Immunomodulatory drugs for psoriasis

With a prevalence of 2-3%, psoriasis is among the most common skin diseases. Clinical hallmarks comprise erythematous plaques covered by silvery scaling and a chronic recurrent course. Psoriasis is now considered an autoimmune disease in which antigen presentation to cutaneous T helper cells triggers secretion of cytokines, causing proliferation of keratinocytes and expression of adhesion molecules on endothelial cells. These attract additional effector T cells from the circulation, which are then activated in an antigen specific manner, leading to secretion of more cytokines and perpetuation of the process.¹

Although topical treatments are sufficient for many patients, about 20% need additional systemic drugs. All of these bear a considerable potential for serious side effects, such as hepatotoxicity and nephrotoxicity (methotrexate, cyclosporine),²,³ teratogenicity (oral retinoids),⁴ and cancer (PUVA, which is psoralen and long wave ultraviolet radiation; cyclosporine),⁵,⁶ which limits their long term use. The limitations of treatments on the one hand and a growing understanding of the pathogenesis of psoriasis on the other have stimulated much interest in the field of immunomodulation for the management of this chronic disease.

Earlier this year the US Food and Drug Administration approved alefacept for use in psoriasis. Alefacept interferes with the activation of T lymphocytes by blocking the co-stimulator CD2 molecule. It also mediates T cell elimination by inducing programmed cell death. Both mechanisms are believed to contribute to the drug's clinical effectiveness.⁷ The availability of alefacept is a major breakthrough in medical and immunological terms. Not only does it prove clinical effectiveness of a strategy rationally deduced from insights in lymphocyte biology at the molecular level, but many contraindications for established systemic treatments do not apply to alefacept, which facilitates its clinical use.

Alefacept can be regarded as the pioneer of a novel class of selective immunomodulatory drugs for the treatment of psoriasis. Since these are either naturally occurring molecules, such as antibodies and cytokines, or modifications thereof, such as soluble receptors or fusion proteins (as in the case of alefacept), they are referred to as biologics. Well over 40 such compounds are being developed for psoriasis, some of which have already been approved by the Food and Drug Administration for other chronic inflammatory diseases mediated by T lymphocytes—for example, rheumatoid arthritis. Given the very similar pathogenesis of these conditions at the molecular level, several of these drugs may prove effective in the management of psoriasis. Evidence supporting this notion is available for infliximab and etanercept, which are both approved for rheumatoid arthritis. These biologics block the effect of the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) and exhibit profound effects on psoriasis.⁸,⁹ Infliximab is a humanised monoclonal antibody, whereas etanercept represents the soluble tumour necrosis factor-α receptor. All three drugs allow moderate to severe psoriasis to be managed on an outpatient basis, since they are administered once (alefacept) or twice weekly (etanercept), or just three times overall with intervals of several weeks (infliximab). This convenient dosing scheme comes with good tolerability of the drugs. The strategies to block the effects of tumour necrosis factor-α seem to be effective also in extremely severe cases of psoriasis that are resistant to other therapeutic regimens. Numerous other biologics are in advanced phases of clinical development. These employ at least one of four strategies, namely reduction of pathogenic T cells denileukin diftitox, inhibition of T cell activation and migration (efalizumab), correction of cytokine deviation (interleukin 10), or blocking pro-inflammatory cytokines (ABX-IL-8).¹⁰

Biologics are still not perfect drugs. They come with an enormous prize tag, resulting in annual costs for treatment of around €10 000 (£6894; $10 827) per patient per year. Moreover, only a minority of patients (about a third) experience a dramatic and fast clinical improvement when taking these drugs (with the exception of infliximab), whereas others respond rather slowly and moderately, and some do not respond at all. It will be therefore particularly important to develop strategies to identify patients who can expect to benefit from these drugs. Finally, since many of these immunomodulatory compounds still should be considered immunosuppressive, increased risks of infection and reactivation of tuberculosis¹¹ or some lymphomas¹² must be considered in determining the long term safety of these agents.

Biologics have defined modes of action developed by purpose rather than found by chance and will make many patients not qualifying for established systemic treatments eligible to receive exactly this. Understanding their exact mechanisms of action provides the basis for rationally designed rather than empirically generated strategies for combination therapies. On the other hand—with the exception of infliximab—only subgroups of patients with psoriasis show moderate clinical improvement.¹³ The long term safety profile of biologics still needs to be established. Promising new biologics are on the horizon.¹⁴