Ocular involvement in BD is a diagnostic criteria according to the international study group and also is one of the most frequent manifestation. Non granulomatous type of anterior uveitis sometimes with hypopion or posterior involvement including vitritis, retinal infiltrates, sheathing of retinal veins, occlusive vasculitis, and macular edema are the main presentations of ocular disease. Male patients, especially younger ones, have a worse prognosis and visual loss is more frequent among this group. Current treatment goals for ocular disease are rapid suppression of intraocular inflammation, preservation of vision, prevention of recurrences, and achievement of remission. For patient with posterior uveitis and retinal vasculitis, interferon alpha and TNF alpha blockers have successfully improved the visual prognosis and after the usage of these two agents for refractory cases, blindness is no more a common problem.

With the beginning of the millennium, efficacy of interferon alpha for refractory ocular disease has been reported and in 2008 EULAR has also recommended IFN alpha for patients with refractory disease in the first step. The major adverse effects of IFN alpha are cytopenia and depression.

Kotter I. et al., have reported that 94% of the patients with active uveitis have benefit from IFN alpha in the first 4 weeks and more than half of the patients had long-term remission after 15 months of therapy. Revascularization of the retinal vein and regression of neovascularization were also observed [9] . Deuter C.M. et al., have reported 98.1% response rates INF alpha and 50% drug free remission after 4 years. The recovery in visual acuity was long lived and women had better prognosis. Furthermore, IFN alpha 2a was reported to be more effective than IFN alpha 2b [10] . In a systematic review by Kotter I. in 2004, 338 patient treated with interferon alpha were reviewed and 94% of the patients with uveitis had partial or complete response [11] .

Another important biologic agent for the ocular involvement is infliximab. In a multicenter analysis from Japan, 164 patients with refractory uveitis on infliximab therapy were evaluated and a prominent decrease in number of attacks was provided, as well as a 55% increase in best visual acuity [12] .

Keino H. et al., reported 9 patients with Behçet’s uveitis and stated that infliximab reduced ocular attacks and mean background retinal/disc vascular leakage. Similarly, Kaburaki T. et al., have reported decrease in number and severity of attacks [13] [14] . Okada A.A. and collegues have evaluated the safety of infliximab for uveitis in BD and have reported that infliximab was very effective and also safe for these patients [15] .

Perra D. et al., have used adalimumab for refractory BD and all the 8 patients with Behçets uveitis and retinal vasculitis responded adalimumab rapidly [16] .

Arida A. et al., reviewed the literature for anti-TNF in BD and found that etanercept, adalimumab and infliximab were all effective and safe options for refractory patients with BD [17] . In 2014, the expert panel recommendations were published and both infliximab and adalimumab were recommended as first line therapy for patients with Behçets uveitis and switch between two agents were accepted to be safe and effective to keep remission [18] .

Blockage of IL-1 and 6 may also work in refractory Behçets uveitis because these two cytokines take place in the pathophysiology of the disease but there are no adequate data. Tocilizumab is an IL-6 blocker and have been used for takayasu and giant cell arteritis but not for Behçet uveitis. On the other hand, there are some data showing that tocilizumab has favorable response in NBD [19] .

In conclusion, for refractory ocular disease IFN alpha 2a, infliximab and perhaps adalimumab may be effective treatment options but further trials are necessary with other novel biologic agents.

Neurologic manifestations of BD are not as common as ocular manifestations but are life threatening and may cause severe disability. Therefore, NBD should be treated rapidly and effectively as well. For years high dose corticosteroids and ımmunosuppressive agents were prescribed but novel biologic agents are also effective [7] .

Borhani Haghighi A. et al., reported 4 patients with NBD and 2 patients on 3 mg/kg dose without any adjacent agent had unfavorable results but the other two who took 5 mg/kg dose and monthly cyclophosphamide besides achieved good response [20] .

Kanemura H. et al., reported a patient with good response to infliximab with long-term follow up [21] . Hirohata S. et al., studied the cytokines responsible for the development of NBD and reported that especially IL 6 and 8 levels were increased in the cerebrospinal fluid, which may mean that blockade of these two cytokines may be other future therapies for NBD [22] . Shapiro L.S. and collegue have reported a refractory NBD patient with an excellent response to IL-6 blocker tocilizumab [23] .

Although not adequate, experience with INF alpha is also present for NBD. For dural sinus thrombosis with headache and increase in intracranial pressure a brief course of steroid therapy is recommended [24] . In our study group, all the patients with parenchymal NBD had taken pulse corticosteroid and intravenous cyclophosphamide therapy, and for remission induction and for maintenance of remission other immune-suppressive agents were preferred. Therefore, further trials are necessary and therapy decision must be tailored to the patient’s characteristic features.

Gastrointestinal involvement in BD may be complicated by serious comorbidities, such as gastrointestinal bleeding and perforation, with poor prognosis. For decades high-dose corticosteroids (CSs) and immuno-sup- pressants were widely used for treatments, but refractory or steroid depended entero-BD was difficult to be managed, and effective treatment regimens are necessary. Biologic agents may be an option for these refractory patients.

There are some reports declaring response to infiliximab plus thalidomide or infliximab plus methotrexate for patients with refractory entero-BD and also a small study is also present with infliximab [25] -[31] . On the other hand, case reports with etanercept, interferon and a trial with adalimumab are also present but tocilizumab was not sufficiently investigated for entero-BD [32] -[37] . In our study population, there were only 2 patients with entero-behçets disease and one was treated with infliximab, colchicine and steroid combination and the other one with interferon and azathioprine combination. Both had favorable responses.

Although BD is known as a large vessel vasculitis, all vessels of any size may be affected. Thrombosis and arterials aneurysms are common and anti-coagulation with immune-suppression for venous thrombosis is recommended. For arterial disease high dose corticosteroids with other immune-suppressive agents are necessary [24] .

Schäfer VS has reviewed the literature for biologic agents in large vessel vasculitis and have recommended usage of anti-TNF agents and tocilizumab for refractory patients [38] .

Adler and colleagues reported 7 patients with vascular BD responding to infliximab, three with aortic involve- ment, one with recurrent venous thrombosis of the pelvic veins, one with recurrent venous and arterial thromboses of the thigh, and two with retinal vasculitis. Inflammation has been rapidly suppressed and infliximab was found to be effective for both inducing and maintaining remission in vascular BD and the authors have recommended infliximab for refractory patients with vascular manifestations [39] . Lee et al, in 2010 have tested adalimumab for bilateral pulmonary arterial aneurysm and reported acceptable response [40] .

In our study population, there were 6 patients with arterial involvenment and 17 patients with venous disease. Three of them were treated with intravenous pulse steroid plus cyclophosphamide combination and 3 with high dose corticosteroids plus azathioprine combinations. Patients with venous disease used colchicine, low dose steroids and azathioprine (13/17; 76.4%).

Arthritis in BD is usually mild and non-deforming type of arthritis mostly involving the knee. Colchicine is mostly adequate for arthritis in BD and rarely sulfasalazine and methotrexate with low dose steroid have been used. Biologic agents are very rarely necessary. Donghi D has reported a very refractory patient with arthritis, NBD, uveitis and entero-behçet’s disease treated with infliximab [41] . On the other hand, ankylosing spondylitis may accompany BD and for these patients anti-TNF agents are prescribed but for purely behçets arthritis colchicine is mostly enough. In our study population there were 20 patients with arthritis and 8 of them had accompanying ankylosing spondylitis and other 12 patients were on colchicine therapy (± low dose corticosteroids).