Anti-TNF therapy in the management of Behcet's disease--review and basis for recommendations

Abstract

Behçet's disease (BD) is a multisystem, chronic-relapsing, inflammatory disorder classified among the vasculitides [ 1 , 2 ]. It has a worldwide distribution being more prevalent in the Middle East, Far East and the Mediterranean basin [ 3 ]. The diagnosis is entirely based on clinical grounds since no pathognomonic laboratory findings exist. International study group classification criteria used for BD patients participating in research protocols depend on the presence of recurrent oral ulceration plus any two of the following: recurrent genital ulcerations, ocular lesions (anterior or posterior uveitis, or cells in the vitreous on slit lamp examination, or retinal vasculitis), typical skin lesions (erythema nodosum, pseudofollicullitis) and a positive pathergy (skin hyperreactivity) test [ 4 , 5 ]. The clinical picture of BD is diverse and while recurrent mucocutaneous lesions are usually the only symptoms at the onset of the disease, most patients develop ocular and/or articular, vascular, central nervous system and gastrointestinal inflammation later on. Vital organ involvement may lead, despite treatment, not only to severe morbidity but also to increased mortality especially among young males [ 1 , 2 , 6 ]. Adequately powered, randomized, controlled clinical trials are few in BD. This is especially true for the use of anti-tumour necrosis factor (TNF) agents, which reportedly result in impressive remissions in BD patients, especially in those with manifestations refractory to conventional treatments. During the last 6 yrs, over 70 publications have appeared in the English literature suggesting that inhibition of TNF actions, using mainly the anti-TNF monoclonal antibody infliximab, is a promising therapeutic approach for this disease. However, the current evidence of therapeutic efficacy is low grade, and there is only one randomized trial available, which assessed the effects of the soluble TNF receptor etanercept in mucocutaneous manifestations and found it to be very effective [ 7 ]. An expert panel meeting was held in May 2006, in order to review the currently available treatment options for BD and the unmet medical needs for those patients with severe disease, and to develop a consensus on the positioning of anti-TNF agents in their treatment. Clinical scientists who have contributed with relevant publications and physicians with specific expertise in BD management participated in the discussion, aiming: (i) to assess the available information on the efficacy of anti-TNF therapies, alone or in combination therapy with currently used regimens, in the treatment of BD; and (ii) to formulate recommendations for optimal use of anti-TNF agents in these patients, filling gaps in evidence with their expert opinion. An extended summary of the discussion and the conclusions reached is presented herein, intended to help physicians in their practice with BD patients. These recommendations do not constitute treatment guidelines but aim to improve the uniformity of clinical practice in the management of BD, until higher grades of evidence are obtained. Several effective anti-inflammatory and immunosuppressive regimens for BD currently exist, but none results in disease cure [ 1 , 2 , 8 , 9 ]. Moreover, the long-term use of these regimens can be associated with significant adverse effects, especially in those patients in whom treatment is introduced at a young age [ 8 , 9 ]. Physicians taking care of patients with BD should be aware that the disease is intermittent in its manifestations in the majority of patients, and that symptoms vary both in their recurrence rate and healing time; accordingly, the therapeutic approach should be strictly individualized. Although the course of BD is unpredictable, spontaneous remissions often occur and the disease may even burn out in some patients with time [ 6 ]. Still, a significant proportion of patients may suffer a progressive disease course resulting eventually in permanent organ damage [ 1 , 6 , 9 ]. No prognostic criteria to identify these patients exist, although there is evidence that young men are at higher risk in general [ 6 ], particularly with respect to losing useful vision, or developing vascular and neurological manifestations [ 10 ], than women. Moreover, there are no established criteria to define the subgroup of patients with severe BD. However, most physicians consider that patients with vital organs at threat, mainly with ocular, parenchymal, neurological and major vascular involvement have severe disease. In addition, some patients with chronic articular and mucocutaneous manifestations, which significantly impair their quality of life, can also be classified as having severe disease. Controlled studies have shown that colchicine [ 11 ], thalidomide [ 12 ], dapsone [ 13 ], azathioprine [ 14 ], interferon-alpha [ 15 ] and etanercept [ 7 ] are effective to some degree in treating various mucocutaneous manifestations in patients who are not intolerant to