Elsevier

The Lancet

Volume 357, Issue 9271, 9 June 2001, Pages 1842-1847
The Lancet

Fast track — Early Report
Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial

https://doi.org/10.1016/S0140-6736(00)04954-0Get rights and content

Summary

Background

Currently available treatments for moderate to severe psoriasis are either incompletely effective in some patients, or are associated with toxic effects. Since tumour necrosis factor α (TNF-α) is thought to have a role in the pathogenesis of psoriasis, we did a double-blind, randomised trial to assess the clinical benefit and safety of infliximab-a monoclonal antibody against TNF-α.

Methods

33 patients with moderate to severe plaque psoriasis were randomly assigned intravenous placebo (n=11), infliximab 5 mg/kg (n=11), or infliximab 10 mg/kg (n=11) at weeks 0, 2, and 6. Patients were assessed at week 10 for the primary endpoint (score on the physician's global assessment [PGA]). Analysis was by intention to treat.

Findings

Of the 33 patients enrolled, three dropped out. Nine of 11 (82%) patients in the infliximab 5 mg/kg group were responders (good, excellent, or clear rating on PGA), compared with two of 11 (18%) in the placebo group (difference 64% [95% CI 20–89], p=0·0089), and ten of 11 (91%) patients in the infliximab 10 mg/kg group were responders (difference from placebo 73% [30-94], p=0·0019). The median time to response was 4 weeks for patients in both infliximab groups. There were no serious adverse events, and infliximab was well tolerated.

Interpretation

In this controlled trial, patients receiving the anti-TNF-α agent infliximab as monotherapy experienced a high degree of clinical benefit and rapid time to response in the treatment of moderate to severe plaque psoriasis compared with patients who received placebo. These findings suggest that TNF-α has a pivotal role in the pathogenesis of psoriasis.

Introduction

Psoriasis is a psychologically and physically disabling disease that affects 1–3% of the US and European population;1 about 25% of patients have moderate to severe disease. The costs and other financial implications of caring for patients with psoriasis can result in lower quality of life for patients with more severe psoriasis.2 Treatments approved by the US Food and Drug Administration for this class of patients include ciclosporin, methotrexate, acitretin, ultraviolet B (UVB), and ultraviolet A with psoralen (PUVA). Ciclosporin is the most effective of these treatments, but exposure to this drug can result in toxic effects such as hypertension and irreversible renal insufficiency.3 Methotrexate can take 4–8 weeks to produce significant improvement, and there is a risk of toxic effects on the liver and bone marrow. Acitretin alone is only partly effective and rarely clears the disease. Additionally, it causes substantial mucocutaneous toxic effects and is a teratogen, as is methotrexate. UVB and PUVA require an intensive treatment regimen (about three times per week for many months), thereby reducing patients' compliance. Additionally, PUVA has been associated with skin cancers including malignant melanoma. Overall, the treatments available for moderately to severely active psoriasis are either incompletely effective in some patients or are associated with serious toxic effects.4 There is therefore a need for highly efficacious treatments that are safe to use in a long-term regimen.

The two major pathological lesions seen in psoriasis are epidermal hyperproliferation with abnormal differentiation, and inflammatory infiltration in the epidermis and dermis. These processes are mainly driven by activated T cells or antigen-presenting cells, which release various chemokines and cytokines that signal the keratinocyte to hyperproliferate, and which ultimately leads to abnormal differentiation.5, 6, 7, 8, 9 These signalling molecules include tumour necrosis factor α (TNF-α), interleukin 6, interleukin 8, granulocyte macrophage colony stimulating factor, and interferon gamma. The cytokine TNF-α in particular is believed to have a major role in this process: increased concentrations have been detected in psoriatic skin lesions.10 TNF-α, via activation of nuclear factor αB (NFκB), induces synthesis of numerous cytokines, including interleukin 8, interleukin 6, and colony-stimulating factors. Also, TNF-α potentially contributes to the accumulation of inflammatory cells seen in epidermis and dermis by inducing expression of intracellular adhesion molecule (ICAM)-1 on endothelial cells and keratinocytes.11 TNF-α therefore has a potential role in both of the major pathological lesions in psoriasis.9 Consequently, blockade of TNF-α activity should, in theory, reduce inflammation and keratinocyte proliferation and differentiation abnormalities in psoriasis.

Infliximab is a chimeric monoclonal antibody that has high specificity, affinity, and avidity for TNF-α12 and is currently approved in the USA and Europe for the treatment of rheumatoid arthritis and Crohn's disease. The scientific rationale for blocking TNF-α in psoriasis and our own anecdotal experience with infliximab in psoriatic patients13 led us to design a randomised, placebo-controlled trial of infliximab monotherapy in patients with moderate to severe psoriasis.

Section snippets

Patients

Adult patients who had moderate to severe plaque psoriasis involving at least 5% of the body surface area and who were in good general health were referred to us by the Divisions of Dermatology and Clinical Pharmacology at UMDNJ-Robert Wood Johnson Medical School or were identified through general advertisements. Patients had a history of plaque psoriasis for a minimum of 6 months and a history of topical corticosteriod failure. All patients had a clear chest radiograph within 1 month of

Patients

33 patients, ranging in age from 21 to 69 years, were included in the study. 11 were assigned infliximab 5 mg/kg, 11 infliximab 10 mg/kg, and 11 placebo. Three patients withdrew during the course of the study, one from each treatment group (figure 1). One patient from the infliximab 5 mg/kg group was withdrawn at week 2, secondary to a mild rash. Another patient in the 10 mg/kg group was withdrawn, 7 days after his first infusion, because of worsening psoriasis. The third patient, in the

Discussion

This study was designed to assess the clinical benefit and safety of infliximab monotherapy in patients with moderate to severe plaque psoriasis. A second aim was to use infliximab as a targeted therapeutic probe to determine the role of TNF-α in the pathogenesis of psoriasis.

Patients who received infliximab in this study experienced a higher degree of clinical benefit and a more rapid time to response than patients who received placebo. The response seen was similar to that of ciclosporin in

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