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New treatments for an old disease
Behçet‘s syndrome, a major cause of posterior uveitis and visual loss in the Third World, has probably existed for more than 4000 years. It is a multisystem, inflammatory disorder whose principal manifestations are oral and genital aphthosis as well as inflammation of the eye, skin, and joints. The principal causes of death are from vascular and neurological involvement. No aetiological agent has yet been identified for the disease; current evidence suggests that the normal flora of mucosal tracts induce immunological hyper-reactivity in genetically predisposed individuals.
The visual prognosis in patients with Behçet‘s disease is poor, the principal cause of visual loss being consecutive inflammatory ischaemic retinal vein occlusions and macular oedema. Treatment is directed at suppressing the inflammatory response using corticosteroids and a variety of second line immunosuppressive agents. Despite different treatment regimens used in different countries the visual prognosis is much the same, with a hard core of 15–20% of patients seemingly resistant to therapy and progressing relentlessly to blindness.1 Randomised trials have shown some efficacy of both azathioprine and cyclosporin A, but the results are only reported in the short term and there is little reliable evidence that they have a substantial effect long term. In this issue of the BJO, Kötter et al (p 423) report their experience using subcutaneous injections of recombinant human interferon alfa-2a for the treatment of this disease in a group of patients resistant to high dose corticosteroids. Remarkably, 40% of their patients were disease free off all medication at 3 years (range 12–72 months), while others were maintained at a low dose of interferon alfa-2a and prednisolone. Reported side effects included a universal flu-like illness at the start of treatment, with leucopenia (40%), hair loss (24%), itching (10%), and depression (8%) also occurring. All side effects were reversible with a reduction in dosage. The development of autoantibodies was noted during treatment, but clinically detectable autoimmune disease (thyroiditis) only occurred in two patients. Certainly, the side effect profile was considerably better than that associated with other immunosuppressive drugs, a fact reflected by the low non-compliance rate in the present study. These results are extremely promising, especially considering that the entry criteria for patients in the study was failure to control disease at doses of prednisolone of 1 mg/kg/day or relapse when the dose was reduced to less than 30 mg/day. Although there are caveats to the study, in that it was an open, non-randomised and uncontrolled trial, the results fully justify the development of prospective, randomised studies.2 Recent pharmaceutical advances have resulted in a formulation of interferon alfa that need only be given once a week (IFN-PEG), and other even longer acting formulations are in the pipeline, which hopefully will improve patient acceptability and the side effect profile even further.
It is currently unclear how interferon alfa works in this clinical scenario. The drug is widely used as a myelosuppressive agent in the treatment of a variety of haematological malignancies and has found a place in the alleviation of chronic hepatitis C. Suggested mechanisms include the enhancement of a type 1 (Th1) responses by T cells as well as upregulation of MHC class I expression on cells. Both these mechanisms serve to aid viral clearance after infection and herpes virus has been proposed as an aetiological agent in Behçet‘s disease. Furthermore, interferon has recently been shown to inhibit γδ+ T cells which have been implicated in the initial lesions of Behçet‘s disease.3 Paradoxically, there are reports of a Behçet‘s-like syndrome occurring in patients treated with the drug for chronic myeloid leukaemia, possibly by increasing neutrophil reactivity. Clearly, further work is required to elucidate the exact mechanisms involved.
Behçet‘s disease has existed for thousands of years but we are still ignorant of its pathogenesis and treatment
Other treatments for Behçet‘s disease are being tested. Currently, there is considerable interest in the potential role of anti-tumour necrosis factor (TNF) antibody therapy. TNF has been implicated in Behçet‘s disease, in that patients show higher serum levels of the cytokine than controls. TNF genetic polymorphisms that predispose to greater stimulated production of TNF from monocytes are associated with worse disease and drugs such as thalidomide and pentoxifyline, which are potent anti-TNF medications, are very effective in certain forms of the disease, particularly mucosal ulceration. Early results with the monoclonal antibody against TNF have shown benefit in ocular,4 orogenital,5 and gastrointestinal6 Behçet‘s disease, but long term efficacy is unknown.
Behçet‘s disease has existed for thousands of years but we are still ignorant of its pathogenesis and treatment. We do not know what causes it, why certain populations are more susceptible, why men tend to get worse disease, why it burns out in later life, and what is the best treatment. Much work remains to answer these questions and to devise specific therapy. However, new treatments are in development and hold promise for the future especially in those patients who do not respond to conventional therapy.
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New treatments for an old disease