key: cord-1021298-rdbypcxk
authors: Alibaz-Oner, Fatma; Direskeneli, Haner
title: Advances in the Treatment of Behcet’s Disease
date: 2021-05-20
journal: Curr Rheumatol Rep
DOI: 10.1007/s11926-021-01011-z
sha: a9d68fd79d0757972b9677206cf1d5319c730f18
doc_id: 1021298
cord_uid: rdbypcxk

PURPOSE OF REVIEW: To assess current management of Behcet’s disease (BD). Controversies on therapeutic approaches to different manifestations, whether conventional immunosuppressives (IS) or biologic agents, should be chosen, and options for refractory disease are discussed. RECENT FINDINGS: Glucocorticoids are still the main agents for remission-induction and azathioprine the first-line conventional IS in maintenance phase to prevent relapses of major organ involvement. Apremilast is shown to be a safe and effective option approved by the FDA for oral ulcers. Large case series confirmed the efficacy and safety of TNFα inhibitors and Interferon-α. Promising results are observed with IL-1 inhibitors, ustekinumab, secukinumab, and tocilizumab for refractory BD. SUMMARY: Although both conventional IS and biologic agents are effectively used to suppress inflammation in BD, there is still an unmet need for clear therapeutic strategies in the management for different manifestations. Further controlled studies with new biologic agents, anticoagulants and the benefit of concomitant IS usage with biologics are needed to optimize the management of BD.

Behcet's disease (BD) is a chronic, multisystemic, inflammatory syndrome characterized by recurrent attacks of oralgenital ulcers, skin lesions, and ocular, musculoskeletal, vascular, central nervous system (CNS), and gastrointestinal (GI) involvements (Table 1) . Despite optimal immunosuppressive (IS) treatments, relapses are common, and disease-related damage develop in a significant subgroup of patients, especially in ones with ocular, vascular, and neurological involvement. Young males are the group with the highest risk of morbidity and mortality [1] . As a multi-systemic disorder, management of BD requires a thorough evaluation of the se-verity and damage risk of different manifestations in each patient visit.

Colchicine, non-steroidal anti-inflammatory drugs (NSAIDs) and topical/low-dose oral treatment with glucocorticoids (GC) are often sufficient for mucocutaneous (MC) and joint involvement, whereas major organ disease such as ocular, vascular, neurological, and gastro-intestinal manifestations are treated with long-term immunosuppression. However, each manifestation has its own subsets of "mild vs severe" forms such as anterior vs posterior uveitis/retinitis or dural sinus thrombosis vs parenchymal neurological disease. Careful assessment of long-term damage risk is thus essential to determine the duration of treatment, choice of IS agents, and an adequate protection of patients from GC-associated drug toxicities.

The pathogenesis of BD is poorly understood. As activation of neutrophils and monocytes leading to interleukin-1 (IL-1) release is observed, BD is accepted by some as an autoinflammatory disease. However, autoimmune T-cell responses and spondyloarthropathic features are also observed [2] . In the light of recent data elucidating the pathogenesis, biologic treatments targeting proinflammatory cytokines or intra-cellular pathways are important new therapeutic options for BD. In this review, we aimed to summarize the current treatment approaches in light of recent studies and personal experiences of a tertiary Behcet's Center. This 

Most mild forms of major organ involvement are sufficiently controlled by conventional ISs (cISs) such as GCs, azathioprine, cyclosporine A, and mycophenolate mofetil (MMF).

Comparative controlled data, especially in uveitis patients, show the efficacy of cISs as the first-line treatment also in severe major organ involvement [3] . However, there is currently limited data on the role of cISs in routine practice, leading to an overuse of biologics especially for mild major organ disease. In our series, 59% of patients with BD uveitis are treated with cISs such as azathioprine and cyclosporine A, with GCs used as necessary "bridging" therapy [4] . Although widely used as low dose (5-10 mg/day prednisolone) for MC manifestations and high-dose (0.5-1 mg/kg/day prednisolone)/pulse (0.5-1 g methylprednisolone) regimens for remission-induction of major organ disease, studies on the optimal dose and duration of GCs, as well as the extent of GC-associated damage are limited with controversial results in BD [5, 6] . Interestingly, in a validation cohort of a recently developed Behcet's syndrome overall damage index (BODI), "ever use of GCs" are not found to be associated with overall damage score [7] . This surprising observation either reflects the young age and overall lack of comorbidities in BD population or the limitation of the tool to adequately assess GC-related damage. Azathioprine, a cornerstone of mild major organ involvement, is also possibly efficacious for the prevention of the most new-onset major organ BD in patients with mucocutaneous onset, such as gastrointestinal involvement, anterior uveitis, or venous vascular disease, and can be a prophylactic agent [8] (unpublished observations).

Although randomized-controlled trials (RCT) are lacking, many biologic agents targeting proinflammatory cytokines, such tumor necrosis factor alpha (TNFα), IL-1, IL-6, IL-12, and IL-17 licensed for other rheumatological disorders, became part of the treatment choices in BD. A broad consensus emerging from the case series and few RCTs suggest that TNFα inhibitors and Interferon (IFN)-α are effective for the most common major organ involvements in BD, namely, ocular and vascular disease. Among TNFα inhibitors, monoclonal antibodies are more effective than the soluble forms-similar to the situation in inflammatory bowel disease.

A recent controversial issue of biologic use is the "optimization" of advanced therapies in BD before discontinuation. Among biological agents, both infliximab (IFX) and IFNα have flexibilities for dose adjustment in both remissioninduction and maintenance use. IFX is usually started at 3-10 mg/0-2-6 weekly and then every 4-8 weeks. In a recent study, after complete remission, IFX dose was decreased to 3-5 mg/kg every 8-12 weeks with similar outcomes as compared to the standard regimen of 5 mg/kg every 8 weeks. The authors calculated a 51% annual cost reduction by dose reduction [9] . Similarly, our group suggested a low-dose remission-induction (3 million IU/day-14 days) and maintenance (3 million IU/3 weekly) regimen with IFNα, with dose escalations if necessary [10] .

Recently, biosimilars are also used in BD patients. Although a first study has shown a loss of efficacy in 3 patients after switch to an IFX biosimilar, subsequent studies reported good efficacy and safety profile of IFX biosimilar after a start or switch from the originator [11] [12] [13] [14] .

Some of the critical questions that are unresolved in BD management are similar to other multi-systemic disorders such as systemic lupus erythematosus and vasculitides. These are the duration and choice of treatments for remission-induction, duration/discontinuation of therapies during remission, "treat-to-target" strategies and whether GC can be stopped early.

Finally, although biologic agents seem to be safely continued in the COVID-19 era in rheumatological disorders, the reluctance of patients and physicians to start new biologics due to safety concerns require a careful approach in decisions of switching from cISs to biologics, especially in mild forms of organ involvement in BD patients [15] .

Our expert-opinion approach to the management of different organ manifestations in BD is summarized in Table 2 . 

Behcet's disease usually starts with mucocutaneous manifestations which have a limited impact on vital organ functions and general quality of life (QoL). Despite conflicting results of controlled studies, colchicine alone or combined with shortterm topical GCs is considered as the first-line treatment for oral/genital ulcers and nodular-type skin manifestations in daily practice due to its safety and tolerability. Similarly, "2018 EULAR recommendations for the Management of BD" suggests topical GCs/colchicine as first-line of treatments for oral/genital ulcers, papulopustular, and acne-like lesions [16••] . This safe approach, however, leads to an insufficient suppression of mucocutaneous symptoms. Up to 60% of the patients followed in our cohort had at least one oral ulcer in the last month before each clinical visit, demonstrating the "unmet need" in routine practice [17] . A close look at especially oral-QoL studies also suggest that patients are usually uncomfortable with their frequency of oral ulcers under colchicine/ topical treatments. Although a study with depo methylprednisolone preparation did not show any benefit on oral/genital ulcers [5] , a significant subset of patients with oral ulcers can be managed with oral low-dose prednisolone (<7.5 mg/day) intermittently in our clinic with favorable results (unpublished observations).

Thalidomide is not used in daily practice due to its side effects, especially irreversible neurotoxicity even at low doses. Among TNFα inhibitors, only etanercept was studied in a randomized controlled, 4-week trial in male BD patients and significantly decreased the number of oral ulcers and erythema nodosum-like lesions compared to placebo [18] . Several observational studies and case series also confirmed the beneficial effects of IFX and adalimumab (ADA) on mucocutaneous lesions [19] . According to these data, TNFα inhibitors can be considered for resistant MC lesions in BD [16••] .

Apremilast, an oral phosphodiesterase-4 inhibitor, was observed to be effective in suppressing oral ulcers in a phase 2 study [20] . A phase 3, multicenter, placebo-controlled 52week study which included 207 patients with BD who had active ulcers (but no major organ involvement) confirmed the efficacy of apremilast 30 mg/bid [21••] . No major differences were observed between the groups for serious side effects, but diarrhea, nausea, and headache were more common in the apremilast group. Apremilast is now approved by the FDA for oral ulcer treatment in BD patients. Recent case series supported the efficacy of apremilast in real life; however, 28% (7/25) of patients stopped apremilast due to side effects [22, 23] . Apremilast-colchicine combination also seemed to work well in a recent observational study [24] . With a good safety profile without an increase in infections and malignancies, apremilast may become the second-line choice after colchicine for MC manifestations of BD in countries where it is reimbursed. However, the high cost of the original molecule may influence its approval by reimbursement authorities for only MC manifestations in some countries until generic forms become available. Present data do not allow any conclusions [25, 26] . In a study by Grayson et al., complete (n=2) or partial responses (n=3) were observed in 5 of 6 patients with anakinra 200 mg/day in 6 months. Increasing anakinra to 300 mg/day did not result in further improvement [27] . In another study of 36 patients, flares during long-term (> 12 month) treatment were frequent for MC symptoms [28•] . In two open-label prospective studies, ustekinumab, a humanized monoclonal antibody targeting IL-12/IL-23, appeared to be effective for the treatment of oral ulcers in patients with BD resistant to colchicine [29, 30] . According to other case reports, tocilizumab seems to be ineffective for MC manifestations or might even lead to paradoxical exacerbations [31, 32] . A retrospective case series reported that secukinumab may be safe and effective for the treatment of patients with MC and articular involvement [33•] .

Our first choice for refractory oral ulcers, however, is still azathioprine, as it might also decrease the risk of new major organ involvement with a good safety profile. Other MC symptoms such as genital ulcers and follicular and nodular lesions are either responsive to colchicine, antibiotics, or low-dose GCs or do not relapse frequently (azathioprine is rarely required).

Management of leg ulcers associated with deep vein thrombosis and chronic arterial ischemia should be planned with experienced dermatologists and vascular surgeons, since evidence is currently limited to expert opinion. Treatment options include ISs (especially when leg ulcers are associated with pyoderma gangrenosum), antibiotics if infection is present, debridement, or occlusive measures.

Joint involvement in BD is usually monoarticular, non-erosive, and present with self-limiting attacks of short duration. Intra-articular GCs may help in acute monoarticular disease. Most patients with articular BD are responsive to colchicine, sulfasalazine, or methotrexate. Rare cases necessitating biologics have usually a spondyloarthropathic like course with axial involvement. TNFα inhibitors should be chosen first in these cases. INFα, anti-IL-1 therapies, or secukinumab may be tried in further refractory cases.

Azathioprine or cyclosporine A are traditionally first-line treatment options for the treatment of ocular involvement since their efficacy for protecting visual acuity and preventing uveitis relapses were confirmed in RCTs [34] [35] [36] [37] . INFα is a widely used alternative for the treatment of ocular involvement [38, 39] . INFα have immunomodulatory effects in BD with suppression of Th17 cells, increase of IL-10 expression, and recovery of Treg function [40•] . In a literature review, IFNα was found effective for all manifestations of BD. Almost all (94%) patients with ocular involvement achieved partial or complete remission within 2-4 weeks of IFNα treatment. Complete remission rate was better in patients treated with higher (> 3 million IU) IFNα dosages [41] . In long-term follow-up studies (mean 8 years), at least half of patients with ocular involvement remained in remission for 5 years of follow-up after the discontinuation of IFNα (usually with 2 years of treatment) [42, 43] . In a prospective head-to-head RCT comparing IFNα with cyclosporine A, IFNα was better in ocular remission rates, maintenance of visual acuity, and improvement of posterior uveitis score [44] . Recently, comparisons of IFX vs IFNα are also published revealing a similar efficacy of both drugs for uveitis [45, 46] . There are also some open-label cases showing the efficacy of pegylated IFNα in BD uveitis [47, 48] . Discontinuation of standard IFNα production by pharmaceutical industry and advantage of weekly use may lead to pegylated IFNα use in routine practice. Flulike symptoms, depression, leukopenia, thrombocytopenia, alopecia, and transaminase elevations are reported as side effects with IFNα.

IFX and to a lower extend ADA have been used in open studies and case series revealing a lower relapse rate and reduced GC dosage in BD patients with ocular involvement [49] [50] [51] [52] . A literature review on TNFα inhibitors showed a sustained response in 89% of patients with uveitis treated with IFX and in all patients with ADA [19] . Two RCTs reported the efficacy of ADA in patients with non-infectious uveitis [51, 53] . ADA has been approved for the treatment of noninfectious intermediate, posterior, and panuveitis by the European Medicines Evaluation Agency and Food and Drug Administration based on these RCTs. However, these studies included few BD patients, and the data of BD patients was not reported separately.

There are also some studies comparing the responses of IFX vs ADA for ocular involvement in BD [54] . In a multicenter, observational study including 160 patients, IFX and ADA were found equally effective [55] . In another study of 177 patients from Spain, patients receiving ADA had significantly better improvement in vitritis and best-corrected visual acuity than those receiving IFX. Improvement in retinal vasculitis, however, was similar in both groups. The drug retention rate was also higher in the ADA group [56•] . Other studies confirmed the efficacy and safety of IFX [57] and ADA [51] for the treatment of ocular involvement. Discontinuation of IFX after remission is also possible. In one study, 32% were able to discontinue IFX after 20 months of treatment and had only 12.5% relapse rate in 38 months of follow-up [58] . Two studies also reported that early initiation of IFX (<18 months) in BD uveitis led to better outcomes of ocular involvement in BD (best-corrected visual acuity 100%) [59, 60] .

Observational studies reported that IL-1 inhibition can be an effective and safe option for the treatment of refractory ocular involvement in BD [61] [62] [63] . In an open-label pilot study and a randomized phase 2 trial, XOMA-052 (gevokizumab), a recombinant humanized anti-interleukin-1β antibody, provided a rapid response and decreased ocular inflammation in BD patients refractory to cISs [64, 65] . In the phase 3 trial, however, gevokizumab did not reach the primary end-point which was "the time to the first acute ocular exacerbation" [66] . There are also some data indicating the possible efficacy of tocilizumab [67, 68] , rituximab [69] , and alemtuzumab (humanized monoclonal antibody against CD52) in refractory ocular involvement in BD patients [70] .

Ocular involvement contributes most to the morbidity in BD. Despite IS treatments, up to 15% of the patients with uveitis may still have severe vision loss in recent series. Early onset (< 25 years of age) and male gender are the main risk factors for disease severity. Therefore, close collaboration with an expert ophthalmologist is essential for early diagnosis and treatment initiation. All BD patients should be seen by an ophthalmologist at the onset and at regular intervals of 1-2 years even without ocular symptoms, especially during the first 5-10 years of diagnosis. According to 2018 EULAR recommendations for the management of BD, "any ocular BD patient presenting with posterior segment involvement should be treated with systemic GCs in combination with systemic ISs including azathioprine, cyclosporine A, IFNα or monoclonal TNFα inhibitors. If the patient has initial or recurrent acute sight-threatening uveitis, IFX or INFα in combination with high-dose systemic GCs are recommended. Intravitreal glucocorticoid injection can also be added to the systemic regimen especially in unilateral cases. In patients presenting with isolated anterior uveitis, topical agents are often beneficial, but systemic ISs may be needed when hypopyon is present or when patients are at high risk for ocular disease progression (young male patients with earlyonset disease)" [16••] .

Vessel-wall inflammation (vasculitis) is the primary pathology of vascular involvement in BD requiring ISs in the vast majority of cases. Recently, increased venous vessel-wall thickness is shown with Doppler US assessment in femoral and other lower extremity veins and suggested as a diagnostic test for BD [71•] . However, there are no controlled studies of ISs in vascular BD. In an early RCT of ocular disease, vascular and neurological involvement was less present among patients who had been treated with azathioprine [8] . Retrospective case series also confirmed the beneficial effects of azathioprine on vascular inflammation [72, 73] . In a recent prospective, uncontrolled study comparing azathioprine with IFNα, the relapse rate was lower and recanalization rate higher with IFNα [74•] . Another retrospective study comparing biological treatments and cISs including azathioprine, cyclosporine A, and cyclophosphamide in patients with vascular involvement indicated that vascular relapse rate was lower in patients treated with ADA-based regimens compared to patients treated with cISs [75] . TNFα inhibitors seem to be effective treatment options in all types of refractory vascular involvement of BD [76] [77] [78] [79] . There are limited data suggesting the efficacy of other biological agents such as anakinra [26] , alemtuzumab [70] , and tocilizumab [80] in refractory cases. Tofacitinib was also reported to lead to a favorable outcome in patients with BD-related vasculitis [81] .

There is no consensus for the use of anticoagulant, antiplatelet, or antifibrinolytic agents in vascular BD. Data for anticoagulation comes from retrospective studies only. In a large vascular BD cohort from France with 99% anticoagulation, 63% GC, and 47% IS use, only ISs are associated with lower venous relapse rate in multivariate analysis [73] . Although 15% of patients in this cohort had arterial aneurysms (8 of which were pulmonary), only 2% of patients had hemorrhagic complications. In a multi-center study from Turkey, the relapse rate was similar between patients using ISs vs those receiving anticoagulants plus ISs [82] . A meta-analysis of three retrospective studies also showed that ISs and anticoagulants are superior to anticoagulants alone (RR 0.17), and adding anticoagulants to ISs provided no additional benefit (RR 0.75) [16••] .

According to EULAR 2018 recommendations, GCs and ISs such as azathioprine, cyclophosphamide, or cyclosporine A are recommended for the management of acute deep venous thrombosis (DVT) in BD. Monoclonal TNFα inhibitors can be considered in refractory patients. For the management of arterial aneurysms and/or occlusion, cyclophosphamide and high-dose GCs are recommended. As a general approach in daily practice, life-threatening conditions such as pulmonary arterial aneurysms and Budd-Chiari syndrome are managed with more aggressive medical treatments including cyclophosphamide and GC pulses. Monoclonal TNFα inhibitors should be considered in refractory cases. Anticoagulants are not routinely recommended due to fatal bleeding risk from coexisting pulmonary arterial aneurysm. They can be added to ISs provided the risk of bleeding is generally low and coexistent pulmonary artery aneurysms are ruled out [16••] .

Neurologic involvement manifests either as parenchymal involvement or cerebral venous sinus thrombosis (CST). Both types are rarely seen together in the same patient. When a patient is diagnosed with CST, the patient should be screened for other vascular sites especially for DVT, as extraneurologic vascular involvement is frequently present (62.5% in one series) in these patients [83] . No controlled studies are present for the management of neurologic involvement in BD (NBD). According to EULAR 2018 recommendations, azathioprine and daily IV GC pulses (up to 7 day) are usually prescribed as first-line treatment of an acute attack of parenchymal involvement. There are increasing data indicating efficacy of both IFX and ADA in refractory NBD [84] [85] [86] . TNFα inhibitors should be used for relapsing or refractory patients and patients with chronic progressive neurologic involvement. For the treatment of CST, high-dose GCs and a short 6-month course of anticoagulation are recommended [16••] . Azathioprine should be the first choice of maintenance treatment in these patients with CST.

Treatment with IV pulse cyclophosphamide, which is considered first-line option in primary CNS vasculitis, led to a lower relapse rate in NBD as compared to azathioprine but only during the first year of follow-up. After up to 10 years of follow-up, there was no difference between IV pulse cyclophosphamide and azathioprine anymore [87] . Event-free survival was also similar among patients receiving cyclophosphamide, azathioprine, or GSs alone [88] . A meta-analysis of observational studies revealed that cyclosporine A increased the risk of neurologic involvement in uveitis patients (RR: 12.7). Therefore, EULAR recommends avoiding cyclosporine A in BD with neurologic involvement. In small retrospective case series, tocilizumab was also reported as an effective treatment option in refractory NBD patients [89] [90] [91] . There are also a few case reports suggesting effectiveness of intravenous immunoglobulins and rituximab in refractory NBD [92] [93] [94] .

Treatment approaches for the management of gastrointestinal disease in BD are based on retrospective observational studies or extrapolations from studies on inflammatory bowel disease since there are no controlled trials. 5-aminosalicylic acid (ASA) derivatives with/without GCs are suggested as firstline treatment options for mild GI involvement in BD [95] . Azathioprine is used as the first-line treatment in more moderate-severe cases and as an alternative in patients who are refractory to 5-ASA derivatives [96] . Azathioprine also reduced the relapse risk after surgical interventions [97] .

In an open-label uncontrolled study including patients with refractory GI involvement, ADA led to the improvement of symptoms and to a reduction of endoscopic findings in most patients. Complete remission was achieved in 20% of patients after 52-week follow-up [98] . In another open-label study, IFX induced clinical improvement and resulted in a decrement of inflammatory markers within 2 weeks [76] . Many case series have confirmed that treatment with either IFX or ADA achieved complete remission rates of 20-64% in patients with refractory GI involvement [86, [99] [100] [101] . Data for IL-1 and IL-6 inhibition for the treatment of this manifestation are limited to case reports [26, 63, 102] .

With similar efficacies, safety issues may affect the choice of treatment especially between TNFα inhibitors and IFNα in BD patients with refractory major organ involvement. Possibly due to concomitant high-dose GCs, opportunistic infections, especially tuberculosis, are more commonly observed in BD patients under TNFα inhibitors compared to patients with other rheumatological disorders (7.5% vs 0.8% in our series, 3.9% vs 0.9% in a literature summary of 4 series) (unpublished observation). This issue is important in countries with a high background rate of tuberculosis prevalence and require careful scrutiny of latent-tuberculosis in these patients.

IFNα do not seem to increase the risk of infections. However, constitutional symptoms, especially with daily high doses during remission-induction phase, lead to a poor QoL and high drug discontinuation rates in BD patients. A higher incidence of depression is also reported when using IFNα [103] . No new safety signals are reported with other biological agents.

BD patients have a higher risk of malignancies, especially hematological (RR: 2.58) and thyroid cancers (RR: 1.25) [104] . Interestingly, azathioprine is associated with a lower cancer risk in BD patients. This observation may be explained by selection (funneling) bias, as azathioprine is used more in mild cases, whereas biologics are preferred in patients with severe disease manifestations [104, 105] . Among cISs, cyclophosphamide should be reserved for remission induction in patients with severe arterial disease due to its high teratogenicity and risk for causing malignancy [106] . Hepatotoxicity, cytopenias, and gastro-intestinal intolerance are among the main limitations of cIS use; however, their relative safety for infections is important for long-term management decisions.

Oral health is impaired in BD patients, and oral ulcers affect oral quality of life [107] . Oral health is also a mediator of disease severity [108] . Modulation of oral health by dental/ periodontal treatments improve oral health in BD patients and decrease the number and duration of oral ulcers [109] . Therefore, all BD patients should be encouraged to have routine oral examinations in addition to urgent dental/periodental care. In cases where standard oral interventions are not feasible or sufficient, short-term macrolide treatment (azithromycin 500 mg/3 days) might decrease both periodontal infections and oral ulcers [110] .

There are only a few RCTs in BD, mostly conducted in patients with mucocutaneous and/or ocular involvement. There are no RCTs for vascular, neurological, and gastrointestinal disease. Apremilast is now accepted as a new safe and effective treatment option for oral ulcers and is approved by the FDA. Azathioprine is still the first-line conventional IS agent for both major organ disease and refractory mucocutaneous involvement. Increasing data coming from large case series confirmed both the efficacy and safety of TNFα inhibitors for refractory major organ involvements such as ocular, vascular, neurological, and GI disease. In refractory ocular and vascular disease, long-term studies also confirmed the efficacy and safety of IFNα. There are quite promising results with anakinra and ustekinumab for the treatment of refractory mucocutaneous disease. IL-1 inhibitors and tocilizumab may be alternatives in patients with refractory ocular involvement. Further randomized controlled studies with biologic agents are needed for the assessment of efficacy, safety, and optimal treatment duration in BD. Also the role of anticoagulants for vascular disease and the benefit of concomitant IS usage with biologics should be investigated in BD.

Conflict of Interest Haner Direskeneli participated in the phase 3 study of apremilast by Celgene as a local Principal Investigator. Fatma Alibaz-Oner declares that she has no conflict of interest.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study

Safety and efficacy of gevokizumab in patients with Behçet's disease uveitis: results of an exploratory phase 2 study

Use of gevokizumab in patients with Behçet's disease uveitis: an international, randomized, double-masked, placebocontrolled study and open-label extension study

Anti-interleukin 6 receptor tocilizumab in refractory uveitis associated with Behçet's disease: multicentre retrospective study

Tocilizumab for the treatment of Behçet uveitis that failed interferon alpha and antitumor necrosis factor-alpha therapy

Rituximab in intractable ocular lesions of Behcet's disease; randomized single-blind control study (pilot study)

Alemtuzumab as remission induction therapy in Behçet disease: a 20-year experience

Femoral vein wall thickness measurement: a new diagnostic tool for Behcet's disease. Rheumatology (Oxford). 2020. Study demonstrating a high sensitivity and specificity of Doppler US to measure venous-wall thickness in BD

Vascular involvement in Behçet's syndrome: a retrospective analysis of associations and the time course

Immunosuppressants reduce venous thrombosis relapse in Behçet's disease

Clinical course of acute deep vein thrombosis of the legs in Behçet's syndrome

Adalimumab-based treatment versus disease-modifying antirheumatic drugs for venous thrombosis in Behçet's syndrome: a retrospective study of seventy patients with vascular involvement

Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients

Efficacy of TNFα inhibitors for refractory vascular Behçet's disease: a multicenter observational study of 27 patients and a review of the literature

Infliximab treatment in refractory vascular Behcet's disease: a single-center experience

Tocilizumab in the treatment of severe and/or refractory vasculo-Behçet's disease: a single-centre experience in China

A pilot study of tofacitinib for refractory Behçet's syndrome

Behçet disease with vascular involvement: effects of different therapeutic regimens on the incidence of new relapses

Cerebral venous thrombosis in Behçet's disease

Infliximab is a plausible alternative for neurologic complications of Behçet disease

Efficacy of anti-TNFα in severe and refractory neuro-Behcet disease: an observational study

Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: multicenter study of 124 patients

Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations

Long-term outcome of neuro-Behçet's disease

Tocilizumab for severe refractory neuro-Behçet: three cases IL-6 blockade in neuro-Behçet

Refractory neuro-Behçet treated by tocilizumab: a case report

Tocilizumab treatment for neuro-Behcet's disease, the first report

Efficacy and safety of intravenous immunoglobulin treatment in refractory Behcet's disease with different organ involvement: a case series

Rituximab is effective in severe treatment-resistant neurological Behçet's syndrome

Neuro-Behçet's disease presenting with tumour-like lesions and responding to rituximab

Long-term clinical outcomes and factors predictive of relapse after 5-aminosalicylate or sulfasalazine therapy in patients with intestinal Behcet disease

Clinical outcomes and prognostic factors for thiopurine maintenance therapy in patients with intestinal Behcet's disease

Characteristics, treatment, and long-term outcome of gastrointestinal involvement in Behcet's syndrome: a strobe-compliant observational study from a dedicated multidisciplinary center

Adalimumab for the treatment of Japanese patients with intestinal Behçet's disease

Long-term outcomes and predictors of sustained response in patients with intestinal Behcet's disease treated with infliximab

Long-term safety and efficacy of adalimumab for intestinal Behçet's disease in the open label study following a phase 3 clinical trial

Efficacy of infliximab in intestinal Behçet's disease: a Korean multicenter retrospective study

A case of refractory intestinal Behçet's disease treated with tocilizumab, a humanised anti-interleukin-6 receptor antibody

Interferon alfa-associated depression in patients with Behçet's syndrome: a prospective controlled study

Cancer risk in Korean patients with Behçet's disease: a nationwide populationbased study

Cancer incidence in Behçet's disease

Long term follow-up of Behçet's syndrome patients treated with cyclophosphamide

Triggering agents and microbiome as environmental factors on Behçet's syndrome

Oral health is a mediator for disease severity in patients with Behçet's disease: a multiple mediation analysis study

The close association between dental and periodontal treatments and oral ulcer course in Behcet's disease: a prospective clinical study

Effects of azithromycin on intracellular cytokine responses and mucocutaneous manifestations in Behçet's disease

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