1. Aetna considers biological therapies alefacept (Amevive), efalizumab (Raptiva), infliximab (Remicade), and etanercept (Enbrel) medically necessary for adults aged 18 years and older with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy when the following selection criteria are met:

   1. Ten percent or more body surface area is affected by plaque psoriasis or member has a PASI score of 10 or more*; and

   2. Member has failed to adequately respond to or is intolerant to a 3-month trial of one of the following photo therapies (unless contraindicated):

      1. psoralens (methoxsalen, trioxsalen) with UVA light (PUVA); or
      2. UVB with coal tar or dithranol; or
      3. UVB (standard or narrow-band). 

   * In exceptional circumstances (for example, disabling acral disease), patients with severe disease may fall outside of this definition, but may be considered for treatment.

   Further treatment is not considered medically necessary for persons whose psoriasis has not adequately responded after 12 weeks.

2. Alefacept and efalizumab are considered experimental and investigational for all other indications.

Notes:

More than two treatments of alefacept are considered experimental and investigational. According to the FDA, data on the safety and efficacy of alefacept treatment beyond two courses are limited.

Alefacept is considered experimental and investigational in members with CD4+ T lymphocyte counts less than 250 cells/mm3  because its safety in persons with this contraindication to alefacept has not been established.

See also CPB 315 - Enbrel (Etanercept), CPB 341 - Remicade (Infliximab), CPB 205 - Phototherapy and Photochemotherapy (PUVA) for Skin Conditions, and CPB 577 - Psoriasis Laser Treatment.

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.

Guidelines on psoriasis from the Finnish Medical Society Duodecim (2005) state that biologicals such as alefacept, efalizumab, etanercept and infliximab may have a role in the treament of moderate to severe psoriasis refractory to other treatments or when other treatments are contraindicated or unsuitable.

Guidelines on psoriasis from the British Association of Dermatologists (2005) state that most patients with moderate to severe disease achieve satisfactory disease control (i.e., significant or complete clearing of disease) in the short term with at least one of the systemic agents currently available. Long-term disease control frequently requires some form of continuous therapy and consequent, predictable risks of toxicity. The guidelines state that, at present, the risks and benefits of anti-tumor necrosis factor (anti-TNF) agents, or efalizumab, relative to standard systemic therapy, are unknown. The guidelines state that early, widespread use of these agents in uncomplicated moderate to severe psoriasis is inappropriate and is not supported by the licensed indications for etanercept or efalizumab.

The British Association of Dermatologists state that candidates for biological therapies for psoriasis should have severe disease and fulfill at least one of the following criteria:

• have developed or are at higher than average risk of developing clinically important drug-related toxicity and where alternative standard therapy cannot be used; or
• are or have become intolerant to or cannot receive standard therapy; or
• are or have become unresponsive to standard therapy; or
• have disease that is only controlled by repeated inpatient management; or
• have significant, coexistant, unrelated comorbidity which precludes the use of systemic agents such as cyclosporine or methotrexate; or
• have severe, unstable, life-threatening disease (erythrodermic or pustular psoriasis); or
• have psoriatic arthritis fulfilling the British Society for Rheumatology (BSR) eligibility criteria for treatment with anti-TNF agents, in association with skin disease.

For purposes of the British Association of Dermatology guideline, standard systemic therapy was defined to include acitretin, cyclosporine, methotrexate, narrow-band UVB, and PUVA. According to these guidelines, a person is considered unresponsive to standard therapy if there is an unsatisfactory clinical response (a less than 50 percent improvement in baseline PASI score or precentage body surface area, and a less than 5 percent improvement in DLQI) to at least 3 months of treament in the therapeutic dose range of standard systemic therapy.

According to the British Association of Dermatology guideline, the following standard dose ranges apply:

• cyclosporine 2.5 to 5 mg per kg daily;
• methotrexate single weekly dose (oral, subcutaneous, intramuscular) 15 mg, max 25 to 30 mg;
• acitretin 25 to 50 mg daily;
• narrow band UVB or psoralen photochemotherapy (nonresponse, rapid relapse, or exceeding recommended maximum doses) 150-200 treatments for PUVA, 350 treatments for narrowband UVB.

Alefacept (Amevive; Biogen, Cambridge, MA) was evaluated in two randomized, double-blind, placebo-controlled studies in adults with chronic (greater than 1 year) plaque psoriasis and a minimum body surface area involvement of 10% who were candidates for or had previously received systemic therapy or phototherapy.  Each course consisted of once-weekly administration for 12 weeks of placebo or alefacept.  Patients could receive concomitant low potency topical steroids. Concomitant phototherapy or systemic therapy was not allowed.

In one study involving 553 patients, 14% of patients treated with one 12-week course of intravenous alefacept achieved a 75% or greater improvement in psoriasis, compared with 4% of patients receiving placebo.  In another study involving 173 patients, 21% of patient treated with one course of intramuscular alefacept achieved a 75% or greater improvement in psoriasis, compared to 5% of patients assigned to placebo.

The most frequently reported side effects to alefacept included sore throat, dizziness, cough, headache, nausea, pruritus, muscle aches, chills, and pain and inflammation at the injection site.  The most serious side effects were lymphopenia, malignancies, serious infections requiring hospitalization, and allergic reactions.

The recommended dose of alefacept is 7.5 mg given once weekly as an IV bolus or 15 mg given once weekly as an IM injection.  The recommended regimen is a course of 12 weekly injections. Retreatment with an additional 12-week course may be initiated provided that CD4+ T lymphocyte counts are within the normal range, and a minimum of a 12-week interval has passed since the previous course of treatment. Data on retreatment beyond two cycles are limited.

The CD4+ T lymphocyte counts of patients receiving alefacept should be monitored weekly before initiating dosing and throughout the course of the 12-week dosing regimen. Dosing should be withheld if CD4+ T lymphocyte counts are below 250 cells/µL. The drug should be discontinued if the counts remain below 250 cells/µL for one month.

The Canadian Coordinating Office for Health Technology Assessment (Shukla, 2003) concluded that in clinical trials of patients with moderate to severe psoriasis, alefacept showed a modest but statistically significant increase in the number of responders compared to placebo.  However, due to a lack of direct comparative data, it is difficult to predict exactly how alefacept will fit into the current rotational psoriasis therapy paradigm.

Efalizumab (Raptiva), developed by Xoma Ltd. (Berkeley, CA) and Genentech Inc. (South San Francisco, CA), gained FDA approval in October 2003 for the treatment of moderate-to-severe psoriasis in people at least 18 years old.  Efalizumab, a once-weekly subcutaneously injected drug, is a humanized anti-CD11a monoclonal antibody.

In an open-label, multicenter, dose escalation study,  Gottlieb et al (2002) examined the effects of intravenous infusions of efalizumab (Emab) in 39 patients with moderate-to-severe psoriasis.  Efalizumab was administered for 7 weeks at doses of 0.1 mg/kg every other week or 0.1 mg/kg weekly (Category 1), 0.3 mg/kg weekly (Category 2), and 0.3 increasing to 0.6 or 1.0 mg/kg weekly (Category 3).  Skin biopsies were performed on days 0, 28, and 56.  The main outcome measures were serum Emab levels, levels of total and unoccupied T-cell CD11a, T cell counts, epidermal thickness, cutaneous intercellular adhesion molecule 1 (ICAM-1) and keratin 16 (K16) expression, Psoriasis Area and Severity Index (PASI) scores.  Category 1 failed to maintain detectable serum Emab or T cell CD11a down-modulation between doses.  Category 2 achieved both.  Category 3 achieved both and additionally maintained sustained T-cell CD11a saturation between doses.  A dose-response relationship was also observed clinically and histologically.  The mean decrease in the PASI score was 47% in Category 3, 45% in Category 2, and 10% in Category 1 (p < 0.001).  Epidermal and dermal T-cell counts, epidermal thickness, and ICAM-1 and K16 expression decreased in Categories 2 and 3, but not in Category 1.  Circulating lymphocyte counts increased in Categories 2 and 3.  The authors concluded that at doses of 0.3 mg/kg or more per week, intravenous Emab produced significant clinical and histological improvement in psoriasis, which correlated with sustained serum Emab levels and T-cell CD11a saturation and down-modulation.

Data submitted to the FDA included a randomized, double-blind, placebo-controlled Phase III study that showed 44% (161/368) of patients treated continuously with 1 mg/kg of Raptiva for up to 24 weeks achieved a 75% or greater improvement in PASI scores (PASI 75).  Additional data included follow-up (84 weeks) results from a separate open-label study.  In this study, patients received 2 mg/kg of Raptiva weekly for an initial 12 weeks and subsequently received a once-weekly dose of 1 mg/kg of Raptiva starting at week 13.  For each successive 3-month period of treatment, dropouts during that period were analyzed using their last available PASI assessment, but were excluded from subsequent cohorts.  Among the 194 patients who remained in the trial through week-84, 67% (130/194) of patients achieved PASI 75 and 34% of patients (66/194) achieved PASI 90.  Some side effects of Raptiva included headaches, chills, fever and nausea.

In an international consensus conference on the use of biological therapies in the systemic management of psoriasis, Sterry and colleagues (2004) stated that given the apparent lack of traditional end-organ toxicity (e.g., nephrotoxicity or hepatotoxicity), biologicals may be used for significant periods of time.  The authors noted that efalizumab has shown sustained effectiveness without increased toxicity during continuous dosing of up to 24 months.  They noted that data and experience suggest that biologicals promise to provide psoriasis patients with long-term control of their disease.

Gottlieb, et al. (2006) assessed the safety and effectiveness of long-term, continuous efalizumab therapy.  Of 339 patients enrolled in an ongoing, open-label, phase III clinical trial, after 3 months 290 qualified for and entered the maintenance treatment phase.  Results for the first 27 months of this 36-month continuous therapy trial were presented.  At month 3, 41 % of patients achieved at least a 75 % reduction in PASI score; at month 27, 47 % achieved at least a 75 % reduction in PASI score (intent to treat, n = 339).  Among patients eligible for maintenance therapy (n = 290), 56 % achieved at least a 75 % reduction in PASI score at month 27.  Moreover, the at least 90 % reduction in PASI score rate increased through 18 months (33 %).  The safety profile with efalizumab was sustained throughout 27 months of continuous treatment with no new common events over time.  The authors concluded that these findings suggest that efalizumab maintains, and in some patients continues to improve, efficacy during long-term therapy.  The major drawback of this study is that because the extended treatment period was not a randomized clinical trial, no formal comparative analyses versus placebo were conducted.  Based on the findings of Gottlieb et al (2006), Menter et al (2006) stated that patients who are maintaining effectiveness and tolerating efalizumab favorably can receive efalizumab on a continuous basis.

Poulin and associates (2006) reported that phase III clinical trials for efalizumab have demonstrated its short- and long-term (12-week, 6-month, and 3-year) safety and effectiveness for the treatment of psoriasis.  The authors stated that efalizumab has emerged as an important addition to the dermatological pharmacopeia for the long-term treatment of psoriasis.  Furthermore, Shear (2006) noted that efalizumab has been associated with thrombocytopenia and hemolytic anemia.  Data on the safety of greater than 2.5 years' continuous treatment with efalizumab are reassuring and a valuable beginning to understanding the role and risk of harm of long-term therapy for a chronic disease.  The author stated that longer follow-up studies and safety databases, for each of the biologicals used in psoriasis, are needed to ensure both prolonged effectiveness and minimal risk of harm.

Guidelines from the National Institute for Health and Clinical Excellence (NICE, 2006) state that efalizumab is recommended for the treatment of adults with plaque psoriasis only when the following criteria are met:

• The disease is severe as defined by a total Psoriasis Area Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10; and
• The psoriasis has failed to respond to standard systemic therapies, including cyclosporin, methotrexate, and PUVA, or the person is intolerant to, or has a contraindication to, these treatments.
• The psoriasis has failed to respond to etanercept.

According to NICE guidelines, further treatment with efalizumab is not recommended in patients unless their psoriasis has responded adequately at 12 weeks. Further treatment cycles are not recommended in these patients. AAccording to NICE, an adequate response is defined as either: 1) a 75 percent reduction in the PASI score from when treatment started (PASI 75); or 2) a 50 percent reduction in the PASI score (PASI 50) and a five-point reduction in DLQI from when treatment started.

Guidelines from the British Association of Dermatologists (2005) state that efalizumab should be considered first choice of biological therapy for patients with a high risk of latent tuberculosis (and therefore requiring tuberculosis prophylaxis) or with evidence of demyelinating disease.

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 two 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) state 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.

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 two 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 two of 11 patients assigned to placebo.  In initial studies, remissions seemed to be durable, with many patients improving for six 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) state 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.

Appendix

• A description of the Psoriasis Area and Severity Index (PASI) is available from the following reference: http://ard.bmj.com/cgi/content/full/64/suppl_2/ii65
• The Dermatology Life Quality Index (DLQI) is available at the Wales College of Medicine Department of Dermatology website: http://www.dermatology.org.uk/index.asp?portal/quality/dlqi.html.