New biological drugs might be useful in the treatment of alopecia areata

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  Biological Drugs for the Treatment of Alopecia Areata
 

It is now well established that alopecia areata is a T- cell mediated autoimmune disease. Its genetic molecular and cellular features are now fairly well known. Alopecia areata, like other autoimmune diseases, is associated with specific leukocyte antigens, which determine susceptibility, severity, chronicity and resistance of the disease. New biological drugs that have been developed or are under development for other autoimmune diseases will very likely be effective in alopecia areata also.

Biological agents are proteins, which have pharmacologic activity and can be extracted from tissue. Today using recombinant DNA technology large quantities of biological agents can be synthesized for specific action. Biological agents target cell surface receptors. They have the theoretical advantage of more specificity, thus, ensuring greater safety. Biologics are larger than “small molecule” drugs and are administered by injections.

The T-cells are activated by two signals between T-cells and antigen presenting cells or APCs. Several interactions have to follow these signals for the onset of the disease. The biological drugs target the molecules involved in these interactions to block T-cell activation.

Four such drugs are discussed below. They are etanercept, infliximab, efalizumab and alefacept. These drugs were originally developed for arthritis, psoriatic arthritis, Crohn’s disease and psoriasis. They are untested in alopecia areata but since medications used in these diseases have also been effective in alopecia areata, clinical trials are in order in alopecia areata.

Etanercept: Etanercept is FDA approved drug for treating rheumatoid arthritis, juvenile rheumatoid arthritis and psoriatic arthritis. It is a human fusion protein that inhibits the inflammatory cytokine TNF-alpha. It is subcutaneously injected twice a week and shows promise in treating psoriasis. In psoriasis it had good safety margins but its long-term safety is yet to be determined.

Infliximab: Infliximab is also a TNF-alpha inhibitor and a FDA approved drug for treating rheumatoid arthritis and Crohn’s disease. Controlled clinical trials in psoriasis have demonstrated its rapid effect. The drug is given by intravenous injection over 90 minutes.

The long-term effects of TNF-alpha inhibition are being studied. Rare cases of side effects like tuberculosis activation, multiple sclerosis, positive antinuclear antibodies and lymphoma have been reported. Most patients with such side effects were on concomitant immunosuppressive treatment for rheumatoid arthritis and Crohn’s disease but no link was found between these events and TNF-alpha.

Efalizumab: Efalizumab is a humanized monoclonal antibody that has potentially several positive effects for alopecia affected patients. It binds CD11a, a component of LFA-1 that binds to ICAM-1 on APCs thereby disturbing this costimultory signal. It also blocks T-cell adhesion to endothelial cells and T-cell migrations into inflamed tissues. Measured by the Psoriasis Activity and Severity Index the 62% of the patients showed 50% improvement and 30% showed 75% improvement. These clinical did not report any serious side effects. There were reports of only some mild flu like symptoms, which were effectively treated by drugs. Efalizumab is injected subcutaneously, once a week, by the patient. FDA approval has been applied for.

Alefacept: Alefacept is a fusion protein that brings about apoptosis in T-cells manifesting high CD2 levels. It can also block the costimulatory signal between LFA-3 and CD-2. Alefacept also depletes the high CD2- expressing memory cells in circulation. Treatment with alefacept requires monitoring of CD4+T cell count. It has received FDA approval for treatment of psoriasis. In phase II trials on psoriasis it showed excellent results with very good safety margins.

In one of these psoriasis clinical trials, measured by PASI, 71% of the patients showed 50% or more improvement and 40% of them had 75% or more improvement. There were no reports of any side effects or infections. There was eight months remission in the case of some patients, which may be due to slow regeneration of the skin with T-cells. This drug is administered either intramuscularly or by an intravenous bolus or push.

Future Therapies

The four drugs discussed will certainly be available for treatment some time in the near future. Hopefully more effective drugs are now in the conceptual stage. We will now briefly discuss about the strategies that are adopted to treat alopecia areata.

Reduction of pathogenic T-cells: It is known that bothCD+4 and CD+8 T-cells are required to interact to cause onset of alopecia areata. Therefore drugs are being developed to deplete any of these two types of pathogenic T-cells.

Inhibition of T-cell activation and migration: In mouse, blocking of T-cell activation by CTLA4Ig delayed the onset of alopecia areata. CTLA4Ig is undergoing clinical trials for psoriasis and a similar trial for alopecia areata is expected.

Also in mouse, the anti-CD44V10 monoclonal antibody has been effective in stopping T-cell migration. CD44V10 is a lymphocyte cell surface receptor found on T-cells of alopecia areata affected skin. Therefore, using anti-CD44V10 may be a future treatment strategy for alopecia areata.

Shifting type I cytokine response to type II response: Before treatment, alopecia areata expresses type I cytokine response and post treatment with a contact sensitizer IL-10, a type II cytokine expression is observed. It is also believed that hair follicles are not destroyed in alopecia areata due to a shift from type I to type II cytokine response. IL-10, therefore holds promise as a possible future therapeutic agent for treating alopecia areata.

Results from initial trials were not positive. Recently, however, IL-4 therapy, which also produces type II response, on psoriasis patients showed significant improvement in their condition. IL-4 therapy therefore has the potential to treat alopecia areata, which shows type I pattern.

Blocking inflammatory cytokine activity: The strategy here is to selectively target inflammatory cytokines. Two TNF-alphas were discussed earlier. In psoriasis the expression of the cytokine IFN-gamma is increased. Presently, humanized monoclonal antibody is going through clinical trials. It is hoped that the trials are successful because global immune suppression is not possible by blocking this cytokine.

Conclusion

Alopecia areata is a T-cell mediated autoimmune disease and shows type I cytokine response. The biological drugs developed or under development will use the strategy of targeting specific immunological responses. This it is hoped will see the emergence of new methods of treatment for these pathogenic T-cells and the cytokines they produce.



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