Expert opinion - TNF inhibitors in psoriasis

This therapy holds promise for the treatment of psoriasis. By Dr Richard Warren and Professor Christopher Griffiths

Two TNF inhibitors are licensed in the UK for severe psoriasis and psoriatic arthritis – infliximab and etanercept. A third, adalimumab, is licensed for psoriatic arthritis and is currently in phase III trials for use in psoriasis. Psoriatic arthritis accompanies psoriasis in about 15 per cent of patients.

The first, infliximab, is a human-murine chimeric monoclonal antibody that binds to TNF. It is delivered by slow intravenous infusion at a dose of 5mg/kg as a loading dose regimen at zero, two and six weeks, and at eight-weekly intervals thereafter.

The second, etanercept, a human recombinant TNF receptor p75 fusion protein, binds soluble TNF, but forms less stable complexes with membrane-bound TNF. It is self-administered as a subcutaneous injection and is licensed for use at 25mg and 50mg twice weekly for up to 24 weeks.

The third, adalimumab, is a human recombinant monoclonal antibody identical to human immunoglobulin G. In psoriatic arthritis, it is self-administered as a single 40mg subcutaneous injection every other week.

Evidence for anti-TNF Therapies
Infliximab
Two trials in patients with moderate to severe stable plaque psoriasis have shown infliximab to be highly effective at inducing disease remission.1,2 Improvement was seen within the first two to four weeks of treatment.

A recent study of 378 patients with moderate to severe plaque psoriasis has shown significant promise for infliximab as an effective maintenance therapy.3 At week 24, 82 per cent of patients achieved at least a 75 per cent improvement in clinical severity of disease, as measured by the psoriasis area and severity index (PASI), compared with 3 per cent for placebo. At week 50, 61 per cent had a 75 per cent improvement in PASI.

Etanercept
Two key phase III trials involving more than 1,000 patients with moderate to severe chronic plaque psoriasis demonstrate the effectiveness of etanercept.4,5

Efficacy is dose-related, with 34 per cent and 49 per cent of patients receiving 25mg and 50mg twice weekly, respectively, achieving a PASI 75 response by week 12.

Treatment up to 24 weeks improves response further, with 44 per cent and 59 per cent of patients receiving 25mg and 50mg twice weekly, respectively, achieving a PASI 75 response. A more recent study has also shown etanercept to provide meaningful improvement in fatigue and symptoms of depression.6

Adalimumab
A completed phase II trial in the treatment of patients with moderate to severe psoriasis showed impressive results, with 53 per cent of patients on 40mg every other week and 80 per cent of patients on 40mg weekly achieving a PASI 75 response.7

Adverse effects and toxicity
Concerns regarding serious infections, malignancy, worsening of heart failure and development of demyelinating disease remain with this class of drug. Reactivation of TB may occur following treatment with anti-TNF agents and TB tests are recommended before the treatment is carried out. Long-term data are required for patients treated with anti-TNF agents; skin cancer is a particular concern.

Receiving biological therapy
NICE has recently published guidance on the use of etanercept and efalizumab for psoriasis, and infliximab and etanercept for psoriatic arthritis,8 which follow the previously published British Association of Dermatologists (BAD) guidelines.9

Patients with severe disease (PASI >10), significant impairment in quality of life (Dermatology Life Quality Index >10) and unsuitability for, and/or failure to respond to, other systemic therapies are eligible for biological therapies.

The long-term risks of biological agents for the treatment of psoriasis are unknown, so although effective, these agents should be used according to BAD and NICE guidance.

- Dr Richard Warren is MRC clinical research fellow in dermatology, University of Manchester; Professor Christopher Griffiths is foundation professor of dermatology, University of Manchester

References
1. Chaudhari U, Romano P, Mulcahy LD et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 35: 1842-7.
2. 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: 534-42.
3. Reich K, Nestle FO, Papp K et al. Infliximab induction and maintenance therapy for moderate-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 2005; 336: 1367-74.
4. Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349: 2014-22.
5. Papp KA, Tyring SK, Lahfa M et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect on dose reduction. Br J Dermatol 2005; 152: 1304-12.
6. Tyring S, Gottlieb A, Papp K et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 2006; 367: 29-35.
7. Chen DM, Gordon K, Leonardi MD et al. Adalimumab efficacy and safety in patients with moderate to severe chronic plaque psoriasis. Preliminary findings from 12-week dose-ranging trial. J Am Acad Dermatol 2004; 50 (3pt II) and Ps 491; Ps.
8. NICE. Etanercept and efalizumab for the treatment of adults with psoriasis. NICE technology appraisal guidance 103. London, 2006.
9. Smith CH, Anstey AV, Barker JNWN et al. British Association of Dermatologists guidelines for use of biological interventions in psoriasis 2005. Br J Dermatol 2005; 153: 486-97.

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