severity within 3 months of completion of any treatment) off a therapy that cannot be continued in the long-term (e.g. narrowband ultraviolet B).

Abatacept

Abatacept is a selective costimulation modulator which inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of psoriatic arthritis (PsA) and are found in the synovium of patients with PsA. In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which Orencia exerts its clinical effects is unknown (BMS, 2017).

In July 2017, the U.S. Food and Drug Administration (FDA) approved Orencia (abatacept) for the treatment of adults with active psoriatic arthritis (PsA). PsA is a chronic, inflammatory disease that can affect the skin and musculoskeletal system, which can cause joint pain, stiffness and reduced range of motion.

FDA approval of Orencia for active PsA was based on the results from two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II) in 594 adult patients with disease duration more than seven years. Patients had active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF inhibitors (TNFi) previously. A higher proportion of patients treated with Orencia 10 mg/kg IV or 125 mg SC achieved an ACR20 response at week 24 compared to placebo, 47.5% versus 19.0% and 39.4% versus 22.3% (p< 0.05), respectively. Responses were seen regardless of prior anti-TNFi treatment and regardless of concomitant non-biologic DMARD treatment. Improvements in enthesitis and dactylitis were seen with Orencia treatment at week 24 in both IV and SC (BMS, 2017).

For the adult patient, Orencia (abatacept) may be administered as an IV infusion or a subcutaneous (SC) injection, with or without non-biologic DMARDs.  The safety and efficacy of Orencia ClickJect autoinjector for subcutaneous injection have not been studied in patients under 18 years of age.

Concurrent therapy with Orencia and a TNF antagonist (such as adalimumab, etanercept, and infliximab) is not recommended because such combination therapy may increase risk for infections. In controlled clinical trials, adult RA patients receiving concomitant intravenous Orencia and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important enhancement of efficacy. Furthermore, it is not recommended that patients receive Orencia concomitantly with other biologic RA therapy, such as anakinra, because there is not enough informaton to assess the safety and efficacy of such comination therapy (BMS, 2017).

Maltose is present in Orencia for intravenous (IV) administration, which can result in falsely elevated blood glucose reading on the day of the infusion. When receiving Orencia through IV administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

Orencia for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.

Common side effects of Orencia include: headache, upper respiratory infection, sore throat, and nausea (not an all-inclusive list).

Adalimumab

Adalimumab has been approved by the FDA for the treatment for adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.  According to the FDA-approved labeling, adalimumab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.  Chronic plaque psoriasis is an autoimmune disease characterized by inflammed, scaly skin lesions known as plaques, which may crack and bleed.  While psoriasis can occur in people of all ages, it typically appears in patients between the ages of 15 and 35 years.  Approximately 25 % of persons with chronic plaque psoriasis exhibit moderate to severe disease.  Up to 30 % of psoriasis patients develop psoriatic arthritis.  Treatment may include topical agents, phototherapy or oral or injectable medications.

The FDA approval of adalimumab for chronic plaque psoriasis was based on 2 pivotal trials, REVEAL and CHAMPION, showing that approximately 3 out of 4 patients achieved 75 % clearance or better at week 16 of treatment versus placebo.  Both studies evaluated the efficacy and safety of Humira in clearing skin in moderate to severe adult plaque psoriasis patients versus placebo.  In addition, CHAMPION compared a biologic medication to methotrexate, a standard systemic treatment for psoriasis.   In each trial, reduction in disease activity was determined by the Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA).  In REVEAL, a 52-week trial, the short-term and sustained clinical efficacy and safety of adalimumab were evaluated in 1,212 patients with moderate to severe chronic plaque psoriasis.  Patients experienced a significant reduction in the signs and symptoms of their disease at 16 weeks when treated with adalimumab.  Specifically, 71 % of patients receiving adalimumab achieved PASI 75 compared to 7 % of patients receiving placebo at week 16.  At week 16, 62 % of adalimumab-treated patients achieved a PGA score of clear or minimal compared to 4 % of placebo-treated patients.  In CHAMPION, a 16-week study evaluating 271 psoriasis patients, adalimumab-treated patients experienced a significant reduction in the signs and symptoms of their disease compared with methotrexate or placebo-treated patients.  Seventy-eight percent of patients treated with adalimumab (n = 99) achieved a PASI 75 response, compared to 19 % of patients treated with placebo (n = 48).  Seventy-one percent of patients treated with adalimumab achieved a PGA score of clear or minimal at 16 weeks of treatment, compared with 10 % of placebo-treated patients.  The safety profile of adalimumab in the plaque psoriasis clinical trials was reported to be similar to that seen in adalimumab clinical trials for rheumatoid arthritis.  The most commonly reported adverse events in adalimumab psoriasis trials were upper respiratory tract infection, nasopharyngitis (inflammation of the nose and pharynx), headache, sinusitis and arthralgia.  In clinical studies of plaque psoriasis, patients are treated with an initial 80 mg dose of adalimumab (2 40-mg injections) followed by 1 adalimumab injection (40 mg) 1 week later.  After that, a maintenance dose of 40 mg  was administered every other week.

Apremilast

Otezla (apremilast) is a phosphodiesterase‐4 inhibitor specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action in psoriatic arthritis patients is not well defined.

Otezla (apremilast) is indicated for the treatment of adult patients with active psoriatic arthritis and patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. The FDA approved apremilast (Otezla) to treat adults with active psoriatic arthritis. The safety and effectiveness of apremilast, an inhibitor of phosphodieasterase-4 (PDE-4), were evaluated in three clinical trials involving 1,493 patients with active psoriatic arthritis. Patients treated with apremilast showed improvement in signs and symptoms of psoriatic arthritis, including tender and swollen joints and physical function, compared to placebo. In clinical trials, the most common side effects observed in patients treated with apremilast were diarrhea, nausea, and headache. The FDA is requiring a pregnancy exposure registry as a post-marketing requirement to assess the risks to pregnant women related to apremilast exposure.

The FDA approved apremilast (Otezla) for the treatment of patients with moderate to severe plaque psoriasis for whom phototherapy or systemic therapy is appropriate (Celgene, 2014). The approval of apremilast was based primarily on safety and efficacy results from two multi-center, randomized, double-blind, placebo-controlled studies – ESTEEM 1 and ESTEEM 2 – conducted in adult patients with moderate to severe plaque psoriasis: body surface area (BSA) involvement of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe disease), Psoriasis Area and Severity Index (PASI) score ≥12, and candidates for phototherapy or systemic therapy (Celgene, 2014).

ESTEEM 1 and 2 are two large pivotal phase III randomized, placebo-controlled studies evaluating apremilast in patients with a diagnosis of moderate to severe plaque psoriasis for at least 12 months prior to screening, and who were also candidates for phototherapy and/or systemic therapy (Celgene, 2014). Approximately 1,250 patients were randomized 2:1 to receive either apremilast 30 mg twice daily or placebo after an initial five-day titration period, for the first 16 weeks, followed by a maintenance phase from weeks 16-32 in which placebo patients were switched to apremilast 30 mg twice daily through week 32, and a randomized withdrawal phase for responders from week 32 to week 52 based on their initial apremilast randomization and PASI-75 response. In the ESTEEM studies, apremilast treatment resulted in significant and clinically meaningful improvements in plaque psoriasis as measured by PASI scores at week 16. Clinical improvement as measured by sPGA scores of clear to almost clear were also demonstrated in both studies. The safety of apremilast was assessed in 1,426 patients from three clinical trials (Celgene, 2014). Side effects of apremilast were diarrhea, nausea, upper respiratory tract infection, tension headache, and headache.

According to the labeling, patients treated with apremilast should have their weight monitored regularly by a healthcare professional. If unexplained or clinically significant weight loss occurs, the weight loss should be evaluated and discontinuation of treatment should be considered. Treatment with apremilast was also associated with an increase in reports of depression compared to placebo.

Warnings and Precautions:

Depression ‐ Treatment with Otezla is associated with an increase in adverse reactions of depression. Prescribers should carefully evaluate the risks and benefits of initiation and continuation with Otezla.

Weight decrease ‐ Patients treated with Otezla should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, discontinuation of Otezla should be considered.

Drug interactions:

Use with strong CYP450 enyme inducers (e.g. rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur.

Brodalumab

The FDA approved brodalumab (Siliq) injection, a monoclonal antibody that targets the IL-17 receptor for patients with moderate-to-severe plaque psoriasis.  Brodalumab is indicated for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies.

Brodalumab works by binding to IL-17RA with high affinity, therefore blocking the inflammatory downstream activity of IL-17A, IL-17F, IL-17A/F heterodimer and IL-17E. By targeting the IL-17 receptor, brodalumab prevents skin cells from accumulating. In three clinical studies that have been completed, more than 50% of patients who used brodalumab achieved total skin clearance within a year.

Brodalumab’s safety and efficacy were established in three AMAGINE randomized, placebo-controlled clinical trials with a total of 4,373 adult participants with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. More patients treated with brodalumab compared to placebo had skin that was clear or almost clear, as assessed by scoring of the extent, nature and severity of psoriatic changes of the skin. At the 210 mg dose, approximately twice as many patients on brodalumab achieved total skin clearance compared to ustekinumab at week 12 in two replicate comparator trials involving over 2,400 patients.

Brodalumab has a Black Box Warning for the risks in patients with a history of suicidal thoughts or behavior. Brodalumab was approved with a Risk Evaluation and Mitigation Strategy (REMS) involving a one-time enrollment for physicians and one-time informed consent for patients. Notable requirements of the Siliq REMS Program include the following:

  • Prescribers must be certified with the program and counsel patients about this risk. Patients with new or worsening symptoms of depression or suicidality should be referred to a mental health professional, as appropriate.
  • Patients must sign a Patient-Prescriber Agreement Form and be made aware of the need to seek medical attention should they experience new or worsening suicidal thoughts or behavior, feelings of depression, anxiety or other mood changes.
  • Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Siliq.

Siliq is also approved with a Medication Guide to inform patients of the risk of suicidal ideation and behavior, and that because Siliq is a medication that affects the immune system, patients may have a greater risk of getting an infection, or an allergic or autoimmune condition. Patients with Crohn’s disease should not use Siliq. Health care providers should also evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Siliq. Health care providers should not administer Siliq to patients with active TB infection, and should avoid immunizations with live vaccines in patients being treated with Siliq.

The most common adverse reactions were headache, arthralgia, fatigue, oropharyngeal pain, and diarrhea. Brodalumab is contraindicated in patients with Crohn’s disease. Suicidal ideation and behavior have been reported. Serious infections have occurred therefore caution should be exercised when considering the use of brodalumab in patients with a chronic infection or a history of recurrent infection. Patients should be evaluated for tuberculosis infection prior to initiating treatment.

Certolizumab

On May 29, 2018, the U.S. Food and Drug Administration (FDA) approved the biologic Cimzia (certolizumab pegol) for the treatment of adults with psoriasis who are eligible for systemic therapy or phototherapy. Certolizumab is already approved in moderately to severely active Crohn’s disease, moderately to severely active rheumatoid arthritis, active psoriatic arthritis, and active ankylosing spondylitis. Certolizumab is a recombinant, humanized antibody Fab’ fragment that binds to and blocks human TNFα, a key pro-inflammatory cytokine with a central role in inflammatory processes. A potential advantage of certolizumab pegol is minimal transfer across the placenta; unlike other anti-TNF biologics, certolizumab pegol does not bind the neonatal Fc receptor because it does not contain a fragment crystallizable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood-derived monocytes or lymphocytes, nor does certolizumab pegol induce neutrophil degranulation.

FDA approval of certolizumab in adult plaque psoriasis was based on three multicenter, randomized, double-blind studies (CIMPASI-1 (NCT02326298), CIMPASI-2 (NCT02326272), and CIMPACT (NCT02346240)) that enrolled subjects 18 years of age or older with moderate-to-severe plaque psoriasis who were eligible for systemic therapy or phototherapy. Subjects had a Physician Global Assessment (PGA) of 3 or greater (“moderate”) on a 5-category scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score 12 or greater, and body surface area (BSA) involvement of 10% or more.

Gottlieb et al (2018) stated certolizumab pegol, the only Fc-free, PEGylated anti-tumor necrosis factor biologic, demonstrated clinically meaningful improvements suggestive of a positive risk-benefit balance in phase 2 studies in adults with moderate-to-severe chronic plaque psoriasis. The authors assessed certolizumab (CZP) efficacy and safety versus placebo in two phase 3 studies (CIMPASI-1 (NCT02326298) and CIMPASI-2 (NCT02326272)). Of 587 participants screened for both studies, 234 were randomized in CIMPASI-1 and 227 were randomized in CIMPASI-2. At the baseline visit, patients were assigned to subcutaneous treatment with CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks (after loading dose of CZP 400 mg at weeks 0, 2, and 4), or placebo every 2 weeks until week 16 (initial treatment period) according to the randomization schedule produced by an independent biostatistician (2:2:1, stratified by site). Studies CIMPASI-1 and CIMPASI-2 assessed the co-primary endpoints of the proportion of patients who achieved a 75% reduction in Psoriasis Area and Severity Index (PASI 75) and Physician’s Global Assessment of “clear” or “almost clear” (PGA of 0/1 ) with at least a 2-point improvement at Week 16. Secondary endpoints included week-16 PASI 90 responder rate, change in Dermatology Life Quality Index (DLQI) between baseline and week 16, and PASI 75 and PGA 0/1 responder rates at week 48. Other efficacy variables included PASI 90 responder rate at week 48 and PASI 100 (100% reduction in PASI from baseline PASI) and DLQI 0/1 (no/small impact of psoriasis on patient’s quality of life) responder rates at week 16 and week 48. Safety was assessed via treatment-emergent adverse events (TEAEs). Eligible patients were 18 years of age or older with plaque psoriasis for at least 6 months with baseline PASI 12 or greater, body surface area affected 10% or more, and a Physician’s Global Assessment (PGA) 3 or greater on a 5-point scale. All participants were candidates for systemic therapy, phototherapy, or photochemotherapy.

At week 16, significantly higher PASI 75 responder rates were observed for CZP 400 mg (CIMPASI-1, 75.8%; CIMPASI-2, 82.6%) and CZP 200 mg (CIMPASI-1, 66.5%; CIMPASI-2, 81.4%) than placebo (CIMPASI-1, 6.5%; CIMPASI-2, 11.6%; P < .0001 for all), and responses were maintained through week 48 for both CZP doses. At week 16, significantly higher PGA 0/1 responder rates were observed for CZP 400 mg (CIMPASI-1, 57.9%; CIMPASI-2, 71.6%) and CZP 200 mg (CIMPASI-1, 47.0%; CIMPASI-2, 66.8%) than placebo (CIMPASI-1, 4.2%; CIMPASI-2, 2.0%; P < .0001 for all); responses were maintained through week 48 for both CZP doses. No unexpected safety signals were identified. The safety profile was consistent with the therapeutic class. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection. The limitations of this trial were that there was no active comparator arm and patients were excluded from the study for having a history of primary failure to biologic therapy. In addition, sample sizes are smaller than other phase 3 psoriasis trials, making it difficult to discern whether observed study variations are simply a consequence of patient numbers. The authors concluded that treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate-to-severe psoriasis. The 400-mg dose could provide additional clinical benefit.

Lebwohl et al (2018) assessed the safety and efficacy of certolizumab (CZP) in adults with moderate-to-severe chronic plaque psoriasis in a phase 3, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled study, followed by a placebo-controlled maintenance period and open-label follow-up period (CIMPACT; NCT02346240). During the initial period, 559 patients were randomized 3:3:1:3 (stratified by site) to CZP 400 mg every 2 weeks or CZP 200 mg every 2 weeks (after 400-mg loading doses at weeks 0, 2, and 4) for 16 weeks, placebo every 2 weeks for 16 weeks, or etanercept 50 mg twice weekly for 12 weeks. At week 16, patients in the CZP-treatment groups achieving a PASI 75 (≥75% reduction in the Psoriasis Area and Severity Index (PASI) from baseline) were re-randomized (2:2:1): from CZP 400 mg every 2 weeks to CZP 400 mg every 2 weeks, CZP 200 mg every 2 weeks, or placebo; and from CZP 200 mg every 2 weeks to CZP 400 mg every 4 weeks, CZP 200 mg every 2 weeks, or placebo for the 32-week maintenance period. Placebo-treated PASI 75 responders continued placebo for the maintenance period, and etanercept-treated PASI 75 responders, after a 4-week washout, were re-randomized (2:1) to CZP 200 mg every 2 weeks (after 400 mg loading doses at weeks 16, 18, and 20) or placebo. PASI 75 nonresponders at week 16 entered an escape arm and received treatment with CZP 400 mg every 2 weeks. Patients who were rerandomized and were PASI 50 nonresponders (had a <50% reduction in PASI from baseline PASI) at any visit during the maintenance period and patients who completed the double-blind maintenance period entered the open-label safety extension, which was ongoing at the time of publication, and received CZP 400 mg every 2 weeks. The primary efficacy endpoint was PASI 75 responder rate for both CZP doses versus placebo at week 12. Secondary efficacy endpoints were PASI 75 responder rate versus placebo at week 16; PGA 0/1 responder rate (clear/almost clear with ≥2-point improvement from baseline PGA score) versus placebo at weeks 12 and 16; PASI 90 responder rate versus placebo at weeks 12 and 16; PASI 75 responder rate versus etanercept at week 12; and PASI 75 responder rates at week 48 for patients achieving PASI 75 at week 16. Safety was assessed by treatment-emergent adverse events (TEAEs). Eligible patients were 18 years of age or older with plaque psoriasis for at least 6 months with baseline PASI 12 or greater, body surface area affected 10% or more, and a Physician's Global Assessment (PGA) 3 or greater on a 5-point scale. All participants were candidates for systemic therapy, phototherapy, or photochemotherapy.

By week 12, PASI 75 responder rate was significantly greater for CZP-treated patients versus placebo-treated patients (66.7% CZP 400 mg, p<00001; 61.3% CZP 200 mg, p<00001; 5.0% placebo). Differences were evident between the drug groups and the placebo group as early as week 4 and increased through week 16. At week 12, CZP 400 mg was superior and CZP 200 mg was non-inferior to etanercept for PASI 75 responder rate (66.7% CZP 400 mg, p=0.0152; 61.3% CZP 200 mg, p=0.1523; 53.5% Etanercept). Similar trends occurred for PGA 0/1 and PASI 90 responder rates for both doses of CZP versus placebo. All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. No new safety signals were observed. Adverse events were consistent with the anti-tumor necrosis factor class of drugs. The most common adverse reactions (incidence ≥7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection. The limitation for this study was that etanercept was administered by un-blinded study staff or self-administered, but efficacy assessments were performed by a blinded assessor. The authors concluded that both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose.

Etanercept

Etanercept (Enbrel) (Immunex Corporation, Thousand Oaks, CA) gained FDA approval for the treatment of chronic moderate-to-severe chronic plaque psoriasis in April 2004.  The FDA approved a twice-weekly dose of 50 mg for the first 3 months of psoriasis treatment followed by a maintenance dose of 50 mg per week thereafter.  The FDA approval was based on the results of 2 phase III clinical studies involving adults with psoriasis who were treated for up to 12 months.  These studies reported nearly half (46 %) of those who received etanercept had a 75 % or greater improvement on the PASI after 3 months of treatment.  That response was sustained for an additional 3 months at the lower dose (25 mg once-weekly).

According to guidelines from the National Institute for Health and Clinical Excellence (NICE, 2006), etanercept, administered at a dose not exceeding 25 mg twice-weekly is recommended for the treatment of adults with plaque psoriasis only when their disease is severe and they have failed to respond to standard systemic therapies, as described above.

According to NICE guidelines, etanercept treatment should be discontinued in patients whose psoriasis has not responded adequately at 12 weeks.  Further treatment cycles are not recommended in these patients.

Guidelines from the British Association of Dermatologists (2005) stated that etanercept should be considered first choice for patients with significant, uncontrolled psoriatic arthritis, and for patients with stable psoriasis where a decision to treat with an tumor necrosis factor inhibitor has been made.

According to the FDA-approved labeling of Enbrel, the recommended dose of etancercept for psoriatic arthritis is 50 mg once weekly with or without methotrexate (MTX). The recommended dose of etanercept for adult plaque psoriasis is 50 mg twice weekly for 3 months, followed by 50 mg once weekly.

The FDA approved the supplemental Biologics License Application (sBLA) for the expanded use of etanercept) to treat pediatric patients (ages 4-17) with chronic moderate-to-severe plaque psoriasis (Amgen, 2016). The approval was based on results from a Phase 3 one-year study and its five-year open-label extension study to evaluate the safety and efficacy of etanercept in pediatric patients, ages 4 to 17, with chronic moderate-to-severe plaque psoriasis. In addition to demonstrating efficacy, the adverse events were similar to those seen in previous studies in adults with moderate-to-severe plaque psoriasis.

Paller, et al. (2008) sought to assess the efficacy and safety of etanercept in children and adolescents with moderate-to-severe plaque psoriasis. In a 48-week study, 211 patients with psoriasis (4 to 17 years of age) were initially randomly assigned to a double-blind trial of 12 once-weekly subcutaneous injections of placebo or 0.8 mg of etanercept per kilogram of body weight (to a maximum of 50 mg), followed by 24 weeks of once-weekly open-label etanercept. At week 36, 138 patients underwent a second randomization to placebo or etanercept to investigate the effects of withdrawal and retreatment. The primary end point was 75% or greater improvement from baseline in the psoriasis area-and-severity index (PASI 75) at week 12. Secondary end points included PASI 50, PASI 90, physician’s global assessment of clear or almost clear of disease, and safety assessments. At week 12, 57% of patients receiving etanercept achieved PASI 75, as compared with 11% of those receiving placebo (P<0.001). A significantly higher proportion of patients in the etanercept group than in the placebo group had PASI 50 (75% vs. 23%), PASI 90 (27% vs. 7%), and a physician's global assessment of clear or almost clear (53% vs. 13%) at week 12 (P<0.001). At week 36, after 24 weeks of open-label etanercept, rates of PASI 75 were 68% and 65% for patients initially assigned to etanercept and placebo, respectively. During the withdrawal period from week 36 to week 48, response was lost by 29 of 69 patients (42%) assigned to placebo at the second randomization. Four serious adverse events (including three infections) occurred in three patients during treatment with open-label etanercept; all resolved without sequelae. The investigators concluded that etanercept significantly reduced disease severity in children and adolescents with moderate-to-severe plaque psoriasis.

Paller, et al. (2016) reported on an extension study to evaluate long-term safety and efficacy of etanercept in children and adolescents with moderate to severe plaque psoriasis. The investigators reported on a 5-year, open-label extension study enrolled patients aged 4 to 17 years who had participated in a 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections, and rates of 75% and 90% improvement in Psoriasis Area and Severity Index score and clear/almost clear on static physician global assessment. Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 serious AEs; only 1 (cellulitis) was considered treatment-related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement in Psoriasis Area and Severity Index score (∼ 60%-70%) and 90% improvement in Psoriasis Area and Severity Index score  (∼ 30%-40%) and static physician global assessment status clear/almost clear (∼40%-50%) were maintained through week 264. The investigators noted that one limitation of this study was that the number of patients remaining on study at week 264 was small. The investigators concluded that etanercept in pediatric patients was generally well tolerated and efficacy was maintained in those who remained in the study for up to 264 weeks.

Golimumab

On October 20, 2017, Janssen Biotech, Inc. announced that the U.S. Food and Drug Administration (FDA) approved an intravenous (IV) formulation of Simponi Aria, golimumab, for the treatment of adults with active psoriatic arthritis (PsA). The approval was based on a pivotal Phase 3 study (GO-VIBRANT) which demonstrated significant efficacy of Simponi Aria over placebo, along with a consistent safety profile across all indications.

Go-VIBRANT was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study which evaluated the efficacy and safety of Simponi Aria in biologic-naïve adults (18 years of age and older) with active PsA.  Criteria included a diagnosis of PsA for at least six months and had symptoms of active disease (≥5 swollen joints and ≥5 tender joints and a CRP level of ≥ 0.6 mg/dL). Patients who were on stable doses of methotrexate (MTX) were allowed to enroll in the study and remained on MTX during the double-blind phase. Patients (n=480) were randomized one-to-one to receive Simponi Aria 2 mg/kg (N=241) or placebo (N=239) as a 30-minute IV infusion at Weeks 0, 4, 12 and 20. All patients on placebo received Simponi Aria at Week 24, Week 28 and every 8 weeks thereafter through Week 52. Patients in the Simponi Aria treatment group continued to receive Simponi Aria infusions at Week 28 and every 8 weeks through Week 52. The primary endpoint was ACR20 response at week 14. Multiplicity-controlled endpoints at week 14 or 24 included ACR50, ACR70, at least a 75 percent improvement in the Psoriasis Area Severity Index (PASI 75) and change from baseline in Health Assessment Questionnaire Disability Index (HAQ-DI), enthesitis, dactylitis, van der Heijde Sharps (vdH-S) and Short Form (SF)-36 Physical Component (PC)/Mental Component (MC) scores. The study continued through 60 weeks (Janssen, 2017).

Guselkumab

In July 2017, the U.S. Food and Drug Administration (FDA) approved Tremfya (guselkumab) for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Guselkumab, an interleukin-23 (IL-23) blocker, is a human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines (FDA, 2017).

Tremfya received FDA approval based on results from Phase 3, multicenter, randomized, double-blind trials (VOYAGE 1, VOYAGE 2, and NAVIGATE studies). In VOYAGE 1 and VOYAGE 2, 1443 subjects, 18 years and older, were randomized to either Tremfya (100 mg at Weeks 0 and 4 and every 8 weeks thereafter), placebo or adalimumab (80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week thereafter). At 16 weeks, at least seven out of ten Tremfya-treated patients achieved at least 90 percent clearer skin, and more than 80 percent demonstrated cleared or almost cleared skin. Improvements were also demonstrated in psoriasis involving the scalp and in symptoms of plaque psoriasis including itch, pain, stinging, burning and skin tightness. Treatment resulted in clearer skin that lasted, as nearly nine out of ten patients who achieved PASI 90 at week 28 maintained that response at week 48. At week 24, more than seven out of ten patients treated with Tremfya reported at least 90 percent clearer skin compared with more than four out of ten patients treated with adalimumab (FDA, 2017; Johnson & Johnson, 2017).

NAVIGATE findings demonstrated the effectiveness of Tremfya in patients who had an inadequate response to treatment with ustekinumab. NAVIGATE evaluated the efficacy of 24 weeks of treatment with Tremfya in subjects (N=268) who had not achieved an adequate response, defined as IGA ≥2 at Week 16 after initial treatment with ustekinumab (dosed 45 mg or 90 mg according to the subject’s baseline weight at Week 0 and Week 4). These subjects were randomized to either continue with ustekinumab treatment every 12 weeks or switch to Tremfya 100 mg at Weeks 16, 20, and every 8 weeks thereafter. In subjects with an inadequate response (IGA ≥2 at Week 16 to ustekinumab), greater proportions of subjects on Tremfya compared to ustekinumab achieved an IGA score of 0 or 1 with a ≥2 grade improvement at Week 28 (31% vs 14%, respectively; 12 weeks after randomization) (FDA, 2017).

The most common adverse reactions associated with Tremfya include upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea, gastroenteritis, tinea infections, and herpes simplex infections (FDA, 2017).

A Phase 3 study evaluating Tremfya in the treatment of active psoriatic arthritis is ongoing, and a Phase 3 program evaluating the efficacy of Tremfya compared with Cosentyx® (secukinumab) in the treatment of moderate to severe plaque psoriasis is underway (Johnson & Johnson, 2017).

Infliximab

The U.S. Pharmacopeial Convention (2003) has concluded that psoriatic arthritis and psoriasis are accepted indications for infliximab.  A controlled clinical study (Chaudhari et al, 2001) has demonstrated the short-term effectiveness of infliximab in plaque psoriasis.  In a controlled clinical trial in which patients and investigators were blinded for the first 10 weeks, participants were assigned to either of 2 doses of infliximab (5 mg/kg or 10 mg/kg at baseline, 2 weeks, and 6 weeks) or to placebo.  Nineteen of 22 patients assigned to infliximab achieved good or better physician’s overall assessments, compared with 2 of 11 patients assigned to placebo.  In initial studies, remissions seemed to be durable, with many patients improving for 6 months or longer.  Subsequent randomized controlled clinical studies have confirmed the efficacy of infliximab for treatment of plaque psoriasis (Reich et al, 2005; Feldman et al, 2005; Gottlieb et al, 2004).

Guidelines from the British Association of Dermatologists (2005) stated that infliximab is useful in clinical circumstances requiring rapid control of psoriasis, e.g., in unstable erythrodermic or pustular psoriasis, due to its very rapid onset of action and high response rate.

Infliximab (Remicade/Avsola/Inflectra/Renflexis) is FDA approved for treatment of reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in persons with psoriatic arthritis. Furthermore, it has the FDA approval for treatment of adults with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate (Amgen, 2019; Janssen, 2018; Merck, 2019; Pfizer, 2019).

ixekizumab

Taltz (ixekizumab) is a humanized interleukin‐17A antagonist. Ixekizumab is a humanized IgG4 monoclonal antibody that selectively binds with the interleukin 17A (IL‐17A) cytokine and inhibits its interaction with the IL‐17 receptor. IL‐17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.

Taltz (ixekizumab) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with moderate‐to‐severe plaque psoriasis who are candidates for systemic therapy or phototherapy. The FDA approval of Taltz was based on findings from a phase III study of 3,800 patients with moderate-to-severe plaque psoriasis (Lilly, 2016). This number includes patients who began the trial on Taltz or placebo, or active comparator (U.S.-approved etanercept). This clinical program included three double-blind, multicenter, Phase 3 studies—UNCOVER-1, UNCOVER-2 and UNCOVER-3—which demonstrated the safety and efficacy of Taltz in patients with moderate-to-severe plaque psoriasis. All three studies evaluated the safety and efficacy of Taltz (80 mg every two weeks, following a 160-mg starting dose) compared to placebo after 12 weeks. UNCOVER-2 and UNCOVER-3 included an additional comparator arm in which patients received etanercept (50 mg twice a week) for 12 weeks. UNCOVER-1 and UNCOVER-2 also evaluated response rates with Taltz during the maintenance period through 60 weeks.

In these studies, the co-primary efficacy endpoints at 12 weeks were a 75 percent improvement in the composite Psoriasis Area Severity Index (PASI) score and static Physician’s Global Assessment (sPGA) 0 or 1 and at least a 2-point improvement from baseline (Lilly, 2016). In all three studies, at 12 weeks, 87 to 90 percent of patients treated with Taltz saw a significant improvement of their psoriasis plaques (PASI 75).  In addition, 81 to 83 percent of patients treated with Taltz achieved sPGA 0 or 1. The majority of patients treated with Taltz, 68 to 71 percent, achieved virtually clear skin (PASI 90) and 35 to 42 percent of patients saw complete resolution of their psoriasis plaques (PASI 100, sPGA 0). Among those patients treated with placebo, 7 percent or fewer achieved PASI 75, 7 percent or fewer achieved sPGA 0 or 1, 3 percent or fewer achieved PASI 90 and 1 percent or fewer achieved PASI 100 and sPGA 0. In UNCOVER-1 and UNCOVER-2, of patients who responded to Taltz (sPGA 0 or 1 and at least a 2-point improvement from baseline) at 12 weeks, 75 percent consistently maintained that response at the 60-week endpoint.

Taltz was also statistically superior to etanercept at all skin clearance levels, including PASI 75 and sPGA 0 or 1 at 12 weeks (Lilly, 2016). In an integrated analysis of the U.S. sites in the two active comparator studies—UNCOVER-2 and UNCOVER-3—the respective response rates for Taltz versus.  etanercept were 87 percent vs. 41 percent for PASI 75 and 73 percent vs. 27 percent for sPGA 0 or 1.

Taltz may increase the risk of infection. Patients treated with Taltz had a higher rate of infections than patients treated with placebo (27 percent vs. 23 percent) (Lilly, 2016). Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in patients treated with Taltz compared to placebo. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Other warnings and precautions for Taltz include pre-treatment evaluation for tuberculosis, hypersensitivity reactions, inflammatory bowel disease and immunizations.

In UNCOVER-2 and UNCOVER-3, the rate of serious adverse events during the controlled induction period (weeks 0-12) was 0.7 percent for U.S.-approved etanercept and 2 percent for Taltz, and the rate of discontinuation from adverse events was 0.7 percent for etanercept and 2 percent for Taltz (Lilly, 2016). The incidence of infections was 18 percent for etanercept and 26 percent for Taltz. The rate of serious infections was 0.3 percent for both  etanercept and Taltz.

The most common adverse reactions (greater or equal to 1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections (Lilly, 2016).

Warnings and precautions:

  • Infections: serious infections have occured. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.
  • Tuberculosis (TB): evaluate for TB prior to initiating treatment.
  • Hypersensivity: if a serious allergic reaction occurs, discontinue Taltz immediately and initate appropriate therapy.
  • Inflammatory bowel disease: Crohn’s disease and ulcerative colitis, including exacerbations, occurred during clinical trials. Patients who are treated with Taltz and have inflammatory bowel disease should be monitored closely.

On December 1, 2017, Eli Lilly and Company announced the U.S. FDA approval of Taltz (ixekizumab) injection 80 mg/mL for the treatment of adults with active psoriatic arthritis (PsA) (Eli Lilly, 2017).

FDA approval was based on findings from two randomized, double-blind, placebo-controlled phase 3 studies (SPIRIT-P1 and SPIRIT- P2). Across both studies, patients were required to have a diagnosis of active PsA for at least six months and at least three tender and three swollen joints. The primary efficacy endpoint was the proportion of patients at 24 weeks achieving ACR20 response.

The SPIRIT-P1 study (NCT01695239) assessed the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in patients with active psoriatic arthritis (PsA). Patients were randomized to receive subcutaneous injections of placebo (n=106), adalimumab 40 mg once every 2 weeks (n=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (n=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (n=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo. Findings showed that significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and found less progression of structural damage at week 24 (p≤0.01). At week 24, 58% of patients treated with ixekizumab achieved ACR20, than 30% for placebo. The authors concluded that ixekizumab improves disease activity, physical function, and inhibits structural damage progression in biologic-naïve patients with active PsA (Mease et al., 2017).

The SPIRIT-P2 study (NCT02349295) evaluated the safety and efficacy of ixekizumab compared to placebo in tumor necrosis factor inhibitor (TNFi)-experienced patients with active PsA who failed one or two TNF inhibitors. Patients (aged 18 years and older) who had psoriatic arthritis for at least 6 months, and who had previous inadequate response to tumour necrosis factor inhibitors (TNFi) were enrolled in the study. Patients (n=363) were randomized to receive a placebo (n=118) or subcutaneous injection of 80 mg ixekizumab every 4 weeks (n=122) or every 2 weeks (n=123) after a 160 mg starting dose. The investigators found at week 24, a higher proportion of patients attained ACR20 with ixekizumab (53% of patients) than placebo (20%). Serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. The authors concluded that the safety profile was consistent with previous ixekizumab, and that both the 2-week and 4-week ixekizumab dosing regimens improved signs and symptoms of patients with active PsA who previously had inadequate response to TNFi (Nash et al., 2017).

In March 2020, the U.S. FDA approved a supplemental Biologics License Application for Taltz (ixekizumab) injection, 80 mg/mL for the treatment of pediatric patients (ages 6 to under 18 years) with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. FDA approval was based on the safety and efficacy demonstrated in a randomized, double-blind, placebo-controlled Phase 3 study that included 171 patients (ages 6 to under 18 years) with moderate to severe plaque psoriasis. The co-primary endpoints of the study were the proportion of patients achieving a 75 percent improvement from baseline on their Psoriasis Area and Severity Index score (PASI 75) and a static Physician’s Global Assessment of clear or almost clear skin (sPGA 0,1) at Week 12. Patients were randomized to receive Taltz (20 mg for <25 kg, 40 mg for 25-50 kg or 80 mg for >50 kg through Week 12, with 40 mg, 80 mg or 160 mg starting doses, respectively) or placebo. At 12 weeks, the proportion of patients achieving the co-primary endpoints was superior to placebo with statistically significant difference (p<0.001): 89 percent of patients treated with Taltz achieved PASI 75 compared to 25 percent of patients treated with placebo, and 81 percent of patients treated with Taltz achieved sPGA 0,1 compared to 11 percent of patients treated with placebo. Taltz also met all major secondary endpoints in the study (p<0.001), which included the proportion of patients achieving PASI 90, sPGA (0) and PASI 100 at Week 12, and at least a four-point improvement in Itch Numeric Rating Scale (Itch NRS ≥4) among patients with baseline Itch NRS ≥4 at Week 12, as well as PASI 75 and sPGA 0,1 at Week 4. Overall, the safety profile observed in pediatric patients with plaque psoriasis treated with Taltz every four weeks is consistent with the safety profile in adult patients with plaque psoriasis, with the exception of the frequencies of conjunctivitis (3%), influenza (2%) and urticaria (2%) (Lilly, 2020).

Risankizumab-rzaa

On April 23, 2019, AbbVie Inc (Chicago, IL) announced the FDA approval of Skyrizi (risankizumab-rzaa), an interleukin-23 (IL-23) inhibitor, for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

FDA approval was based on four multicenter, randomized, double-blind, placebo and/or active-controlled pivotal studies: ULTIMMA-1, ULTIMMA-2, IMMHANCE and IMMVENT (NCT02684370, NCT02684357, NCT02672852, NCT02694523).

In the ULTIMMA-1 and ULTIMMA-2 trials, 997 subjects with moderate-to-severe chronic plaque psoriasis, ages 18 years or older, who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12 were enrolled. Of the 997 subjects, 598 were randomized to the risankizumab-rzaa 150 mg group, 200 were randomized to the placebo group, and 199 to the biologic (ustekinumab) active control group. Risankizumab-rzaa was administered subcutaneously at Weeks 0, 4, and every 12 weeks thereafter. Both studies assessed the responses at Week 16 compared to placebo for two co-primary endpoints, the proportion of subjects achieving a 90% reduction from baseline in the Psoriasis Area Severity Index (PASI 90), and the proportion of subjects who achieved a sPGA score of 0 (“clear”) or 1 (“almost clear”). Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and Psoriasis Symptom Scale (PSS) 0 (“none”) at Week 16 versus placebo. Co-primary endpoints were met for both studies. At Week 16 both ULTIMMA-1 and ULTIMMA-2 found that PASI 90 was achieved in 75 percent of people treated with risankizumab-rzaa (Skyrizi), compared to 5 and 2 percent receiving placebo, respectively (p<0.001). PASI 100 was achieved in 36 and 51 percent of people treated with risankizumab-rzaa, compared to 0 and 2 percent receiving placebo, respectively (p<0.001). At one year (52 weeks), 82 and 81 percent of people treated with risankizumab-rzaa achieved PASI 90, and 56 and 60 percent achieved PASI 100, respectively (p<0.001); in addition, 58 and 60 percent achieved sPGA 0, respectively. An integrated analysis of ULTIMMA-1 and ULTIMMA-2 showed most people treated with risankizumab-rzaa who achieved PASI 90 and PASI 100 at Week 16 maintained this response at one year (88 and 80 percent, respectively) (AbbVie, 2019a; AbbVie, 2019b; Gordon et al., 2018).

In the IMMHANCE trial (NCT02672852), subjects who were originally on risankizumab-rzaa and had sPGA 0 or 1 at Week 28 were re-randomized to continue risankizumab-rzaa every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with risankizumab-rzaa had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of risankizumab-rzaa (AbbVie, 2019b).

Most common adverse reactions (≥ 1%) are upper respiratory infections, headache, fatigue, injection site reactions, and tinea infections.

Phase 3 trials of risankizumab-rzaa (Skyrizi) in psoriatic arthritis are ongoing (AbbVie, 2019a).

Secukinumab

The FDA has approved secukinumab (Cosentyx) injection for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy (Novartis, 2015). Secukinumab (previously known as AIN457) is a human monoclonal antibody (mAb) that selectively binds to interleukin-17A (IL-17A) and inhibits its interaction with the IL-17 receptor.

The Phase III clinical program included four placebo-controlled studies which examined secukinumab 300 mg and 150 mg in patients with moderate-to-severe plaque psoriasis (Novartis, 2015):

  • ERASURE

    (Efficacy of response and safety of two fixed secukinumab regimens in psoriasis) was a randomized, double-blind, placebo-controlled, multicenter, parallel-group Phase III study involving 738 patients with moderate-to-severe plaque psoriasis.

  • FIXTURE

    (the full year investigative examination of secukinumab vs. etanercept using 2 dosing regimens to determine efficacy in psoriasis) was a randomized, double-blind, placebo and active controlled, multicenter, parallel-group Phase III study involving 1306 patients with moderate-to-severe plaque psoriasis.

  • FEATURE

    (First study of secukinumab in prefilled syringes in subjects with chronic plaqUe-type psoriasis response) was a randomized double-blind, placebo-controlled, multicenter, Phase III study involving 177 subjects with moderate-to-severe plaque psoriasis. In this study, prefilled syringes (PFS) were introduced into the Cosentyx clinical program.

  • JUNCTURE

    (Judging the efficacy of secukinumab in patients with psoriasis using autoinjector: a clinical trial evaluating treatment results) was a double-blind, placebo-controlled, multicenter, Phase III study involving 182 subjects with moderate-to-severe plaque psoriasis. In this study, the autoinjector/pen (AI) was introduced into the Cosentyx clinical program.

In these studies, secukinumab met its primary endpoint and key secondary endpoints, including Psoriasis Area and Severity Index (PASI) 75 and 90 and Investigator’s Global Assessment modified 2011 (IGA) 0/1 responses, showing significant skin clearance at Week 12 (Novartis, 2015).

The recommended dose of secukinumab is 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks (Novartis, 2015). For some patients, a dose of 150 mg may be acceptable.

Cosentyx is contraindicated in patients with a previous serious hypersensitivity reaction to secukinumab or to any of the excipients (Novartis, 2015). Most common adverse reactions (> 1%) with sekukinumab are nasopharyngitis, diarrhea, and upper respiratory tract infections.

In placebo-controlled clinical trials, higher rates of common infections such as nasopharyngitis (11.4% versus 8.6%), upper respiratory tract infection (2.5% versus 0.7%) and mucocutaneous infections with candida (1.2% versus 0.3%) were observed with secukinumab compared with placebo (Novartis, 2015).  The incidence of some types of infections appeared to be dose-dependent in clinical studies. The labeling of Consentyx recommends exercising caution when considering the use of secukinumab in patients with a chronic infection or a history of recurrent infection. If a patient develops a serious infection, the patient should be closely monitored and secukinumab should be discontinued until the infection resolves.

The labeling recommends that patients be evaluated for tuberculosis (TB) infection prior to initiating treatment with secukinumab (Novartis, 2015).  Secukinumab should not be administered to patients with active TB infection. Treatment of latent TB should be initiated prior to administering secukinumab.  The labeling also states that anti-TB therapy should be considered prior to initiation of secukinumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed.  Patients receiving secukinumab should be monitored closely for signs and symptoms of active TB during and after treatment.

The labeling recommends caution when prescribing secukinumab to patients with active Crohn’s disease, as exacerbations of Crohn’s disease, in some cases serious, were observed in secukinumab-treated patients during clinical trials (Novartis, 2015). The labeling recommends close monitoring of patients with active Crohn’s disease who are treated with secukinumab.

Anaphylaxis and cases of urticaria occurred in secukinumab-treated patients in the clinical trials (Novartis, 2015).  The labeling recommends immediate discontinuation of secukinumab and initiation of appropriate therapy if an anaphylactic or other serious allergic reaction occurs.

The labeling states that patients treated with secukinumab should not receive live vaccines (Novartis, 2015). Non-live vaccinations received during a course of secukinumab may not elicit an immune response sufficient to prevent disease. The labeling recommends completion of all age-appropriate immunizations prior to initiating therapy with secukinumab.

In a phase 3, double-blind, placebo-controlled study (McInnes, et al., 2015) undertaken at 76 centers in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 (54%) patients; odds ratio versus placebo 6·81, 95% CI 3·42-13·56; p<0·0001), 150 mg (51 (51%) patients; 6·52, 3·25-13·08; p<0·0001), and 75 mg (29 (29%) patients; 2·32, 1·14-4·73; p=0·0399) versus placebo (15 (15%) patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four (4%), eight (8%), ten (10%), and seven (7%) with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six (6%), four (4%), six (6%), and eight (8%), respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. The investigators concluded that subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder.

McInnes, et al. (2014) evaluated the efficacy and safety of secukinumab in patients with psoriatic arthritis (PsA). Investigators randomly assigned (2:1) 42 patients with active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). ACR20 responses at week 6, the primary endpoint, were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. The investigators concluded that, although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. The investigators stated that secukinumab exhibited satisfactory safety.

Tildrakizumab

Ilumya (tildrakizumab) is humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. In March 2018, the FDA approved tildrakizumab (Ilumya) for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Reich et al (2017) conducted two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician’s Global Assessment (PGA) score ≥3, and Psoriasis Area and Severity Index (PASI) score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. The reSURFACE 1 trial ran from Dec 10, 2012, to Oct 28, 2015. The reSURFACE 2 trial ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) (corrected) in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. The authors concluded that in the two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis.

Tofacitinib (Xeljanz, Xeljanz XR)

On December 14, 2017, Pfizer announced the U.S. Food and Drug Administration (FDA) approval of Xeljanz (tofacitinib) and Xeljanz XR for the treatment of adults with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs) (Pfizer, 2018).

The recommended dose of Xeljanz and Xeljanz XR is in combination with nonbiologic DMARDs. Tofacitinib (Xeljanz, Xeljanz XR) is not be used concomitantly with apremilast, biologic DMARDs (e.g., adalimumab, infliximab), or potent immunosuppressants (i.e., azathioprine, cyclosporine).

FDA approval and dosing recommendations for Xeljanz were based on the results from two pivotal studies, OPAL Broaden and OPAL Beyond, as well as data from an ongoing long-term extension trial, OPAL Balance (Pfizer, 2018).

Mease et al. (2017) conducted a 12-month, double-blind, active-controlled and placebo-controlled, randomized, phase 3 clinical trial (OPAL Broaden, NCT01877668) to evaluate tofacitinib in patients with active psoriatic arthritis (PsA) who previously had an inadequate response to non-biologic, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and who were tumor necrosis factor inhibitor (TNFi) naive. Patients were randomized to receive either: tofacitinib at a 5-mg dose taken orally twice daily (n=107), tofacitinib at a 10-mg dose taken orally twice daily (n=104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (n=106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (n=52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (n=53). Primary end points were at 3 months were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI). The authors found that ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group. The rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was -0.35 in the 5-mg tofacitinib group and -0.40 in the 10-mg tofacitinib group, as compared with -0.18 in the placebo group. The score change was -0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. The authors concluded that at 3 months, tofacitinib was superior to that of placebo in patients with active PsA who had previously had an inadequate response to conventional synthetic DMARDs.

Gladman et al. (2017) conducted a 6 month randomized, placebo-controlled, double-blind, phase 3 trial (OPAL Beyond, NCT01882439) to evaluate tofacitinib in patients with active psoriatic arthritis (PsA) who had previously had an inadequate response to TNFi.  Patients (n=395) were randomized to receive either 5 mg of tofacitinib administered orally twice daily (n=132); 10 mg twice daily (n=132), placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (n=66), or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (n=65). At 3 months, the rates of ACR20 response were 50% with the 5-mg dose of tofacitinib and 47% with the 10-mg dose, as compared with 24% with placebo. The corresponding mean changes from baseline in HAQ-DI score were -0.39 and -0.35, as compared with -0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5-mg dose of tofacitinib continuously and in 6% who received the 10-mg dose continuously. The authors concluded that over 3 months, tofacitinib was more effective than placebo for reducing disease activity in patients with active PsA who had an inadequate response to TNF inhibitors.

In both the OPAL Broaden and OPAL Beyond, all patients were required to receive a stable background dose of a single nonbiologic DMARD.

Ustekinumab

Stelara (ustekinumab) is a human IgG1κ monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the interleukin (IL)‐12 and IL‐23 cytokines. IL‐12 and IL‐23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T‐cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL‐12 and IL‐23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell‐surface receptor chain, IL‐12 β1. Stelara is produced in a well characterized recombinant cell line and is purified using standard bio‐processing technology. The manufacturing process contains steps for the clearance of viruses.

Stelara (ustekinumab) is indicated for the treatment of adolescents (12 years or older) and adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy and for the treatment of adult patients with active psoriatic arthritis, either alone or with methotrexate. Stelara is also indicated for persons with moderate to severe Crohn’s disease.

In September 2009, the FDA approved ustekinumab (Stelara) for the treatment of  adults with moderate-to-severe psoriasis.  Ustekinumab is a fully human monoclonal antibody that binds with high specificity and affinity to the cytokines interleukin (IL)-12 and IL-23, thereby suppressing IL-12- and IL-23-mediated inflammation associated with psoriasis.  In a review on the use of biological agents in the treatment of psoriasis, Tzu et al (2008) noted that IL-12/IL-23 inhibitors are new agents.  Furthermore, Rozenblit and Lebwohl (2009) stated that new biologic therapies for psoriasis and psoriatic arthritis include antibodies to IL-12 and IL-23.

Weber and Keam (2009) noted that in 2 large, phase III trials in patients with moderate-to-severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as 2 injections 4 weeks apart) than placebo recipients achieved a 75 % improvement on the PASI 75 score at 12 weeks.  Other efficacy measures, including the physician’s global assessment (PGA) of clinical response at week 12, also favored ustekinumab over placebo.  Psoriatic symptom control was maintained during ustekinumab maintenance therapy (administered once every 12 weeks) for up to 76 weeks.  In a phase II trial in patients with active plaque psoriasis and psoriatic arthritis, signs and symptoms of arthritis and psoriatic symptom control were improved to a greater extent with ustekinumab than with placebo at 12 weeks, based on the proportion of patients achieving a 20 % improvement in ACR response criteria (arthritis) or PASI 75 (skin symptoms).  Health-related quality of life, assessed using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index, was improved to a significantly greater extent with ustekinumab than with placebo at week 12.  Subcutaneous ustekinumab was generally well-tolerated in clinical trials, with most treatment-emergent adverse events being of mild severity.

In a phase III, parallel, randomized, double-blind, placebo-controlled trial (PHOENIX 1), Leonardi et al (2008) examined the safety and effectiveness of ustekinumab for the treatment of psoriasis.  A total of 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n = 255) or 90 mg (n = 256) at weeks 0 and 4 and then every 12 weeks; or placebo (n = 255) at weeks 0 and 4, with subsequent cross-over to ustekinumab at week 12.  Patients who were initially randomized to receive ustekinumab at week 0 who achieved long-term response (at least 75 % improvement in psoriasis area and severity index (PASI 75) at weeks 28 and 40) were re-randomized at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response.  Both randomizations were done with a minimization method via a centralized interactive voice response system.  The primary endpoint was the proportion of patients achieving PASI 75 at week 12.  Analyses were by intention-to-treat.  All randomized patients were included in the efficacy analysis.  Overall, 171 (67.1 %) patients receiving ustekinumab 45 mg, 170 (66.4 %) receiving ustekinumab 90 mg, and 8 (3.1 %) receiving placebo achieved PASI 75 at week 12 (difference in response rate versus placebo 63.9 %, 95 % confidence interval (CI): 57.8 to 70.1, p < 0.0001 for 45 mg and 63.3 %, 57.1 to 69.4, p < 0.0001 for 90 mg).  At week 40, long-term response had been achieved by 150 patients in the 45-mg group and 172 patients in the 90-mg group.  Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal.  PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p < 0.0001 by log-rank test).  During the placebo-controlled phase, adverse events occurred in 278 (54.5 %) of the 510 patients receiving ustekinumab and 123 (48.2 %) of the 255 receiving placebo.  Serious adverse events occurred in 6 (1.2 %) of 510 patients receiving ustekinumab and in 2 (0.8 %) of 255 receiving placebo in this phase.  The pattern of adverse events was much the same in the placebo cross-over and randomized withdrawal phases as it was in the placebo-controlled phase.  The authors concluded that ustekinumab seems to be effective for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least 1 year in most patients.

In a multi-center, phase III, double-blind, placebo-controlled trial (PHOENIX 2), Papp et al (2008) assessed the safety and effectiveness of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders.  A total of 1,230 patients with moderate-to-severe psoriasis (defined by a PASI score greater than or equal to 12, and at least 10 % total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n = 409) or 90 mg (n = 411) at weeks 0 and 4, then every 12 weeks, or placebo (n = 410).  Partial responders (i.e., patients achieving greater than or equal to 50 % but less than 75 % improvement from baseline in PASI) were re-randomized at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks.  Both randomizations were done with a minimization method via a centralized interactive voice response.  The primary endpoint was the proportion of patients achieving at least PASI 75 at week 12.  Analyses were by intention-to-treat.  All randomized patients were included in the efficacy analysis.  Overall, 273 (66.7 %) patients receiving ustekinumab 45 mg, 311 (75.7 %) receiving ustekinumab 90 mg, and 15 (3.7 %) receiving placebo achieved the primary endpoint (difference in response rate 63.1 %, 95 % CI: 58.2 to 68.0, p < 0.0001 for the 45-mg group versus placebo and 72.0 %, 67.5 to 76.5, p < 0.0001 for the 90-mg group versus placebo).  More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 (68.8 %) versus 11 (33.3 %); difference in response rate 35.4 %, 95 % CI: 12.7 to 58.1, p = 0.004).  There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg.  During the placebo-controlled phase, 217 (53.1 %) patients in the 45-mg group, 197 (47.9 %) in the 90-mg group, and 204 (49.8 %) in the placebo group experienced adverse events; serious adverse events were seen in 8 (2.0 %) patients in the 45-mg group, 5 (1.2 %) in the 90-mg group, and 8 (2.0 %) in the placebo group.  The authors concluded that although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen.

Landells et al (2015) stated safe and effective therapies are needed for pediatric patients with psoriasis. On October 13, 2017, Janssen Biotech, Inc., announced that the FDA approved an expanded indication for Stelara (ustekinumab) for the treatment of adolescents (12 years of age or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. The FDA-approval of ustekinumab in adolescents (12 years or older) was based on data from a multicenter, randomized, double blind, placebo-controlled study that evaluated ustekinumab in patients age 12 to 17 years who had moderate-to-severe psoriasis. Patients (n = 110) were randomly assigned to ustekinumab standard dosing (SD; 0.75 mg/kg (≤60 kg), 45 mg (>60-≤100 kg), and 90 mg (>100 kg)) or half-standard dosing (HSD; 0.375 mg/kg (≤60 kg), 22.5 mg (>60-≤100 kg), and 45 mg (>100 kg)) at weeks 0 and 4 and every 12 weeks or placebo at weeks 0 and 4 with crossover to ustekinumab SD or HSD at week 12. Clinical assessments included the proportion of patients achieving a Physician’s Global Assessment of cleared/minimal (PGA 0/1), at least 75% improvement in Psoriasis Area and Severity Index (PASI 75), and at least 90% in PASI (PASI 90). Adverse events (AEs) were monitored through week 60. At week 12, 67.6% and 69.4% of patients receiving ustekinumab HSD and SD, respectively, achieved PGA 0/1 versus 5.4% for placebo (P < .001). Significantly greater proportions receiving ustekinumab achieved PASI 75 (HSD, 78.4%; SD, 80.6%; placebo, 10.8%) or PASI 90 (HSD, 54.1%; SD, 61.1%; placebo, 5.4%) at week 12 (P < .001). Through week 12, 56.8% of placebo patients, 51.4% of HSD patients, and 44.4% of SD patients reported at least one AE; through week 60, 81.8% reported AEs. The study was small relative to adult trials. The authors concluded that in this patient population (12-17 years), the standard ustekinumab dose provided response comparable to that in adults with no unexpected AEs through 1 year.

In a phase II, randomized, double-blind, placebo-controlled, cross-over study, Gottlieb et al (2009) evaluated the safety and effectiveness of ustekinumab for psoriatic arthritis.  Patients with active psoriatic arthritis were randomly allocated via interactive voice response system to either ustekinumab (90 mg or 63 mg) every week for 4 weeks (weeks 0 to 3) followed by placebo at weeks 12 and 16 (n = 76; Group 1) or placebo (weeks 0 to 3) and ustekinumab (63 mg) at weeks 12 and 16 (n = 70; Group 2).  The first 12 weeks of the study were placebo-controlled.  Masking was maintained to week 16, and patients were followed-up to week 36 (corrected).  The primary endpoint was American College of Rheumatology 20 % improvement (ACR20) response at week 12.  Analysis was by intention-to-treat.  At week 12, 32 (42 %) patients in Group 1 and 10 (14 %) in Group 2 achieved the primary endpoint (difference 28 % (95 % CI: 14.0 to 41.6); p = 0.0002).  Of 124 (85 %) participants with psoriasis affecting 3 % or more body surface area, 33 of 63 (52 %) in Group 1 and 3 of 55 (5 %) in Group 2 had a 75 % or greater improvement in psoriasis area and severity index score at week 12 (47 % (33.2 to 60.6); p < 0.0001).  During the placebo-controlled period (weeks 0 to 12), adverse events arose in 46 (61 %) patients in Group 1 and 44 (63 %) in Group 2; serious adverse events were recorded in 3 (4 %) Group 2 patients (none in Group 1).  The authors concluded that ustekinumab significantly reduced signs and symptoms of psoriatic arthritis and diminished skin lesions compared with placebo, and the drug was well-tolerated.  They stated that larger and longer term studies are needed to further characterise ustekinumab safety and effectiveness for the treatment of psoriatic arthritis.

Ryan et al (2010) examined the safety and efectiveness of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.  Ustekinumab has shown significant effectiveness in the treatment of chronic plaque psoriasis in phase III studies, and promising results in phase II studies in psoriatic arthritis.  Effectiveness has been shown in Crohn’s disease only in non-responders to infliximab.  Furthermore, ustekinumab did not show benefit in the treatment of multiple sclerosis.

The effectiveness of ustekinumab in treating psoriasis were reproduced in the phase III, multi-center, randomized ACCEPT trial (2008).  This head-to-head study comparing ustekinumab and etanercept for the treatment of moderate-to-severe psoriasis showed ustekinumab superior to etanercept according to primary and major secondary efficacy endpoints.  The primary endpoint of the trial was the percentage of participants achieving at least a 75 % reduction in psoriasis at week 12 as measured by PASI 75.  At week 12, after 2 subcutaneous injections at weeks 0 and 4, 68 % and 74 % of patients receiving ustekinumab 45 mg or ustekinumab 90 mg, respectively, achieved a PASI 75 compared with 57 % of patients receiving etanercept 50 mg subcutaneous injections twice-weekly for 12 weeks (p = 0.012 for ustekinumab 45 mg; p < 0.001 for ustekinumab 90 mg, each compared with etanercept).

In a phase II clinical trial, Kavanaugh et al (2010) evaluated the effect of ustekinumab on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA).  Patients with active PsA were randomized (1:1 ratio) to receive either ustekinumab at weeks 0, 1, 2, and 3 and placebo at weeks 12 and 16 (n = 76) or placebo at weeks 0, 1, 2, and 3 and ustekinumab at weeks 12 and 16 (n = 70).  Physical function was assessed using the disability index from the Health Assessment Questionnaire-Disability Index (HAQ-DI) in all randomized patients.  HRQoL was evaluated using the DLQI in a subset of patients (84.9 %) with at least 3 % body surface area (BSA) psoriasis involvement at baseline.  At baseline, overall mean HAQ-DI and DLQI scores were 0.9 and 11.5, respectively, indicating impaired physical function and moderate effect on HRQoL.  At week 12, ustekinumab patients had significantly more improvement (decrease) in the mean HAQ-DI (-0.31) and DLQI (-8.6) scores versus placebo (-0.04 and -0.8, respectively; p < 0.001 for both comparisons).  At week 12, 58.7 % (37/63) of ustekinumab-treated patients had a DLQI score of 0 or 1 (no negative effect of disease or treatment on HRQoL) versus 5.5 % (3/55) for placebo (p < 0.001).  The results also indicated a positive but weak correlation between improvement in physical function and HRQoL, pain, and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo.  The authors concluded that ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3 % BSA.  Limitations of the study included the short duration of the placebo-controlled period and the relatively small patient population.

Kurzeja et al (2011) stated that interleukin (IL)-23 is an important regulator of T helper-17 lymphocytes, which influence the cutaneous immune system by production of IL-17 and several other pro-inflammatory cytokines.  This pathway has been recently linked to the pathogenesis of psoriasis and numerous other skin diseases.  A newly developed biologic drug, ustekinumab, which targets the p40 subunit of IL-12 and IL-23, was approved by the U.S. FDA and the European Medicines Agency in 2009 for the treatment of moderate to severe psoriasis.  Administered as subcutaneous injections of 45 mg at weeks 0 and 4, and then every 12 weeks, ustekinumab produces a 75 % improvement in the PASI in 66.4 to 75.7 % of patients and a DLQI score of 0 or 1 in 55 to 56 % of patients after 12 weeks of therapy.  A recent clinical trial also indicates the possible efficacy of ustekinumab in psoriatic arthritis.  The proportion of patients who had at least 1 adverse event through 12 weeks in clinical studies was 51.6 to 57.6 % in the ustekinumab group and 50.4 % in the placebo group.  Serious adverse events were observed in 1.4 to 1.6 % of patients treated with ustekinumab and in 1.4 % of patients receiving placebo.  Injection-site reactions occurred in 1 to 2 % of patients and 5 % of patients developed anti-ustekinumab antibodies.  The authors concluded that further studies are needed to evaluate the long-term safety and effectiveness of ustekinumab.

U.S. Food and Drug Administration (FDA) has approved ustekinumab (Stelara), a fully human anti–IL-12/23p40 monoclonal antibody, alone or in combination with methotrexate for the treatment of adult patients (18 years or older) with active psoriatic arthritis. The approval was supported by findings from two pivotal phase 3 multicenter, randomized, double-blind, placebo-controlled trials of ustekinumab administered subcutaneously in subjects with active psoriatic arthritis (PSUMMIT I and PSUMMIT II), which evaluated the efficacy and safety of subcutaneously administered ustekinumab 45 mg or 90 mg at weeks 0, 4 and then every 12 weeks. The trials included 927 patients diagnosed with active psoriatic arthritis who had at least five tender and five swollen joints and C-reactive protein (CRP) levels of at least 0.3 mg/dL in spite of previous treatment with conventional therapy. PSUMMIT II also included 180 patients with previous exposure to 1-5 tumor necrosis factor (TNF) inhibitors. Results from PSUMMIT 1 showed that at week 24, 42 percent and 50 percent of patients receiving ustekinumab 45 mg and 90 mg, respectively, achieved at least 20 percent improvement in signs and symptoms according to the American College of Rheumatology criteria (ACR 20), the primary endpoint for both studies. In PSUMMIT II, 44 percent of patients receiving ustekinumab 45 mg and 44 percent of patients receiving ustekinumab 90 mg achieved ACR 20 at week 24. Additionally, ustekinumab improved soft tissue components of the disease, including dactylitis (inflammation of the finger or toe), enthesitis (inflammation of the entheses, the sites where tendons or ligaments attach to bone) and skin component as measured by Psoriasis Area and Severity Index score (PASI) 75.

The product labeling for Stelara has the following warnings and precautions:

  • Infections: Serious infections have occurred. Do not start Stelara during any clinically important active infection. If a serious infection develops, stop Stelara until the infection resolves.
  • Theoretical Risk for Particular Infections: Serious infections from mycobacteria, salmonella and Bacillus Calmette‐Guerin (BCG) vaccinations have been reported in patients genetically deficient in IL‐12/IL‐23. Diagnostic tests for these infections should be considered as dictated by clinical circumstances.
  • Tuberculosis (TB): Evaluate patients for TB prior to initiating treatment with Stelara.
  • Initiate treatment of latent TB before administering Stelara.
  • Malignancies: Stelara may increase risk of malignancy. The safety of Stelara in patients with a history of or a known malignancy has not been evaluated.
  • Anaphylaxis or other clinically significant hypersensitivity reactions may occur.
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): One case was reported. If suspected, treat promptly and discontinue Stelara.

Appendix

Examples of Clinical Reasons to Avoid Pharmacologic Treatment with Methotrexate, Cyclosporine or Acitretin

  1. Clinical diagnosis of alcohol use disorder, alcoholic liver disease, or other chronic liver disease
  2. Breastfeeding
  3. Drug interaction
  4. Cannot be used due to risk of treatment-related toxicity
  5. Pregnancy or currently planning pregnancy
  6. Significant comorbidity prohibits use of systemic agents (examples include liver or kidney disease, blood dyscrasias, uncontrolled hypertension)
Table: Brands of Targeted Immune Modulators and FDA-approved Indications
Brand Name Generic Name FDA Labeled Indications
Actemra tocilizumab

Giant cell arteritis

Juvenile idiopathic arthritis

Rheumatoid arthritis

Systemic juvenile idiopathic arthritis

Cytokine release syndrome (CRS)

Avsola infliximab-axxq

Ankylosing spondylitis

Crohn’s disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Cimzia certolizumab

Ankylosing spondylitis or axial spondyloarthritis

Crohn’s disease

Plaque psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Cosentyx secukinumab

Ankylosing spondylitis

Plaque psoriasis

Psoriatic arthritis

Enbrel etanercept

Ankylosing spondylitis

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Entyvio vedolizumab

Crohn’s disease

Ulcerative colitis

Humira adalimumab

Ankylosing spondylitis

Crohn’s disease

Hidradenitis suppurativa

Juvenile idiopathic arthritis

Plaque psoriasis

Psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Uveitis

Ilaris canakinumab

Periodic fever syndromes

Systemic juvenile idiopathic arthritis

Ilumya tildrakizumab-asmn

Plaque psoriasis

Inflectra infliximab

Ankylosing spondylitis

Crohn’s disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Kevzara sarilumab

Rheumatoid arthritis

Kineret anakinra

Cryopyrin-associated periodic syndromes

Rheumatoid arthritis

Olumiant baricitinib

Rheumatoid arthritis

Orencia abatacept

Juvenile idiopathic arthritis

Psoriatic arthritis

Rheumatoid arthritis

Otezla apremilast

Oral ulcers associated with Behçet’s Disease

Plaque psoriasis

Psoriatic arthritis

Remicade infliximab

Ankylosing spondylitis

Crohn’s disease

Psoriatic arthritis

Plaque psoriasis

Rheumatoid arthritis

Ulcerative colitis

Rinvoq

upadacitinib

Rheumatoid arthritis

Rituxan rituximab

Granulomatosis with polyangiitis

Microscopic polyangiitis

Pemphigus vulgaris

Rheumatoid arthritis

Siliq

brodalumab

Plaque psoriasis

Simponi golimumab

Ankylosing spondylitis

Psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Simponi Aria golimumab intravenous

Ankylosing spondylitis

Psoriatic arthritis

Rheumatoid arthritis

Skyrizi risankizumab-rzaa

Plaque psoriasis

Stelara ustekinumab

Crohn’s disease

Plaque psoriasis

Psoriatic arthritis

Taltz ixekinumab

Ankylosing spondylitis

Plaque psoriasis

Psoriatic arthritis

Tremfya guselkumab

Plaque psoriasis

Tysabri natalizumab

Crohn’s disease

Multiple sclerosis

Xeljanz tofacitinib

Rheumatoid arthritis

Psoriatic arthritis

Ulcerative Colitis

Xeljanz XR tofacitinib, extended release

Rheumatoid arthritis

Psoriatic arthritis

Ulcerative colitis



Table: CPT Codes / ICD-10 Codes / HCPCS Codes

Information in the (brackets) below has been added for clarification purposes.  &nbspCodes requiring a 7th character are represented by “+”:

Other CPT codes related to the CPB:

71045 – 71048 Radiologic examination, chest
86359 – 86361 T cells: total count; absolute CD4 and CD8 count, including ratio; or absolute CD4 count
86480 – 86481 Tuberculosis test, cell mediated immunity antigen response measurement; (interferon-release assay (IGRA))
86580 Skin test; tuberculosis, intradermal
96365 – 96368 Intravenous infusion, for therapy, prophylaxis, or diagnosis
96369 – 96371 Subcutaneous infusion for therapy or prophylaxis (specify substance or drug)
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379 Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
96401 Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
96409 – 96411 intravenous, push technique, single or initial, or each additional
96413 – 96417 Chemotherapy administration; intravenous infusion technique
96900 Actinotherapy (ultraviolet light)
96910 – 96922 Photochemotherapy; tar and ultraviolet B (Goeckerman treatment) or petrolatum and ultraviolet B, psoralens and ultraviolet A (PUVA), photochemotherapy (Goeckerman and/or PUVA), for severe photo-responsive dermatoses requiring at least four to eight hours of care under direct supervision of the physician (includes application of medication and dressings), laser treatment for inflammatory skin disease (psoriasis); total area less than 250 sq cm, 25

Abatacept (Orencia):

HCPCS codes covered if selection criteria are met:

J0129 Injection, abatacept, 10 mg

ICD-10 codes covered for indications listed in the CPB (not all inclusive):

L40.0 – L40.9 Psoriasis

Siliq, Guselkumab (Tremfya) :

Guselkumab (Tremfya):

HCPCS codes covered if selection criteria are met:

J1628 Injection, guselkumab, 1 mg

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis (for adults with moderate-to-severe chronic plaque psoriasis)

ICD-10 codes not covered for indications listed in the CPB:

K50.00 – K50.919 Crohn’s disease

Infliximab:

HCPCS codes covered if selection criteria are met:

Avsola, infliximab-axxq – no specific code
J1745 Injection, infliximab, 10 mg excludes biosimilar, 10 mg (Remicade)
Q5103 Injection, infliximab-dyyb, biosimilar, (Inflectra), 10 mg
Q5104 Injection, infliximab-abda, biosimilar, (Renflexis), 10 mg
Q5109 Injection, infliximab-qbtx, biosimilar, (Ixifi), 10 mg

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis (for adults with moderate-to-severe chronic plaque psoriasis)
L40.52 Psoriatic arthritis mutilans (active psoriatic arthritis (PsA))

Tildrakizumab:

HCPCS codes covered if selection criteria are met:

J3245 Injection, tildrakizumab, 1 mg

Secukinumab (Cosentyx):

No specific code

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis

Golimumab (Simponi):

HCPCS codes covered if selection criteria are met:

J1602 Injection, golimumab, 1mg for intravenous use

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis

Etanercept (Enbrel):

HCPCS codes covered if selection criteria are met:

J1438 Injection, etanercept, 25 mg

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis (for ages 4 and older with moderate-to-severe chronic plaque psoriasis)

Adalimumab (Humira):

HCPCS codes covered if selection criteria are met:

J0135 Injection, adalimumab, 20 mg

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis (for adults with moderate-to-severe chronic plaque psoriasis)

Apremilast (Otezla):

No specific code

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis

Ustekinumab (Stelara):

HCPCS codes covered if selection criteria are met:

J3357 Ustekinumab, for subcutaneous injection, 1 mg
J3358 Ustekinumab, for intravenous injection, 1 mg

Other HCPCS codes related to the CPB:

A4633 Replacement bulb/lamp for ultraviolet light therapy system, each
E0691 – E0694 Ultraviolet light therapy systems
J7500 Azathioprine, oral, 50 mg
J7501 Azathioprine, parenteral, 100 mg
J7502 Cyclosporine, oral, 100 mg
J7515 Cyclosporine, oral, 25 mg
J7516 Cyclosporine, parenteral, 250 mg
J8610 Methotrexate, oral, 2.5 mg
J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg

ICD-10 codes covered if selection criteria are met:

K50.00 – K50.919 Crohn’s disease
L40.0 – L40.9 Psoriasis (for ages 12 and older with moderate-to-severe chronic plaque psoriasis) (not covered for erythrodermic psoriasis)

Certolisumab (Cimzia):

HCPCS codes covered if selection criteria are met:

J0717 Injection, certolizumab pegol 1 mg

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis

Tofacitinib (Xeljanz, Xeljanz XR):

No specific code

ICD-10 codes covered if selection criteria are met:

L40.50 – L40.59 Arthropathic psoriasis

Ixekizumab (Taltz):

No specific code

ICD-10 codes covered if selection criteria are met:

L40.50 – L40.59 Arthropathic psoriasis

Risankizumab-rzaa (Skyrizi):

HCPCS codes covered if selection criteria are met:

Risankizumab-rzaa (Skyrizi) – no specific code:

ICD-10 codes covered if selection criteria are met:

L40.0 – L40.9 Psoriasis (for adults with moderate-to-severe chronic plaque psoriasis)


The above policy is based on the following references:

General References

  1. Bansback N, Sizto S, Sun H, et al. Efficacy of systemic treatments for moderate to severe plaque psoriasis: Systematic review and meta-analysis. Dermatology. 2009;219(3):209-218.
  2. Boudreau R, Blackhouse G, Goeree R, Mierzwinski-Urban M. Adalimumab, elefacept, efalizumab, etanercept, and infliximab for severe psoriasis vulgaris in adults: Budget impact analysis and review of comparative clinical- and cost-effectiveness. Technology Report No. 97. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); December 2007.
  3. Brimhall AK, King LN, Licciardone JC, et al. Safety and efficacy of alefacept, efalizumab, etanercept and infliximab in treating moderate to severe plaque psoriasis: A meta-analysis of randomized controlled trials. Br J Dermatol. 2008; 159(2):274-285.
  4. British Association of Dermatologists (BAD). Psoriasis Guideline 2006. London, UK: BAD; 2006.
  5. Centers for Disease Control and Prevention (CDC), Division of Tuberculosis Elimination. Basic TB facts. TB risk factors. Atlanta, GA: CDC; March 2016.
  6. Coates LC, Kavanaugh A, Mease PJ, et al. Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment recommendation for psoriatic arthritis. Arthritis Rheumatol. 2016 May;68(5):1060-71.
  7. Ferrandiz C, García A, Blasco AJ, Lazaro P. Cost-efficacy of adalimumab, etanercept, infliximab and ustekinumab for moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2012;26(6):768-777.
  8. Finnish Medical Society Duodecim. Psoriasis. In: EBM Guidelines. Evidence-Based Medicine (CD-ROM). Helsinki, Finland: Duodecim Medical Publications Ltd.; May 25, 2005.
  9. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499-510.
  10. Menter A, Korman NJ, Elmets CA, et al. American Academy of Dermatology Work Group. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: Case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011;65(1):137-74.
  11. Naldi L, Rzany B. Psoriasis (chronic plaque). In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; August 2007.
  12. National Institute for Health and Care Excellence (NICE). Psoriasis: Assessment and management. Clinical Guideline 153. London, UK: NICE; updated September 2017.
  13. Rozenblit M, Lebwohl M. New biologics for psoriasis and psoriatic arthritis. Dermatol Ther. 2009;22(1):56-60.
  14. Sbidian E, Chaimani A, Garcia-Doval I, et al. Systemic pharmacological treatments for chronic plaque psoriasis: A network meta-analysis. Cochrane Database Syst Rev. 2017;12:CD011535.
  15. Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis. Arthritis Rheum. 2018;71:5-32.
  16. Smith CH, Anstey JNWN, Barker AD, et al. British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol. 2005;153:486-497.
  17. Smith CH, Jabbar-Lopez ZK, Yiu ZZ, et al. British Association of Dermatologists guidelines for biologic therapy for psoriasis 2017. Br J Dermatol. 2017;177:628–636.
  18. Thaler KJ, Gartlehner G, Kien C, et al. Targeted immune modulators. Drug Class Review. Final Update 3 Report. Produced by the RTI-UNC Evidence-based Practice Center, Cecil G. Sheps Center for Health Services Research, and the Drug Effectiveness Review Project, Oregon Evidence-based Practice Center. Portland, OR: Oregon Health & Science University; March 2012.
  19. Tzu J, Krulig E, Cardenas V, Kerdel FA. Biological agents in the treatment of psoriasis. G Ital Dermatol Venereol. 2008;143(5):315-327.

Abatacept (Orencia)

  1. Bristol-Myers Squibb Co. (BMS). Bristol-Myers Squibb’s Orencia (abatacept receives FDA approval for treatment of active psoriatic arthritis (PsA) in adults. Press Release. Princeton, NJ: BMS; July 6, 2017.
  2. Bristol-Myers Squibb Co. (BMS). Orencia (abatacept) injection. Prescribing Information. Princeton, NJ: BMS; revised March 2019.

Adalimumab (Humira)

  1. Abbott Laboratories. Abbott’s Humira (adalimumab) receives FDA approval for moderate to severe chronic plaque psoriasis. Press Release. Abbott Park, IL: Abbott Laboratories; January 18, 2008.
  2. Abbott Laboratories. Humira (adalimumab) injection, solution for subcutaneous use. Prescribing Information. Abbott Park, IL: Abbott Laboratories; revised February 2008.
  3. AbbVie Inc. Humira (adalimumab) injection, for subcutaneous use. Prescribing Information. North Chicago, IL: AbbVie; revised January 2019.
  4. Boudreau R, Blackhouse G, Goeree R, Mierzwinski-Urban M. Adalimumab, alefacept, efalizumab, etanercept, and infliximab for severe psoriasis vulgaris in adults: Budget impact analysis and review of comparative clinical- and cost-effectiveness. Technology Report No. 97. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2007.
  5. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106-115.
  6. National Horizon Scanning Centre (NHSC). Adalimumab (Humira) for moderate to severe chronic plaque psoriasis – horizon scanning review. Birmingham, UK: NHSC; 2006.
  7. National Institute for Health and Clinical Excellence (NICE). Adalimumab for the treatment of adults with psoriasis. NICE Technology Appraisal Guidance 146. London, UK: NICE; June 2008.
  8. Revicki D, Willan MK, Saurat JH, et al. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: Results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2008;158(3):549-557.

Alefacept (Amevive)

  1. Bailey EE, Ference EH, Alikhan A, et al. Combination treatments for psoriasis: A systematic review and meta-analysis. Arch Dermatol. 2012;148(4):511-522.
  2. Bin Dayel S, AlGhamdi K. Failure of alefacept in the treatment of vitiligo. J Drugs Dermatol. 2013;12(2):159-161.
  3. Biogen, Inc. Amevive (alefacept) package insert. I63007-1. Cambridge, MA: Biogen; February 2003.
  4. Danish Centre for Evaluation and Health Technology Assessment (DACEHTA). Alefacept (Amevive) for the treatment of severe psoriasis – Early Warning on New Health Technology. Copenhagen, Denmark: DACEHTA; 2003;2(3).
  5. Ellis CN, Mordin MM, Adler EY. Effects of alefacept on health-related quality of life in patients with psoriasis: Results from a randomized, placebo-controlled phase II trial. Am J Clin Dermatol. 2003;4(2):131-139.
  6. Frampton J, Wagstaff A. Alefacept. Am J Clin Dermatol. 2003;4(4):277-286; discussion 287.
  7. Granstein RD. New treatments for psoriasis. N Engl J Med. 2001;345(4):284-287.
  8. Hankin CS, Feldman SR, Szczotka A, et al. A cost comparison of treatments of moderate to severe psoriasis. Drug Benefit Trends. 2005;17(5):200-214.
  9. Kraan MC, van Kuijk AW, Dinant HJ, et al. Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum. 2002;46(10):2776-2784.
  10. Krueger GG, Papp KA, Stough DB, et al. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol. 2002;47(6):821-833.
  11. Luba KM, Stulberg DL. Chronic plaque psoriasis. Am Fam Physician. 2006;73(4):636-644.
  12. Manno R, Boin F. Immunotherapy of systemic sclerosis. Immunotherapy. 2010;2(6):863-878.
  13. National Horizon Scanning Centre (NHSC). New treatments for psoriasis. Birmingham, UK: NHSC; 2002.
  14. National Psoriasis Foundation (NPF). Amevive (alefacept) voluntarily discontinued in the U.S. News. Alexandria, VA: National Psoriasis Foundation; January 5, 2012.
  15. Psoriasis. In: General Practice Notebook. Cambridge, UK: Oxbridge Solutions Ltd., 2003.
  16. Shukla V K. Alefacept: Potential new therapy for patients with moderate-to-severe psoriasis. Issues in Emerging Health Technologies. Issue 45. Ottawa, ON: Canadian Coordinating Office for Health Technology Assessment (CCOHTA); April 2003.
  17. Strober BE, Menon K, McMichael A, et al. Alefacept for severe alopecia areata: A randomized, double-blind, placebo-controlled study. Arch Dermatol. 2009;145(11):1262-1266.
  18. Wollina U, Haroske G. Pyoderma gangraenosum. Curr Opin Rheumatol. 2011;23(1):50-56.

Apremilast (Otezla)

  1. Celgene Corporation. Oral Otezla (apremilast) approved by the U.S. Food and Drug Administration for the treatment of patients with moderate to severe plaque psoriasis. Press Release. Summit, NJ: Celgene; September 23, 2014.
  2. Celgene Corporation. Otezla (apremilast) tablets, for oral use. Prescribing Information. APRPI.003. Summit, NJ: Celegene; revised September 2014.
  3. Celgene Corporation. Otezla (apremilast) tablets, for oral use. Prescribing Information. Summit, NJ: Celegene; revised July 2019.
  4. Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6):1020-6.
  5. Schett G, Wollenhaupt J, Papp K, et al. Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2012;64(10):3156-3167.
  6. U.S. Food and Drug Administration (FDA). FDA approves Otezla to treat psoriatic arthritis. FDA News Release. Silver Spring, NJ: FDA; March 21, 2014.

Brodalumab (Siliq)

  1. AstraZenica. Siliq (brodalumab) approved by the US FDA for adult patients with moderate-to-severe plaque psoriasis. Press Release. Cambridge, UK: AstraZenica; February 16, 2017.
  2. Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373(14):1318-1328.
  3. Papp KA, Reich K, Paul C, et al. A prospective phase III, randomized, double-blind, placebo-controlled study of brodalumab in patients with moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;175(2):273-286.
  4. U.S. Food and Drug Administration (FDA). FDA approves a new psoriasis drug. FDA News Release. Silver Spring, MD: FDA; February 15, 2017.
  5. Valeant Pharmaceuticals International, Inc. Valeant receives FDA approval of Siliq (brodalumab) for moderate-to-severe plaque psoriasis. News Release. Laval, QC: Valeant; February 16, 2017.
  6. Valeant Pharmaceuticals North America LLC. Siliq (brodalumab) injection, for subcutaneous use. Prescribing Information. Reference ID: 4056898. Bridgewater, NJ: Valeant; revised February 2017.

Certolizumab (Cimzia)

  1. Feldman SR. Treatment of psoriasis in adults. UpToDate (online serial). Waltham, MA: UpToDate; reviewed July 2018.
  2. Gottlieb AB, Blauvelt A, Thaçi D, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018;79(2):302-314.e6.
  3. Lebwohl M, Blauvelt A, Paul C, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018;79(2):266-276.e5.
  4. UCB, Inc. Cimzia (certolizumab pegol) for injection, for subcutaneous use. Prescribing Information. Smyrna, GA: UCB; revised April 2019.

Efalizumab (Raptiva)

  1. Dedrick RL, Walicke P, Garovoy M. Anti-adhesion antibodies efalizumab, a humanized anti-CD11a monoclonal antibody. Transpl Immunol. 2002;9(2-4):181-186.
  2. Feldman SR, Garton R, Averett W, et al. Strategy to manage the treatment of severe psoriasis: Considerations of efficacy, safety and cost. Expert Opin Pharmacother. 2003;4(9):1525-1533.
  3. Gottlieb AB, Hamilton T, Caro I, et al. Long-term continuous efalizumab therapy in patients with moderate to severe chronic plaque psoriasis: Updated results from an ongoing trial. J Am Acad Dermatol. 2006;54(4 Suppl 1):S154-S163.
  4. Gottlieb AB, Krueger JG, Wittkowski K, et al. Psoriasis as a model for T-cell-mediated disease: Immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a antibody. Arch Dermatol. 2002;138(5):591-600.
  5. Lynde C. Efalizumab: Integrating a new biologic agent into the long-term management of moderate to severe plaque psoriasis. J Cutan Med Surg. 2006;9 Suppl 1:1-3.
  6. Menter A, Leonardi CL, Sterry W, et al. Long-term management of plaque psoriasis with continuous efalizumab therapy. J Am Acad Dermatol. 2006;54(4 Suppl 1):S182-S188.
  7. National Institute for Health and Clinical Excellence (NICE). Etanercept and efalizumab for the treatment of adults with psoriasis. NICE Technology Appraisal Guidance 103. London, UK: NICE; July 2006.
  8. Papp KA, Miller B, Gordon KB, et al. Efalizumab retreatment in patients with moderate to severe chronic plaque psoriasis. J Am Acad Dermatol. 2006;54(4 Suppl 1):S164-S170.
  9. Pariser DM. Management of moderate to severe plaque psoriasis with biologic therapy. Manag Care. 2003;12(4):36-44.
  10. Poulin Y, Papp KA, Carey W, et al. A favourable benefit/risk ratio with efalizumab: A review of the clinical evidence. J Cutan Med Surg. 2006;9 Suppl 1:10-17.
  11. Shear NH. Fulfilling an unmet need in psoriasis: Do biologicals hold the key to improved tolerability? Drug Saf. 2006;29(1):49-66.
  12. Sterry W, Barker J, Boehncke WH, et al. Biological therapies in the systemic management of psoriasis: International Consensus Conference. Br J Dermatol. 2004;151 Suppl 69:3-17.
  13. Tutrone WD, Kagen MH, Barbagallo J, Weinberg JM. Biologic therapy for psoriasis: A brief history, II. Cutis. 2001;68(6):367-372.
  14. U.S. Food and Drug Administration (FDA). FDA statement on the voluntary withdrawal of Raptiva from the U.S. market. FDA News. Rockville, MD: FDA; April 9, 2009.
  15. Weinberg JM, Saini R, Tutrone WD. Biologic therapy for psoriasis–the first wave: Infliximab, etanercept, efalizumab, and alefacept. J Drugs Dermatol. 2002;1(3):303-310.
  16. Weinberg JM, Tutrone WD. Biologic therapy for psoriasis: The T-cell-targeted therapies efalizumab and alefacept. Cutis. 2003;71(1):41-45.
  17. Woolacott N, Hawkins N, Mason A, et al. Etanercept and efalizumab for the treatment of psoriasis: A systematic review. Health Technol Assess. 2006;10(46):1-252.
  18. Xoma (US) LLC. Product Development: Raptiva. Berkeley, CA: Xoma; 2003. Available at: http://www.xoma.com/product_development/raptiva.jsp. Accessed November 4, 2003.

Etanercept (Enbrel)

  1. Amgen, Inc. Enbrel (etanercept) injection, for subcutaneous use. Prescribing Information. Thousand Oaks, CA: Amgen; revised November 2016.
  2. Amgen, Inc. FDA approves expanded use Of Enbrel (etanercept) to treat children with chronic moderate-to-severe plaque psoriasis. News Releases. Thousand Oaks, CA: Amgen; November 4, 2016.
  3. Gottlieb AB, Leonardi CL, Goffe BS, et al. Etanercept monotherapy in patients with psoriasis: A summary of safety, based on an integrated multistudy database. J Am Acad Dermatol. 2006;54(3 Suppl 2):S92-S100.
  4. Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol. 2003;139(12):1627-1632; discussion 1632.
  5. Immunex Corporation (Amgen). Enbrel (etanercept) injection, for subcutaneous use. Prescribing Information. Thousand Oaks, CA: Amgen; revised June 2019.
  6. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-2022.
  7. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: A randomised trial. Lancet. 2000;356(9227):385-390.
  8. Mease PJ. Etanercept, a TNF antagonist for treatment for psoriatic arthritis and psoriasis. Skin Therapy Lett. 2003;8(1):1-4.
  9. National Institute for Health and Clinical Excellence (NICE). Etanercept and efalizumab for the treatment of adults with psoriasis. NICE Technology Appraisal Guidance 103. London, UK: NICE; July 2006.
  10. Paller AS, Siegfried EC, Langley RG, et al.; Etanercept Pediatric Psoriasis Study Group.. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241-251.
  11. Paller AS, Siegfried EC, Pariser DM, et al. Long-term safety and efficacy of etanercept in children and adolescents with plaque psoriasis. J Am Acad Dermatol. 2016;74(2):280-7.e1-e3.
  12. Woolacott N, Hawkins N, Mason A, et al. Etanercept and efalizumab for the treatment of psoriasis: A systematic review. Health Technol Assess. 2006;10(46):1-252.

Golimumab (Simponi)

  1. Janssen Biotech, Inc. Simponi (golimumab) injection, for subcutaneous use. Prescribing Information. Horsham, PA: Janssen Biotech; May 2018.

Golimumab (Simponi Aria)

  1. Janssen Biotech, Inc. Janssen receives two U.S. FDA approvals for Simponi Aria (golimumab) for the treatment of adults with active psoriatic arthritis or active ankylosing spondylitis. News Release. Horsham, PA: Janssen Biotech; October 20, 2017.
  2. Janssen Biotech, Inc. Simponi Aria (golimumab) injection, for intravenous use. Prescribing Information. 082541-171019. Horsham, PA: Janssen Biotech; May 2018.

Guselkumab (Tremfya)

  1. Blauvelt A, Papp KA, Griffiths, CEM, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. Am J Clin Dermatol. 2017;76(3):405-417.
  2. Janssen Biotech, Inc. Tremfya (guselkumab) injection, for subcutaneous use. Prescribing Information. Horsham, PA: Janssen Biotech; revised November 2019.
  3. Janssen Biotech, Inc. Tremfya (guselkumab) injection. Prescribing Information. Reference ID: 4123919 1. Horsham, PA: Janssen Biotech; revised July 2017.
  4. Johnson & Johnson Services, Inc. Janssen announces U.S. FDA approval of Tremfya (guselkumab) for the treatment of moderate to severe plaque psoriasis. Press Release. Horsham, PA: Johnson & Johnson; July 13, 2017.
  5. Reich K, Armstrong, AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator–controlled VOYAGE 2 trial. Am J Clin Dermatol. 2017;76(3):418-431.

Infliximab (Remicade/Avsola/Inflectra/Renflexis)

  1. Amgen, Avsola (infliximab-axxq) for injection, for intravenous use. Prescribing Information. Thousand Oaks: CA: Amgen; revised December 2019.
  2. Chaudhari U, Romano P, Mulcahy LD, et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: A randomised trial. Lancet. 2001;357(9271):1842-1847.
  3. Feldman SR, Gordon KB, Bala M, et al. Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: A double-blind placebo-controlled trial. Br J Dermatol. 2005;152(5):954-960.
  4. Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534-542.
  5. Janssen Biotech, Inc. Remicade (infliximab) lyophilized concentrate for injection, for intravenous use. Prescribing Information. Horsham, PA: Janssen Biotech; revised June 2018.
  6. Merck & Co, Inc. Renflexis (infliximab-abda) for injection, for intravenous use. Prescribing Information. Whitehouse Station, NJ: Merck; revised June 2019.
  7. National Horizon Scanning Centre (NHSC). Infliximab for psoriasis. Horizon Scanning Review. Birmingham, UK: NHSC; 2004.
  8. National Institute for Health and Clinical Excellence (NICE). Infliximab for the treatment of adults with psoriasis. NICE Technology Appraisal Guidance 134. London, UK: January 2008.
  9. Pfizer Inc. Inflectra (infliximab-dyyb) lyophilized concentrate for injection, for intravenous use. Prescribing Information. New York, NY: Pfizer; revised June 2019.
  10. Reich K, Nestle FO, Papp K, et al. Improvement in quality of life with infliximab induction and maintenance therapy in patients with moderate-to-severe psoriasis: a randomized controlled trial. Br J Dermatol. 2006;154(6):1161-1168.
  11. Reich K, Nestle FO, Papp K, et al.; EXPRESS study investigators. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: A phase III, multicentre, double-blind trial. Lancet. 2005;366(9494):1367-1374.

Ixekizumab (Taltz)

  1. Eli Lilly and Company. Lilly’s Taltz® (ixekizumab) receives U.S. FDA approval for the treatment of moderate-to-severe plaque psoriasis. News Release. Indianapolis, IN: Lilly; March 22, 2016.
  2. Eli Lilly and Company. Lilly’s Taltz® (ixekizumab) receives U.S. FDA approval for the treatment of active psoriatic arthritis. News Release. Indianapolis, IN: Lilly; December, 1, 2017.
  3. Eli Lilly and Company. Lilly’s Taltz® (ixekizumab) receives U.S. FDA approval for the treatment of pediatric patients with moderate to severe plaque psoriasis. News Release. Indianapolis, IN: Lilly; March 30, 2020,
  4. Eli Lilly and Company. Taltz (ixekizumab) injection, for subcutaneous use. Prescribing Information. TAL-0001-USPI-20160322. Indianapolis, IN: Lilly; revised March 2016.
  5. Eli Lilly and Company. Taltz (ixekizumab) injection, for subcutaneous use. Prescribing Information. TAL-0004-USPI-20171201. Indianapolis, IN: Lilly; revised December 2017.
  6. Eli Lilly and Company. Taltz (ixekizumab) injection, for subcutaneous use. Prescribing Information. Indianapolis, IN: Lilly; revised August 2019.
  7. Eli Lilly and Company. Taltz (ixekizumab) injection, for subcutaneous use. Prescribing Information. Indianapolis, IN: Lilly; revised March 2020.
  8. Griffiths CE, Reich K, Lebwohl M, et al.; UNCOVER-2 and UNCOVER-3 investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): Results from two phase 3 randomised trials. Lancet. 2015;386(9993):541-551.
  9. Mease PJ, van der Heijde D, Ritchlin CT, et al.; SPIRIT-P1 Study Group.. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87.
  10. Nash P, Kirkham B, Okada M, et al.; SPIRIT-P2 Study Group.. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389(10086):2317-2327.

Risankizumab-rzaa (Skyrizi)

  1. AbbVie, Inc. AbbVie expands immunology portfolio in the U.S. with FDA approval of SKYRIZI™ (risankizumab-rzaa) for moderate to severe plaque psoriasis. Press Release. North Chicago, IL: AbbVie; April 23, 2019a.
  2. AbbVie, Inc. Skyrizi (risankizumab-rzaa) injection, for subcutaneous use. Prescribing Information. North Chicago, IL: AbbVie; revised August 2019b.
  3. Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): Results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392(10148):650-661.

Secukinumab (Cosentyx)

  1. Blauvelt A, Prinz JC, Gottlieb AB, et al.; the FEATURE Study Group. Secukinumab administration by pre-filled syringe: Efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172(2):484-93.
  2. Langley RG, Elewski BE, Lebwohl M, et al.; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis–results of two phase 3 trials. N Engl J Med. 2014;371(4):326-338.
  3. McInnes IB, Mease PJ, Kirkham B, et al.; FUTURE 2 Study Group. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;386(9999):1137-46.
  4. McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: A 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis. 2014;73(2):349-356.
  5. Novartis Pharmaceutical Corp. Cosentyx (secukinumab) injection, for subcutaneous use. Prescribing Information. T2015-11. East Hanover, NJ: Novartis; January 2015.
  6. Novartis Pharmaceuticals Corp. Cosentyx (secukinumab) for injection, for subcutaneous use. Prescribing Information. East Hanover, NJ: Novartis; revised June 2018.
  7. Novartis Pharmaceuticals Corp. Novartis announces FDA approval for first IL-17A antagonist Cosentyx (secukinumab) for moderate-to-severe plaque psoriasis patients. Press Release. East Hanover, NJ: Novartis; January 21, 2015.
  8. Paul C, Lacour JP, Tedremets L, et al.; the JUNCTURE study group. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: A randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol. 2015;29(6):1082-90.

Tildrakizumab (Ilumya)

  1. Merck & Co., Inc.Ilumya (tildrakizumab-asmn) injection, for subcutaneous use.Prescribing Information. Whitehouse Station, NJ: Merck & Co., Inc.; revised March 2018.
  2. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017 Jul 15;390(10091):276-288.

Tofacitinib (Xeljanz and Xeljanz XR)

  1. Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med. 2017;377(16):1525-1536.
  2. Mease P, Hall S, FitzGerald O, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537-1550.
  3. Pfizer Inc. Pfizer announces FDA approval of Xeljanz (tofacitinib) and Xeljanz XR for the treatment of active psoriatic arthritis. Press Release. New York, NY: Pfizer; December 14, 2017.
  4. Pfizer Inc. Xeljanz (tofacitinib) tablets, for oral use. Xeljanz XR (tofacitinib) extended release tablets, for oral use. Prescribing Information. New York, NY: Pfizer; revised July 2019.

Ustekinumab (Stelara)

  1. Centocor, Inc. Findings from landmark study show ustekinumab demonstrated superior efficacy to Enbrel (etanercept) in treatment of moderate to severe plaque psoriasis. News. Horsham, PA: Centocor; September 18, 2008.
  2. Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: Randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009;373(9664):633-640.
  3. Griffiths CE, Strober BE, van de Kerkhof P, et al; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362(2):118-128.
  4. Janssen Biotech, Inc. Janssen announces U.S. FDA approval of Stelara (ustekinumab) for the treatment of adolescents with moderate to severe plaque psoriasis. Press Release. Horsham, PA: Janssen Biotech; October 13, 2017.
  5. Janssen Biotech, Inc. Janssen announces U.S. FDA approval of Stelara (ustekinumab) for the treatment of adolescents with moderate to severe plaque psoriasis. Press Release. Horsham, PA: Janssen Biotech; October 13, 2017.
  6. Janssen Biotech, Inc. Stelara (ustekinumab) injection, for subcutaneous use. Prescribing Information. 003199-130922. Horsham, PA: Janssen Biotech; revised September 2013.
  7. Janssen Biotech, Inc. Stelara (ustekinumab) injection, for subcutaneous or intravenous use. Prescribing Information. Reference ID: 077382-170727. Horsham, PA: Janssen Biotech; revised October 2017.
  8. Janssen Biotech, Inc. Stelara (ustekinumab) injection, for subcutaneous or intravenous use. Prescribing Information. Horsham, PA: Janssen Biotech; revised June 2018.
  9. Janssen Biotech, Inc. Stelara (ustekinumab) receives FDA approval to treat active psoriatic arthritis. First and only anti-IL-12/23 treatment approved for adult patients living with psoriatic arthritis. News Release. Horsham, PA: Janssen Biotech; September 23, 2013.
  10. Kavanaugh A, Menter A, Mendelsohn A, et al. Effect of ustekinumab on physical function and health-related quality of life in patients with psoriatic arthritis: A randomized, placebo-controlled, phase II trial. Curr Med Res Opin. 2010;26(10):2385-2392.
  11. Kurzeja M, Rudnicka L, Olszewska M. New interleukin-23 pathway inhibitors in dermatology: Ustekinumab, briakinumab, and secukinumab. Am J Clin Dermatol. 2011;12(2):113-125.
  12. Landells I, Marano C, Hsu MC, et al. Ustekinumab in adolescent patients age 12 to 17 years with moderate-to-severe plaque psoriasis: Results of the randomized phase 3 CADMUS study. J Am Acad Dermatol. 2015;73(4):594-603.
  13. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665-1674.
  14. McInnes IB, Kavanaugh A, Gottlieb AB, et al.; PSUMMIT 1 Study Group. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet. 2013;382(9894):780-789.
  15. National Institute for Health and Clinical Excellence (NICE). Ustekinumab for the treatment of adults with moderate to severe psoriasis. NICE Technology Appraisal Guidance 180. London, UK: NICE; September 2009.
  16. Papp KA, Langley RG, Lebwohl M, et al; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675-1684.
  17. Ryan C, Thrash B, Warren RB, Menter A. The use of ustekinumab in autoimmune disease. Expert Opin Biol Ther. 2010;10(4):587-604.
  18. Santos-Juanes J, Coto-Segura P, Mas-Vidal A, Galache Osuna C. Ustekinumab induces rapid clearing of erythrodermic psoriasis after failure of antitumour necrosis factor therapies. Br J Dermatol. 2010;162(5):1144-1146.
  19. U.S. Food and Drug Administration (FDA). FDA approves new drug to treat psoriasis. FDA News. Rockville, MD: FDA; September 25, 2009.
  20. Weber J, Keam SJ. Ustekinumab. BioDrugs. 2009;23(1):53-61.

Psorilax:a cosa serve |crema per psoriasi tallone

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Psorilax: prezzo, funziona, recensioni, opinioni, quanto costa

Chi dovrei consultare per i trattamenti della psoriasi?

È meglio parlare con un medico che si concentra su ed è ben addestrato in tutte le cose relative alla pelle, che è un dermatologo. Ancora meglio è un derma specializzato in psoriasi. Conoscerà i dettagli di questa condizione, le opzioni di trattamento, gli effetti collaterali e altro ancora.

Puoi curare la psoriasi?

Sfortunatamente, non esiste una cura per questa condizione cronica. Ma le opzioni di trattamento sono ampie. Con l'aiuto del tuo medico e un po 'di prove ed errori, puoi trovare quello che ti aiuta a gestire la tua psoriasi e vivere una vita piena con questa malattia.

Gli stessi trattamenti sono usati per la psoriasi e l'artrite psoriasica?

Esistono alcuni trattamenti, come alcuni farmaci biologici e orali, che funzionano in entrambe le condizioni. Tuttavia, è meglio consultare un reumatologo per la tua artrite psoriasica poiché i reumatologi sono specializzati in tutti i tipi di artrite.

Come faccio a sapere se il mio trattamento per la psoriasi funziona?

Gli obiettivi da trattare a target aiutano pazienti e medici a valutare l'efficacia del trattamento. L'obiettivo è che la tua psoriasi copra l'1% o meno del tuo corpo in tre mesi. In caso contrario, tu e il tuo dottore di ricerca potete rivalutare il vostro piano.

Psorilax:Acquista |trosyd crema anche per psoriasi

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Psorilax: prezzo, funziona, recensioni, opinioni, originale

Avrai la pelle migliore della tua vita una volta terminata la quarantena.

Speriamo che ami i prodotti che consigliamo! Solo per questo, BuzzFeed può raccogliere una quota delle vendite o altri compensi dai link in questa pagina. Oh e FYI – i prezzi sono precisi e gli articoli in stock al momento della pubblicazione.

1.

Una bottiglia di acqua micellare Garnier, un liquido multiuso per i neofiti della bellezza. È un toner fantastico, uno struccante delicato (anche se potresti aver bisogno di qualcosa di più duro per il mascara impermeabile), un detergente (non è necessario il risciacquo), un idratante e un aggiornamento della pelle in movimento e un detergente per pennelli da trucco. Non importa come lo usi, ti piacerà che funziona per quasi tutti i tipi di pelle.

@garnierusa / Via instagram.com

Questa è la nostra scelta economica per il miglior struccante su BuzzFeed Recensioni!

Recensione promettente: “Questo è intorno alla nostra nona bottiglia. Lo uso per rimuovere il mio trucco senza sforzo. Stavo notando che stavo comprando una bottiglia più velocemente di quanto dovrei essere fino a quando mio marito non ha pensato di usarlo per pulirsi il viso! Lo adora assolutamente per gestire la sua pelle grassa che è divertente perché ho la pelle SUPER secca. Funziona con entrambi i nostri tipi di pelle, quindi lo conserviamo il più possibile e ottieni i multipack quando sono disponibili! Questa roba è oro liquido. “—Kendall Forsythe

Ricevilo da Amazon per $ 6,78.

2.

Una combinazione di detergente per schiuma Aveeno + struccante realizzato con camomilla per lenire la pelle. Questo ti evita di doverti lavare due volte (prima con uno struccante e poi con un detergente) * e * è super delicato.

Aveeno

Recensione promettente: “Non riesco a credere quanto bene mi lavi la faccia! Indosso un trucco pesante per coprire la mia rosacea e me la toglie così bene. È così leggero, arioso e spumoso. Nessuna irritazione per me. Molto contento di questo. Mi è stato consigliato dal mio dermatologo e continuerò a usarlo. “—Amazon Customer

Ricevilo da Amazon per $ 5,99.

3.

Un detergente alla vitamina C che lava via la pelle secca e desquamata mentre penetra in profondità per lasciare oli idratanti. La vitamina C può aiutare ad aumentare l'idratazione della pelle nutrendo e rinforzando la barriera di ritenzione dell'umidità della pelle, quindi questo è un modo semplice per sfruttare i benefici della vitamina C senza preoccuparsi di sieri e toner confusi.

amazon.com

Recensione promettente: “Questo è un fantastico detergente per il viso! Ho una pelle super sensibile che è soggetta a sblocchi di un mese e lavoro in un ambiente molto secco, quindi ho anche problemi di umidità. Questo lavaggio fa sentire la mia pelle come la vera pelle del bambino. Ho avuto zero sblocchi da quando ho iniziato a usare (~ 6 settimane). Prima di truccarmi, mescolo una pompa di questo detergente per il viso con 1/2 cucchiaino di sale, e fa una macchia esfoliante FANTASTICA. Rende tutte le mie patch traballanti belle e lisce, e abbinate a un buon primer rendono l'applicazione del trucco impeccabile. Nessuna patch visibilmente testurizzata: un GRANDE vantaggio quando sei un barista sotto i riflettori tutta la notte con le persone che ti fissano in faccia !! Se potessi dare tre pollici in su lo farei, ma avrei solo due pollici !! “—Katie

Ricevilo da Amazon per $ 19,97.

4.

Un detergente per il viso CeraVe per le persone con pelle secca che non vogliono andare in giro con un milione di prodotti diversi.

amazon.com

Recensione promettente: “All'inizio ero un po 'titubante perché la consistenza è come una lozione, ma non lasciarti ingannare! È un ottimo lavaggio del viso! Ho lottato con la mia acne per anni e ho provato un miliardo di prodotti diversi e nessuno di loro ha funzionato come questo. Ci sono voluti circa un mese di uso costante ma ha reso la mia pelle quasi impeccabile. Non sto truccando in nessuna delle due foto. “—Cassidy Cooper

Ricevilo da Amazon per $ 13,79.

5.

Una nebbia tonificante Thayers senza alcool che non vedrai l'ora di usare perché è così spaventosamente veloce. È anti-infiammatorio, il che significa che potresti essere in grado di baciare il rossore addio. Inoltre, è un significato astringente che aiuta a stringere i pori e asciuga gli oli in eccesso.

@thayersnatural / Via instagram.com

Recensione promettente: “Questo lascia la tua pelle così fresca e pulita. La uso prima della crema idratante nelle ore 13:00 e nelle ore pomeridiane. Aspetta che sia inzuppata nella pelle e metta la crema idratante sopra e la tua pelle risplenderà!” —Amazon Customer

Ricevilo da Amazon per $ 10,95.

6.

Un gel d'acqua esfoliante per sciogliere la pelle morta sul viso, perché trovare un esfoliante chimico che funzioni può essere complicato. Meno male che abbiamo fatto il duro lavoro per te! Scherzi a parte, sarai in grado di vedere piccole “perle” di sporco, detriti e pelle morta che scendono nello scarico.

amazon.com, amazon.com

Recensione promettente:L'ho comprato per un capriccio pensando che sarebbe stato OK ma non all'altezza dei rave … mi sbagliavo! Il prezzo è in linea (o in realtà meno !!) con i prodotti di bellezza di fascia alta e la spedizione è stata incredibilmente veloce. Il prodotto in sé è fantastico. Mi sono spruzzato una mezza pompa sul dito e mi sono massaggiato sulle guance / sulla fronte / sul naso / sul mento / sul collo applicando un po 'di più dove necessario, l'ho sfregato intorno e ho avuto piccoli globi bianchi che mi sono lavato via facilmente, senza bruciare / arrossare / tenerezza, solo pelle liscia. L'ho usato di nuovo due giorni dopo, e ho notato alcune recenti cicatrici da acne già alleggerite (recente come all'inizio della settimana) ma nessun impatto reale su alcuni vecchi punti più scuri. Lo darò del tempo. Pelle ancora liscia, ma il livello generale di “schiarimento” non è stato così drammatico come la prima volta. Probabilmente userà una o due volte a settimana e annullerà quegli appuntamenti per i trattamenti per il viso. Sul serio. -K. Welto

Ricevilo da Amazon per $ 38.


7.

O uno scrub viso schiarente senza crudeltà perché esfoliare costantemente è solo una buona cura della pelle 101. Una combinazione di alghe marine, scorza di limone, argilla verde francese e giglio di Madonna può eliminare le cellule secche e squamose della pelle morta e de-gunk i pori per contribuire a ridurre i breakout.

amazon.com

Recensione promettente: “Giuro che la tua pelle NON può essere più pulita dopo aver usato questo glorioso prodotto. Ho anche il mio ragazzo che lo usa, quando in precedenza aveva appena usato il sapone sul viso, ugh. Ma questo detergente esfoliante è la perfezione! Puoi sentire una differenza istantanea e non meravigliarti perché Allure lo abbia valutato come uno dei loro prodotti di bellezza migliori e altamente recensiti. Non puoi perdere con queste cose. “—Brian Shocklee

Ricevilo da Amazon per $ 9,99.

8.

Un siero di acido ialuronico se stai cercando un modo semplice e sicuro per iniettare il tuo viso con un'idratazione intensa. L'acido ialuronico è un umettante, nel senso che attira l'umidità dall'ambiente circostante. Il risultato = pelle più grassa, più morbida, più liscia, più idratata.

amazon.com

Recensione promettente: “La prima recensione che ho mai scritto per un prodotto esce su questa gemma. Ha fatto una tale differenza nella mia pelle! La mia fronte non è più coperta da quei dossi grossolani, la mia pelle è liscia, le rughe sono meno pronunciate e la mia pelle appare luminosa e idratata. Continuerà assolutamente ad usare. Consiglio vivamente! “—Amazon Customer

Ricevilo da Amazon per $ 10,95.

9.

Una miscela di olio multiuso calmante in modo da poter bloccare l'umidità invece di utilizzare circa 50 milioni di prodotti che dicono che idratano la pelle … e poi no. La sua formula delicata non irrita la rosacea, la psoriasi o l'eczema, ma ti aiuterà a dire addio alla pelle secca e ai capelli crespi.

amazon.com

Recensione promettente: “Inizialmente ho avuto un capriccio perché ero stanco di acquistare gli oli di cui avevo bisogno separatamente e volevo provare qualcosa di nuovo. NON SONO STATO DELUSTO. Ho i capelli crespi, ricci, asciutti e li tingo / decolorano spesso. Lo uso per l'umidità e i miei capelli lo adorano. Lo aggiungo anche alle maschere per capelli o ad una pre-cacca. Per la mia pelle, mescolo questo con la mia lozione e il mio burro di karité. La mia pelle è idratata tutto il giorno e prospera. Lo uso anche in piedi in inverno quando vado a dormire e aiuta un sacco con i talloni screpolati. Per il mio viso, una pompa fa più che abbastanza. Se le mie mani sono umide, posso usare una pompa per il viso e il collo. Questo è ora un punto fermo nella mia routine di cura della pelle. Ho smesso di avere sblocchi, la mia pelle è luminosa e fiorente, anche il mio tono è aumentato. Anche mia sorella è ora attratta da questo perché è uno dei pochi idratanti che le hanno aiutato con l'acne, il tono e non infastidisce la sua pelle sensibile. “

Ricevilo da Amazon per $ 14,99.


10.

Una scatola di bellezza BuzzFeed x Birchbox degna di una pazzia per chiunque desideri che qualcun altro curi la propria routine di cura della pelle per loro. Ogni confezione include nove prodotti (venduti al dettaglio per oltre $ 200 combinati), quindi scommettendo che troverai qualcosa che ami.

Birchbox

Comprende: Pronto soccorso Beauty Arnica Relief & Rescue Mask (a grandezza naturale); Saturday Skin Pretty Pop Probiotic Power Panna montata (full-size); Glamsquad The Untamed Spray di finitura testurizzante (dimensioni del viaggio); maschera nutritiva amika Soulfood (dimensioni del viaggio); Kevyn Aucoin The Precision Liquid Liner (dimensioni del viaggio); ColourPop Cosmetics Lippie Stix in Love Life (full size); GLAMGLOW® BUBBLESHEET ™ Maschera per pulizia profonda ossigenante (full size); Bumble and bumble. Primer protettivo per calore olio / raggi UV invisibile per parrucchiere (dimensione intera); e Smashbox Cosmetics Photo Finish Foundation Primer (dimensioni del viaggio).

Risparmia $ 10 sulla tua Beauty Box degna di BuzzFeed quando inserisci il codice Buzzfeed alla cassa.

Ricevilo da Birchbox per $ 62 (un valore di $ 205).

11.

Idratante viso e corpo di CeraVe per goderti 24 ore di idratazione testa a testa con circa 10 secondi di sforzo da parte tua. Contiene tre ceramidi, che sono lipidi che aiutano la pelle a trattenere la sua umidità, oltre all'acido ialuronico, un altro ingrediente noto per mantenere la pelle rimpolpata e idratata.

amazon.com

Recensione promettente: “Ho usato questa crema idratante solo per circa una settimana e mezza e devo dire, è stato fantastico per la mia pelle! L'autunno / inverno di solito mi fa soffrire la pelle e la rende molto secca. Dal primo giorno di utilizzo, ho già potuto fare la differenza. Non ti fa sentire unta. È ottimo per le pelli sensibili, in quanto non ha profumo. Lo uso almeno una volta al giorno, ma cerco davvero di usarlo due volte al giorno. La mia pelle ha fatto un completo cambiamento!“—Candace chavez

Ricevilo da Amazon per $ 16,08.


12.

Un abbonamento Geologie che personalizzerà la tua routine per adattarsi alle esigenze personalizzate della tua pelle. Qual è la differenza tra retinolo e niacinamide? Chi se ne frega – ecco perché hai ordinato Geologie!

13.

Una buccia per il viso durante la notte per darti la pelle luminosa che sogni praticamente da un giorno all'altro. È formulato con acidi glicolici e lattici, due alfa idrossiacidi (AHA) che sono A + per esfoliare la pelle e stimolare la produzione di collagene.

versato

Recensione promettente: “Adoro questo prodotto. Ho 27 anni con pelle da normale a grassa e acne periodica. Questa roba fa miracoli per la mia pelle. Lo mantiene umido ma non grasso per tutto il giorno seguente (sì, anche dopo la pulizia) e cancella il mio ciclo di acne. Incredibile applicazione leggera roba che si assorbe rapidamente. 11/10 “—Kirby279

Ricevilo da Versed per $ 19,99.

14.

Una soluzione peeling perché la pelle ruvida e le rughe sottili ti fanno impazzire ma non sei sicuro di cosa diavolo puoi usare per trattarli. Questo riemergerà la tua pelle con una miscela di acido glicolico, lattico e salicilico. I primi due sono gli alfaidrossiacidi (AHA) che esfoliano lo strato esterno della pelle mentre l'ultimo, un beta idrossiacido (BHA), riduce la congestione dei pori.

amazon.com, amazon.com

Recensione promettente:Se potessi dare a questa cosa 10 stelle, lo farei. L'ho usato due volte nell'arco di circa una settimana e mezza. Avevo paura che potesse pungere, ma non lo faceva affatto. Ho notato quanto fosse pulita la mia faccia dopo averla sciacquata. Non mi trucco né prodotti sul viso, quindi per i successivi quattro giorni sono stato in grado di valutare i risultati. Ho notato che la mia pelle è molto più morbida e anche i vecchi segni di sfaldamento si stanno sbiadendo. Anche la seconda applicazione è andata perfettamente. Ancora una volta, morbidezza e migliore aspetto della pelle. Non ho mai avuto un “bagliore” prima d'ora – adesso lo faccio! Non posso essere abbastanza soddisfatto delle meraviglie di questo prodotto. Dovrebbe essere tre volte il prezzo per i benefici che ne traggono. Home run !!! “—Amazon Customer

Ricevilo da Amazon per $ 14,95.


15.

Uno spray rinfrescante per il viso all'acqua di rose Mario Badescu in modo da poter iniziare la tua scorta di prodotti per la cura della pelle con qualcosa che praticamente non puoi usare in modo errato. Ravviva e idrata la pelle sempre e ovunque, sia dopo un estenuante allenamento o tre ore sul divano.

@mariobadescu / Via instagram.com

Leggi la recensione della mia collega sullo spray Mario Badescu per saperne di più sul perché le piace così tanto! (# 1)

Recensione promettente: “Devo ammettere che non sono il migliore quando si tratta di sapere quali prodotti per la cura della pelle comprare (e che l'unica ragione per cui ho scelto questo è perché ho sentito che i Kardashian lo usano), ma lo giuro su questa roba. Trovo persino che il mio ragazzo me lo stia rubando. Dona al tuo viso un aspetto perfetto durante il trucco. Mi sento sempre molto più rinfrescato con solo uno spray o due di questo. Tengo una versione da viaggio nella mia borsa per gli spritz di lavoro di mezzogiorno. “—Jennifer

Ottieni da Amazon per $ 7+ (disponibile in una varietà di pacchetti di dimensioni).

16.

Balm Dotcom, un balsamo per le labbra idratante per quei giorni in cui hai l'energia per applicare il balsamo per le labbra prima di andare a letto e basta, questa è la tua routine di cura della pelle (e va bene!). Questo è fatto con olio di ricino, lanolina e cera d'api per bloccare l'umidità e creare una barriera protettiva.

Sarah Han / BuzzFeed

Recensione promettente: “Come collezionista di balsamo per labbra professionale, vorrei uscire su un arto e dirlo questo è probabilmente il miglior balsamo che ho usato. esso rimane per sempre, non si asciuga con cibo, bevande o vita ed è super nutriente. Ha anche un ottimo rapporto qualità-prezzo e dura per sempre. “—Aayushi S.

Ottieni da Glossier per $ 12 (disponibile in otto stili).

Dai un'occhiata alla recensione di Balm Dotcom del mio collega qui per ulteriori informazioni! (# 1)


17.

Una crema solare SPF 50 che proteggerà la pelle senza avere la sensazione di ostruire i pori. Una buona protezione solare è un must per la cura della pelle ed è un semplice ultimo passo (o solo un passo!) Prima di uscire.

Dr. Jart +

Sono ossessionato da questa protezione solare e non riesco a smettere di pubblicarla su chiunque ascolterà (che è stato solo il mio partner perché siamo messi in quarantena insieme, e penso che si stia stancando di me mentre glielo dico e ancora). Questa roba è davvero leggera; si assorbe rapidamente nella mia pelle e non si sente mai appiccicoso, il che è importante perché indosso sempre una maschera quando esco e odio sentire la mia maschera aderire alla mia pelle. Non ha un odore funky o lascia un cast bianco. Davvero, lo è il perfetta protezione solare IMO.

Ricevilo da Sephora o dal Dr. Jart + per $ 39.

18.

Un cerotto per l'acne facile da usare per eliminare i brufoli che sembrano sempre comparire nel momento * peggiore * possibile. L'idrocolloide, l'olio dell'albero del tè e l'olio di calendula sono delicati sulla pelle mentre estrae ancora liquidi e pus dal brufolo.

amazon.com, amazon.com

La nostra recensione approfondita dei cerotti per l'acne di Avarelle ci mette alla prova: perché funzionano, come usarli e perché oltre 2000 persone non riescono a smettere di delirarli.

Recensione promettente: “Dove sono stati questi per tutta la mia vita? Ho avuto un brufolo che non sarebbe scoppiato o guarito. Ho trovato questi e dopo quattro giorni è andato. Stanno molto bene e si spengono quando vuoi. Oggetto perfetto. Ne ho anche usati alcuni per aiutare a ridurre il gonfiore di una cicatrice che il mio partner ha avuto sul suo viso; ora è solo rosa. Consiglio vivamente “—Cindy Howard

Ottieni 40 patch rotonde da Amazon per $ 8,50.


19.

Una crema per l'acne perché contiene perossido di benzoile che uccide i batteri che può aiutare a liberare i tuoi sblocchi se in passato hai rinunciato alle creme per l'acne perché l'acido salicilico non funzionava. Combatterà i breakout con una formula concentrata di perossido di benzoile al 5,5% e LHA esfoliante (acido lipoidrossilico) per rimuovere la pelle morta e i detriti che ostruiscono i pori.

amazon.com

Recensione promettente: “Uso questo prodotto da diversi anni e non sono mai stato deluso. Riduce delicatamente i brufoli per alcuni giorni e la mia pelle non diventa mai screpolata o secca. Per riferimento ho 46 anni con la pelle grassa, ma la mia pelle può asciugarsi usando il perossido di benzoile normale. Inoltre, se lasciato a se stesso, il mio viso si romperà con l'acne cistica. Non molto, ma abbastanza. Questo prodotto lo mantiene liscio e brufoli al minimo. Lo so, perché quando finisco e cerco di usare qualcos'altro per risparmiare denaro, inevitabilmente scoppio ancora una volta. Quando ricomincio a usarlo, lo uso mattina e sera per tenere sotto controllo il breakout e quindi posso tornare all'applicazione notturna. Finché non sei sensibile alla BP, motivo per cui alcuni potrebbero non aver avuto buona fortuna con questo prodotto, questa crema aiuta davvero l'acne da lieve a moderata. “—Josephine517

Ricevilo da Amazon per $ 29,99.

20.

Un olio per la cura della pelle multiuso se hai rinunciato a alleggerire le cicatrici da acne anni fa. Questo dovrebbe fare il trucco, inoltre potrebbe aiutare a sbarazzarsi delle smagliature e trattare un tono della pelle non uniforme. I recensori dicono che si assorbe rapidamente nella pelle in modo da non sentirti unti.

amazon.com

Recensione promettente:Se potessi dare a questo prodotto più di cinque stelle, lo farei. Lascia che ti racconti la mia storia. Qualche mese fa ho acquistato un nuovo prodotto realizzato con carbone (non menzionerò il marchio o il nome) ed è stato formulato per ridurre al minimo i pori. Mi ha bruciato la pelle. Le mie guance, il mento e la fronte erano in fiamme. La mia pelle era screpolata, rossa, pruriginosa, gonfia ed ESTREMAMENTE secca. Ho provato ad usare una crema idratante, aloe vera, vaselina … TUTTO mi faceva ancora più male alla pelle. Un amico mi ha parlato di Bio-Oil e ho deciso di provarlo. Immediatamente dopo la prima applicazione la mia pelle si è sentita molto meglio. Mentre massaggiavo l'olio nella mia pelle, sentivo la pelle pelata che si staccava. La mia faccia non avvertiva più prurito e la secchezza scomparve immediatamente. Ci sono volute solo due applicazioni di questo olio per far guarire la mia pelle quasi completamente. Ora lo uso quotidianamente, due volte al giorno (mattina e sera) e la mia pelle non è mai stata così sana. Questo è il miglior prodotto che abbia mai provato e, credetemi, ho provato MOLTO. “—Natalia Vazquez

Ricevilo da Amazon per $ 8,89 + (disponibile in tre dimensioni).

21.

Una scatola di maschere per il viso che stringono i pori e ti sollevano la pelle in modo da poter ottenere i risultati di più prodotti con una sola maschera. Ti terrorizzerà davvero perché 1. ti fa sembrare uno zombi quando si trova sul tuo viso, e 2. è così dannatamente efficace nel ridurre la comparsa delle rughe.

amazon.com

Recensione promettente: “Ha un ottimo profumo! Questa maschera per il viso fa esattamente quello che dice. La mia pelle è bella e sollevata, idratata, notevole riduzione delle linee sottili, miglioramento della struttura, riduzione delle dimensioni dei miei pori ed eliminazione di alcune macchie ruvide di recente sviluppo che si formano attorno all'attaccatura dei capelli. sii più soddisfatto di questo prodotto! Ho una pelle abbastanza buona per 37 anni, ma questa maschera mi ha davvero aiutato a portare la mia pelle al livello successivo “—VeganVixen

Ottieni una scatola di otto maschere da Amazon per $ 24,97.

22.

Un pacchetto di maschere per gli occhi al collagene per ingannare tutti nel pensare che hai dormito otto ore riposanti. Queste maschere per occhi d'oro sono ricche di collagene e acido ialuronico che riportano l'idratazione e l'elasticità necessarie per la pelle, così come la vitamina A e l'olio di rosa per calmare, illuminare e proteggere il viso dai danni UV.

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Recensione promettente: “Questi sono davvero i migliori! Mio marito e io li usiamo dopo lunghe notti con il nostro bambino e ora con il nuovo bambino in arrivo questi torneranno sicuramente utili! Aiuta con entrambi i nostri gonfiori e occhiaie.“—Steve Russo

Ottieni 12 coppie da Amazon per $ 24.

23.

O una vasca di crema per gli occhi illuminante, rassodante e ringiovanente che ti aiuterà almeno a dormire un po '(anche se eri sveglio fino alle 2 del mattino a scorrere su Instagram).

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Recensione promettente:Darei a questo prodotto 100 stelle. Vedo una differenza drammatica nella mia pelle. Questo è di gran lunga il miglior prodotto per la cura della pelle che abbia mai usato. Lo uso davvero per tutto il mio viso. Rende la mia pelle pulita e la rende opaca. Mi aiuta anche a mantenere la mia faccia libera. Adoro l'odore e adoro come ci si sente quando viene applicato. Questo è un prodotto davvero straordinario. “—William B Michel

Ricevilo da Amazon per $ 19,99.


24.

Una serie di 16 maschere in foglio per coccolare la pelle e aiutarti a tornare alla routine della cura della pelle se ti sei arreso durante la quarantena.

Amazon

Recensione promettente: “Uso queste maschere una volta alla settimana per idratare la pelle e concentrarmi su un po 'di cura di sé. Sono sensibile ad alcuni prodotti per il viso, ma non ho avuto problemi con queste maschere. Sono ottimi per l'idratazione e dopo l'uso vedo una differenza visibile di luminosità sotto gli occhi / sulla fronte.“—Millie Simmons

Ottieni un set di 16 da Amazon per $ 9,99.

Dai un'occhiata alla nostra recensione completa delle maschere in foglio di essenza di collagene dermico.

25.

Un aspirapolvere per la rimozione di punti neri con una potente testa di aspirazione perché guardarlo mentre assorbe punti neri, punti bianchi, grasso e il trucco rimanente è stranamente soddisfacente. Inoltre, è molto più facile da usare rispetto a quelle dolorose strisce per rimuovere i punti neri.

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Recensione promettente: “Questa è la cosa migliore che ho acquistato nella mia vita !!! Ho una pelle molto chiara tranne il mio naso. Per qualche ragione i miei pori sul naso raccolgono così tanto sporco e sporcizia e sono sempre oleosi. Mi prendo davvero cura di il mio viso, compro prodotti costosi e non ho lamentele. Il mio naso è solo un mio problema. Ho avuto questo per capriccio e pensavo che non guastasse mai provarlo. Quindi mi sono lavato la faccia prima di pensare che non avrebbe fatto molto. RAGAZZO ERA SBAGLIATO !!! La quantità di cose che mi è uscita dal naso era così disgustosa. Mi ha ricordato un episodio di Dr. Pimple Popper. L'ho usato su tutto il viso e fa ancora un lavoro fantastico. Esce cose che non riesco a vedere. Ho notato un'enorme differenza nei miei pori e la mia faccia non è grassa come prima. Il mio unico consiglio è di assicurarti di non tenerlo a lungo in un punto o di ottenere un hickey. Sto pensando di inviare uno di questi a mia sorella. “—Sweettulip

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La tua pelle ti guarda aggiungere questi prodotti al carrello:

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Le recensioni per questo post sono state modificate per lunghezza e chiarezza.

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Psorilax:Ridotto |crema per il trattamento della psoriasi sull’organo maschile

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La psoriasi gotta colpisce il 10% dei pazienti segnalati, molto meno della psoriasi a placche. Quali sono i trattamenti esistenti per trattarlo?


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Fai clic sulla parte che ti interessa

Cos'è la psoriasi gotta?

I migliori trattamenti naturali per la psoriasi gotta

Come parte delle informazioni sul psoriasi, ecco un focus sulla psoriasi gotta, anche se, vedrai, il suo trattamento è simile a quello della psoriasi a placche.

Descrizione della psoriasi gotta

La psoriasi gotta colpisce il 10% della popolazione psoriasica.

La psoriasi a placche è una malattia autoimmune che colpisce l'80% della popolazione psoriasica. Le altre forme di psoriasi sono leggermente più rare: psoriasi ungueale (psoriasi ungueale), psoriasi palmoplantare, psoriasi pustolosa, psoriasi inversa, psoriasi eritrodermica e artrite psoriasica (artrite psoriasica).

La psoriasi gotta, o psoriasi guttata, è una forma abbastanza speciale di psoriasi. Oltre al favorevole terreno genetico (caratteristica comune a tutte le forme di psoriasi), si dice che questa malattia della pelle abbia un'origine essenzialmente infettiva.

Cos'è la psoriasi gotta?

A differenza della psoriasi a placche o della psoriasi vulgaris, che si manifesta in ampie aree della pelle, la psoriasi gotta assume la forma di piccole macchie rosse di forma molto circolare, che sono spesso accompagnate da prurito. Queste macchie fino a 1 cm appaiono diffuse sulla pelle. Il loro aspetto sgradevole è più sottile delle macchie rosse e la pelle non si stacca necessariamente come nella psoriasi a placche.

La psoriasi gotta può comparire su tutte le parti del corpo, in generale, e può interessare il viso, il tronco, in particolare la schiena, la parte bassa della schiena e il busto, le braccia e le gambe. La psoriasi gotta non influisce su mani e piedi, unghie o capelli. Questa forma di psoriasi colpisce principalmente i bambini, dal 10 al 30% dei casi di psoriasi gotta secondo uno studio (1), nonché gli adulti fino a 30 anni.

Come inizia la psoriasi gotta?

Come con qualsiasi tipo di psoriasi, una predisposizione genetica favorevole allo sviluppo di questa condizione è la causa primaria dell'insorgenza della malattia. Successivamente, fattori ambientali ed eventi esterni possono scatenare la crisi.

Avvertimento ! Chi dice campo genetico, non dice necessariamente “malattia ereditaria” (solo circa il 30% dei casi). È un gruppo di geni organizzato in modo caratteristico che rende il soggetto suscettibile allo sviluppo della malattia.

Nella psoriasi gotta, è stato osservato che le lesioni cutanee iniziano ad apparire tra 1 e 3 settimane dopo l'inizio dell'angina (origine batterica). La goccia immunitaria causata da questi batteri attiverà un bagliore della psoriasi sotto forma di piccole gocce sulla pelle. Il legame tra la presenza di streptococco e la comparsa di psoriasi nelle gocce è stato osservato nel 60% dei casi (2). Gli studi hanno anche scoperto la presenza di anticorpi streptococcici negli attacchi di psoriasi gotta, che tendono a confermare questa affermazione (3).

Altrimenti, è stato stabilito il legame tra dieta e problemi della pelle. Dovresti monitorare ed equilibrare la tua dieta e soprattutto eliminare alcuni alimenti che potrebbero danneggiare la salute della pelle come il glutine.

Altri fattori, come una reazione a determinati farmaci forti e trattamenti prescritti per la psoriasi grave (con farmaci anti-TNF) possono innescare o peggiorare un attacco (come il cortisone).

Infine, questa forma di psoriasi potrebbe anche apparire a seguito di una complicazione della psoriasi a placche cronica. Vedi un parere dermatologico.

Come si evolve la psoriasi gotta?

I pazienti che soffrono di psoriasi possono essere suddivisi in 3 categorie:

  • Alcuni pazienti (1/3 delle persone con psoriasi) avranno solo una riacutizzazione. L'attacco durerà circa 1 mese e i sintomi scompariranno in 2 o 3 mesi, senza trattamento.
  • 1/3 dei pazienti affetti vedranno la loro psoriasi gotta progredire direttamente alla psoriasi a placche.
  • Finalmente 1/3 vedrà la loro psoriasi guarire naturalmente, con una fase di remissione variabile a seconda delle persone, quindi una recidiva della malattia verso una psoriasi in placca.

I migliori trattamenti naturali per la psoriasi gotta

Se la psoriasi si manifesta in gocce o in placche, i trattamenti per questa malattia cronica sono gli stessi.
Contrariamente alla credenza popolare, nessun trattamento può “curare” la psoriasi. D'altra parte, i trattamenti naturali e i rimedi per la psoriasi possono essere molto efficaci. Qui stabiliamo una classificazione che combina efficienza e praticità, perché questo criterio ci sembra essenziale. Il trattamento vincolante spesso non viene seguito fino alla fine. Praticità e semplicità sono fattori chiave di successo.

Trattamenti locali naturali per la psoriasi gotta

Per evitare l'effetto di rimbalzo causato dalla dipendenza da alcuni trattamenti e anche per beneficiare di trattamenti più amiche della pelle, esiste un trattamento locale naturale che migliora i sintomi della psoriasi nelle gocce e allevia il prurito. Il complesso rigenerante Pso Natura è un trattamento dermo-cosmetico. È un dispositivo medico.

La sua comprovata efficacia del 94% in un mese lo rende già una stella. La sua facilità di applicazione ti convincerà. Basta massaggiare (delicatamente per non spogliare la pelle) per dieci secondi, la psoriasi si abbassa e quindi risciacquare per ritrovare la pelle sana entro circa 1 mese.

Vedi anche il nostro Crema Ristrutturante Ricca per combattere il prurito della psoriasi e integrare l'azione del complesso.

Per la psoriasi del cuoio capelluto, il nostro shampoo aiuta a lenire il prurito e purifica il cuoio capelluto.

Infine, per un approccio alle cause legate al verificarsi di riacutizzazioni della psoriasi, vedere le capsule Detox e Zen Pso Natura.

Per sbiancare le tracce della psoriasi in gocce e aiutare ad alleviarne i sintomi, 3 azioni principali saranno essenziali:

  • Limita l'infiammazione
  • Elimina i batteri
  • Aiuta la guarigione

La nostra relazione:

Efficienza: 9.4 / 10
Qualità / Prezzo: 9/10 In 100 ml = 4 a 6 settimane di trattamento
Convenienza: 10/10, può anche essere applicato sotto la doccia per risparmiare tempo

Inoltre, considera anche l'assunzione di vitamina (la vitamina A per esempio) buona per la psoriasi.

Bagni del Mar Morto efficaci sulla psoriasi

Sono davvero molto efficaci se praticati sul posto, in Israele o in Giordania. Richiede una cura di 2-3 settimane, che può essere rimborsata dalla previdenza sociale.

Cura del Mar Morto

Il successo di queste cure può essere spiegato da due fattori:

– Fanghi, carichi di potassio. A questo proposito, non è proprio il sale ad essere efficace, contrariamente alla credenza popolare, ma il potassio.

– Il fatto che come cura beneficiate di massaggi, dovete immergervi con calma nell'acqua, quindi rivestirvi di fango e lasciare asciugare al sole. Il tempo dedicato a prendersi cura di te riduce lo stress e diventa un ulteriore fattore nella lotta contro la psoriasi.

Inoltre, essendo il Mar Morto al di sotto del livello del mare, i raggi del sole hanno un particolare obliquo lì, e forma una sorta di nuvola di evaporazione che protegge dai cattivi raggi UV e consente un'esposizione prolungata, che Alla fine sembra fototerapia. È quindi un trattamento efficace.

A seconda della gravità della psoriasi, i periodi di remissione della psoriasi possono durare fino a 6 mesi, quindi preparati a trascorrere le tue vacanze lì regolarmente.

Se si sceglie di ordinare i fanghi, è possibile, ma lì, diventa difficile, nella vita di tutti i giorni, trascorrere un totale di circa 30 minuti per lasciare asciugare il fango senza muoversi, prima di risciacquare. Inoltre, non avrai l'effetto del sole.

La nostra relazione:

Efficienza: 9/10
Qualità / Prezzo: 5/10 (se si è rimborsati dalla sicurezza sociale)
Convenienza: 2/10

Anche i trattamenti benessere possono essere interessanti, anche se sembra che i risultati ottenuti siano inferiori rispetto a un trattamento nel Mar Morto.

Aloe vera FRESCA per aiutare a eliminare la psoriasi

L'aloe vera è un'ottima erba per aumentare l'idratazione e agire sulle irritazioni. Questo è un buon punto, ma la psoriasi è una malattia testarda che non si idrata e vede scomparire le tracce. Il trattamento della psoriasi in gocce o placche richiede l'uso di cure realmente dedicate e trattamenti anti-psoriasi.

psoriasi gotta

Tutte le creme e gel di aloe vera sono interessanti, ma il loro effetto è molto limitato in termini di scomparsa di tracce.

Per sbarazzarsi davvero della psoriasi, l'aloe vera fresca è essenziale. Apporta un reale miglioramento visibile delle condizioni della pelle.

Apri uno stelo di Aloe Vera e rimuovi la polpa. Massaggia le aree da trattare con questa polpa come un unguento e lascia agire per 5-10 minuti. Sciacquare.

Fai attenzione, l'aloe vera fresca macchia i tessuti in modo irreparabile e non ha un buon odore.

La nostra relazione:

Efficienza: 7/10
Qualità / prezzo: 9/10 (una pianta non è molto costosa)
Convenienza: 2/10

I rimedi della nonna per la psoriasi della gotta

Metteremo insieme diverse soluzioni naturali contro i problemi della pelle come la psoriasi. Molto spesso, si tratta di tisane che hanno effetti antistress o depurativi. Riuniscono varie piante per infusione e ingestione orale. Per beneficiare di tutte le virtù, preferisci il biologico!

Le soluzioni purificanti consentono un'azione di disintossicazione del sistema digestivo eliminando le tossine, spesso responsabili di disturbi della pelle.

tè acne e brufoli

Le tisane antistress agiscono su una delle cause della psoriasi: lo stress. Tuttavia, quando si verifica un attacco di psoriasi, queste tisane possono limitarlo, in nessun caso agire sulle tracce già presenti. Puoi prendere in considerazione, su consiglio del tuo farmacista perché alcuni non sono bevibili, di aggiungere alcune gocce di olio essenziale nella tua tisana.

Questi rimedi sono quindi generalmente una buona soluzione per arginare una crisi di psoriasi, ma non possono agire per far scomparire il male già fatto: le gocce o le placche della psoriasi esistente.

Includiamo qui tisane, decotti, zuppe di erbe.
Citiamo in particolare per le virtù purificanti: carciofo, salsapariglia
Contro lo stress e le tendenze nervose: lavanda, melissa, camomilla

La nostra relazione:

Efficienza: 3/10
Rapporto qualità / prezzo: 7/10
Praticità: 3/10 il tempo trascorso è importante e il gusto di queste tisane o zuppe non è sempre piacevole

Per tutto ciò che è naturale, puoi anche avere il riflesso di chiama un naturopata.

Leggi anche:

Informazioni sulla psoriasi

Suggerimenti e trucchi per la psoriasi

Informazioni sull'eczema

Eczema: consigli e suggerimenti

Cura e consulenza per la psoriasi delle unghie

Psoriasi a placche

Trattamento della psoriasi palmoplantare

Psoriasi del cuoio capelluto: i nostri consigli

Psoriasi facciale: 10 consigli

Shampoo dermatologico Pso Natura

Pso Natura Detox Capsules

fonti:

(1) Tollefson MM, Crowson CS, McEvoy MT, Maradit KH. Incidenza della psoriasi nei bambini: uno studio basato sulla popolazione. J Am Acad Dermatol. 2010; 62 (6): 979-987.
(2) DERMATOLOGIA E INFEZIONI SESSUALMENTE TRASMESSE. 5a edizione: Jean-Hilaire Saurat, Jean-Marie Lachapelle, Dan Lipsker, Luc THOMAS
(3) Ledoux M1, Chazerain V, Saiag P, Mahé E. (dermatite perianale streptococcica e psoriasi guttata). Ann Dermatol Venereol. 2009 gennaio; 136 (1): 37-41.
(4) Hone SW, Donnelly MJ, Powell F, Blayney AW. Liquidazione della psoriasi recalcitrante dopo tonsillectomia.
Clin Otolaryngol. 1996 dic; 21 (6): 546-7

Psorilax:Online |creme piu efficaci per psoriasi

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Copyright 2019 ideo – DIRITTI ll formaggio di cellulosa conservato ornofilme und Ratis vóvil Ornos eutschsex ontactar aa aaa aaa aaacn aaah AAAI AAAS aab AABB aac AACC AACE Aquisgrana Aacom AACS AACSB aad aadey AAE AAF AAFP AAG ay ay ay AAO AAP AAPG AAPL AAPS aapt aar aardvark aarhus aaron aarons aarp aas aasb aashto aat aau aauw aau aavso ab ababa abacavir aback abaco abacus abacuslaw abal abbandonato abajono abab fig Abba abbadox Abbas Abb Abb Abb Abcam Abcaz abccom ABCD abcde abcdefghijklmnopqrstuvwxyz abce a ABCNEWS abcnewscom abc abd Abdallah Abdel abdicate abdicazione addominale addominoplastica abdotto rapito rapimenti rapiti aber aber aber aber aber aber aber aber Aberrazioni Aberyst wyth Abe istigare complice complice Abid abd abd abd abd Abingdon Abington abiótico un fiammelle Abitibi Abiword estrema Abkhazia ABL ablazione Ables abili grado della rilassata ablestockcom Ableton ablum ablum Abom 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amundsen amundson amur amuse amused amusem ent amusementpark amusements amusing amv amw amway amx amy amygdala amyl amylase amyloid amyloido sis amyotrophic amz an ana anaal anabaena anabaptist anabel anabolic anachronism anachronistic anaconda anacortes anacostia anadarko anadolu anadromous anaemia anaerobic anaesthesia anaesthetic anaesthetics anagement anagram anagrams anaheim anais anak anakin anal analdehnung anale analfick analfisting analfuck analfucking analgesia analge sic analgesics analize anally analog analogic analogical analogies analogous analogously analogs analogue analogues analogy analphilosopher analsex analverkehr analvideo analy analyse analysed analyser analysers analyses analysing analysis analyst analystreporthtml analysts analyte analytes analytic analytica analytical analytically analytics analyze analyzed analyzer analyzers analyzes analyzing aname anamorphic anan anand ananda anandtech ananova anansi anao anaphase anaphylactic anaphylaxis anaplastic 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anheuser anhui anhydrase anhydride anhydrous ani ania anibal anika anil aniline anillos anim anima animaciones animados animal animale animales animali animalia animalporn animals animalsex animaniacs animas animate animated animates animati animating animation animations animator animators animatrix animaux anime animes animism animosity animus anion anionic anions anipike anis anise anish anisotropic anisotropy anisou aniston anita anja anjali anjou anjuta ank anka ankara ankaro anke anken y anker ankerberg ankh ankle ankles ankleshwar anklet anklets ankur ankylosing anl anleitung anm anmelden anmeldung ann anna annabel annabell annabella annabelle annalee annalen annales annals annan annandale annapolis annapurna annas annatopia anne annealed annealing annecy annemarie annenberg annes annette annex annexation annexe annexed annexes annexin annexure anni annick annie annihilate annihilated annihilation annihilator annika annis anniston anniv anniversaire anniversaries anniversary 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commences commencing commend commendable c ommendation commendations commended commending commends commensurate comment commentaire commentaires commentaries commentary commentator commentators commentblog commented commenter commenters commenti commenting commentor comments commentsblog commer commerce commercial commerciale commercialisation commercialism commercialization commercialize commercialized commercializing commercially commercials commercio commerical commie commies comming commingled commis commision commissar commissary commission commissioned commissioner commissioners commissioning c ommissions commit commited commitee commitment commitments commits committal committe comm itted committee committees committer committers committing committment commn commode commodification commodities commodity commodore commodores common commonalities commonality commoner commoners commonest commonly commonphp commonplace commons commonsense commonwealth commotion comms commu commun communal communautaire commune communes commun i communica communicable communicate communicated communicates communicating communication communications communicative communicator communicators communigate communion communique communis communism communist communists communities communitiespartnersmy community commutation commutative commutator commute commuted commuter commuters commutes commuting commweb como comodo comorbid comorbidity comoros comox comp compa compact compacted compactflash compacting compaction compactly compactness compactor compactors compactpci compacts compagnia compagnie compal compan companies companiestop companion companions companionship company companyname company productswho companys compaq compar compara comparability comparable comparables comparably comparaison comparatif comparative comparatively comparator comparators compare compared comparer compares comparestorepricescouk comparez comparing comparision comparison comparisons comparometer compartment compartments compass compasses compassion co mpassionate compat compatability compatable compath compatibilities compatibility compatible compatibles compatriot compatriots compcompilers compe compel compelled compelling compels compendium compensable compensate compensated compensates compensating compensation compensations compensator compensatory competative compete competed competence competences competencies competency competent competently competes competi competing competition competitions competitive competitively competitiveness competitor competitors compex compilation compilations compile compiled compiler compilers compiles compiling comping compl complacency complacent complain c omplainant complainants complained complaining complains complaint complaints comple compleanno compleat complement complementarity complementary complementation complemented complementing complements complet completa completamente complete completed completely completeness completers completes completing completion completions completly com pleto completos complex complexed complexes complexion complexities complexity compli compliance compliant complicate complicated complicates complicating complication complications complicit complicity complied complies compliment complimentary complimented complimenting compliments comply complying compnd compo component componentartscstamp componentes componentone components comport compose composed composer composers composes composing composite composites compositing composition compositional compositions compositor compost composted compostela compo sting composure compote compound compounded compounding compounds compr compra compradores compr ar compras compre comprehend comprehended comprehending comprehensible comprehension comprehensive comprehensively comprehensiveness compress compressed compressedfilenames compresses compressibility compressible compressing compression compressive compressor compressors compris comprise comprised comprises comprising compro compromise comp romised compromises compromising compromiso comps compte comptes comptia comptoir compton comptroller compu compulsion compulsive compulsory compusa compusacom compuserve compuservecom comput computability computable computador computation computational computationally computations compute computed computer computeractive computerised computerization computerized computers computershare computerwoche computerworld computerzencom computes computing computingcareerscouk computingnet computingreviewcom compuvest compuware comrade comrades comreg coms comsat comscore comstar comstock comte comtec comtech comtex comune comunicazione comunidad comunidades comunity con conagra conair conakry conan conant conason conaway conc concacaf concat concatenate concatenated concatenation concave conceal concealed concealer concealing concealment conceals concede conceded concedes conceding conceit conceited conceivable conceivably conceive conceived conceiving concen concentra concentrate concentrated concentrates concentrating concentration concentrations concentrator concentrators concentric concepcion concept conception conceptions concepts conceptual conceptualization conceptualize conceptualized conceptualizing conceptually concern concernant concerned concerning concerns concert concerted concerti concertina concerto concertos concerts concession concessionaire concessional concessionary concessions conch concha conchita concho concierge concierto conciliation conciliatory concise concisely conclave conclude concluded concludes concluding concl usion conclusions conclusive conclusively concocted concoction concoctions concom concomitant conc omitantly concord concordance concordances concorde concordia concours concourse concrete concretely concretes concubine concur concurred concurrence concurrency concurrent concurrently concurring concurs concussion cond condado conde condemn condemnation condemned condemning condemns condensate condensates condensation condense condensed condenser condensers condensing condescending condescension condi condiciones condiment condiments condit condition conditional conditionality conditionally conditionals conditioned conditioner conditioners conditioning conditions condizioni condo condoleeza condoleezza condolence condolences condom condomi condominium condominiums condoms condon condone condoned condoning condor condors condos condosaver condosavercom conds conducive conduct conductance conducted conducting conduction conductive conductivity conductor conductors conducts conduit conduit s condylox cone conect conectiva conejo cones conestoga conexant coney conf confdefsh confection co nfectionary confectioner confectioners confectionery confections confederacy confederate confederated confederates confederation confederations confer conferees conference conferences conferencia conferencing conferred conferring confers confess confessed confesses confessing confession confessional confessions confessor confetti confi co nfidant confide confided confidence confidences confident confidential confidentiality confidentially confidently config configcache configguess configh configlog configphp configs configstatus configsub configsys configurable configuration configurations configurator configurators configure configureac configured configurein configures configuring configxml confine confined confinement confines confining confirm confirmation confirmations confirmatory confirmed confirming confirms confiscate confiscated confiscation conflagration conflict conflicted co nflicting conflicts confluence confluent confocal conform conformal conformance conformant conformati on conformational conformations conformed conforming conformist conformity conforms confort confortable confound confounded confounding confront confrontation confrontational confrontations confronted confronting confronts conftest conftestc conftesterr confucian confucianism confucius confuse confused confuses confusing confusingly conf usion confusions cong conga congas congdon congeners congenial congeniality congenital conger congested congestion congestive congleton conglomerate conglomerates conglomeration congo congolese congrats congratulate congratulated congratulates congratulating congratulation congratulations congratulatory congregate congregation congregational congregations congres congreso congress congresses congressional congressionally congressman congressmen congresso congresswoman congruence congruent coni conic conical conifer coniferous conifers coniston conj con jecture conjectured conjectures conjoined conjoint conjugal conjugate conjugated conjugates conjugating conjugation conjunct conjunction conjunctions conjunctive conjunctivitis conjunto conjure conjured conjures conjuring conker conklin conley conlin conlon conn connacht connaissance connally connaught conneaut connec connect connected connectedness connecticut connecting connection connectionist connectionless connections connective conn ectives connectivity connector connectors connects conned connell connellsville connelly connemara conner conners connery connex connexion connexions connick connie conning connoisseur connoisseurs connolly connor connors connotation connotations conny conocer conoco conocophillips conor conosco conover conquer conquered conquering conqueror conquerors conquers conquest conquests conquistador conrad conrail conran conroe conroy cons conscience consciences conscientious conscientiously conscious consciously consciousness conscript conscription conse co nseco consecrate consecrated consecration consectetuer consecutive consecutively conseil conseils consej o consejos consensual consensus consent consented consenting consents consequat consequence consequences consequent consequential consequently conser conserv conserva conservancy conservation conservationist conservationists conservatism conservative conservatively conservatives conservatoire conservator conservatories conservators cons ervatorship conservatory conserve conserved conserves conserving consett conshohocken consid consider considerable considerably considerate consideration considerations considered considering considers considine consigli consiglio consign consigned consignee consignment consignments consignor consis consist consistant consisted consistency consistent consistently consisting consists consol consolation console consoled consoles consolewriteline consoli consolidate consolidated consolidates consolidating consolidation consolidations consolidator consol idators consoling consonant consonants consort consortia consortium conspicuous conspicuously conspiracies conspiracy conspirator conspirators conspire conspired conspiring const constable constables constabulary constance constancy constant constanta constantia constantin constantine constantinople constantly constants constel constellation constellations consternation constipated constipation constituencies constituency constituent consti tuents constituentsmake constitute constituted constitutes constituting constitution constitutional constitutionalism constitutionality constitutionally constitutions constitutive constitutively constr constrain constrained constraining constrains constraint constraints constricted constriction constrictor construc construct constructed constructing construction constructions constructive constructively constructivism constructivist constructor constructors constructs construe construed construing consuelo consul consular consulate consulates consul s consult consulta consultancies consultancy consultant consultants consultation consultations consultative consulted consultees consulter consulting consults consumable consumables consume consumed consumer consumerism consumerreportsorg consumerreviewcom consumers consumes consuming consummate consummated consummation consumo consumption consumptive cont conta contact contactabout contactcontact contacted contacter contactez contacting con tactless contacto contactor contactors contactos contacts contactsmanager contactus contador contagion contagious contain contained container containers containing containment contains contaminant contaminants contaminate contaminated contaminating contamination contattaci contatti contax contaxg contd conte contemp contemplate contemplated contemplates contemplating contemplation contemplative contempo contemporain contemporaneous contemporaries contemporary contempt contemptible contemptuous contend contended contender contenders contending conte nds contenido contenidos content contented contention contentions contentious contentment contents contentty pe contenu contenuto contessa contest contestant contestants contested contesting contests context contexts contextual conti contiene contig contigs contiguous contiki contin continence continent continental continents contingencies contingency contingent contingents continous continu continua continual continually continuance continua tion continuations continue continued continues continuing continuity continuo continuous continuously continuum contl conto contorted contour contoured contouring contours contr contra contraband contraception contraceptive contraceptives contract contracted contractile contractility contracting contraction contractions contractor contractors contracts contractual contractually contracture contradict contradicted contradicting contradiction contradictions contradictory contradicts contraindicated contraindications contralateral contraption contra ptions contrarian contrary contras contrast contrasted contrasting contrasts contrat contrato contratto contra vene contravened contravenes contravention contre contreras contri contrib contribs contribu contribute contributed contributer contributes contributing contribution contributions contributor contributors contributory contrition contrivance contrived contro control controle controled controler controll controllability controllable con trolled controller controllers controlling controls controversial controversies controversy contruction contv conundrum conundrums conus conv convalescent convection convective conven convene convened convener convenes convenience conveniences convenient conveniently convening convenor convent convention conventional conventionally conventions conver converge converged convergence convergent converges converging convergys conversant conversation conversational conversations converse conversed conversely conversing conversion conversions convert c onvertable converted converter converters convertible convertibles converting convertir convertor convertors con verts convex convexity convey conveyance conveyances conveyancing conveyed conveying conveyor conveyors conveys convict convicted conviction convictions convicts convince convinced convinces convincing convincingly convivial convo convocation convoluted convolution convoy convoys convulsions convulsive conway conwell conwy conyers co nz coo coober cooder coogan coogee cooh cook cookbook cookbooks cooke cooked cooker cookers cookery cookeville cookie cookies cookiestxt cookin cooking cookingcom cookman cookout cooks cookscom cookson cookstown cooktop cooktops cooktown cookware cool coola coolangatta coolant coolbeanbagscom cooldown cooled cooler coolermaster coolers coolest cooley coolidge cooling coolio coolly coolmax coolness coolpix cools coolscan coolum cooma coombe coombes coombs coon cooney coonhound coons coop cooper cooperate cooperated cooperates cooperating cooperat ion cooperative cooperatively cooperatives cooperators coopers cooperstown coops coor coord coordi coordinate coor dinated coordinates coordinating coordination coordinator coordinators coords coors coos coosa coot cooter coots cop copa copacabana copains copan copay copayment copayments copco copd cope coped copeland copenhagen copepods copernic copernicus copes copia copiague copie copied copier copiers copies copilot coping copious copland co pley copolymer copolymers copp coppa coppell copper copperas copperfield copperhead coppermine copperplate coppers coppice coppie coppin coppola copps coprocessor cops copter copthorne coptic copulation copy copycat copyfight copying copyjpg copyleft copyright copyrightable copyrighted copyrights copystar copywrite copywriter copywriters copywriting coq coquette coquille coquitlam cor cora coral corals coralville coram corante coranto coraopolis corazon corba corbet corbett corbin corbis corbusier corby corcoran cord corda cordage corded cordel e cordelia cordell corder cordero cordes cordial cordially cordials cordillera cording cordis cordless cordoba cordo n cordova cords cordura corduroy cordy core corea cored coreg corel coreldraw corelle corelli corenucleotide corequisite corequisites cores coretta coreutils corey corfu corgan corgi cori corian coriander corin corina coring corinna corinne corinth corinthia corinthian corinthians corinto coriolis cork corks corkscrew corkscrews co rky corleone corley corliss cormac cormack corman cormier cormorant cormorants corn cornbread corne cornea corneal corned cornel cornelia cornelis cornelius cornell corner cornerback cornered cornering corners cornerstone cornerstones cornet cornett cornfield cornflower cornhill cornhuskers cornice corniche corning corningware cornish cornmeal corns cornstarch cornucopia cornus cornwall cornwallis cornwell corny cornyn coro coroa corolla corollary coromandel corona coronado coronal coronary coronation coronavirus coroner coroners coronet corp corpo corpor corpora corporal corporate corporates corporati corporatio corporation corporations corporeal corpphp cor ps corpse corpses corpus corr corrado corral corrales corratec corre correa correct correctable corrected correcting correction correctional corrections corrective correctly correctness corrector corrects correia correlate correlated correlates correlating correlation correlations correlative correlator correll corrente correo cor res corresp correspond correspondance corresponded correspondence correspondences correspondent correspondents corresponding correspondingly corresponds corridas corridor corridors corrie corrigan corrigendum corrigir corrine corroborate corroborated corroborating corroboration corrode corroded corrosion corrosive corrs corrugated corrupt corrupted corrupting corruption corruptions corrupts corry cors corsa corsage corsages corsair corse corset corsets corsi corsica corsican corsicana corso corson corsten cort corte cortes cortese cortex cort ez corti cortical corticosteroid corticosteroids corticosterone corticotropin cortina cortislim cortisol cortisone cortl and cortlandt corto cortona corum coruna corunna corus coruscant corvair corvallis corvette corvettes corvus corwin cory corydon coryell corynebacterium corzine cos cosa cosabella cosas cosatu cosby cosc cosco cose cosenza cosgrove cosh coshocton cosi cosimo cosine cosmetic cosmetics cosmetology cosmic cosmid cosmo cosmological c osmology cosmonaut cosmonauts cosmopolitan cosmos coso cosplay cosponsor cosponsored cosponsors cossack cossacks cost costa costal costanza costanzo costar costas costcentralcom costco coste costed costello coster costing costly costner costo costruzione costs costume costumed costumer costumes costuming cosworth cosy cot cota cotati cote cotes cotillion coto coton cotonou cots cotswold cotswolds cott cotta cottage cottages cotten cotter cottingham cottle cotton cottons cottonseed cottontail cottonwood cottrell coty cou couch couched couches cougar cougars cough coughed coughing coughlan coughlin coughs couk could coulda couldn couldnt coulee couleur couleurs c oulomb coulson coulter coulthard coumadin coun council councillor councillors councilman councilmember councilmembers councilor councilors councils councilwoman counsel counseled counseling counsell counselling counsellor counsellors counselor counselors counsels count countable countdown counted countenance counter counteract c ounterattack counterbalance counterclaim counterclockwise counterculture countered counterexample counterfactual counterfeit counterfeiting countering counterinsurgency counterintelligence counterintuitive countermeasure countermeasures counteroffer counterpart counterparties counterparts counterparty counterpoint counterproductive counterpunch counters counterspy counterstrike countersunk counterterrorism countertop countertops countervailing counterweight countess countfiles counties counting countless countries country countrybookshop co untryman countrymen countrys countryside countrywide counts county countywide coup coupe coupes coupland couple coupled coup ler couplers couples couplet coupling couplings coupon coupons coups cour courage courageous courageously courant courchevel couric courier couriers couristan courmayeur courreges 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credence credential credentialed credentialing credentials credenza credibility credible credibly credit creditable creditcard creditcards credited crediting c redito creditor creditors credits creditworthiness credo credulity cree creech creed creedence creeds creek creeks creekside creel creep creeper creepers creeping creeps creepy creer cref creighton crema cremated cremation crematorium crematory creme cremona crenshaw creo creole creosote crepe crepes crept cres crescat crescendo crescent crescenta crespo cress cressida cresson cresswell crest cresta crested crestline creston crestor crestron crests crestview crestwood creswell cretaceous cretan crete creuset creutzfeldt creve crevice cr evices crew crewe crewed crewman crewmember crewmembers crewmen crewneck crews crf crg crh cri cria crib cribbage cribs crichton cr icinfo cricinfocom crick cricket cricketer cricketers crickets cricos cricshop crider cried crieff crier cries crikey crim crime crimea crimean crimes crimestoppers criminal criminality criminalization criminalize criminally criminals criminology crimp crimped crimper crimping crimson cringe cringely crinkle crip cripple cri ppled crippling cripps crips cris crisco crises crisis crisp crispads crisper crispin crisps crispy criss crisscross crissy crist cristal cristian cristiano cristianos cristina cristo cristobal cristy criswell crit criteria criterion criterium critic critica critical criticality critically criticise criticised criticises criticising criticism criticisms criticize criticized criticizes criticizing critics critique critiqued critiquer critiques critiquing crittenden critter critters crj crk crl crlf crls crm crn crna cro croak croat croa tia croatian croats crobar croc croce crochet crocheted crocheting crock crocker crockery crockett crockpot croco crocodile crocodile s crocs crocus croft crofton crofts crohn crohns croissance croissant croissants croix croke cromarty crombie cromer crompton cromwell cron crond crondaily crone 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crucifix crucifixes crucifixion crucify crucis crud crude crudely crue cruel cruella cruelly cruelty cruft cruickshank cruikshank cruise cruisecom cruised cruiser cruise rs cruises cruiseshipcenters cruisin cruising crum crumb crumble crumbled crumbles crumbling crumbly crumbs crummy crump crumpled crumpler crunch crunched cruncher crunches crunching crunchy crunk crusade crusader crusaders crusades crusading cruse crush crushed crusher crushers crushes crushing crusie crusier crusoe crust crustacea crustacean crustaceans crustal crusted crusts crusty crutch crutcher crutches crutchfield crutchfieldcom crux cruxshadows cruz cruze cruzer cruzi crv crw crx cry crybaby cryer cryin crying cryo cryogenic cryogenics cryonics cryopreservation cryostat cryosurgery crypt cryptanalysis cryptic crypto cryptococcus cryptographic cryptography cryp tologic cryptology cryptopsy cryptosporidium crys cryst crystal crystalline crystallization crystallize crystallized crystallographic crystallography crystals crystalspace cs csa csaba csap csb csc csce cscf csci cscl csco cscs cscw csd cse cseq cset csf csfb csg csh csharp csi csic csir csiro csis csk cska csl csm csma c smecher csmonitorcom csn cso csos csound csp csps csr csrees csrs css cssa csskim cssrule cst cstr cstring cstv cstyle csu csulb csun csus csv csw cswpkggz csx ct cta ctag ctags ctan ctb ctbt ctc ctd cte ctf ctfmonexe ctg cth cthulhu cti ctia ctime ction ctk ctl ctm ctn cto ctor ctp ctr ctrl ctrs cts ctt cttw ctu ctv ctvca ctw ctx ctxt cty ctype cu cua cual cualquier cuando cuatro cub cuba cuban cubana cubano cubans cubase cubby cube cubecart cubed cubes cubic cubicle cubicles cubism cubist cubit cubits cubs cuc cucamonga cucina cuc ine cuckold cuckoo cucumber cucumbers cucusoft cud cuda cudahy cuddle cuddled cuddles cuddling cuddly cuddy cudna cue cued cueing cuellar c uenca cuenta cuentas cuentos cuernavaca cuero cuerpo cuervo cues cuesta cuevas cuff cuffed cufflinks cuffs cuft cug cuhk cui cuidado cuir cuisinart cuisine cuisines cujo cul culberson culbertson culebra culinaire culinary culkin cull culled cullen culligan cullinan culling cullman cullmann culloden cullum cully culminate culminated culminates culminating culmination culo culos culp culpa culpability culpable culpeper culpepper culprit culprits cult cultivar cultivars cultivate cultivated cultivates cultivating cultivation cultivator cultivators cults cultura cultural culturally culture cultured cultures culturing culver culvert culverts cum cumback cumberland cumbernauld cumbersome cumbia cumbria cumbrian cumface cumfiesta cumin cuming cumm cummed cumming cummings cummins cums cumshot cumshots cumslut cumtv cumulative cumulatively cumulus cun cuna cunard cuneiform cuneo cung cunha cunliffe cunni cunnilingus cunning cunningham cunningly cunny cunt cunts cuny cuo cuoi cuomo cuore cup cup ar cupboard cupboards cupcake cupcakes cupe cupertino cupholders cupid cupids cupola cuppa cupped cupping cups cupsys cur cura curable curacao curate curated curation curative curator curatorial curators curb curbed curbing curbs curbside curcumin curd cure cured cures curfew curfews curia curiae curiam curie curing cur io curios curiosities curiosity curious curiouser curiousity curiously curitiba curl curled curler curlers curlew curley curling curls curly curmudgeon curr curran currant currants curren currencies currency current currentcontrolset currently currentpoint currents currentversion curric curricula curricular curriculum curriculums currie curried currier curries currituck curry currys curs curse cursed curses cursing cursive curso cursor cursors cursory cursos cursus curt curtail curtailed curtailing curtailment curtain curtains curt in curtis curtiss curvature curve curveball curved curves curveto curvilinear curving curvy curzon cus cusack cusco cush cushing cushion cushi oned cushioning cushions cushman cushy cusick cusip cusp cuss cussed cussing cussler cust custard custer custo custodial custodian 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cybernetics cyberpower cyberpunk cyberread cybersecurity cybersex cybershot cyberskin cybersource cyberspace cyberstore cybertron cybertronpc cyberwyre cybex cyborg cyborgs cyc cyce cyclades cyc lamen cyclase cycle cycled cyclen cycler cycles cyclesinfo cyclic cyclical cyclin cycling cyclist cyclists cyclo cyclobenzaprine cyclocross cycloheximide cyclone cyclones cyclonic cyclooxygenase cyclopedia cyclophosphamide cyclops cyclosporin cyclosporine cyclotron cyd cyg cygd cygdrive cygnet cygnus cygwin cyl cylinder cylinders cylindrical cylon cym cymbal cymbals cymbalta cymdeithasol cymorth cymraeg cymru cyn cyndi cyngor cynic cynical cynically cynicism cynics cynllun cynllunio cynnwys cynon cynthia cynulliad cynwyd cyp cyph er cypress cyprian cypriot cypriots cyprus cyr cyrano cyril cyrillic cyrix cyrus cys cyst cysteine cystic cystine cystitis cysts cyswllt cysylltia dau cysylltwch cyt cytherea cyto cytochrome cytodyne cytogenetic cytogenetics cytokine cytokines cytokinesis cytological 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enthalpy enthralled enthralling enthroned enthused enthusiasm enthusiast enthusiastic enthusiastically enthusiasts entice enticed enticing entier entire entirely entirety entities entitle entitled entitlement entitlements entitles entitling entity ento entombed entomol entomological entomologist entomology entourage entr entra entrada entrails entrained entrainment entrance entranced entrances entransit entrant entrants entrapment entrapped entrar entre entreat entree entrees entrenched entreprene ur entrepreneurcom entrepreneurial entrepreneurs entrepreneurship entreprise entreprises entretien entrez entries entropia entropic entropy entrust entrusted entry entrydate entryway ents entuitive entwicklung entwined entwistle enu enuff enum enumclaw enumerate enumerated enumerates enumerating enumeration enumerations enumerator enunciated env envelop envelope enveloped envelopes enveloping envi enviable enviada enviado enviar envie envied envious envir enviro enviroment envirome ntal environ environmen environment environmental environmentalism environmentalist environmentalists environmentally environments environnement environs envisage envisaged envisages envisat envision envisioned envisioning envisions envoy envo yer envoys envy enw enwikipediaorg enya enyce enz enzi enzo enzymatic enzyme enzymes enzymol enzymology enzyte eo eob eoc eocene eod eoe eof eog eoi eoin eol eom eon eons eop eople eor eos eosinophil eosinophilic eosinophils eot eowyn ep epa epagov epan epartment epc ep cot epcra epd epdm epe epee epf epfl epg eph epharmacist ephedra ephedrine ephemera ephemeral ephemerides ephemeris ephesians ephesus ephilosopher ephone ephraim ephrata epi epia epic epica epicenter epicentre epicmediainccom epicor epics epicure epicurean epicurious epicurus epidemic epidemics epidemiol epidemiologic epidemiological epidemiologist epidemiologists epidemiology epidermal epidermis epidural epigenetic epilepsy epileptic epilogue epinephrine epinions epinionscom epip hany 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cations identified identifier identifiers identifies identify identifying identities identity ideo ideograph ideological ideologically ideologies ideologues ideology ides idet idf idg idgnet idi idiocy idiom idioma idiomas idiomatic idioms idiopathic idiosyncrasies idiosyncratic idiot idiotarian idiotic idiots iditarod idk idl idle idleness idler idlewild idling idly idm idn ido idol idolatry idols idot idp id ps idr idrc idris ids idt idtheftcom idu idus idvd idw idx idyll idyllic idyllwild ie iea iec iechyd ied iee ieee ief ieg iei iel ielts iem ien iep iepm ieps ier ierr ies iesaf iesg iet ietf ietforg iew iexplore if ifa ifac iface ifad ifanc ifas ifat ifb ifc ifccartesianpoint ifconfig ifd ifdef ife ifelse ifex iff iffy ifg ifi ified ifilm ifindex ifip ifis ifj ifl ifla ifm ifn ifndef ifo ifor ifp ifpri ifq ifr iframe iframes ifreelancecom ifriends ifroggy ifrs ifs ifsp ift iftrue ifx ig iga igames igbo igbt igc igd igda ige iger iges igf igg iggy igh ight igi iglesia iglesias igl 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llmatic illness illnesses illogical ills illum illumina illuminate illuminated illuminates illuminati illuminating illumination illuminations illuminator illus illusion illusionist illusions illusive illusory illustrate illustrated illustrates illustrating illustration illustrations illustrative illustrator illustrators illustrious illy ilm ilmi ilo ilocano ilocos ilog iloilo ilona ilounge ilp ilr ils ilsa ilse ilt ilu ilug ilugc ily ilya ilyich im ima imac imacs imag image imagebase imageclass imaged imagedata imagegif imageline imagem imagemagick imagemap imagemate imagen imagenes imagens im agepixel imager imageready imagers imagerunner imagery images imageshackus imagestate imageurl imaginable imaginarium imaginariumcom imaginary imagination imaginations imaginative imaginatively imagine imagined imagines imaging imagining imaginings imago imai imail imake imam imams iman imao imap imapd imari imate imation imax imb imba imbalance imbalances imbedded imbruglia imbued imc imcs imd i 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rvine irving irvington irwin irwindale is isa isaac isaacs isaacson isaak isabel isabela isabell isabella isabelle isac isadora isaf isaiah isakmp isam isan isang isanti isao isapi isas isat isatori isb isbe isbell isbl isbn isbndbcom isbnnu isbns isc ischaemia ischaemic ischemia ischemic ischia isco iscsi isd isda isdn ise isearch ised isee iselin isempty isenberg isere iseries isf isfahan isg ish isha isham ishares isherwood ishi ishida ishiguro ishih ara ishii ishikawa ishmael ishop ishtar isi isiah isic isidore isidro isight isilo isin ising isinstance isis isk iskcon iskin isl isla islam islamabad islami islami c islamicfinder islamism islamist islamists islamorada islan island islander islanders islandgr islandia islandnorthern islands islandschilecolombiacosta islandsmicronesianaurunew islandsuruguayvenezuelavirgin islandsvirgin islas islay isle isles islet islets isleworth isley islington islip islpalaupapua isls ism ismael ismail isms isn isna isniiniisosonisonexe isns isnt is nta isnull iso isobaric isobel isoc isoelectric isoenzymes isoflavones isoform isoforms isola isolate isolated isolates isolating isolation isolationism isolationist isolator isolators isold isolde isoleucine isom isomer isomerase isomers isometric isomorphic isomorphism ison isoniazid isopropyl isoproterenol isopure isos isosorbide isospin isotherm isothermal isotonic isotope isotopes isotopic isotropic isotype isound isozyme isp ispa ispcom ispell isps ispynow isr israel israeli israelis israelite israelites isreal iss issa issac issaquah isset issey issforum issj issn isso issuance issuances issue issued issuer is suerinfo issuers issues issuing ist ista istanbul istar istat istc iste istep isthmus istituto istock istockphotocom istream istria ists istudy istvan isu isubscribe isup isuzu isv isvalid isvs isync isys isystem it ita itaa ital italeri italia italian italiana italiane italiani italiano italians italic italicized italics italie italien italo italy itanium itar itasca itat itb itc itch itching itchy itcom itd ite itec itech ited item itemid itemize itemized items itemsshow itemswidestrings iter iterate iterated iterates iterating iteration iterations iterative iteratively iterator iterators ites itesm itext itf itg ith ithaca iti ities itil itinerant itineraries itinerary itip itis itk itknowledge itl itll itm itmj itms itn ito itoh itp itr itraconazole itrader itravel itrc itri itrip itron itronix its itsa itself itsg itsm itsy itt itto ittoolbox itty itu itunes itv itw itweb itworld itworldcom itx ity itz itza itzhak iu iub iucn iud iue iui iuma iun iuniverse iup iupac iupui ius iut iv iva ivan ivana ivanhoe ivanov ivanova ivar ivb ivc ivd ive iveco iver ivermectin iversen iverson ives ivete ivey ivf ivi iview ivillage ivins ivo ivoire ivor ivory ivp ivr ivs ivtools ivtv ivy iw iwa iwai iwan iwasaki iwata iway iwc iweb iwf iwi iwill iwin iwm iwo iwon iwork iws iww ix ixc ixi ixo ixos ixtapa ixus ixwidth ixy iy iyengar iyer iyrics iywidth iz iza izak i 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ring jarrod jarrow jars jarvis jas jasc jase jasjar jasmin jasmine jason jasper jaspers jass jat jaton jaume jaundice jaune jaunt jaunty java javaawt javaawtcomponent javabeans javac javadoc javadocs javahelp javaio javaiofilenotfoundexception javaioioexception javaioserializable javalangclass javalangexception javalangobject javalangstring javalangthrowable javalobby javamail javanese javanet javaone javascript javascripts javaserver javasolaris javaspaces ja vasqlsqlexception javautil javautillist javautilmap javautilvector javaworld javax javaxservlethttphttpservletservice javea javed javelin javier javits jaw jawa j awaharlal jawbone jawbreaker jawed jaworski jaws jax jaxp jaxx jay jaya jayallen jayasuriya jaycees jayco jayden jaye jayhawk jayhawks jayme jayna jayne jaynes jays jayskicom jayson jaz jazeera jazz jazzanova jazzy jb jba jbc jbl jbod jboss jbp jbs jbuilder jbutton jc jca jcaho jcb jcc jce jcf jch jci jck jcl jcm jcn jcp jcpenney jcr jcs jcsg jct jcu jcwhitneycom jd jda 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ands meadowlark meadows meads meadville meagan meager meaghan meagher meagre meakin meal meals mealtime mealy mean meander meandering meanderings meanders meaner meanest meaning meaningful meaningfully meaningless meanings meanness means meant meantime meanwhile meany meap mears meas measles measly measurable measurably measure measured measurement measurements measures measuring meat meatball meatballs meath meatless meatloaf meatpacking meats meaty meb mebane mec meca mecca meccano mech mecha mechanic mechanical mechanically mechanics mechanicsburg mechanicsvill e mechanism mechanisms mechanistic mechanix mechanization mechanized mechatronics mechelen mechs mechwarri or mecklenburg med meda medal medalist medallion medallions medallist medals medan medco medcompare meddle meddling medea medecine medeiros medela medellin medem medeski medfield medford medi media mediabistrocom mediacom mediacrazy mediaeval mediaguardiancouk medial medialab mediamatic median medians mediante mediaplaye r medias mediaspan mediastinal mediate mediated mediates mediating mediation mediations mediator mediators mediatype mediaweek mediawiki mediaworks medic medica medicago medicaid medical medically medicalnet medicap medicare medicated medication medications medici medicina medicinal medicinals medicine medicinefilmscom medicinenet medicinenetcom medicines medico medicom medics medicus medien medienkritik medieval medigap medill medina medindia medio mediocre mediocrity medioimages medion medios mediresource medispecialtycom meditate meditated meditatie meditating me ditation meditations meditative mediterranean mediterraneo medium mediums medizin medizinische medley med line medlineplus medlock medora medpix medroxyprogesterone meds medscape medserv medtronic medulla medullary medusa medved medway mee meedio meehan meek meeker meekly meekness meeks meen meena meer meera meerkat meerut meese meest meet meetic meeting meetingplace meetings meets meetup meetupcom meetups mef mefi meg mega 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melodie melodies melodious melodrama melodramatic melody melon melons melrose melt meltdown melted melting melton melts meltzer melua melville melvin melvins melvyn mem memb member membered memberlist memberlistmemberlist members membership memberships membersmemberlist membrane membranes membranous membre membres membro membros memcpy meme memento mementos memeorandum memes memetics memo memoir memoire memoirs memorabilia memorable memoranda memorandum memorandums memorex memoria memorial memorials memoriam memories memorise memorization memorize memorized memorizing memory memorystick memoryten memos memphis memri mems memset men mena menace menachem menacing menage me nagerie menai menard menasha mencken mend mended mendel mendelian mendelsohn mendelson mendelssohn mendenhall mendes mendez mendham mending mendip mendocino mendon mendota mendoza menelaus menendez menezes meng menge menhir menial meniere menifee meningioma meningitidis meningitis meningococcal menino meniscus menlo m enno mennonite mennonites meno menominee menomonee menomonie menon menopausal menopause menor menorah menorca menos mens mensa mensagem mensagens mensaje mensajes mensch menschen mensen menses menstrual menstruation menswear ment mental mentality mentally mentation mente mented mentee menthol mention mentioned mentioning mentions menton mentone mentor mentored mentoring mentors mentorship ments menu menubar menuitem menuphp menuphtml menus menzel menzies meo meon meow mep mephisto mepis meps meq mequon mer mera merak merc mercado mercantila mercantilcom mercantile mercat o mercator merce merced mercedes mercedez mercenaries mercenary mercer merch merchandise merchandiser m erchandisers merchandising merchant merchantability merchants merchantshowever merci mercia mercial mercier mercies merciful mercifully merciless mercilessly merck mercosur mercredi mercruiser mercure mercurial mercurio mercury mercy mercyful mercyhurst mere meredith merely merengue merganser merge merged mergedfield 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essenger messengers messer messermeister messerschmitt messes messiah messianic messick messier messin messina messing messner messrs messsage messy mest mesto mestre mesure mesures mesylate met meta metab metabo metabolic metabolife metabolism metabolite metabolites metabolized metabolizing metacity metacrawler metacritic metacriticcom metadata metafile metafilter metaframe metairie metajy metal metalcore metalic metall metallic metallica metallicity metallics metallized metalloproteinase metallothionein metallurgical metallurgy metals metalware metalwork metalworking metam ail metamodel metamora metamorphic metamorphism metamorphoses metamorphosis metaobj metaphase metapho r metaphorical metaphorically metaphors metaphysical metaphysics metar metarating metareview metart metasearch metastable metastases metastasis metastatic metastock metatalk metatarsal metazoa metcalf metcalfe mete meted meteo meteor meteora meteoric meteorite meteorites meteorobs meteorological meteorologist meteo rologists meteorology meteors meteosat meter metered metering meters metetra metformin meth methacrylate methadone methamphetamine methane methanococcus methanol metheny methicillin methinks methionine method methode methodical methodically methodism methodist methodists methodological methodologies methodology methods methodsfor methos methotrexate methoxy methuen methuselah methyl methylated methylation methylene methylmercury methylphenidate methylprednisolone methyltransferase metical meticulous meticulously metis metlife metoclopramide metolius metoprolol metra metre metr es metric metrical metrics metrix metro metroblogging metrodome metroguide metroguidecom metroid met rokane metrolink metrologic metrology metrolyrics metromixcom metronidazole metronome metronomes metroplex metropol metropole metropolis metropolitan metrorail metros metrosexual metrostars metrowerks metrowest mets metta mette mettle mettler mettre metuchen metus metz metzger metzler meu meucci meuk meunier meur 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crocode microcomputer microcomputers microcontroller microcontrollers microcosm microcredit microcrystalline microdata microdermabrasion microdrive microeconomic microeconomics microelectronic microelectronics microenterprise microfiber microfibre microfiche microfilm microfilms microfinance microfleece microflora microfluidic microform microformats microforms microg microgaming microgram micrograms micrograph micrographs microgravity microlight microline microm micromark micromedex micrometer micrometers micron micronesia micronet micronics micronized microns micronutrient micron utrients microorganism microorganisms microphone microphones microplate micropolitan micropower mi croprobe microprocessor microprocessors micros microsano microsatellite microscale microscope microscopes microscopic microscopically microscopy microsecond microseconds microsemi microsite microsites microsoft microsoftcom microsoftmsn microsomal microsomes microsound microspheres microstar microstation microst rategy microstrip microstructural microstructure microstructures microsuede microsurgery microsystem microsystems microtech microtek microtel microtubule microtubules microvascular microvision microwarehouse microwave microwaves mics mid midas midazolam midbrain midcap midday midden middle middleboro middlebrook middleburg middlebury middlefield middleman middlemen middlesbrough middlesex middleton middletown middleware middleweight middling middot mideast midfield midfielder midgard midge midget midgets midgley midhurst midi midis midland midlands midler midlet midlife midline midl othian midmarket midnight midnite mido midob midori midp midpoint midrand midrange midrash mids m idseason midshipman midshipmen midsize midsized midsole midsomer midst midstream midsummer midterm midterms midtown midvale midway midweek midweight midwest midwestern midwife midwifery midwinter midwives midyear mie miel miele mielke miembro miembros mien mientras miers mies mietwagen mieux mif miffed miffli m ifflin mig miga might mightier mightiest mightily mighty miglia miglin migliori mignon migo migraine migraines migrant migrants migrate migrated migrates migrating migration migrations migrator migratory migs miguel mihai mihi miho mii miike mij mijas mijn mik mika mikado mikael mikasa mike mikel mikem mikemannix mikes mikey mikhail miki mikkel mikkelsen mikki mikko miklos mikmaq miko mikulski mil mila milady milage milagro milam milan milanese milano milbank milblogs milburn mild mildenhall milder mildew mildly mildred mildura mile mileage milena milepost miler miles milestone milest ones miley milf milfcruiser milfhunter milfhunters milford milfrider milfriders milfs milfseeker milfseekers mili milian milieu mililani militaire militancy militant militants militar militaria militaries militarily militarism militaristic militarization military militarycom militia militiamen militias militum milk milked milken milking milkman milks milkshake milkweed milky mill milla millage millan mill 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ss minding mindless mindmanager minds mindsay mindscape mindset mindstorms mindy mine mined minefield minehead mineola miner mineral mineralisation mineralization mineralized mineralogical mineralogy minerals miners minerva mines minesweeper mineta minette ming mingle mingled mingling mingo mingus mingw minh minha mini miniature miniatures miniaturization miniaturized minibar minibuffer minibus minibuses minichamps miniclip minicom minidisc minidv miniempire minifig minigames minigolf minim minima minimal minimalism minimalist minimalistic minimally minimax minimis minimisation minimise minimised minimises minimising minimization minimize minimized minimizer minimizes minimizing m inimoto minimum minimums mining mininova minion minions miniportal minis minisat miniscule minisd miniseries minish miniskirt miniskirts minister ministered ministerial ministering ministerio ministero ministers ministre ministries ministry minisync minit minitab minivan minivans minix minixmlbuttongif minixm 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tions modulator modulators module modulename modules moduletextsanitizerphp moduli modulo modulus modus modutils moe moebius moeller moen moese moesen moet mof mofaz moffat moffatt moffett moffitt mofo mofos mog mogadishu moglie mogul moguls mogwai moh mohaa mohair mohali mohamad mohamed mohammad mohammed mohan mohandas mohanty mohave mohawk mohd mohegan mohican mohicans mohler mohr mohs mohsen moi moieties moiety moin moines moinmoin moins moir moira moire mois moises moissanite moist moisten moistened moisture moisturiser moisturising moisturize moisturizer moisturizers moisturizes moisturizin g moive moives mojave mojo mok moka mokena mol mola molar molars molasses mold moldavia mol davian molded molding moldings moldova moldovan molds moldy mole molecular molecule molecules moles molesey moleskin moleskine moleskines molest molestation molested molester molesters molesting molesworth molex moley moliere molina molinard molinari moline molino molise moll molle moller mollie mollige molloy mollusca molluscs mollusk mollusks molly molnar molokai moloko moloney molotov molson molt molten molto molton moly molybdenum molyneux mom moma mombasa moment momenta momentarily momentary momento momentous moments momentum momentus momjian momma mommas mommies mommy momo moms momsanaladventure momson mon mona monaco monacor monad monadic monadnock monaghan monahan monarch monarchies monarchs monarchy monaro monash monasteries monastery monastic monasticism monatsabo monaural monbiot moncton mond mondadori mondale mondavi monday mondays monde mondeo mondera mondial mondiale mondo mondrian mone moneda monedas monet moneta monetary monetization monetize monette money moneybookers moneycom moneydance moneymaker moneys moneysaving mong monger mongering mongers mongo mongol mongolia mongolian mongols mongoose mongrel moni monica monies monika moniker monique monit monitor monitored monitores monitoring monitors monk monkees monkey monkeys monkfish monks monkton monmouth monmouthshir e monnet monnier mono monoamine monochromatic monochrome monoclonal monocular monoculars monoculture monocyte monocytes monocytogenes monodevelop monofilament monofone monofoniche monogamous monogamy monogram monogrammed monograms monograph monographs monohydrate monoid monokini monolayer monolayers monolingual monolith monolithic monologue monologues monomer monomeric monomers monona monongahela monongalia mononoke mononuclear mononucleosis monooxygenase monophonic monophosphate monopod monopods monopole monopolies monopolist monopolistic monopolize monopoly monorail monos monospace monospaced mo notheism monotheistic monotherapy monotone monotonic monotonically monotonicity monotonous monotony monotype monounsaturated monoxide monro monroe monroeville monrovia mons monsanto monsieur monsignor monson monsoon monster monstercom monstercommerce monstermarketplace monsters monstrosity monstrous mont montag montage montages montagna montagne montagu montague montaigne montalcino montalvo 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orhead moorhen moorhouse mooring moorings moorish moorland moorlands moorman moorpark moors moos moose moosejaw moot mooted mop mopar moped mopeds mopping mops moq mor mora morabito moraes morag moraga moraine moraira moral morale morales morality morally morals moran morass moratorium moravia moravian moray morayshire morbi morbid morbidity morbidly morbus morcheeba mordecai mordechai morden mordor mordred more moreau morecambe moree morehead morehouse moreinfo moreira morel moreland morelia morell morelli morello morelos moremi morena morenas moreno moreover mores moresby moreso moreton moretrade m oretti morey morgage morgages morgan morgana morgane morgans morganton morgantown morgen morgenstern morgue mori moria moriah moriarty moribund moriches morimoto morin morison morissette morita moritz mork morland morley mormon mormonism mormons morn mornin morning mornings morningside morningstar mornington morningwood moro moroccan morocco moron morongo moroni moronic morons morose morpe th morph morphed morpheme morpheus morphine morphing morphism morphisms morpho morphogenesis morphogenetic morphologic morphological morphologically morphology morphometric morphs morphy morr morrell morricone morrie morrigan morrill morris morrison morrisons morrissey morristown morrisville morro morrow morrowind mors morse morsel morsels mort mortage mortal mortalities mortality mortally mortals mortar mortars morte mortem morten mortensen mortenson mortgage mortgaged mortgagee mortgagemavericksonline mortgages mortgagor morticia mortician mortification mortified mortimer mortis mortise morton mortu ary morty moruya morzine mos mosaic mosaics mosby mosca moschino moscone moscow mose mo sel moseley moselle moser moses mosfet mosfets mosh moshe mosher moshi mosier mosinee mosk moskowitz moskva moslem moslems mosley mosman mosnewscom mosque mosques mosquito mosquitoes mosquitos moss mossad mossberg mossel mosses mossimo mossman mossy most mostafa mostar mostly mostra mostrar mostyn mosu l mot mota motd mote motel moteles motels motes moteur moth mother motherboard motherboards mothercare motherfucker motherfuckers motherhood mothering motherland motherless motherly mothernaturecom mothers mothership motherwell moths moti motif motifs motile motility motion motioned motionless motions motivate motivated motivates motivating motivation motivational motivations motivator motivators motive motives motley moto motocross motogp motor motorbike motorbikes motorboat motorcade motorcars motorcoach motorcross motorcycle motorcycles motorcycling motorcyclist motorcyclists motore motoren motores m otorhead motorhome motorhomes motori motoring motorised motorist motorists motorized m otorola motors motorsport motorsports motorway motorways motos motown motrin mots mott motta motte mottled motto mottram motu mou mould moulded moulder moulders moulding mouldings moulds moulin moulinex moulton moultrie moun mound mounds mount mountable mountain mountainbiking mountaineer mountaineeri ng mountaineers mountainous mountains mountainside mountainsmith mountaintop mountbatten mounted mounting mountings mountlake mounts moura mourinho mourn mourne mourned mourners mournful mourning mourns mous mouse mousemats mouseover mousepad mousepads mouser mousetrap moussa moussaoui mousse mousses moustache moutain mouth mouthed mouthfeel mouthful mouthfuls mouthing mouthpiece mouthpieces mouths mouthshut mouthshutcom mouthwash mouthwatering mouton mouvement mov movable movabletype movado move moveable moved movei moveis movem movement movements movenpick moveon moveonorg mover movers moverscom moves m oveto movi movie movieclip moviefone moviegoers moviegoods moviemail moviemarz movies moviescom moviestars movieticketscom movieweb moviez movil moviles movimiento movin moving movis movistar movl movs movx mow mowat mowbray mowed mower mowers mowing mowry mox moxie moy moya moyen moyenne moyer moyers moyes moyle moyne moynihan moz mozambique mozart mozilla mozillaorg mozillazine mozz arella mp mpa mpaa mpas mpb mpc mpca mpd mpe mpeg mpegs mpf mpg mpgs mph mphil mpi mpich mpio mpirt mpl mplayer mpls mpltext mpm mpn mpo mpp mpr mps mpsc mpt mpu mpumalanga mpv mpw mpx mq mqseries mr mra mrad mraz mrb mrc mrcp mrcs mrd mre mres mrf mrg mrgadget mri mris mrk mrl mrm mrn mrna mrnas mro mrp mrprogressive mrq mrr mrrat mrs mrsa mrsid mrskin mrt mrtg mrtones mru mrv mrx ms msa msac msas msb msc msci msconfig mscs msd msde msdn msdos msdp msds mse msec msf msfc msft msg msgbox msgfmt msgid msgr msgs msgstr msgt msh msha mshowa msi msia msie msk msl msm msmail msmq msmsgsexe msn msnbc msnbccom ms nbotmsncom msncom msnshopping msnsign mso msonormal msp msps msql msr msrp mss mssg mssm mssql mst mstp msu msv msvc msw msword msx msxml msy mt mta mtas mtasc mtb mtbe mtbf mtbreviewcom mtc mtd mtdna mte mtech mtekk mtetra mtext mtf mtg mth mths mti mtime mtl mtm mtn mtnl mtns mto mtools mtp mtr mtrr mtrs mts mtsu mtt mtu mtune mtv mtvcom mtvn mtvu mtw mtwr mtwrf mtx mu mua muah mua ng muay mubarak muc much mucha muchas mucho muchos mucin muck mucking mucky mucosa mucosal mucous mucus mud mudd muddle muddled muddy mudge mudgee mudguards mudhoney muds mudstone mudvayne mudville muebles mueller muenchen muenster muerte muertos muesli muestra muff muffdived muffdiving muffin muffins muffled muffler mufflers muffs muffy mufti mug mugabe mugen mugged mugger mugging muggle mughal mugler mugs mugshot mugu muh muhammad muhammed muharram muhlenberg mui muir muirhead muito mujahideen mujer mujeres mukesh mukherjee mukilteo mul mula mulan mulatto mulayam mulberry mulcahy mulch mulching mulder mul doon mule mules mulford mulgrave mulgrew mulher mulholland mulhouse mull mullah mul lahs mullally mullan mulled mullen muller mullet mullets mulligan mullin mulling mullingar mullins mulls mulroney mult multan multi multiage multiagent multibillion multibyte multicast multicasting multicellular multicenter multichannel multicolor multicolore multicolored multicolour multicomponent m ulticore multicultural multiculturalism multidapt multidimensional multidisciplinary multidrug multiethnic multifaceted multifamily multifocal multiformat multiforme multifunction multifunctional multigrid multikey multilanguage multilateral multilateralism multilayer multilayered multilevel multiline multilingual multilink multimap multimapcom multimedia multimediacard multimeter multimeters multimillion multimodal multimode multinational multinationals multinomial multipack multipage multipart multiparty multipass multipath multiphase multiplatform multiplayer multiple multiples multiplex multiplexed multip lexer multiplexers multiplexes multiplexing multiplication multiplications multipl icative multiplicity multiplied multiplier multipliers multiplies multiply multiplying multipoint multipole multiport multiprocessing multiprocessor multiprocessors multiprotocol multipurpose multiracial multiregion multiresolution multiscale multiservice multisite multispectral multisport multistag 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stache mustafa mustang mustangs mustapha mustard mustards mustek mustela muster mustered musto mustve musty mut mutable mutagen mutagenesis mutagenic mutagenicity mutagens mutandis mutans mutant mutants mutate mutated mutating mutation mutational mutations mutatis mutator mutcd mutch mute muted mutes mutex muth mutha muti mutilated mutilation muting mutiny muto mutt mutter muttered muttering mutterings mutton mutts mutual mutuality mutually mutuel muvo mux muy muyo muzak muze muzi muzic muzica muzicom muziek muzik muzikitecom muzyka muzzle muzzleloader mv mva mvc mvd mvl mvm mvn mvp mvpcom mvps mvr mvs mvskip mvt mw mwa mwah mwavecom mwc mwd mwe mweb mwf mwh mwi mwk mwm mwp mwr mws mwst mwy mw yn mx mxdj mxl mxn mxp mxpx mxr my mya myabsolutearts myaccount myadsl myanmar myasthenia myb mybb myc mycareer mycareercomau myclass mycobacteria mycobacterial mycobacterium mycology mycoplasma mycorrhizal mycotoxins mydd mydomaincom mydoom myearthlink myeclipse myelin myelodysplastic myelogenou 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rs mywashingtonpostcom myx myyahoo myz mz mzm n na naa naacp naam naan naaqs naar naas nab nabbed nabble nabi nabil nabisco nablus nabokov naboo nabp nabs nabu nac naca nace nach nachi nachlin nacho nachos nachricht nachrichten nacht nachtleben nacimiento nacional nack nacked nackt nackte nacl naco nacogdoches nacs nad nada nadal nadeau nadeem nadel nader nadezhda nadh nadi nadia nadie nadine nadir nadja nadler nadp nadph nads nadu nady nae naep naf nafta nag naga nagai nagaland nagano nagar nagasaki nagata nagel nagging nagin nagios nagle nagler nago nagorno nagoya nagpur nags nagy nah naha nahant nahb nahi nahum na i naia naic naics naidoo naidu naik nail nailed nailer nailers nailing nails na iltiques naim nain naipaul nair naira nairn nairobi nais naish naissance naive naively naj naja najaf nak naka nakagawa nakai nakajima nakamichi nakamura nakanishi nakano nakashima nakata nakayama nakd nake naked nakedness nakhon naki nakuru nal nala nalbandian nalgene nalin nalini nall nalle n ally naloxone nals naltrexone nalysis nam nama naman namaste namazu nambe nambour namco name namebase namecite named nameless namelist namely namen nameplate nameplates namer names namesake nameserver nameservers namespace namespaces nami namib namibia namibian namic naming namm namo namorada namorado nampa namur namyemen nan nana nanaimo nanak nance nanci nancial nancy nand nanda nandi nando nandrolone nanette nang nani nanjing nanking nanna nannie nannies nanno nannofossil nannofossils nanny nano nanocomposites nanocrystals nanog nanomaterials nanometer nanometers nanoparticle nanoparticles nanos nanoscale nanoscienc e nanosecond nanoseconds nanostructured nanostructures nanotech nanotechnologi es nanotechnology nanotube nanotubes nanowires nanowrimo nant nantahala nantes nanticoke nantucket nantwich nanuet nanyang nao naoh naoki naomi naot nap napa napalm nape naperville naphtha naphthalene napier napili napisy napkin napkins naples napoca napolean napoleon napoleonic napoli napolit ano napp nappa nappies napping nappy naprosyn naproxen naps napster naqada nar nara narada narain naral naranjo narayan narayana narayanan narberth narbonne narc narciso narcissism narcissist narcissistic narcissus narco narcolepsy narconon narcotic narcotics nardi nardin narendra naresh nari narita narnia naropa narr narrabri narragansett narrate narrated narrates narrating narration narrative narratives narrator narrators narrow narrowband narrowed narrower narrowest narrowing narrowly narrows nars naruto narwhal nary nas nasa nasacort nasagov nasal nasb nascar nascarcom nascent nascimento nascita nasd nasdaq nash nash bar nashik nashua nashville nasi nasir nasm nason nasonex nasopharyngeal nasr nass nassau nasse nasser nast nasties nastiest nastiness nastolatki nasty nasw nat nata natal natale natalee natalia natalie natalya natan natasha natchez natchitoches nate nated nates nath nathalie nathan nathanael nathaniel nathanson nati natick nation national nationale nationalism nationa list nationalistic nationalists nationalities nationality nationalization nationalized nationally nationals nationcom nationhood nationmaster nationmastercom nations nationstates nationwide native natively natives nativity natl nato natori natriuretic natrol natrona nats natsume natty natu natur natura naturade natural naturale naturales naturalism naturalist naturalistic naturalists naturalization naturalized naturalizer naturally naturallyspeaking naturalness naturals nature natured naturel naturelle natures naturino naturism naturist naturists naturopathic naturopathy natursekt natwest nau naudia naugatuck naught naugh ton naughty naughtyoffice nauk nauka naumann nauru nausea nauseating nauseou s nauseum nautica nautical nautilus nauvoo nav nava navajo naval navan navarra navarre navarro navassa navbar nave naveen navegador navel navi navidad navier navies navigable navigate navigated navigates navigating navigation navigational navigations navigator navigators navigon navin navioni cs navision navman navpod navsari navstudio navy naw nawaz naxos nay nayak naylor nays naysayers naz nazarene nazareth nazca nazi nazionale nazis nazism nb nba nbaa nbacom nbc nbcolympicscom nbd nber nbi nbii nbl nbm nbn nbp nbpts nbr nbs nbsp nbt nbx nbytes nc nca ncaa ncaab ncaaf ncaasportscom ncac ncar ncate ncb ncba ncbi ncc ncd ncdc nce ncea ncep nces ncf nch nchs nchum nci ncic ncis ncix ncixcom ncj nckum ncl nclb nclex ncm ncn ncnum nco ncos ncp ncpa ncpfs ncq ncqa ncr ncs ncsa ncsc ncsl ncsoft ncsu nct ncte nctm nctum ncua ncum ncurses ncv ncvo nd nda ndad ndb ndc nde ndf ndh ndhum ndi ndis ndiswrapper ndn ndp ndr n ds ndsu ndt ndvi ne nea neal neale neanderthal neanderthals neapolitan near nearby neared nearer nearest nearing nearly nearness nears nearshore neary neas neat neath neatly neatness neato neb nebo nebraska nebuchadnezzar nebula nebulae nebulizer nebulous nec neca necc neccessary neces necesita necessaries necessarily necessary necessitate necessitated necessitates necessitating necessities necessity neches neck necked necklace necklaces neckline necks necktie neckties neckwear necro necromancer necronomicon necropolis necropsy necrosis necrotic necrotizing nectar nectarine nected ned neda nedbank nederland nederlands nederlandse nedis nedit nedlands nedstat nedved nee need needapresentcom needbatterycom needcontractor needed neededforbuild needful needham needing needle needlecraft needlenose needlepoint needles needless needlessly needlework needs needy neel neeley neely neem neenah neer neering nees neeson nef nefarious nefertiti neff neg nega negara negate negated negates negating negation negative negatively negatives negativity negeri negev negi neglect neglected neglecting neglects negligence negligent negligently negligible negocios negotiable negotiate negotiated negotiates negotiating negotiation negotiations negotiator negotiators negra negras negreanu negri negril negro negroes negroponte negros neh neha nehemiah nehru nei neige neigh neighbor neighborhood neighborhoods neighboring neighborly neighbors neighbour neighbourhood neighbourhoods neighbouring neighbours neil neill neilson neiman nein neisseria neither nejm nek neked nekkid neko nekromantix nel nell nella nelle nellie nellis nelly nels nelson nelsons nelspruit nem nema nemaha nematic nematode nematodes nemechek nemesis nemeth nemo nemours nen nena nenad nenagh nene nent nents neo neoclassical neocon neocons neoconservative neoconservatives neodymium neodys neoformans neogeo neohapsis neohapsiscom neoliberal neoliberalism neolithic neomycin neon neonatal neonate neonates neonatology neonode neon s neooffice neopets neophyte neoplasia neoplasm neoplasms neoplastic neopr ene neos neoseeker neosho neotropical neots neovascularization neovo neoware neowin neowinnet nep nepa nepad nepal nepalese nepali nepean nepenthes nephew nephews nephi nephilim nephrectomy nephritis nephrol nephrologists nephrology nephropathy nephrotic nepotism neptune neptunes neq neque n er nera nerc nerd nerds nerdy nerf nergy neri nerja nero neroli ners neruda nerv nerve nerves nervosa nervous nervously nervousness nes nesara nesbit nesbitt nescac nesco nesdis nesgc neshap neshoba nesmith nesoi nespresso ness nessa nesses nessie nessus nest nesta neste nested nester nesting nestle nestled nestles nestling neston nestor nests net neta netanyahu netapp netatalk netattdial netaya netbackup netball netbeans netbios netblk netbook netboot netbsd netcdf netcom netcomm netconcepts netconf netconnect netcraft netdj neteller netfilter netfinity netfirms netflix netflow netg netgear netguide neth nethack nether nether land netherlands netic netid netinet netiq netiquette netlabels netlibrar y netlink netlist netmag netmagazines netmask netmeeting netnews netnewswire netnz neto netobjects netop netopia netpbm netpro netra netratings nets netscape netscreen netserver netstat netsuite netsuke nett nette netted netter nettie nettime netting nettle nettles nettleton nettwerk netvau lt netview netvision netvista netw netware netweaver netwerk network networkcom networked networker networkers networking networks networld netz netzero netzwerk neu neubauer neuberger neue neuen neuer neues neuf neufeld neuhaus neuheiten neuigkeiten neuken neuman neumann neur neural neuralgia neuraminidase neuritis neuro neuroanatomy neurobiol neurobiology neuroblastoma neurochem neurodegenerative neurodevelopmental neuroendocrine neurofibromatosis neurogenic neuroimaging neurol neuroleptic neurologic neurological neurologist neurologists neurology neuroma neuromancer neuromuscular neuron neuronal neurones neurons neurontin neu ropathic neuropathology neuropathy neuropeptide neuropeptides neurophysi ol neurophysiological neurophysiology neuroprotective neuropsychiatric neuropsychiatry neuropsychological neuropsychology neuroradiology neuros neurosci neuroscience neurosciences neurosis neurospora neurosurg neurosurgeon neurosurgeons neurosurgery neurosurgical neurotic neurotoxic neurot oxicity neurotransmitter neurotransmitters neurotrophic neuse neustadt neustar neut neuter neutered neutering neutral neutrality neutralization neutralize neutralized neutralizer neutralizing neutrals neutrik neutrino neutrinos neutrogena neutron neutrons neutropenia neutrophil neutrophils neuve nev neva nevada neve never neverending neverland nevermind nevermore nevers nevertheless neverwinter neves neville nevin nevins nevirapine nevis nevsky new newark newaygo newb newberg newberry newbery newbie newbies newbin newbold newborn newborns newbridge newburg newburgh newbury newburyport newby newcastle newcomb newcombe newcomer newc omers newcommand newegg neweggcom newell newer newest newfield newfound newfoundland newgrounds newhall newham newhart newhaven newhouse newid newington newkirk newland newlands newletter newlib newline newlines newly newlyn newlywed newlyweds newman newmap newmar newmark newmarket newmont newname newnan newness newnham newpath newport newquay newratingscom n ewry news newsagent newsagents newsalerts newsbackupcom newsblog newsboys newsbrief newsburst newsbytes newscast newscasts newscenter newschannel newscientistcom newscom newscomau newsday newsdaycom newsdesk newsfactor newsfeed newsfeeds newsflash newsforge newsgator newsgroup newsgroups newshounds newshour newsisfree newsletter newsletters newslettersnewsletters newsline newslink newslinks newsmagazine newsmaker newsmakers newsman newsmax newsmaxcom newsnet newsnight newsom newsome newson newspaper newspapers newsprint newsquest newsradio newsre newsreader newsreaders newsreel newsreels newsroom newsrooms newsrx newsstand newsstan ds newstalk newstead newstext newsvac newswatch newsweek newswire news wires newsworthy newt newtech newtek newtelligence newton newtonian newtons newtown newtownabbey newtownards newvalue neww newydd newyddion newyork newz newzealand nex nexgen nexis nexium nexpak nexrad nexstar next nextag nextagcom nextdoor nextel nextgen nextlast nextline nextlink nextst ep nexus ney neyer nez nf nfa nfb nfc nff nfi nfib nfip nfl nflcom nfld nfo nforce nformation nfp nfpa nfr nfs nfsd nft nfu ng nga ngage ngai ngan ngay ngb ngc nge ngf ngfl nghe nghi nghymru ngi ngk ngl ngm ngn ngo ngoc ngorongoro ngos ngr ngs ngt ngu ngultrum nguoi nguy nguyen ngvd nh nha nhac nhan nhanes nhanh nhat nhau nhc nhfb nhgri nhhs nhi nhk nhl nhlbi nhlcom nhlpa nhmrc nhp nhpr nhra nhrc nhrp nhs nht nhtsa nhu nhung nhw nhx ni nia niace niacin niagara niagra niaid niall niamh nian niantic nias nib nibble nibblers nibbles nibbling nibh nibs nic nica nicad nical nicam nicaragua nicaraguan niccolo nicd nice nicely nicene nicer nicest niceties niceville nich nichd niche nichelle niches nichiren ni chol nicholas nicholasville nichole nicholl nicholls nichols nicholson nicht nichts nici nick nickcom nicked nickel nickelback nickell nickelodeon nickels nickerson nicki nicklaus nickle nickles nickname nicknamed nicknames nickolas nicks nicky niclas nico nicobar nicodemus nicol nicola nicolae nicolai nicolas nicolaus nicole nicolet nicolette nicoll nicollet nicolson nicorette nicosia nicotiana nicotinamide nicotine nicotinic nics nicu nicva nid nida niddk nido nids nidulans nie niebuhr niece nieces niederlande niedersachsen niehs niel niels nielsen nielson nieman niemann niemeyer niemi nies niet nieto nietzsche nieuw nieuwe nieuws nieuwsbrief nieve nieves nif nifedipine nifer nificant nifl nifty nig nigam nigel nigella niger nigeria nigerian nigerians nigga niggas niggaz nigger niggers nigh night nightbreeds nightcap nightclub nightclubs nightcrawler nighter nightfall nightfire nightgown nighthawk nightie nightinga le nightlife nightlight nightline nightly nightmare nightmares nightm arish nights nightshade nightstand nightstands nighttime nightwear nightwing nightwish nighty nigms nigra nigroviridis niguel nih nihil nihilism nihilistic nihon nihongo nii niigata niit nij nijmegen nik nika nike nikhil niki nikita nikkei nikki nikko nikkor niklas niko nikola nikolaev nikolai nikolaos nikolas nikolaus nikolay nikon nikos nikwax nil nila nile niles nilly nilo nilpotent nils nilsen nilson nilsson nim nima nimble nimbus nimda nimes nimh nimitz nimmo nimoy nimrod nims nin nina ninds nine ninemsn niner niners nines nineteen nineteenth nineties ninety nineveh ninfeta ning ningbo ningxia ninh ninja ninjas ninn nino ninos nintendo nintendogs ninth nio niobium niobrara niosh nioxin nip nipissing nipped nipper nipping nipple nipples nippon nips nique niques nir nireland niro nirvana nis nisa nisan nisbet nisgaa nish nisha nishi nishida nishikawa nishimoto nishimura nisi nismo nissan nissen nist nistelrooy nisu s nit nita nite nited nites nities nitin nition nitpickit nitrate ni trates nitric nitride nitrification nitrile nitrite nitrites nitro nitrocellulose nitrogen nitroglycerin nitrous nitrox nits nittany nitto nitty nity nitzschner niu niue niuyue niv nivea niveau nivel niven niversity niwa nix nixdorf nixon nized nizhny nizlopi nizoral nj nja njac njc nj com njdep nje njit njn njsa nk nkf nkjv nku nkycom nl nla nlaiagent nlb nlc nld nle nlg nline nlm nln nlo nlp nlr nlrb nls nlt nlug nluug nly nm nma nmac nmake nmap nmax nmb nmc nmd nmda nme nmea nmfs nmh nmi nml nmm nmol nmp nmr nms nmsa nmsu nmt nmu nn nna nnc nndb nne nni nnm nnn nnnn nnp nnrp nns nnsa nnt nntp nntpperlorg nnual nnw no noa noaa noaagov noack noael noah noahs noam noao noarch noatun nob nobby nobel nobile nobilis nobility nobis noble noblecom nobleman nobler nobles noblest noblesville nobly nobo nobody nobr nobs nobuo noc nocd noch noche noches nochex nock nocom nocona nocturnal nocturne nocturnes nod noda nodal nodded nodding noddy node nodelist nodename noderivs nodes nodeshell noding nods nodular nodule nodules noe noel noelle noes nof noflysonus nofollow nofx nog nogales noggin nogroup noguchi noh noi noida noimage noir noire noirs nois noise noiseless noises noisily noisy noize nok nokia nokiacom nokian nokomis nol nola nolacom nolan noland noleggio nolen nolin nolita noll nolo nologo nology nolte nolvadex nom noma nomad nomadic nomads nomail nomar nomatica nombre nombres nome nomen nomenclature nomex nomi nomic nominal nominally nominate nominated nominates nominating nomination nominations nominative nominator nomine nominee nominees nominet nomo noms nomura non nona nonacademic noname nonattainment noncash nonce noncommercial noncommutative noncompetitive noncompliance nonconforming nonconformity noncredit noncurrent noncustodial nondescript nondestructive nondeterministic nondisclosure nondiscrimination nondiscriminatory nondurable none nonemployer nonemployers nonempty nonequilibrium noness ential nonesuch nonetheless nonetype nonexclusive nonexempt nonexis tent nonfamily nonfarm nonfat nonfatal nonfederal nonferrous nonfiction nonfinancial nong nongovernmental nonhuman noni nonimmigrant noninfringement noninstitutionalized noninterest noninvasive nonlinear nonlinearities nonlinearity nonlocal nonmember nonmembers nonmetallic nonn nonneg ative nonnude nono nonoperating nonparametric nonpartisan nonpayment nonpoint nonprescription nonprofit nonprofits nonproliferation nonproprietary nonpublic nonrecurring nonrefundable nonrelatives nonresident nonresidential nonresidents nonresponse nonsampling nonsense nonsensical nonsmokers nonsmoking nonspecific nonstandard nonsteroidal nonstick nonstock nonstop nonstructural nonsurgical nontoxic nontraditional nontrivial nonummy nonuniform nonunion nonverbal nonviolence nonviolent nonvolatile nonwoven nonwovens nonzero noo noob noobs noodle noodles noof nook nookie nooks noon noonan noonday noone nooo noooo noop noor noord noordwijk noos a noose nop nope nor nora norad noradrenaline norah noranda norber g norbert norbizness norbury norcal norcent norco norcross nord nordea norden nordette nordic nordica nordictrack nordisk nordrhein nordsee nordstrom nordstromcom nore noreaster noreen norelco norell norepinephrine noreply norfolk norge norges nori noriega noriko noritake norm norma normal normalcy normale normalisation normalised normality normalization normalize normalized normalizing normally normals norman normand normandie normandy normans normanton normative normblog norml norms noro noronha norquist norrath norridge norrie norris norristown norse norseman norsk norske norstar nort norte nortel north northallerton northam northampton northamptonshire northants northborough northbound northbridge northbrook northcote northeast northeasterly northeastern northen northerly northern northerner northerners northernmost northerntoolcom northfield northgate northglenn northing northlake northland northpoint northport nort hridge northrop northrup northshield northshire northshore norths ide northstar northumberland northumbria northville northward northwards northwave northway northwest northwesterly northwestern northwich northwind northwood northwoods norton nortriptyline norvasc norvegicus norwalk norway norwegen norwegian norwegians norwell norwest norwich norw 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zation parallelogram parallels paralogs paralympic paralympics paralysed paralysis paralytic paralyze paralyzed paralyzing param paramagnetic parame paramedic paramedical paramedics parameter parameterization parameterized parameters parametric parametrization parametrized paramilitaries paramilitary paramount params paramus parana paranoia paranoid paranormal parapet paraphernalia paraphrase paraphrased paraphrasing paraplegia paraplegic paraprofessional paraprofessionals parapsychology paraquat paras parasailing parasite parasites parasitic parasitism parasitol parasitology parasoft parasol parasols parasympathetic parathion parathyroid paratransit paratrooper paratroopers parc parce pa rcel parcelforce parcells parcels parche d parchment parco parcs pard pardee pardo pardon pardoned pardons pardue pare parece pared paredes pareja parejas parekh paren parenchyma parent parentage parental parenteral parentheses parenthesis parenthetical parenthood parenting parents pares pareto parfai 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ally pathfinder pathfinders pathname pathnames patho pathogen pathogenesis pathogenic pathogenicity pathogens pathol pathologic pathological pathologies pathologist pathologists pathology pathophysiology pathos paths pathway pathways pati patiala patience patient patiently patients patil patina patio patios patisserie patmos patna pato paton patong patou patra patras patria patriarch patriarchal patriarchate patriarchs patriarchy patric patrice patricia patrician patricio patrick patricks patrik patrimony patriot patriotic patriotism patriots patrizia patrol patrolled patrolling patrolman patrols patron patronage patronising patronize patronizing patrons pats patsy patt pattaya patted patten pa tter patterico pattern patterned pat terning patterns patterson patti pattie patties patting pattison patton pattr patty patuxent pau paua paucity pauillac paul paula paulding paule paulette pauley pauli paulie paulin paulina pauline pauling paulinka paulista paull paulo pauls paulsen paulson pa 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as ramble rambler ramblers rambles ramblin rambling ramblings rambo rambus ramcomponents ramdisk rame rameau ramen ramesh ramey rami ramifications ramin ramirez ramiro ramjet rammed rammer ramming rammstein ramon ramona ramone ramones ramos ramp rampage rampaging rampant rampart ramparts ramped ramping ramps ramrod rams ramsar ramsay ramsden ramses ramsey ramsgate ramzi ran rana ranbaxy rance ranch rancher rancheria ranchero ranchers ranches ranchi ranching rancho ranchos rancid rand randa randal randall randell randi randis randle rando randolph random randomised randomization randomize randomized randomizer randomly randomness rands randstad randwick randy rane raney rang ranga range ranged rangefinder rangefinders rangel rangeland rangelands rangemaster rangemax rang er range rs ranges ranging rangoon rani ranitidine ranjan ranjit rank ranked rankin ranking rankings ranks ranlib ranma rann rans ransacked ransom ransome ranson rant ranting rantings rantoul rants ranunculus rao raoul rap rapa rapala rapaport rapd rape raped raper rapes rapeseed rapesex raph raphael rapid rapide rapides rapidity rapidly rapido rapids rapidshare rapier raping rapist rapists rapoport rapp rappa rappahannock rappaport rapped rappel rapper rappers rapping rapport rapporteur rapporteurs rapports rapprochement raps rapt raptor raptors rapture rapunzel raq raquel rar rara rare rarely rarer rares rarest raritan rarities rarity rarotonga ras rasa rascal rascals rasch rash rashad rasheed rashes rashi rashid rasiert rasierte raskin rasmol rasmus rasmussen rasp raspberries raspberry rasputin rass rast rasta rastafari raster rasur rat rata ratchet ratcheting ratchets ratcliff ratcliffe rate rateable ratebeer rated rateitall ratemyteacherscom ratepayers rater raters rates ratescom rath rath bone rathbun rather ratification ratifications ratified ratify ratifying rating ratings ratio ration rational rationale rationales rationalisation rationalise rationalism rationalist rationality rationalizatio n rationalize rationalized rationalizing rationally rationing rations ratios ratlam ratliff ratner raton rats ratt rattan rattle rattled rattler rattlers rattles rattlesnake rattlesnakes rattling rattray rattus ratty ratzinger rau rauch raucous rauf raul raum raunch raunchy rausch rauscher rav ravage ravaged ravages rave raved ravel raven ravenclaw ravenna ravenous ravens ravensburger ravenswood ravenwood raveonettes raver ravers raves ravi ravin ravine ravines raving ravings ravioli ravished ravishing ravnica raw rawalpindi rawhide rawk rawlings rawlins rawlinson rawls rawr raws rawson rawsugar rawtenstall rax ray raya rayban rayburn raycom raye rayearth rayleigh raylene rayman raymarine raymer raymond raymondville raynaud rayne rayner raynham raynor raynox rayon rayong rayovac r ays raytheon raytown raz raza razavi raze razed razer razor razorback razorbacks razorgator razorlight razors razr razz razzle rb rba rbc rbd rbf rbh rbi rbis rbk rbl rbm rbr rbs rc rca rcb rcc rccom rccpp rc d rce rcf rch rci rcia rcl rcm rcmp rcn rco rcon rconv rcp rcpt rcr rcra rcs rcsb rct rcts rcu rcv rcvd rcw rcx rd rda rdata rdb rdbms rdc rdd rdf rdfs rdg rdi rdiff rdl rdm rdn rdna rdo rdp rdr rdram rds rdt rdu rdx re rea reac reach reachability reachable reached reaches reaching react reactant reactants reacted reacties reacting reaction reactionary reactions reactivate reactivated reactivation reactive reactivity reactome reactor reactors reactos reacts read readability readable readdir reade reader readers readership readfile readied readies readily readin readiness reading readings readjust readjustment readline readme readmetxt readmission readmitted readonly readout readouts reads ready readying readymade reaffirm reaffirmation reaffirmed reaffirming reaffirms re agan reagee r reagent reagents reaktor real realarcade realaudio realbasic realcities realclearpolitics realcom realcommercialcomau reale reales realestate realestatecom realestatecomau realfooty realign realigned real ignment realisation realise realised realises realising realism realist realistic realistically realists realities reality realizable realizar realization realizations realize realized realizes realizing reall realloc reallocate reallocated reallocation really realm realmedia realmoney realmoneycom realms realnetworks realone realplayer realpolitik reals realtek realtime realtone realtones realtor realtorcom realtors realtree realty realtytrac realvideo realworld realy ream reamed reamer reaming reams reanalysis reap reaped reaper reaping reappear reappearance reappeared reappears reapply reappointed reappointment reappraisal reaps rear reardon reared rearing rearprojectiontelevision rearrange rearranged rearrangement rearrangements rearranging rears rearview rearward rea s reasearch reason reasonable reasonableness reasonably reasoned reasoner reasoning reasons reassemble reassembled reassembly reassert reassess reassessed reassessment reassign reassigned reassignment reassurance reas sure reassured reassuring reauthorization reauthorize reaver reaves reb reba rebalance rebalancing rebar rebate rebaterebate rebates rebbe rebecca rebekah rebel rebelde rebelled rebelling rebellion rebellions rebellious rebels reber rebirth reblog rebol reboot rebooted rebooting reboots reborn rebound rebounded rebounder rebounding rebounds rebranded rebreather rebroadcast rebs rebuffed rebuffs rebuild rebuilder rebuilding rebuilds rebuilt rebuke rebuked rebus rebut rebuttal rebuttals rebutted rec reca recalcitrant recalculate recalculated recalculation recall recalled recalling recalls recap recapitalization recaps recapture recaptured recaro recast recca reccomend reccommend recd recede receded receding receipt receipts receivable receivables receive received receiver re ceiveranalog receiverdvb receivers receivership receives receiving recensione recensioni recent recentchanges recenter recently recep recept receptacle receptacles reception receptionist receptionists receptions rece ptive receptivity receptor receptors receptus recertification recertified recess recessed recesses recession recessions recessive recetas recette recettes rechargable recharge rechargeable recharged recharger recharges recharging recheck recherche rechercher recherches recherchez rechnung recht rechte rechten recidivism reciept recieve recieved reciever recievers recieves recieving recife recip recipe recipebox recipes recipesource recipezaar recipient recipients recipies reciprocal reciprocate reciprocated reciprocating reciprocity recirculating recirculation recital recitals recitation recite recited recites reciting reckless recklessly recklessness reckon reckoned reckoning reckons reclaim reclaimed reclaiming reclamation reclame reclassification reclassifications reclas sified recla ssify recline recliner recliners reclining reclosable recluse reclusive reco recode recodified recoding recog recognisable recognise recognised recognises recognising recognition recognitions recognizab le recognize recognized recognizer recognizes recognizing recoil recollect recollection recollections recom recombinant recombination recomend recomendaciones recomendations recomended recomienda recommend recommendation recommendations recommended recommender recommending recommends recommit recompense recompile recompiled recompiling recon reconcile reconciled reconciliation reconciliations reconciling reconditioned reconditioning reconfigurable reconfiguration reconfigure reconfigured reconfiguring reconfirm reconnaissance reconnect reconnected reconnecting reconnection reconsider reconsideration reconsidered reconsidering reconstitute reconstituted reconstitution reconstruct reconstructed reconstructing reconstruction reconstructions reconstructive reconvene reconvened r ecor record r ecordable recordation recorded recorder recorders recordi recordin recording recordings recordkeeping recordlabel records recordset recoton recount recounted recounting recounts recoup recoupment reco urse recover recoverable recovered recoveries recovering recovers recovery recreate recreated recreates recreating recreation recreational recreations recruit recruited recruiter recruiters recruiting recruitment recruits recruittracker recruting recs rect rectal rectangle rectangles rectangular rectifi rectification rectified rectifier rectifiers rectify rectifying rectilinear rectly recto rector rectory rectron rectum rectus recumbent recuperate recuperation recur recurrence recurrences recurrent recurring recurs recurse recursion recursive recursively recursos recurve recut recv recyclable recyclables recycle recycled recyclenet recycler recyclers recycles recycling red reda redacted redback redbird redbirds redbone redbook redbooks redbridge redcar redcliffe redd redden r eddened redden ing redder reddick redding reddish reddit redditch reddot reddy rede redecorating redeem redeemable redeemed redeemer redeeming redefine redefined redefines redefining redefinition redeggorg redempt ion redemptions redemptive redenvelope redeployment redes redesign redesignated redesigned redesigning redesigns redetermination redevelop redeveloped redevelopment redeye redfern redfield redfish redford redgoldfish redgrave redhat redhawk redhawks redhead redheaded redheads redhill redi redial rediculous redif rediff rediffcom reding redington redir redirect redirected redirecting redirection redirector redirects rediscover rediscovered rediscovering rediscovery redisplay redissemination redistribute redistributed redistributing redistribution redistributions redistricting redken redland redlands redline redman redmond redmuze redneck rednecks redness rednex rednova redo redoing redondo redone redorbit redoute redox redraw redrawing redrawn redress redrum redruth reds redshi ft redshifts re dshirt redskins redstate redstone reduc reduce reduced reducer reducers reduces reducible reducing reductase reductil reduction reductionism reductionist reductions reductive redundancies redundan cy redundant redux redwall redwing redwood redwoods redzipcom ree reebok reece reed reeder reedley reeds reedy reef reefer reefs reek reeks reel reelcom reelected reelection reeled reeling reels reemployment reenable reenact reenacted reenacting reenactment reengineering reenter reentrant reentry rees reese reestablish reestablished reevaluate reevaluation reeve reeves reexamination reexamine ref refacing refactor refactoring refco refcount refe refectory refer referal refere refered referee refereed refereeing referees referen referenc reference referencecom referenced references referencescom referencia referencing referenda referendum referendums referent referential referer referers refering referral referrals referralsrespondcom referred referrer referrers referring refers refi refill ref illable refilled refilling refills refinance refinanced refinances refinancing refine refined refinement refinements refiner refineries refiners refinery refines refining refinish refinished refi nishing refit refl reflect reflectance reflected reflecting reflection reflections reflective reflectivity reflector reflectors reflects reflex reflexes reflexion reflexive reflexivity reflexology reflow reflux refn refocus refocusing reforestation reform reforma reformat reformation reformatted reformatting reformed reformer reformers reforming reformist reforms reformulated reformulation refraction refractive refractor refractories refractory refrain refrained refraining reframing refresh refreshed refresher refreshes refreshing refreshingly refreshment refreshments refried refrig refrigerant refrigerants refrigerate refrigerated refrigerating refrigeration refrigerator refrigerators refs refseq reftype refuel refueling refuelling refuge refugee refugees refuges refugio refun d refundable refu nded refunding refunds refurb refurbish refurbished refurbishing refurbishment refusal refusals refuse refused refuses refusing refutation refute refuted refutes refuting refworks reg rega rega in regained regaining regains regal regalia regalo regan regard regarded regarder regarding regardless regards regatta regattas regd regebro reged regedit regeln regen regence regency regenerate regenerated regenerating regeneration regenerative regenerator regensburg regent regents reger regex regexp reggae reggaeton reggie reggio regi regia regime regimen regimens regiment regimental regiments regimes regina reginald regine regio region regional regionale regionalism regionalization regionally regionals regione regions regis regist register registercom registered registering registerregister registers registersign registrable registrant registrants registrar registrars registrati registration registrations registrazione registre registred registrieren registries registro regis try regle regno re gnow regnum rego regprice regress regressed regression regressions regressive regret regretfully regrets regrettable regrettably regretted regretting regroup regrouping regrowth regs regsoftc om regt regu regula regular regularexpression regularities regularity regularization regularized regularly regulars regulate regulated regulates regulating regulation regulations regulator regulators regulatory regulus regurgitation regus reh rehab rehabil rehabilitate rehabilitated rehabilitating rehabilitation rehabilitative rehabs rehash rehearing rehearsal rehearsals rehearse rehearsed rehearsing reheat rehm rehman rehnquist rehoboth rehydration rei reich reichel reichert reichstag reicom reid reidel reidsville reidy reif reife reigate reign reigned reigning reigns reihe reiki reiko reilly reimbursable reimburse reimbursed reimbursement reimbursements reimburses reimbursing reimer reimplemented reims rein reina reincarnated reincarnation reindeer reine reiner reinforce reinfo rced reinforcement reinforcements reinforces reinforcing reinhard reinhardt reinhart reinhold reining reino reins reinstall reinstalled reinstalling reinstate reinstated reinstatement reinstating reinsurance r einsurer reinsurers reintegration reinterpretation reintroduce reintroduced reintroduction reinvent reinvented reinventing reinvention reinvest reinvested reinvestment reinvigorate reis reise reisen reisenden reiser reiserfs reisman reiss reissue reissued reissues reisterstown reit reiter reiterate reiterated reiterates reiterating reith reits reitz reiv reizen rej reject rejected rejecting rejection rejections rejects rejoice rejoiced rejoices rejoicing rejoin rejoinder rejoined rejoining rejuvenate rejuvenated rejuvenating rejuvenation rekha rekindle rekindled reklama rel rela relacionados relaciones relais relapse relapsed relapses relapsing relase relat relate related relateddiagram relatedness relates relating relation relational relations relationship relationships relative relatively relative s relativism relativistic relativity relato relatos relaunch relaunched relax relaxant relaxants relaxation relaxed relaxer relaxers relaxes relaxing relay relayed relaying relays rele rele ase released releasers releases releasing relegated relegation relented relentless relentlessly relenza relevance relevancy relevant relevent reli reliability reliable reliably reliance reliant relic relicensing relics relied relief reliefs reliefweb relient relies relieve relieved reliever relievers relieves relieving religion religions religiosity religious religiously religous relinquish relinquished relinquishing relinquishment relish relished relishes relishing relist relisted relisys relive reliving rell rellihan relo reload reloaded reloading reloads reloc relocatable relocate relocated relocates relocating relocation relocations reluctance reluctant reluctantly rely relying rem rema remade remailer remain remainder remainders remained remaining remains remake remakes remak ing reman remand rem anded remanufactured remanufacturing remap remapping remark remarkable remarkably remarked remarketing remarking remarks remarriage remarried remarry remaster remastered rematch remax rem brandt remco remeber remedial remediate remediation remedied remedies remedy remedying remember remembered remembering remembers remembrance remembrances remeron remi remicade remind reminded reminder reminders reminding remindme reminds remington reminisce reminiscence reminiscences reminiscent reminiscing remiss remission remit remittance remittances remitted remitting remix remixed remixes remixing remnant remnants remo remodel remodeled remodeler remodelers remodeling remodelling remodels remorse remortgage remortgages remote remotecontrol remotecontrols remotely remoteness remotes remotest remoting removable removal removals remove removeable removed remover removers removes removing remsen remstats remunerated remuneration remus remy ren rena renae renaisance renaissance rena l rename renamed rena mer renames renaming renard renata renate renato renaud renault rence rencontre rencontres rend rendell render rendered renderer renderers rendering renderings renderosity renders rende z rendezvous rending rendition renditions rendu rendus rene renee renegade renegades renegotiate renegotiated renegotiation renesas renew renewable renewables renewal renewals renewed renewing renews renfrew renfrewshire renfro renin renmimbi renminbi rennaisance rennaissance renner rennes rennie reno renoir renormalization renounce renounced renouncing renova renovate renovated renovating renovation renovations renown renowned renseignements renshaw rensselaer rent renta rentacar rental rentalnew rentals rentalscom rentclicks rentcom rented renter renteria renters renting rently renton rents rentz renumber renumbered renumbering renunciation renville renwick renzo reo reopen reopened reopening reopens reorder reordered reordering reorg reorganisation reorganization reorganizations reorganize reorganized reorganizing reorientation rep repack repackaged repackaging repaid repaint repainted repainting repair repairable repaired repairer repairers repairing repairlocal repairman repairs r eparation reparations repartee repatriated repatriation repay repayable repaying repayment repayments repeal repealed repealing repeals repeat repeatability repeatable repeated repeatedly repeater repeaters repeating repeats repec repel repellant repelled repellent repellents repeller repelling repels repens repent repentance repented repercussions reperfusion repertoire repertory repetition repetitions repetitious repetitive rephrase repl replace replaceable replaced replacement replacements replacementscom replacer replaces replacing replanting replay replayed replaying replays replaytv replenish replenished replenishing replenishment replete replica replicas replicate replicated replicates replicating replication replications replicator replicators replie replied replies replogle reply replygif replyi ng repo reponse repor report reportable reportage reportdebt reported reportedly reporter reporters reporting reports repos repose reposition repositioned repositioning repositories re pository repossessed repossession repost reposted reposting repoview repr repre reprehensible represen represent representa representable representation representational representations representative representativeness representatives represented representing represents repress repressed repression repressive repressor reprieve reprimand reprimanded reprint reprinted reprinting reprints reprisal reprisals reprise repro reproach reprocessed reprocessing reprod reproduce reproduced reproduces reproducibility reproducible reproducing reproduction reproductions reproductive reprogram reprogramming reprographics reps repsfa repsol rept reptile reptiles reptilian repub repubblica republic republica republican republicanism republicans republication republicecuadorel republics republik re publika republiky repub lique republish republished republishing repudiate repudiated repudiation repugnant repulse repulsed repulsion repulsive repurchase repurchased repurchases reputable reputation reput ations repute reputed reputedly req reqd reqs request requested requester requesters requestform requesting requestor requests requiem require required requirement requirements requires requiring requisite requisites requisition requisitioning requisitions rer reread rereading rerio reroute rerouting rerum rerun reruns res resa resale resales resampling rescaling reschedule rescheduled rescheduling rescind rescinded rescission resco rescue rescued rescuer rescuers rescues rescuing rese reseach reseal resealable research researched researcher researchers researches researchindex researching researchmidtab resected resection reseda resell reseller resellerratingscom resellers reselling resells resemblance resemble resembled resembles resembling resend resene resent resented resentful r esentment resents reser reserva reservados reservas reservation reservations reserve reserveamerica reserved reserveddesignated reservedweb reserves reserving reservist reservists reservoir reservoirs rese t resetchannel resets resetting resettled resettlement reshape reshaped reshaping reshuffle resi resid reside resided residence residences residencia residencial residencies residency resident residential residents residenza resides residing residual residuals residue residues resign resignation resignations resigned resigning resigns resilience resiliency resilient resin resins resist resistance resistances resistant resisted resisters resisting resistive resistivity resisto resistor resistors resists resizable resize resized resizer resizing resnet resnick reso resold resolute resolutely resolution resolutions resolvconf resolve resolved resolver resolves resolving reson resonance resonances resonant resonate resonated resonates resonating resonator resonators resorption resort reso rted resorting resortque st resorts resouces resound resounding resour resource resourced resourceful resourcefulness resources resourcing resp respawn respec respect respectability respectable respected respectful respectfully respecting respective respectively respects respir respirable respiration respirator respirators respiratory respite resplendent respon responce respond responded respondent respondents responder responders responding responds responsability responsable response responses responsewrite responsi responsibilities responsibility responsibilty responsible responsiblity responsibly responsive responsiveness respuesta ress ressource ressources rest restart restarted restarting restarts restate restated restatement restaurant restaurante restaurantes restaurants restaurateur restaurateurs restauration restcamp reste rested restenosis restful resting restitution restless restlessness resto restock restocking restockit reston restoration restorations restorative restore restored restorer restore rs restores restoring restrain restrained restraining restraint restraints restrict restricted restricting restriction restrictions restrictive restricts restrike restrnt restroo m restrooms restructure restructured restructuring rests restuarant resturant resturants restylane resubmission resubmit resubmitted result resultado resultados resultant resultat resulted resulting results resultscom resultset resume resumed resumen resumes resuming resumption resupply resurface resurfaced resurfacing resurgence resurgent resurrect resurrected resurrecting resurrection resuscitate resuscitation resuspended resv resync ret reta retail retailer retailers retailing retails retain retained retainer retainers retaining retains retake retaliate retaliated retaliation retaliatory retard retardant retardants retardation retarded retarding retards retcode retd rete retell retelling retention retentive retest retford rethink rethinking reti reticence reticent reticle reticular reticulated reticule retic ulum retin retina retinal retinitis retinoblastoma retinoic retinoid retinol retinopathy retire retired retiree retirees retirement retirements retires retiring retna reto retol d retooling retort retorted retorts retouch retouching retour retrace retract retractable retracted retracting retraction retractions retracts retrain retraining retraite retransmission retransmissions retransmit retransmitted retreat retreated retreating retreats retrenchment retrial retribution retries retrievable retrieval retrievals retrieve retrieved retriever retrievers retrieves retrieving retro retroactive retroactively retrofit retrofits retrofitted retrofitting retrograde retroperitoneal retrosheet retrospect retrospective retrospectively retroviral retrovirus retroviruses retry rett return returnable returned returnees returner returning returns returnvalue retval retype reu reuben reunification reunion reunioncom reunions reunite reunited reunites reuniting reuptake reus re usability reusable reuse re used reusing reuter reuters reuterscom reuven rev reva revalidation revaluation revamp revamped revamping revamps revascularization revd reve reveal revealed revealer revealin g reveals revegetation revel revelation revelations revelatory revell revelry revels revelstoke revenge revenu revenue revenues reverb reverberation revere revered reverence reverend reverent reverie reversal reversals reverse reversed reverses reversi reversibility reversible reversing reversion revert reverted reverting reverts revier review reviewable reviewcom reviewed reviewer reviewers reviewing reviewpost reviews reviewscom reviled revinfo revise revised revises revising revision revisionism revisionist revisions revisit revisited revisiting revisits revisor revista revistas revit revitalise revitalization revitalize revitalized revitalizing reviva revival revivals revive revived revives reviving revlon revo revocable revocation revoir revoke revoked revokes revoking revolt revol ted revolting revolts revolu tion revolutionaries revolutionary revolutionise revolutionize revolutionized revolutionizing revolutions revolve revolved revolver revolvers revolves revolving revs revue r evues revulsion revved revving rew reward rewarded rewarding rewards rewind rewinding rewire rework reworked reworking rewritable rewrite rewritecond rewriter rewriterule rewrites rewriting rewritten rewrote rex rexburg rexel rexford rexnl rexroth rexx rey reyes reykjavik reyna reynaldo reynard reynold reynolds reynoldsburg rez reza rezept rezepte reznor rezone rezoning rf rfa rfb rfc rfcnet rfcs rfd rfe rfee rff rfg rfi rfid rfk rfl rflp rfm rfo rfp rfps rfq rfqs rfr rfs rft rfu rg rga rgb rgba rgbcolor rgc rgd rgds rge rgm rgn rgp rgs rgt rh rha rhabdomyolysis rhaglen rhai rhaid rhan rhapsody rhb rhc rhce rhd rhe rhea rhee rheem rheims rhein rheingold rheinland rhel rheoli rheological rheology rhestr rhesus rhetoric rhetorical rhetorically rhett rheum rheumatic rheumatism rheumatoid rh eumatol rheumatology rhf rhi rhiannon rhic rhin rhine rhinebeck rhineland rhinelander rhinestone rhinestones rhinitis rhino rhinoceros rhinoplasty rhinos rhinotek rhizobium rhizome rhizomeorg rhizomes rhl rhn rho rhoades rhoads rhoda rhode rhodes rhodesia rhodesian rhodium rhododendron rhododendrons rhodopsin rhoi rhombus rhona rhonda rhondda rhone rhowch rhp rhs rhsa rht rhubarb rhus rhwng rhyl rhyme rhymes rhyming rhyne rhys rhythm rhythmbox rhythmic rhythmical rhythmically rhythms ri ria riaa riad rial rials rialto rian rias rib riba ribas ribavirin ribbed ribbing ribble ribbon ribbons ribeiro ribera riboflavin ribonuclease ribonucleic ribonucleoprotein ribose ribosomal ribosome ribosomes ribs ric rica ricacubadominicadominican rican ricans ricard ricardo riccardo ricci riccione rice ricerca ricerche rich richard richards richardson riche richelieu richer riches richest richey richfield richie richland richlands richly richman richmond richness richter richtig richton richwood ricin rick rickard rickenbacker ri cker rickets ricketts rickettsia rickety rickey ricki rickie rickman rickmansworth ricks rickshaw ricky rico ricochet ricoh ricosaint ricotta rics rid ridata riddance ridd ell ridden ridder riddick riddim ridding riddle riddled riddler riddles ride rideau ridegear ridenour rideout rider riders ridership rides rideshare ridge ridgeback ridgecrest ridged ridgefield ridgeland ridgeline ridgely ridges ridgeview ridgeville ridgeway ridgewood ridgid ridgway ridicule ridiculed ridiculous ridiculously ridin riding ridings ridley rie ried riedel riegel rieger riehl rieker riel riemann riemannian rien ries riesenschwanz riesgo riesling rieti rieu rif rifampin rife riff riffing riffle riffs rifkin rifle rifled rifleman riflemen rifles riflescope rift rifts rig riga rigby rigel rigg rigged rigger rigging riggins riggs righ right righteous righteousness rightful rightfully righting rightly rightmost rightness rightnow rightphp rights rightwing righty rigid rigidity rigi dly rigoletto rigor rigorous r igorously rigors rigour rigs rihanna rijeka rijn rijndael rik rika riken riker riki rikki rikku rikon ril rila riled riley rilke rill rilo rim rima rimage rimbaud rime r 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