Targeting Tumor Necrosis Factor-α in the Therapy of Psoriasis

Abstract

Tumor necrosis factor-alpha (TNF-alpha) plays a fundamental role in the initiation and persistence of skin inflammation in psoriasis. The best evidence of the essential activity of this cytokine in the pathogenesis of psoriasis came from the observation that selective TNF-alpha blockers are dramatically effective in the therapy of this disease. The TNF-alpha inhibitors, infliximab and etanercept, have been employed with success in moderate to severe psoriasis and in psoriatic arthritis in randomized controlled trials. Anti-TNF-alpha biologicals induce rapid disease resolution and long-lasting remission, suggesting that they may alter the natural course of the disease. Further studies are warranted to more precisely establish the biological bases of the action of anti-TNF-alpha agents, better define which subgroup of patients can benefit most from this treatment, and the modalities of combination therapy with other antipsoriatic agents. Many other TNF-alpha inhibitors have been developed but none of them has been yet used in the therapy of psoriasis. Major limitations to the use of selective TNF-alpha blockers include the reactivation of latent tuberculosis, the risk of opportunistic infections, the development of specific antibodies, which is associated with a reduced duration of response to treatment, and the high cost.

Anti‐TNF drugs in psoriasis and IBD ‐ Where are we going?

“…TNF-α can be produced by many cell types, including activated monocytes, macrophages, neutrophils, mast cells, dendritic cells, endothelial cells and different T cell subsets. 1 When released from activated cells, this ubiquitous cytokine is capable of stimulating the production of other pro-inflammatory molecules such as interleukins (IL-1, IL-6, IL-8, nuclear transcription factor KB) and adhesion molecules such as ICAM-1, P-selectin and E-selectin 7 and together with these agents, TNF-α can be viewed as a key driver and initiator of cytokine cascades that result in major, chronic inflammation and tissue damage.…”

“…After initial proof of concept, safety and tolerability studies, this novel class of drugs, which currently includes among a growing list of entities, infliximab, etanercept, efalizumab, alefacept, onercept and adalimumab, has been studied in a wide array of inflammatory conditions. 1,8 In the management of rheumatoid arthritis, clinical studies of anti-TNF drugs used alone or in combination with methotrexate have shown consistent improvement in signs and symptoms of disease as well as patient function, with a dramatic D I S E A S E M A N A G E M E N T a n t i -T N F t h e r a p i e s slowing of radiographic damage, such that anti-TNF agents combined with optimal doses of methotrexate are currently considered the best therapeutic regimen for patients who fail to respond adequately to traditional diseasemodifying drugs. 10 Investigation of the therapeutic potential of anti-TNF drugs has to consider their efficacy and safety in equal measure.…”

“…Indeed in recent years the role for anti-TNF therapies in managing diseases characterised by chronic inflammation has become an area of intense interest and study, particularly with regards to the prospects for improved management of dermatological and inflammatory bowel disease states at the severe end of the clinical spectrum. [1][2][3][4][5] Diseases such as psoriasis, Crohn's disease and ulcerative colitis can be extremely debilitating, with a huge impact on patients' quality of life, 6 and until recently the prospects for achieving good symptom control have been limited. In this article we look at the current and future role for anti-TNF drugs in the management of inflammatory dermatological conditions and gastrointestinal diseases.…”

Update upon efficacy and safety of TNF-α inhibitors

“…Two agents are currently utilized in the treatment of AS, infliximab and etanercept, and openlabel trials have demonstrated the efficacy and safety of both these drugs [19,20]. Patients treated with etanercept showed an improvement in the Bath Ankylosing Spondylitis Disease Activity Index ‡ 50% [18]. Furthermore, other open-label trials have demonstrated the efficacy and safety of TNF-a inhibitors for the treatment of Ps and PsA [21][22][23].…”

“…Although TNF-a inhibitors were first developed for patients with RA, they were subsequently also approved for the use in patients with AS. The increased expression of TNF-a in serum and at the sacroiliac joints in patients with AS and the close immunological relationship between spondyloarthropathies and CD were the main reason to consider TNF-a inhibitors as a new therapeutic option for these patients [18,19]. Two agents are currently utilized in the treatment of AS, infliximab and etanercept, and openlabel trials have demonstrated the efficacy and safety of both these drugs [19,20].…”