TNF inhibitors in psoriasis and psoriatic arthritis

teaser

Philip Mease
MD
Seattle Rheumatology Associates
Chief
Division of Rheumatology Research, Swedish Medical Center
Clinical Professor
University of Washington School of Medicine
Seattle, WA
USA
E:[email protected]

Psoriasis is a chronic immune-mediated disease affecting 2–3% of the Caucasian population worldwide.(1–3) Approximately 25% of these patients will be diagnosed with moderate or severe disease,(4) which is accompanied by significant psychosocial morbidity and a decrease in health-related quality of life.(5) Studies conducted among this group of patients in both Europe and the USA report a high level of dissatisfaction with current treatments.(6,7) About 30% (range 6–39%) of patients diagnosed with moderate or severe psoriasis will also develop psoriatic arthritis (PsA),(8–10) a spondyloarthropathy with the potential for significant joint destruction, which may impact on quality of life as much as, or more than, rheumatoid arthritis.(11)

Tumor necrosis factor alpha (TNFalpha) has been shown to play a fundamental role in the pathogenesis of both psoriasis and PsA through several pathogenic mechanisms, including the expression of adhesion molecules on the surface of endothelial, keratinocyte and dendritic cells, promoting leukocyte migration.(12) In the joints, TNFalpha triggers intracellular signalling and increases the production of a variety of proinflammation cytokines, which in turn contribute to the inflammatory cascade.(13) Additionally, it triggers a number of different cells within the joint to produce destructive enzymes. In the skin, TNFalpha also leads to decreased keratinocyte apoptosis and cell cycling, thus contributing to a hyperproliferative epidermis.(13) It is reasonable to assume that inhibition of TNFalpha will lead to decreased joint and skin inflammation, as well as reduced tissue destruction.(13) Several TNFalpha inhibitors are either approved or undergoing clinical trials for the treatment of psoriasis and PsA.

Etanercept
Etanercept (Enbrel; Amgen/Wyeth Pharmaceuticals), a naturally occurring cytokine that is involved in normal inflammatory and immune responses, binds specifically to TNF and blocks its interaction with cell surface TNF receptors.(14) It is approved in the USA for the treatment of both psoriasis and PsA, and in Europe and other countries for PsA, as well as rheumatoid arthritis, ankylosing spondylitis and juvenile arthritis.

Clinical trials have demonstrated that etanercept significantly improves psoriatic lesions, reduces joint symptoms and inhibits arthritic disease progression, as evidenced radiographically.(15–17) In a 24-week study in which 672 subjects with psoriasis were assigned to receive etanercept (low [25mg weekly], medium [25mg twice weekly] or high dose [50mg twice weekly]) or placebo, significantly more patients receiving etanercept (14%, 24%, 49%, respectively; p<0.001 versus placebo for all comparisons) showed a 75% improvement in the Psoriasis Area and Severity Index (PASI)-75 score at week 12.(16) The improvement continued up to week 24. Similarly, significant improvements were shown in quality-of-life scores and physician and patient global assessments. In a study of 205 patients with PsA and psoriasis, individuals treated with etanercept 25mg subcutaneously (SC) twice weekly for 24 weeks demonstrated significant improvement (p<0.001) compared with those treated with placebo in the American College of Rheumatology 20% (ACR20) improvement criteria at weeks 12 and 24, as well as in the quality-of-life indicators and PASI-75 scores.(15) Radiographic disease progression was inhibited at month 12. The recommended dose of etanercept for patients with plaque psoriasis is 50mg twice weekly SC for three months followed by a maintenance dose of 50mg once weekly thereafter. The recommended dose for patients with psoriatic arthritis is 25mg twice weekly. Etanercept may be used in combination with methotrexate.

Infliximab
Infliximab (Remicade; Centocor), a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that binds to TNFalpha, was recently approved in the EU, in combination with methotrexate, for the treatment of active and progressive PsA. Approval was based on data from the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) conducted in patients with PsA and psoriasis, which showed significant improvement in ACR20 and PASI-75 scores versus placebo-treated patients,(18–20) as well as inhibition of radiographic disease progression.(21,22) Patients enrolled in IMPACT received infliximab 5mg/kg at weeks 0, 2 and 6, and every eight weeks thereafter.

Clinical trial results have shown that treatment with infliximab may also be effective in reducing skin lesions.(23) In a 30-week multicentre, double-blind, placebo-controlled trial of 249 patients with severe plaque psoriasis, significantly more patients treated with infliximab showed improvement on both the PASI-75 and Physician Global Assessment (PGA) scores versus those treated with placebo (p<0.001) after 10 weeks of therapy. Improvement was seen as early as week 2.(23) Patients in the psoriasis studies received infliximab as an intravenous infusion at doses ranging from 3mg/kg to 10mg/kg at weeks 0, 2 and 6, and every eight weeks thereafter.

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Adalimumab
Adalimumab (Humira; Abbott Laboratories) is a recombinant human lgG1 monoclonal antibody that binds specifically to TNFalpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. It is approved for rheumatoid arthritis and is currently undergoing clinical trials for the treatment of psoriasis and PsA. ACR20 and PASI-75 results in a phase III randomised, placebo-controlled trial of 313 patients with active PsA and psoriasis (n=69) were significantly better for adalimumab-treated patients than for those treated with placebo (57% and 59% versus 15% and 1% ACR20 and PASI-75, respectively; p<0.001) after 24 weeks. Patients treated with adalimumab (40mg SC) every other week responded rapidly, with 27% and 52% achieving an ACR20 response after two and four weeks, respectively, versus 6% and 9% of placebo patients.(24)

Onercept
Another anti-TNF medication, onercept (Serono), is currently in development. This compound shows promises for the treatment of psoriasis and PsA. In a 12-week phase II, multicentre, double-blind, placebo-controlled trial, 126 patients with PsA were treated with onercept (50 or 100mg SC) three times per week. Eighty-six percent of patients treated with onercept 100mg achieved a 75% improvement in PASI score, versus 45% in the placebo group. The secondary endpoint (a 20% improvement in the ACR criteria) was achieved by 67% of the onercept patients, compared with 31% of patients receiving placebo.(25) Additional studies are ongoing.

Safety and tolerability
Etanercept and adalimumab, administered SC, can cause mild and transient reactions at the site of administration. Infliximab, administered intravenously, can infrequently yield infusion reactions. Rare cases of serious infection, including opportunistic infection such as tuberculosis, have been reported in clinical trials and postmarketing surveillance with these agents. It is recommended that tuberculin skin testing be performed on patients who are candidates for anti-TNF therapy, in order to rule out latent infection. If the skin test is positive, appropriate treatment should be initiated before starting treatment with the anti-TNF medication. Anti-TNF therapy is not advised in patients with moderate–to–severe congestive heart failure. Extremely rare instances of demyelinating illness, lupus-like illness and haematological abnormalities have been reported.

Conclusion
Anti-TNF treatment offers a new therapeutic option for patients with moderate-to-severe psoriasis and PsA, one that can be targeted more individually for each patient.

Clinical trials have shown TNFalpha inhibitors to be effective, with significantly more patients receiving active treatment achieving PASI-75 and ACR20 endpoints versus placebo-treated patients. These treatments have also been shown to inhibit disease progression, as measured radiographically. Treatments are generally well tolerated, suggesting the possibility for long-term use. Finally, both physician and patient global assessments indicate impressive improvement in patient quality of life.

Acknowledgement
Ms Maria Vinall of Wyeth Research assisted with the preparation of this article.

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