Your activity: 4 p.v.

Treatment of Behçet syndrome

Treatment of Behçet syndrome
Authors:
Ellison L Smith, MD
Yusuf Yazici, MD
Section Editor:
Peter A Merkel, MD, MPH
Deputy Editor:
Philip Seo, MD, MHS
Literature review current through: Dec 2022. | This topic last updated: Nov 04, 2022.

INTRODUCTION — Behçet syndrome, also known as Behçet disease, is an inflammatory disease characterized by recurrent oral aphthous ulcers and numerous potential systemic manifestations. These include genital ulcers, ocular disease, skin lesions, arthritis, and vascular, gastrointestinal, and neurologic disease.

Most clinical manifestations of Behçet syndrome are believed to be due to vasculitis. Among the systemic vasculitides, Behçet syndrome is remarkable for its ability to involve blood vessels of all sizes – small, medium, and large – on both the arterial and venous sides of the circulation, with a predilection for the venous side.

The treatment of Behçet syndrome will be reviewed here. The pathogenesis, clinical manifestations, and diagnosis are discussed separately. (See "Pathogenesis of Behçet syndrome" and "Clinical manifestations and diagnosis of Behçet syndrome".)

GENERAL PRINCIPLES OF MANAGEMENT — Our treatment guidelines are generally consistent with those developed by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism), and this includes several overarching principles listed below [1-5]:

The syndrome typically runs a relapsing and remitting course, and the goal of treatment is to promptly suppress inflammatory exacerbations and recurrences to prevent irreversible organ damage

A coordinated multidisciplinary approach is necessary for optimal care

Treatment choices should be individualized based on age, sex, type, and severity of organ involvement as well as patient preferences

Ocular, vascular, neurologic, and gastrointestinal involvement may be associated with a poor prognosis

Disease manifestations may improve over time in many patients

Given the clinical heterogeneity of Behçet syndrome, the therapeutic approach is highly variable and is guided by the predominant disease manifestation.

ORGAN-BASED TREATMENT

Overall approach — Due to the clinical heterogeneity of Behçet syndrome and the unpredictable disease course, the management is tailored to the individual patient, taking into account the severity of symptoms and organ involvement along with the sex and age of the patient, as young males tend to have the more severe and complicated course compared with females and older patients, in general. The choice of therapy in active disease is dictated by the predominant disease manifestation.

The following discussion of treatment is organized by the disease manifestations, which include:

Mucocutaneous manifestations

Arthritis

Ocular disease

Gastrointestinal disease

Renal disease

Vascular disease

Neurologic disease

Mucocutaneous manifestations

Oral aphthae and genital ulcers — The treatment of oral and genital ulcers is guided by the severity of symptoms and the presence of other disease manifestations. The following is our general approach to drug therapy in patients with oral and/or genital ulcers:

For isolated oral and genital aphthae, we suggest initial treatment with topical corticosteroids (table 1) such as triamcinolone acetonide cream (0.1% in Orabase). This should be applied three to four times daily and be used until pain from the ulcer ceases. Potent topical corticosteroids may also be used for genital ulcers. The efficacy of topical corticosteroids for the treatment of aphthous ulcers in Behçet syndrome was evaluated in a small study including 60 patients who were given either phenytoin syrup or triamcinolone acetonide ointment [6]. Improvements in the triamcinolone acetonide and phenytoin groups were 87 percent and 53 percent, respectively. Intralesional corticosteroid preparations for large ulcers can be employed in collaboration with a dermatologist. A typical preparation is triamcinolone (5 to 10 mg/mL). Our approach to the use of topical therapies is generally consistent with that used for recurrent aphthous stomatitis and is discussed in detail separately. (See "Recurrent aphthous stomatitis", section on 'Topical corticosteroids'.)

Topical sucralfate can also be used in combination with or as an alternative to topical corticosteroids. Topical sucralfate 1g/5mL four times daily as a mouthwash reduced pain, frequency, and healing time in a randomized controlled trial for oral ulcers in Behçet syndrome [7]. In some countries, including the United States, the commercial sucralfate suspension strength is 1 g/10 mL. Pimecrolimus improved healing time in a randomized trial of 90 patients with genital aphthous ulcers [8]. Although generally less effective, topical anesthetics can also provide temporary relief of discomfort if used prior to eating and performing dental hygiene. (See "Recurrent aphthous stomatitis", section on 'General measures'.)

For prevention of recurrent oral and genital ulcers, we suggest colchicine 1 to 2 mg/day in divided doses (titrated to a dose without gastrointestinal side effects) rather than oral glucocorticoids. In places where 0.5 mg tablets are not available (eg, United States), doses in the range of 1.2 to 1.8 mg can be used. Apremilast, an orally administered phosphodiesterase-4 inhibitor, has also been shown to be effective for prevention of recurrent oral ulcers, and is a reasonable alternative to colchicine as a glucocorticoid-sparing agent for patients with recurrent oral ulcers. Apremilast is typically up-titrated at a rate of 10 mg daily over six days to achieve a maintenance dose of 30 mg twice daily. We wait approximately 12 weeks to confirm an adequate response to either medication. There are no trials that have directly compared colchicine with apremilast, and both have been shown to help improve oral ulcers. However, the authors generally prefer a trial of colchicine first given the rapid onset of action, lower cost, and better tolerability.

Data on the effects of colchicine for patients with minor oral ulcers or genital lesions are mixed, and generally more favorable for genital ulcers [9-13]. In a randomized trial of 116 patients comparing colchicine with placebo, colchicine therapy was associated with a reduction in the number of genital ulcers and erythema nodosum in women [9]. A randomized crossover trial in 169 patients showed improvement in overall disease activity as well as oral aphthosis, genital aphthosis, pseudofolliculitis and erythema nodosum in patients treated with colchicine versus placebo [13]. Patients may develop significant gastrointestinal intolerance of colchicine if the medication is taken at total doses higher than 1.5 mg/day. Colchicine has a narrow therapeutic window and doses should be adjusted if adverse symptoms develop, as cytopenias and other complications may develop. Dose adjustment of colchicine is necessary in patients with renal impairment. Dose adjustments are found in the Lexicomp drug patient information topic within UpToDate (see "Treatment of gout flares", section on 'Safety of colchicine'). Colchicine is also used for patients with arthritis associated with Behçet syndrome. (See 'Arthritis' below.)

Data from randomized trials suggest that apremilast is beneficial in treating oral ulcers, and it is approved in the United States, Canada, and Japan for the treatment of oral ulcers in Behçet syndrome [14-17]. A randomized phase II trial including 111 patients with Behçet syndrome found that patients who received apremilast had a lower mean number of oral ulcers at 12 weeks, as compared with those in the placebo group (0.5 versus 2.1) [14]. A phase III trial with 207 patients also reported an improvement in the mean number of oral ulcers after 12 weeks, with continuation of this benefit out to 64 weeks in 143 patients that completed week 64 [15,16]. Other outcomes that favored the apremilast group included a decrease in pain of oral ulcers as well as the proportion of complete responders for oral ulcer resolution (52.9 versus 22.3 percent), and improvement in quality of life. In both trials, some patients had genital ulcers, and there was a trend towards improvement, but the studies were not designed to assess this outcome. More data are needed to determine whether apremilast is effective for genital ulcers as well as other manifestations of Behçet syndrome. Apremilast has been associated with more adverse events than placebo, including diarrhea, nausea, and headache.

When isolated oral aphthae or genital ulcers are refractory to topical corticosteroids, colchicine, or apremilast or when multiple lesions are present, systemic glucocorticoids should be employed. An appropriate starting dose for mucocutaneous disease in the absence of other disease manifestations is prednisone 15 mg/day (or the equivalent with other glucocorticoids), with tapering of the dose to 10 mg/day after one week and discontinuation of prednisone entirely over a two- to three-week period, assuming that the aphthae are no longer symptomatic. Some patients may require higher initial doses. Patients with recurrent oral aphthae may require longer periods of maintenance treatment with low-dose prednisone (eg, 5 mg/day).

General clinical experience with Behçet syndrome and extrapolation from the treatment of recurrent aphthous stomatitis suggest that systemic glucocorticoids are effective for oral aphthae and genital ulcers resistant to topical therapy [18,19].

Escalation of treatment with other medications for the management of oral and genital ulcers should be determined on a case-by-case basis. We generally reserve these options for patients in whom the combination of daily oral colchicine or apremilast and a daily prednisone dose of more than 10 mg is required to control oral aphthae and genital lesions or if the adverse effects of prednisone and/or colchicine are intolerable even at lower doses. The choice of therapeutic options listed below and can also depend on the presence of other organ involvement. Adverse effects of individual therapeutic agents and patient preferences must also be taken into consideration. Options in order of preference include:

AzathioprineAzathioprine has been shown to improve oral and genital ulceration. In a randomized trial, 73 patients with Behçet syndrome were treated with either azathioprine (2.5 mg/kg per day) or placebo, with glucocorticoids available to both groups [20]. After two years, patients taking azathioprine had less frequent oral and genital ulcers. We generally start with azathioprine 50 mg daily, and then usually increase the daily dose by 50 mg every 4 weeks as tolerated up to the target dose of 2.5 mg/kg/day, while monitoring a complete blood count (CBC) every 2 weeks until therapy has stabilized, and every 6 to 12 weeks thereafter. A lower dose is indicated in patients with renal insufficiency. Before the initiation of azathioprine, we perform genetic testing for mutations in the gene for thiopurine methyltransferase. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)

TNF-alpha inhibitors – Tumor necrosis factor (TNF)-alpha inhibitors (infliximab, adalimumab, or etanercept) have been beneficial for mucocutaneous disease in several case reports/series and prospective studies [21,22], as well as one randomized trial with etanercept [23]. They should be used in combination with an oral disease-modifying antirheumatic drug (DMARD) such as azathioprine to help prevent development of potentially neutralizing antibodies.

The efficacy of TNF-alpha inhibitors for mucocutaneous disease was demonstrated in a retrospective multicenter study of 124 patients with severe or refractory Behçet syndrome treated with infliximab (in 62 percent) or adalimumab (in 30 percent) [22]. In addition to an overall clinical response in 90 percent of patients, a clinical improvement was seen in 88 percent of patients with mucocutaneous disease. A randomized trial in which 40 patients with mucocutaneous disease and/or arthritis were assigned to etanercept (25 mg subcutaneously twice a week) or placebo injections for four weeks found that more patients on etanercept remained free of oral ulcers (45 percent versus 5 percent) and nodular skin lesions (85 versus 25 percent) [23]. However, there was no difference between the two groups in terms of genital ulcers, likely due to the small size and relative infrequency of genital ulcers during the short study period.

Cyclosporine – Although typically used for ocular manifestations, there is some evidence supporting the efficacy of cyclosporine for mucocutaneous disease. In a randomized trial with 96 patients with mucocutaneous manifestations, cyclosporine (10 mg/kg per day in divided doses) was superior to colchicine in the management of oral and genital ulcers as well as other skin lesions [24]. However, adverse effects due to cyclosporine were common and were reversible when the cyclosporine dose was reduced [25]. Hypertension is common with cyclosporine treatment. Neurotoxicity is also frequently seen and may be difficult to differentiate from disease-related neurologic disease; thus, this agent is less preferred in patients with neurologic disease [26]. (See "Pharmacology of cyclosporine and tacrolimus" and 'Neurologic disease' below.)

Interferon alfa – Interferon alfa-2a and interferon alfa-2b (generally given three to six million units three times weekly) have been beneficial for mucocutaneous disease. This was shown in a randomized trial of 50 patients in which interferon alfa-2a significantly decreased the duration and pain of oral ulcers as well as the frequency of genital ulcers and papulopustular lesions [27]. The mean frequency and duration of erythema nodosum-like lesions, thrombophlebitis, and articular symptoms also decreased, but not in a statistically significant fashion. In a systematic review of 32 original articles and four abstracts including 338 patients treated with interferon alfa-2a or alfa-2b, partial or complete responses were seen in 86 percent of the patients with mucocutaneous symptoms [28]. However, flu-like symptoms and other toxicities, including depression, are not uncommon.

Thalidomide – Given the generally greater efficacy of other agents for mucocutaneous Behçet syndrome and the significant risk of neuropathy and teratogenicity associated with thalidomide, thalidomide is now seldom used for this indication in practice. The use of thalidomide should be restricted to clinicians experienced in the management of Behçet syndrome and the use of this medication [29]. The efficacy of thalidomide monotherapy for mucocutaneous manifestations of Behçet syndrome was demonstrated in a trial with 96 patients who were randomly assigned to one of three treatment groups: thalidomide 300 mg/day, thalidomide 100 mg/day, or placebo [30]. At 24 weeks, a complete response occurred in two of the 32 patients receiving 100 mg/day of thalidomide; in five of the 31 patients receiving 300 mg/day; and in none of the 32 patients receiving placebo. Only a minority of thalidomide-treated patients responded to treatment, and some manifestations of disease (erythema nodosum) actually worsened. In addition, 7 percent of the thalidomide-treated patients developed peripheral neuropathy, a condition that is often irreversible.

Mycophenolate mofetil has not been found to be effective in the treatment of mucocutaneous manifestations. A trial of mycophenolate mofetil for the mucocutaneous manifestations of Behçet syndrome was terminated due to lack of efficacy in the first six patients [31]. However, our authors may use mycophenolate mofetil in combination with TNF-alpha inhibitors for patients who do not tolerate azathioprine.

Cutaneous lesions — With the exception of erythema nodosum and pyoderma gangrenosum, most other cutaneous manifestations of Behçet syndrome (acneiform and papulopustular lesions, nodules, superficial thrombophlebitis, and palpable purpura) respond well to the more moderate measures discussed above, particularly colchicine and low to moderate doses of glucocorticoids.

The usual approach to cutaneous disease in Behçet syndrome is to begin with colchicine for mild manifestations (1 to 2 mg daily in divided doses) and to institute prednisone (up to 40 mg/day initially) for lesions that are refractory to colchicine. Prednisone doses maintained between 5 and 10 mg/day are usually sufficient to control most skin manifestations of Behçet syndrome.

Erythema nodosum and pyoderma gangrenosum require special consideration.

Erythema nodosum – Because of the possibility of a dermal vasculitis underlying the clinical presentation of erythema nodosum, clinicians should consider moving quickly to systemic glucocorticoids and other immunosuppressive medications if colchicine is ineffective. Infectious etiologies for erythema nodosum should also be ruled out before adding immunosuppressive therapy. (See "Erythema nodosum".)

The presence of a medium-vessel vasculitis through biopsy or by the clinical appearance of ulcerations of the erythema nodosum lesions is an indication for systemic glucocorticoid treatment combined with another immunosuppressive agent. In this setting, we suggest as initial therapy the combination of oral prednisone (40 to 60 mg daily) and azathioprine. Azathioprine is generally started at 50 mg daily, and the daily dose is increased by 50 mg every 4 weeks as tolerated up to the target dose of 2.5 mg/kg/day, while monitoring a CBC every 2 weeks until therapy has stabilized, and every 6 to 12 weeks thereafter. A lower dose is indicated in patients with renal insufficiency. Before the initiation of azathioprine, we perform genetic testing for mutations in the gene for thiopurine methyltransferase. The prednisone dose is maintained at its initial level for one month and then tapered off over three to four months. Treatment, particularly the rapidity of the prednisone taper, should be dictated by the clinical response (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'). If azathioprine is ineffective, other agents should be considered. (See 'Posterior uveitis' below.)

Pyoderma gangrenosum – Pyoderma gangrenosum associated with Behçet syndrome is often complicated by the pathergy phenomenon. Thus, extensive debridement of pyoderma in Behçet syndrome is discouraged. The treatment of pyoderma gangrenosum is reviewed in detail elsewhere. (See "Pyoderma gangrenosum: Treatment and prognosis".)

Our treatment recommendations are largely in keeping with dermatology guidelines from a consensus conference on treatment of skin and mucosal lesions in Behçet syndrome [32].

Arthritis — The nondeforming arthritis characteristic of Behçet syndrome is seldom the determinant of the level of therapy. When present, joint symptoms are usually accompanied by other manifestations of disease that dictate the intensity of treatment. The following is our general approach to drug therapy in patients with arthritis associated with Behçet syndrome:

For patients with arthritis with or without other non-organ-threatening disease (eg, mucocutaneous involvement), we suggest colchicine 1 to 2 mg daily in divided doses. We may also use nonsteroidal antiinflammatory drugs (NSAIDs) for symptomatic relief of arthritic pain if not otherwise contraindicated. There is no consensus among experts about a preferred NSAID for this indication. (See "Initial treatment of rheumatoid arthritis in adults", section on 'NSAIDs'.)

The efficacy of colchicine for the treatment of arthritis associated with Behçet syndrome was evaluated in a trial comparing colchicine with placebo in 116 patients with Behçet syndrome; colchicine therapy was associated with a decrease in the number of arthritic joints after two years of follow-up [9].

In patients whose arthritis is not controlled by colchicine, low-dose systemic glucocorticoids may be added, with continuous efforts to maintain the minimally effective dose. Prednisone (10 mg/day) is an appropriate starting dose for the arthritis of Behçet syndrome, but if continuous therapy is required, 5 mg/day or even lower doses should be the target dose, as these doses balance the efficacy and long-term side effects of glucocorticoids well. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Oral glucocorticoids'.)

For refractory or persistent arthritis, we use azathioprine and/or TNF-alpha inhibitors instead of colchicine. Although these agents are typically reserved for patients with more severe disease manifestations (eg, ocular disease), they have been shown to be effective for arthritis associated with Behçet syndrome. In a trial of 73 patients with Behçet syndrome, patients were randomized to receive either azathioprine (2.5 mg/kg per day) or placebo and followed for two years [20]. Patients on azathioprine had fewer episodes of new or recurrent eye disease, oral and genital ulcers, and arthritis. The efficacy of TNF-alpha inhibitors for arthritis was demonstrated in a multicenter study of 124 patients with severe or refractory Behçet syndrome treated with TNF-alpha inhibitor therapy (infliximab in 62 percent and adalimumab in 30 percent) [22]. The overall response (ie, complete and partial) rate was 90.4 percent, and the efficacy was similar between the different TNF-alpha inhibitors used. Clinical responses were observed in 70 percent of patients with joint disease.

For patients with arthritis refractory to the aforementioned treatments, other immunosuppressive agents that may be used include interferon alfa or methotrexate. Most of the data for the efficacy of interferon alfa-2a or alfa-2b are based on indications for refractory eye disease [27,28,33-47], but it has also been shown to be effective for arthritis. A systematic review including 338 patients treated with interferon alfa-2a or alfa-2b reported a partial or complete response in 96 percent of patients with arthritis [28]. The use of methotrexate is based on the experience of clinicians specialized in the care of patients with Behçet syndrome and extrapolated from the benefit of methotrexate in inflammatory arthritis in other conditions. The dose, side effects, monitoring, and other considerations associated with methotrexate use are discussed elsewhere. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)

Apremilast may also have some benefit for arthritis in patients with arthritis that has not responded to colchicine or other DMARDs. An observational study of 50 patients with articular or mucocutaneous Behçet syndrome resistant to colchicine or other DMARDs reported complete response of articular symptoms after six months of apremilast in 65 percent and a partial response in 17 percent [48].

Ocular disease — Ocular disease should be managed in collaboration with an ophthalmologist with experience in the evaluation and treatment of uveitis, with the goal of inducing and maintaining remission. The two most common ocular manifestations, anterior and posterior uveitis, have significantly different therapeutic implications. However, isolated anterior uveitis is rare in Behçet syndrome, and patients more commonly present with a panuveitis. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Ocular disease'.)

Anterior uveitis — The anterior uveitis of Behçet syndrome is generally treated with topical corticosteroids and a dilating drop such as scopolamine (0.25%) or cyclopentolate (1%). The dilating drop relieves pain due to spasm of the muscles controlling the pupil and also helps prevent the formation of posterior synechiae that may interfere with the function of the pupil. Failure to use a mydriatic (dilating) agent promptly may lead to the development of pupillary distortion, caused by the formation of scar tissue between the iris and lens. (See "Uveitis: Treatment", section on 'Initial treatment'.)

Patients whose anterior uveitis is not controlled with topical corticosteroids may require a short-term period of therapy with systemic glucocorticoids. Assuming no other organ system involvement that requires higher doses, we recommend oral prednisone at an initial dose of 40 mg daily. The prednisone may be tapered to discontinuation over one month, assuming prompt disease control.

Posterior uveitis — Posterior uveitis (inflammation in the uveal tract that is posterior to the lens) in Behçet syndrome constitutes a threat to vision and requires intensive immunosuppression. The combination of high-dose glucocorticoids and another immunosuppressive agent is required. Data to support the use of any one of these additional immunosuppressive agents over the others are limited, but preferred agents include either azathioprine, cyclosporine, interferon alfa, or a monoclonal TNF-alpha antagonist in combination with azathioprine.

Initial therapy — We and others prefer to use azathioprine together with glucocorticoids for initial therapy for most cases of posterior uveitis, based upon the limited available data, its adverse event profile, and experience with its use in Behçet syndrome [3,20,49]. However, for patients who present with an initial or recurrent episode of sight-threatening uveitis, we suggest initial treatment with TNF-alpha inhibitors in combination with azathioprine. It should be borne in mind that it takes approximately three months for azathioprine to be effective. (See 'Severe or refractory disease' below.)

Depending upon the severity of disease, we generally start prednisone (1 mg/kg per day for one month, with tapering thereafter as tolerated). Initial pulse therapy with intravenous methylprednisolone (1 g/day for three days) is sometimes used empirically for sight-threatening disease [50-53]. Intraocular triamcinolone may be beneficial for panuveitis for two to six months [54]. Systemic glucocorticoids help reduce the acute inflammatory features of serious end-organ disease, but disease activity tends to recur or progress if glucocorticoids are used without other immunosuppressive therapy and thus should not be used as monotherapy.

Azathioprine treatment is usually started at 50 mg/day, and thereafter we usually increase the daily dose by 50 mg every 4 weeks as tolerated up to the target dose of 2.5 mg/kg/day, while monitoring a CBC every 2 weeks until therapy has stabilized, and every 6 to 12 weeks thereafter. A lower dose is indicated in patients with renal insufficiency. Before the initiation of azathioprine, we perform genetic testing for the gene for thiopurine methyltransferase if testing is available. If testing is not available, clinicians should start at a low dose and titrate up slowly as tolerated. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Dose titration and monitoring'.)

In a randomized trial of 73 men with Behçet syndrome both with and without eye involvement, patients were treated with either azathioprine (2.5 mg/kg per day) or placebo and followed for two years [20]. Among the 25 patients without eye disease at the outset, there were fewer new cases of ocular involvement with azathioprine (one versus eight). Among the 48 patients with eye disease, there were fewer cases of hypopyon uveitis (1 versus 15). Azathioprine therapy was also associated with less frequent oral ulcers, genital ulcers, and arthritis. In another study, which included 57 patients from the aforementioned trial who were followed for eight years, a reduction in visual acuity and vision loss were significantly less frequent in those assigned to azathioprine, despite similar treatment for patients in both groups after the two-year trial ended [49]. In an observational study with 157 consecutive patients treated with azathioprine for active posterior uveitis or panuveitis due to Behçet syndrome, 52 percent were complete responders and 41 percent were partial responders [55].

An expert panel from the American Uveitis Society recommends initial treatment with TNF-alpha inhibitors due to the observed improvement in ocular manifestations compared with other treatments [56-58]. The data also suggest that infliximab and adalimumab may be more effective than etanercept [21,50,59]. However, as described in the next section, we reserve the use of TNF-alpha inhibitors if there is an inadequate or no response to azathioprine or in those with severe disease. (See 'Severe or refractory disease' below.)

Severe or refractory disease — In patients without an adequate response to initial therapy or with severe eye disease at presentation, we use a monoclonal TNF-alpha inhibitor (with high-dose glucocorticoids), most commonly infliximab or adalimumab, in addition to an oral DMARD, most commonly azathioprine. Severe eye disease can be defined as greater than two lines of drop in visual acuity on a 10/10 scale and/or retinal disease, such as retinal vasculitis or macular involvement [3]. Infliximab is generally used together with another immunosuppressive agent (usually azathioprine in Behçet syndrome, where the latter drug has been used extensively). The choice between infliximab and adalimumab largely depends upon patient factors such as comorbidities and patient preferences (eg, for route of administration and frequency of treatment), regulatory or insurance restrictions on drug choice, and safety issues, as the two are both effective [60,61]. There are less data available on the other TNF-alpha agents including golimumab and certolizumab [62-64].

Infliximab is typically given at an initial dose of 5 mg/kg at 0, 4, 8, 16, and 24 weeks or 0, 2, 6, and every 8 weeks [56,65]. The US Food and Drug Administration (FDA)-approved doses of adalimumab for the treatment of intermediate, posterior, and panuveitis is to start with a loading dose of 80 mg given once, followed by 40 mg one week later, and 40 mg every two weeks thereafter. These regimens are similar to those used for patients with inflammatory bowel disease or rheumatoid arthritis. Adverse effects of TNF inhibitors are discussed in more detail in the context of these diseases. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Dosing and administration' and "Overview of dosing and monitoring of biologic agents and small molecules for treating ulcerative colitis in adults", section on 'Dosing and administration'.)

A number of observational studies have suggested efficacy of infliximab for the treatment of inflammatory eye disease, major organ involvement, and other symptoms in Behçet syndrome [56,57,65-84]. As an example, a multicenter observational study including 164 patients with Behçet syndrome with uveitis who were treated with infliximab (5 mg/kg/infusion) for more than one year found that infliximab reduced the frequency of ocular attacks per year and improved visual acuity [83]. Uveitis relapsed in approximately 60 percent of all patients after initiating treatment with infliximab, with 80 percent of relapses occurring within the first year. However, 90 percent of relapses were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. In another study of 50 patients with refractory uveitis (n = 36) or idiopathic posterior segment uveitis (n = 14), treatment with infliximab (5 mg/kg) was associated with complete and partial responses in 68 and 22 percent of patients, respectively, with a significant reduction in ocular attacks and cystoid macular edema, compared with baseline, and with stable or improved visual acuity [81]. The mean follow-up period was 37 months. In an open-label prospective cohort study, 555 patients starting infliximab for uveoretinitis in Behçet syndrome were followed for 24 months, and response rate by the physician global assessment was 80.7 percent [85]. In addition, the median frequency of ocular attacks was lower compared with the patient's baseline at the start of treatment, visual acuity was maintained, and adverse events were comparable to those observed in patients treated with infliximab for other diseases.

A number of studies have also shown benefit with adalimumab treatment [86-90]. A retrospective review of 40 patients (66 eyes) with Behçet-associated uveitis treated with adalimumab found a reduction in disease flares, improvement in best corrected visual acuity, reduction in mean central macular thickness on optical coherence tomography (OCT), and a reduction in retinal vasculitis (as assessed by fluorescein angiography) at baseline, 3, and 12 months [90]. In another study with 177 patients with refractory uveitis due to Behçet syndrome, patients were treated with adalimumab or infliximab with glucocorticoids but without other immunosuppressives, and were evaluated at one year [91]. Both groups of patients improved; however, patients treated with adalimumab had better outcomes compared with those on infliximab, including anterior chamber inflammation, vitritis, and visual acuity. Continuation of use of the drug was also higher with adalimumab. A follow-up study of the infliximab patients in this study reported 75 percent reached remission at a mean of 31.5 months of therapy. Once patients reached remission, infliximab doses were reduced or infusion frequency was reduced if possible in collaboration with the patient. Overall, these reductions resulted in similar ocular outcomes but with lower costs and adverse events in those treated with lower doses [92]. In 1 case series, 11 male patients with ocular Behçet syndrome all showed at least some improvement with adalimumab treatment [93]. Seventeen of 69 patients who failed infliximab were treated with adalimumab, and 12 of 17 had a good response [94]. A retrospective study of 45 patients with Behçet syndrome retinal vasculitis compared patients treated initially with conventional treatment (with an immunosuppressive agent and glucocorticoids) with those treated with conventional treatment plus adalimumab, and found that patients treated with adalimumab had better outcomes as measured by fluorescein angiography, risk of relapse, duration of remission, visual acuity, and glucocorticoid requirements, with similar rates of adverse events [95]. A retrospective cohort study of 42 patients (72 eyes) compared outcomes in patients with sight-threatening refractory Behçet syndrome uveitis with vasculitis treated with immunosuppressives and glucocorticoids with or without adalimumab, and found that those patients treated with adalimumab had greater improvement in anterior chamber inflammation, fluorescein angiography scores, and glucocorticoid use with lower risk of relapse [96]. Other studies have also shown effectiveness with other TNF-alpha inhibitors [86,97-99].

Based on limited data from observational studies and case reports, along with our own experience, we generally use the alternative agents listed below in order of preference if there is no response to the treatment approach described above. The choice of therapy also varies with patient and disease characteristics and comorbidities.

Cyclosporine – Cyclosporine (2 to 5 mg/kg/day) can be efficacious in patients with Behçet syndrome with posterior uveitis and may be used together with glucocorticoids and azathioprine as an alternative to infliximab [25,100-104]. In a randomized trial of 23 patients with active uveitis, cyclosporine (5 mg/kg per day) was compared with monthly intravenous pulse cyclophosphamide (1000 mg), and more improvement in visual acuity was seen in the cyclosporine group at six months [100]. However, similar improvement was noted in the two groups at two years. In another randomized trial of 40 patients with ocular Behçet syndrome, cyclosporine was compared with treatment with glucocorticoids or chlorambucil and found that ocular disease was controlled more effectively by cyclosporine, but articular, cutaneous, and mucocutaneous disease manifestations were not [103].

Adverse effects due to cyclosporine are common. Approximately one-half of patients with Behçet syndrome treated with this agent had an elevation in the serum creatinine concentration that was reversible when the cyclosporine dose was reduced [25]. Hypertension is common with cyclosporine treatment. Neurotoxicity is also frequently seen and may be difficult to differentiate from disease-related neurologic disease; thus, cyclosporine is less preferred in patients with neurologic disease [26]. (See "Pharmacology of cyclosporine and tacrolimus".)

Interferon alfa – Patients with retinal vasculitis or ocular disease refractory to the combination of glucocorticoids, cyclosporine, and azathioprine may respond to treatment with interferon alfa-2a alone (generally given three to six million units three times weekly) [28,39,46,47,105,106]. Flu-like symptoms and other toxicities, including depression, are not uncommon and limit the use of this medication. Leukopenia is a significant risk when interferon alfa is used with azathioprine [105].

A 2004 systematic review of 32 original articles and four abstracts included 338 patients treated with interferon alfa-2a or alfa-2b and found partial or complete responses in 94 percent of those with uveitis, in addition to improvement in mucocutaneous symptoms and arthritis [28]. Higher doses of interferon were more effective and produced longer remissions. Many patients with improvement in their uveitis had not achieved benefit from a number of other immunosuppressive agents, and interferon therapy led to long-term remissions in some patients. Combination therapy with glucocorticoids and other agents was common. In such studies, it is difficult to impute efficacy for the interferon agent. Relapse often followed cessation of therapy. Subsequent observational studies have also support benefit from interferon alfa-2a in patients with ocular involvement [38,45-47,84,107].

A randomized trial compared treatment of refractory Behçet uveitis in 26 patients and 44 eyes with interferon alfa-2a plus tapering glucocorticoids versus cyclosporine plus tapering glucocorticoids [108]. Patients on interferon had a better treatment response compared with those on cyclosporine, achieving response in 85.7 versus 66.7 percent, complete response in 50 versus 25 percent, and complete remission in 3.3 versus 7 months. In addition, visual acuity and Behçet syndrome ocular attack scores at study conclusion were better in the interferon group. Tolerability of the treatments was similar between the two groups.

Cyclophosphamide – Cyclophosphamide should be reserved for refractory cases in which overall disease activity warrants the risk of treatment. We sometimes use it before the above options in cases of severe ocular disease. We use dosing regimens that are similar to those typically used for systemic vasculitis (see "General principles of the use of cyclophosphamide in rheumatic diseases"). We generally administer 500 mg/m2 to 1 g/m2 of body surface area (BSA) monthly for six months. Daily oral cyclophosphamide dosing at 2 to 3 mg/kg per day is an alternative option in some patients. Combination therapy with cyclophosphamide (1 g monthly for six months and every two to three months thereafter as needed), prednisolone (0.5 mg/kg daily), and azathioprine (2 to 3 mg/kg daily) was evaluated in 295 patients followed for up to 10 years [109]. Patients on combination therapy demonstrated significant improvements in visual acuity scores as well as improvements across several measures of ocular disease activity.

However, the data regarding the efficacy of cyclophosphamide for the treatment of ocular manifestations are generally mixed. A systematic review from the Cochrane database concluded that there was insufficient evidence to support the use of cyclophosphamide in the treatment of Behçet syndrome, particularly the ocular manifestations [104]. In a single masked trial comparing cyclophosphamide (1 g intravenous bolus monthly) to cyclosporine (5 mg/kg per day) in 23 patients with active and potentially reversible uveitis, visual acuity at six months improved with cyclosporine but not cyclophosphamide [100]. Lack of benefit on ocular disease was noted in another report [11]. On the other hand, an open trial comparing intravenous pulse cyclophosphamide to pulse methylprednisolone for uveitis found benefit only with cyclophosphamide [110], and some observational studies have suggested benefit for ocular and central nervous system disease [111].

Methotrexate – Methotrexate may be considered a less toxic alternative, although data supporting its use for treating ocular manifestations of Behçet syndrome are limited. We generally reserve this therapeutic option for less severe ocular disease. Methotrexate can be administered with the same dosing regimen as that used for rheumatoid arthritis, generally starting at a dose of 15 mg per week and increasing as tolerated up to 25 mg per week. All patients receiving methotrexate should be treated with folic acid 1 mg daily or folinic acid weekly to prevent hematologic and other side effects (see "Use of methotrexate in the treatment of rheumatoid arthritis"). The treatment of posterior uveitis with methotrexate (7.5 to 15 mg/week) and prednisolone (0.5 mg/kg daily) was evaluated in 682 patients followed for up to 15 years [112]. Visual acuity scores, posterior uveitis, retinal vasculitis, and the total adjusted disease activity index improved in 47, 75, 54, and 69 percent, respectively.

Mycophenolate – Mycophenolate can be used despite the paucity of published trials in the absence of other treatment options [113]. We typically start with a lower dose of 500 mg twice daily, and after several days, we increase to the target dose of 1000 mg to 1500 mg twice daily. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration'.)

Rituximab – Rituximab has also shown benefit in a small trial in patients with severe ocular manifestations resistant to cytotoxic agents [114]. Rituximab was administered intravenously at a dose of 1000 mg on days 1 and 15 and repeated every six months or as warranted, which is the same dosing regimen as that used to treat rheumatoid arthritis. In a randomized pilot trial of 20 patients with Behçet syndrome, retinal vasculitis, and edema resistant to cytotoxic treatment, treatment with rituximab plus methotrexate and prednisolone was more effective than treatment with cyclophosphamide plus azathioprine and prednisolone [114]. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Intravitreal glucocorticoid implants – Several small series have reported success with intravitreal dexamethasone implants for patients with severe or refractory Behçet syndrome uveitis or macular edema [115-117].

Gastrointestinal disease — The presence of significant gastrointestinal involvement in Behçet syndrome signals the need for glucocorticoid therapy plus an additional agent designed to limit the long-term need for prednisone [118]. Treatment with prednisone should be instituted in consultation with a gastroenterologist, who can assess the extent and severity of gastrointestinal disease.

For gastrointestinal ulceration (typically involving the terminal ileum, cecum, and ascending colon) in Behçet syndrome, our approach is as follows:

Glucocorticoids plus azathioprine – Typical starting doses for prednisone for gastrointestinal Behçet syndrome are 0.5 to 1 mg/kg daily [119]. The initial dose of glucocorticoids is usually maintained for at least one month or until symptoms improve before the institution of a taper, which is designed to decrease the daily dose to 10 mg/day within two to three months. Subsequent tapering to discontinuation over an additional two months may proceed if disease control is maintained.

Azathioprine should be instituted at essentially the same time as prednisone. Treatment is begun at 50 mg/day, after testing for mutations in the gene for thiopurine methyltransferase, and the daily dose is increased by 50 mg every 4 weeks as tolerated up to the target dose of 2.5 mg/kg/day, while monitoring a CBC every 2 weeks until therapy has stabilized, and every 6 to 12 weeks thereafter. A lower dose is indicated in patients with renal insufficiency. Azathioprine should be maintained for at least six months, with periodic reassessments of its need and serial endoscopies conducted by the gastroenterologist as appropriate. In an observational study including 37 patients with moderate to severe gastrointestinal manifestations of Behçet syndrome who were prescribed azathioprine initially, remission was observed in 65 percent of patients during a mean follow-up of 69 months [120]. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)

TNF-alpha inhibitors – We generally use TNF-alpha inhibitors in patients for whom treatment with glucocorticoids plus azathioprine has failed to control the disease. TNF-alpha inhibitors are generally used in combination with other therapies, preferably azathioprine. Several reports indicate successful treatment of intestinal Behçet syndrome with infliximab and adalimumab using regimens approximating those approved for the treatment of inflammatory bowel disease [82,118,120-126].

The typical schedule of infliximab administration is 5 mg/kg at zero, two, and six weeks, followed by 5 mg/kg every eight weeks. In a retrospective study of 28 patients with moderate to severe intestinal Behçet syndrome, 54 percent of patients who had received infliximab demonstrated lasting control of disease activity and symptom improvement over the follow-up period (median duration of 30 months) [82]. Factors predictive of sustained response included older age at diagnosis, female sex, longer disease duration, concomitant immunomodulator use, and achievement of remission at four weeks.

Sulfasalazine – Though not well studied, sulfasalazine and other aminosalicylate agents are often used to treat gastrointestinal disease in the same fashion as they are used in the treatment of inflammatory bowel disease. Treatment with oral 5-aminosalicyclic acid was studied in 41 patients with intestinal manifestations of Behçet syndrome [127]. At eight weeks in the 28 patients who remained in the study, clinical response occurred in 61 percent and remission in 57 percent. Endoscopic evaluation of 17 patients at 52 weeks demonstrated endoscopic response in 71 percent and remission in 35 percent. In all 41 patients, rescue therapy-free survival occurred in 73 percent and surgery-free survival in 100 percent. As described above, we generally use sulfasalazine in combination with TNF-alpha inhibitors. Pretreatment testing prior to the use of sulfasalazine, including screening patients at high risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency, is discussed in detail separately. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)

Other – Alternative options include mycophenolate and methotrexate. Total parenteral nutrition, enteral nutrition, and surgery may be used when clinically indicated [124]. Recurrence is common after surgery, and medical treatment is indicated to reduce this risk [118].

Renal disease — Treatment of Behçet renal disease varies depending on the type of lesion and may already be part of therapy for other manifestations:

Patients with minimal or mild nephritis (eg, hematuria, protein excretion <500 to 1000 mg/day, and normal creatinine) may require no specific therapy, although monitoring is warranted for possible disease progression. Evaluation for other causes of proteinuria is strongly advised.

Patients with AA (secondary) amyloidosis (rather rare in Behçet syndrome [128]), which results from chronic inflammation, require therapy for Behçet syndrome. The preferred therapy is colchicine (1 to 1.2 mg daily), which treats the Behçet syndrome and thus helps prevent further accumulation of amyloid deposition and accumulated damage. (See "Treatment of AA (secondary) amyloidosis", section on 'Colchicine'.)

The treatment of renal artery aneurysms is discussed below. (See 'Large artery disease' below.)

Clinically important glomerulonephritis is rarely seen in Behçet syndrome; thus, consideration of an alternative diagnosis is warranted. There are only small case series and retrospective reviews to guide therapy. Given the vasculitic nature of Behçet syndrome, a reasonable approach is to extrapolate from the treatment efficacy of medications used in granulomatosis with polyangiitis, particularly in patients with focal necrotizing lesions or crescentic glomerulonephritis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Initial treatment approach'.)

In addition to these specific therapies, all patients with persistent proteinuric renal disease should be treated with general therapies to slow disease progression, such as angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers. (See "Overview of the management of chronic kidney disease in adults", section on 'Slowing the rate of progression' and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Vascular disease

Large artery disease — Arterial involvement in Behçet syndrome is uncommon but can lead to dilatations and aneurysms of medium- and large-sized arteries [129,130]. These complications may require combined medical and surgical or interventional radiology treatments.

The medical approach involves high-dose glucocorticoids and another immunosuppressive agent, typically cyclophosphamide [51]. The approach with both of these medications for this indication is as described above in the treatment of posterior uveitis (see 'Posterior uveitis' above). Several small studies also report improvement with TNF-alpha inhibitors, including infliximab and adalimumab, and tocilizumab [131-135].

When surgery and/or interventional radiology procedures are indicated, it is ideal to perform these interventions when the patient's disease is quiescent. However, it is necessary to intervene urgently for enlarging or ruptured aneurysms or organ-threatening ischemia [136].

The outcomes of interventions for patients with large-vessel arterial disease are mixed [137-140]. A retrospective review of 176 patients with vascular Behçet syndrome evaluated the results of 20 open and 31 endovascular interventions in 36 patients and 51 arterial aneurysms [140]. The risk of recurrent aneurysmal formation at the operative site was lower when patients were treated with both intervention and immunosuppressants than with intervention alone. For extremity arteries, there were more complications with endovascular than open procedures. Perioperative high-dose glucocorticoids may be administered on a case-by-case basis given the potential for increased risk of infection and impaired wound healing associated with glucocorticoid use. Another retrospective study evaluated 47 surgical procedures for Behçet arterial disease in 23 patients with a mean follow-up of 8.4 years [141]. Arterial lesions included aneurysms (85 percent) and thrombosis (15 percent), of which 48 percent were aortic and 52 percent were peripheral. The recurrence rate was 51 percent and consisted of false aneurysms, thrombosis, and true aneurysms. The recurrence rate was 28 percent in patients receiving preoperative medical treatments including glucocorticoids, colchicine, and immunosuppressants and 75 percent in those not treated preoperatively. The recurrence rate was 42.5 percent in patients treated medically postoperatively and 80 percent in patients not treated postoperatively. The recurrence rate was three times lower with the use of a prosthetic sleeving technique.

Techniques or therapies that may decrease the risk of recurrence after surgical intervention for arterial involvement remain uncertain. In a study of 47 surgical procedures in 23 patients with arterial Behçet syndrome, the recurrence rate was 28 percent in patients treated with immune-modulating treatment including colchicine, glucocorticoids, and immunosuppressants, and 75 percent in untreated patients [141]. The recurrence rate was lower with the use of a prosthetic sleeving technique for anastomoses but did not vary otherwise by intervention utilized (vein, prosthetic graft, allograft, stent graft, or direct anastomosis).

Vascular complications following arterial bypass surgery are common in patients with Behçet syndrome. The most frequent are graft occlusion and aneurysm formation at the anastomotic site. A retrospective study of 10 patients who underwent one or more vascular surgical interventions noted a 24 percent rate of graft occlusion and a 13 percent rate of anastomotic pseudoaneurysm formation [142].

Interventional radiologic procedures provide an alternative to surgery for patients with aneurysmal dilation of the aorta or major arteries [137,143,144]. Percutaneous placement of stent-grafts was successful in six of seven patients with a variety of arterial aneurysms (aortic, subclavian, common carotid, brachiocephalic, and iliac) [143]. Arterial occlusion and a recurrent aneurysm beyond the stent-graft occurred in one patient each. In a another study of 22 patients treated with a primary stent graft for Behçet peripheral artery aneurysm, 21 of the 22 had technical success post procedure, but at a mean follow-up of 23 months, 27 percent were occluded by computed tomography angiography [145]. Transcatheter embolotherapy of pulmonary artery aneurysms was beneficial in a study of 17 patients presenting with hemoptysis [146].

A retrospective study reviewed the outcomes of 20 patients with severe aortic regurgitation caused by Behçet syndrome treated with perioperative biologic therapy, immunosuppressants, and glucocorticoids. Paravalvular leakage developed in a smaller-than-expected number of patients, disease activity was reduced, and glucocorticoids and immunosuppressants were successfully reduced, with no serious adverse events [147].

Venous thrombosis — Venous disease in Behçet syndrome is believed to result from endothelial inflammation leading to thrombosis [51,148]. The approach to preventing venous thrombotic events in Behçet syndrome is control of systemic inflammation rather than the institution of primary anticoagulation. Treatment should include glucocorticoids in combination with another immunosuppressive agent used in the same manner as for posterior uveitis (see 'Posterior uveitis' above). However, if venous thrombotic events occur, they should be treated with anticoagulation using standard approaches (see "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)"). Intracranial hypertension and, rarely, seizures may result from cerebral vein thrombosis, requiring other interventions. (See "Cerebral venous thrombosis: Treatment and prognosis".)

A retrospective study of 296 patients with Behçet syndrome with venous thrombosis found that 34 percent of patients suffered at least one relapse of venous thrombosis. Use of immunosuppressants and glucocorticoids reduced risk of relapse [149]. Mortality was 6.4 percent at 4.75 years.

A retrospective study of 70 patients with Behçet-associated venous thrombosis demonstrated more effective and rapid resolution of venous thrombosis with adalimumab-based treatment (35 patients) than with patients treated with agents other than adalimumab, including azathioprine (18 patients), cyclosporine (9 patients), cyclophosphamide (5 patients), and methotrexate (3 patients) [133]. Furthermore, patients on adalimumab were able to taper glucocorticoids more quickly; anticoagulation did appear to demonstrate benefit.

Complicated venous thrombotic events such as cerebral sinus thrombosis and pulmonary vein thrombosis can occur in Behçet syndrome. The management of these conditions must be handled on a case-by-case basis, through consultation with appropriate subspecialists [150]. Treatment with systemic glucocorticoids with or without another immune-modulating treatment is indicated to reduce the inflammation that drives Behçet-associated thrombosis. There is no consensus whether anticoagulation is beneficial in patients with Behçet-associated dural sinus thrombi, and, if patients have Behçet-associated aneurysms, anticoagulation increases the risks of hemorrhage [151,152]. There are case reports of successful use of catheter-directed endovascular thrombolysis for refractory thrombosis [153,154]. (See "Cerebral venous thrombosis: Treatment and prognosis".).

Neurologic disease — The choice of disease-modifying treatment in patients with a significant parenchymal disease depends on severity, responsiveness to glucocorticoids, prior neurologic disease, disease course, and other features of Behçet syndrome [151]. Azathioprine is commonly used as the first-line agent, with alternatives including mycophenolate, methotrexate, and cyclophosphamide. Focal parenchymal lesions, encephalitis, and medium-vessel vasculitis are all potentially life-threatening disease manifestations that should be treated in the same manner as posterior uveitis with high doses of glucocorticoids in combination with an immunosuppressive agent (see 'Posterior uveitis' above). A TNF-alpha inhibitor, such as infliximab, may be used if first-line agents are insufficient or for aggressive clinical features. In a retrospective study of 19 patients treated with infliximab for parenchymal neurologic Behçet syndrome for a mean of 32.3 months, 58 percent achieved disease remission, 37 percent achieved disease stability with no new neurologic findings, and glucocorticoids could be discontinued in 18 patients [155]. Treatment with cyclosporine should be avoided as it has been associated with more episodes of neurologic involvement in patients with Behçet syndrome [3,151,156].

The management of neurologic manifestations of Behçet syndrome is based on limited data from uncontrolled trials and expert opinion. The Japanese national research committee has released recommendations to reflect their approach to the management of neurologic disease, which differs from the approach described above [157]. There are also case reports of benefit with mycophenolate mofetil in some patients with predominantly neurologic manifestations of Behçet syndrome [158]. A case series of 11 patients with refractory parenchymal neurologic Behçet syndrome suggested that treatment with tocilizumab in combination with glucocorticoids was beneficial, and had a glucocorticoid-sparing effect [159].

The treatment of cerebral sinus thrombosis is discussed above. (See 'Venous thrombosis' above.)

DURATION OF THERAPY — It is not clear how long to continue immunosuppressive treatment in patients in whom Behçet syndrome manifestations are inactive. As noted, disease manifestations may improve over time in many patients, and treatment choices should be individualized based on age, sex, type, and severity of organ involvement as well as patient preferences. In patients with severe manifestations, we usually continue some form of immunosuppressive therapy for at least 18 to 24 months. During this time, glucocorticoid therapy is tapered as tolerated, and immunosuppressive agents with the greater potential for toxicity (eg, cyclosporine) are discontinued in favor of medications that are likely to be safer (eg, azathioprine). Some patients require one or more immunosuppressive agents indefinitely to sustain remission. In our experience, up to approximately 50 percent of patients with serious eye disease may be able to completely discontinue immunosuppressive therapy without recurrence. In one study of 87 patients with severe Behçet manifestations refractory to conventional immunosuppression and who responded to TNF-alpha treatment for a median of two years, 41 percent were able to maintain complete remission for three years off TNF-alpha treatment, though some remained on azathioprine treatment [160]. In another study, adalimumab dosing frequency was tapered (from every two weeks to every three, four, six, and eight weeks and then potentially discontinued, as determined by their treating physician) in 23 of 65 patients with Behçet syndrome that required and achieved remission on adalimumab therapy for refractory uveitis [161]. Ocular outcomes were similar in the two groups, and those patients treated with a reduced frequency of adalimumab had fewer associated adverse events and costs.

INVESTIGATIONAL THERAPIES — A number of other therapeutic approaches have been tried or are under investigation for the various manifestations of Behçet syndrome. These include anakinra, canakinumab, gevokizumab, tocilizumab, pentoxifylline, intravenous immune globulin, plasmapheresis, antibiotics, alemtuzumab (Campath 1-H), dapsone, antimalarials, rebamipide, ustekinumab, secukinumab, rituximab, hematopoietic stem cell transplantation (autologous, or derived from allogeneic bone marrow or umbilical cord blood), and granulocytapheresis [7,35,114,159,162-188]. Limited data also suggest that laser therapy may be beneficial for Behçet-associated oral ulcers [189,190].

PROGNOSIS — Behçet syndrome typically has a waxing and waning course characterized by exacerbations and remissions. The disease appears to be more severe in young, male, and Middle-Eastern or Far-Eastern patients [191,192]. However, for some patients, particularly those with predominantly mucocutaneous and articular manifestations, the disease burden dissipates with time and many patients can become asymptomatic [191]. In a series of 2200 patients followed at a specialty clinic in Korea, only seven died from Behçet syndrome over a nine-year period [193]. The mortality in a cohort of 817 patients in France was 5 percent at a median follow-up of 7.7 years [194].

The greatest morbidity and mortality comes from neurologic, ocular, and large-vessel arterial or venous disease (causing pulmonary disease, gastrointestinal bleeding, bowel perforation, superior and inferior vena cava syndrome, and cerebrovascular disease). In a 20-year follow-up of 387 Turkish patients with Behçet syndrome, most were doing better at 20 years, with decreased activity of most manifestations other than central nervous system involvement and major-vessel disease; the latter manifestations may have their onset after 5 to 10 years of disease [191].

Mucocutaneous, articular, and ocular disease are often at their worst in the early years of disease, but central nervous system and large-vessel disease, if they develop, typically do so later in the disease course. Though disease activity may decline with passing years, disease burden may rise due to cumulative ocular, neurologic, or vascular damage. Pulmonary artery aneurysms and associated hemoptysis were previously associated with a very poor prognosis, but survival appears to have improved, possibly as the result of earlier recognition and treatment using glucocorticoids and other immunosuppressive agents. This was illustrated in a retrospective study of 26 patients followed at one center in Turkey [130]. The five-year survival for patients with Behçet syndrome and pulmonary artery aneurysms who were diagnosed and treated in 1992 or later was 80 versus 40 percent for 24 patients in whom the diagnosis was made prior to that year.

Ocular and neurologic lesions may improve with immunosuppressive therapy but are often not fully reversible. Without aggressive therapy, they generally progress. A significant proportion of patients with ocular disease, particularly those of Turkish and Japanese descent, suffer progressive vision loss. Up to one-third of patients with neurologic Behçet syndrome experience relapse, and the risk of relapse may be higher in those with a positive human leukocyte antigen (HLA)-B51 [195].

The prognosis also varies with the type of neurologic process. Those with dural venous thrombosis or other nonparenchymal processes are less likely to have recurrent disease, disability, or premature death. By comparison, patients with parenchymal disease have a worse outcome and may follow a relapsing-remitting or progressive disease course [151,196,197]. As an example, in an observational study including 58 patients with neurologic Behçet syndrome in Iran, 84 percent had parenchymal and 16 percent had nonparenchymal disease [198]. Among those with parenchymal involvement, 31 percent had a monophasic, 27 percent had a polyphasic, and 20 percent had a progressive disease course. Those with a progressive disease course had a significantly higher rate of brainstem atrophy. In another study of 125 patients with neurologic Behçet syndrome, ocular disease was more common in patients with parenchymal disease, and vascular disease was more common in patients with nonparenchymal disease; 33.6 percent experienced at least one relapse, and relapse was more common in younger patients and those with cranial nerve dysfunction [199]. The prognosis was poorest for patients with progressive neurologic disease and those with an initially higher modified Rankin scale.

Cerebrospinal fluid (CSF) analysis may help determine prognosis. In one study, roughly 90 percent of those with elevated CSF protein levels or CSF pleocytosis had additional neurologic events, progressive disability, or death during at least three years of follow-up. Only 25 to 30 percent of those with normal CSF protein levels suffered one such event [196].

Quality of life is impaired by Behçet syndrome, and this varies with disease severity and degree of organ damage [200].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Behçet syndrome" and "Society guideline links: Vasculitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Behçet syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

General management principles – The goal of treatment of Behçet syndrome is to promptly suppress inflammatory exacerbations and recurrences to prevent irreversible organ damage. A coordinated multidisciplinary approach is necessary for optimal care. (See 'General principles of management' above.)

Organ-based treatment approach – Treatment is dictated both by the type of organ system involved and by the severity of disease within that organ system. Because many patients have more than one organ system involved, treatment is often guided by the degree of disease severity in the most critical organ. (See 'Overall approach' above.)

Oral aphthae and genital ulcers – For oral aphthae and genital ulcers, we suggest initial treatment with topical corticosteroids (Grade 2C). Topical anesthetics can also be added to provide temporary relief of discomfort prior to eating and performing dental hygiene. (See 'Oral aphthae and genital ulcers' above.)

For prevention of recurrent oral and genital ulcers, we suggest colchicine 1 to 2 mg/day in two to three divided doses rather than oral glucocorticoids (Grade 2B). In places where 0.5 mg tablets are not available (eg, United States), doses in the range of 1.2 to 1.8 mg can be used. Apremilast is a reasonable alternative to colchicine as a glucocorticoid-sparing agent for patients with recurrent oral ulcers. Apremilast is typically up-titrated at a rate of 10 mg daily over six days to achieve a maintenance dose of 30 mg twice daily. We wait approximately 12 weeks to confirm an adequate response to either medication. There are no trials that have directly compared colchicine with apremilast, and both have been shown to improve oral ulcers. However, the authors generally prefer a trial of colchicine first given the rapid onset of action, lower cost, and better tolerability. (See 'Oral aphthae and genital ulcers' above.)

When isolated oral aphthae or genital ulcers are refractory to topical corticosteroids, colchicine, or apremilast or when multiple lesions are present, we add systemic glucocorticoids typically at a starting dose of prednisone 15 mg/day. Escalation of treatment with other medications should be determined on a case-by-case basis. (See 'Oral aphthae and genital ulcers' above.)

Arthritis – For patients with arthritis with or without other non-organ-threatening disease (eg, mucocutaneous involvement), we suggest colchicine 1 to 2 mg daily in divided doses (titrated to a dose without gastrointestinal side effects) (Grade 2C). We may also use nonsteroidal antiinflammatory drugs (NSAIDs) for symptomatic relief of arthritic pain if not otherwise contraindicated. In patients whose arthritis is not controlled by colchicine, low-dose systemic glucocorticoids can be added. (See 'Arthritis' above.)

For refractory or persistent arthritis, we suggest azathioprine and/or tumor necrosis factor (TNF)-alpha inhibitors instead of colchicine (Grade 2C). For patients with arthritis refractory to colchicine or azathioprine and/or TNF-alpha inhibitors, other immunosuppressive agents such as interferon alfa or methotrexate may be used. (See 'Arthritis' above.)

Ocular disease – Ocular disease should be managed in collaboration with an ophthalmologist with experience in the evaluation and treatment of uveitis.

Anterior uveitis – The anterior uveitis of Behçet syndrome is generally treated with topical corticosteroids and a dilating drop such as scopolamine (0.25%) or cyclopentolate (1%). Patients whose anterior uveitis is not controlled with topical corticosteroids may require a short-term period of systemic glucocorticoid therapy. (See 'Anterior uveitis' above and "Uveitis: Treatment".)

Posterior uveitis – For patients with posterior uveitis, initial treatment consists of high-dose glucocorticoids in combination with a second immunosuppressive agent. (See 'Posterior uveitis' above.)

-Systemic glucocorticoids – We typically employ an initial prednisone dose of 1 mg/kg per day, not to exceed 80 mg/day. Pulse therapy with intravenous methylprednisolone (1 g/day for three days) may be used empirically for sight-threatening disease. (See 'Initial therapy' above.)

-Second immunosuppressive agent – We prefer azathioprine over other immunosuppressive agents as initial therapy for posterior uveitis. For patients with sight-threatening disease at presentation or refractory disease, we use a monoclonal TNF-alpha inhibitor in combination with azathioprine. Alternative options for a second immunosuppressive agent include cyclosporine, interferon alfa, cyclophosphamide, methotrexate, mycophenolate mofetil, or rituximab. (See 'Severe or refractory disease' above.)

Gastrointestinal disease – For patients with gastrointestinal ulcerations, we suggest initial treatment with systemic glucocorticoids plus azathioprine (Grade 2C). Typical starting doses for prednisone are 0.5 to 1 mg/kg daily. We generally use TNF-alpha inhibitors in patients who have failed treatment with glucocorticoids plus azathioprine. (See 'Gastrointestinal disease' above.)

Vascular disease – Complications from arterial involvement in Behçet syndrome, which include dilatations and aneurysms of medium- and large-sized arteries, may require combined medical and surgical or interventional radiology treatments. The medical approach involves high-dose glucocorticoids and another immunosuppressive agent, typically cyclophosphamide. (See 'Large artery disease' above.)

Venous thrombotic events in Behçet syndrome are believed to be related to vascular inflammation rather than inherent problems with coagulation. Thus, immunosuppressive agents are often used in combination with anticoagulation, which is not always indicated. (See 'Vascular disease' above.)

Neurologic disease – The choice of disease-modifying treatment in patients with a significant neurologic parenchymal disease depends on severity, glucocorticoid responsiveness, prior neurologic disease, disease course, and other Behçet syndrome features. Azathioprine is commonly used as the first-line agent, with alternatives including mycophenolate, methotrexate, and cyclophosphamide. Focal parenchymal lesions, encephalitis, and medium-vessel vasculitis are all potentially life-threatening disease manifestations that should be treated in the same manner as posterior uveitis with high doses of glucocorticoids in combination with an immunosuppressive agent. (See 'Neurologic disease' above.)

Prognosis – Behçet syndrome typically has a waxing and waning course characterized by exacerbations and remissions. The disease appears to be more severe in young, male, and Middle-Eastern or Far-Eastern patients. The greatest morbidity and mortality comes from neurologic, ocular, and large-vessel arterial or venous disease. Mucocutaneous, articular, and ocular diseases are often at their worst in the early years of disease, but central nervous system and large-vessel diseases, if they develop, may do so later in the disease course. (See 'Prognosis' above.)

  1. Hatemi G, Christensen R, Bang D, et al. 2018 update of the EULAR recommendations for the management of Behçet's syndrome. Ann Rheum Dis 2018; 77:808.
  2. Hatemi G, Silman A, Bang D, et al. Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease. Ann Rheum Dis 2009; 68:1528.
  3. Hatemi G, Silman A, Bang D, et al. EULAR recommendations for the management of Behçet disease. Ann Rheum Dis 2008; 67:1656.
  4. Ozguler Y, Leccese P, Christensen R, et al. Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations. Rheumatology (Oxford) 2018; 57:2200.
  5. Leccese P, Ozguler Y, Christensen R, et al. Management of skin, mucosa and joint involvement of Behçet's syndrome: A systematic review for update of the EULAR recommendations for the management of Behçet's syndrome. Semin Arthritis Rheum 2019; 48:752.
  6. Fani MM, Ebrahimi H, Pourshahidi S, et al. Comparing the Effect of Phenytoin Syrup and Triamcinolone Acetonide Ointment on Aphthous Ulcers in Patients with Behcet's Syndrome. Iran Red Crescent Med J 2012; 14:75.
  7. Alpsoy E, Er H, Durusoy C, Yilmaz E. The use of sucralfate suspension in the treatment of oral and genital ulceration of Behçet disease: a randomized, placebo-controlled, double-blind study. Arch Dermatol 1999; 135:529.
  8. Chams-Davatchi C, Barikbin B, Shahram F, et al. Pimecrolimus versus placebo in genital aphthous ulcers of Behcet's disease: a randomized double-blind controlled trial. Int J Rheum Dis 2010; 13:253.
  9. Yurdakul S, Mat C, Tüzün Y, et al. A double-blind trial of colchicine in Behçet's syndrome. Arthritis Rheum 2001; 44:2686.
  10. Aktulga E, Altaç M, Müftüoglu A, et al. A double blind study of colchicine in Behçet's disease. Haematologica 1980; 65:399.
  11. Kazokoglu H, Saatçi O, Cuhadaroglu H, Eldem B. Long-term effects of cyclophosphamide and colchicine treatment in Behçet's disease. Ann Ophthalmol 1991; 23:148.
  12. Taylor J, Glenny AM, Walsh T, et al. Interventions for the management of oral ulcers in Behçet's disease. Cochrane Database Syst Rev 2014; :CD011018.
  13. Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, et al. Colchicine versus placebo in Behçet's disease: randomized, double-blind, controlled crossover trial. Mod Rheumatol 2009; 19:542.
  14. Hatemi G, Melikoglu M, Tunc R, et al. Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study. N Engl J Med 2015; 372:1510.
  15. Hatemi G, Mahr A, Ishigatsubo Y, et al. Trial of Apremilast for Oral Ulcers in Behçet's Syndrome. N Engl J Med 2019; 381:1918.
  16. Hatemi G, Mahr A, Takeno M, et al. Apremilast for oral ulcers associated with active Behçet's syndrome over 68 weeks: long-term results from a phase 3 randomised clinical trial. Clin Exp Rheumatol 2021; 39 Suppl 132:80.
  17. Takeno M, Dobashi H, Tanaka Y, et al. Apremilast in a Japanese subgroup with Behçet's syndrome: Results from a Phase 3, randomised, double-blind, placebo-controlled study. Mod Rheumatol 2022; 32:413.
  18. Pakfetrat A, Mansourian A, Momen-Heravi F, et al. Comparison of colchicine versus prednisolone in recurrent aphthous stomatitis: A double-blind randomized clinical trial. Clin Invest Med 2010; 33:E189.
  19. Femiano F, Buonaiuto C, Gombos F, et al. Pilot study on recurrent aphthous stomatitis (RAS): a randomized placebo-controlled trial for the comparative therapeutic effects of systemic prednisone and systemic montelukast in subjects unresponsive to topical therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109:402.
  20. Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behçet's syndrome. N Engl J Med 1990; 322:281.
  21. Arida A, Fragiadaki K, Giavri E, Sfikakis PP. Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients. Semin Arthritis Rheum 2011; 41:61.
  22. Vallet H, Riviere S, Sanna A, et al. Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients. J Autoimmun 2015; 62:67.
  23. Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study. J Rheumatol 2005; 32:98.
  24. Masuda K, Nakajima A, Urayama A, et al. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet's disease. Lancet 1989; 1:1093.
  25. Sajjadi H, Soheilian M, Ahmadieh H, et al. Low dose cyclosporin-A therapy in Behçet's disease. J Ocul Pharmacol 1994; 10:553.
  26. Sakane T, Takeno M. Novel approaches to Behçet's disease. Expert Opin Investig Drugs 2000; 9:1993.
  27. Alpsoy E, Durusoy C, Yilmaz E, et al. Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol 2002; 138:467.
  28. Kötter I, Günaydin I, Zierhut M, Stübiger N. The use of interferon alpha in Behçet disease: review of the literature. Semin Arthritis Rheum 2004; 33:320.
  29. Ehrlich GE. Behçet disease and the emergence of thalidomide. Ann Intern Med 1998; 128:494.
  30. Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128:443.
  31. Adler YD, Mansmann U, Zouboulis CC. Mycophenolate mofetil is ineffective in the treatment of mucocutaneous Adamantiades-Behçet's disease. Dermatology 2001; 203:322.
  32. Nakamura K, Iwata Y, Asai J, et al. Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication. J Dermatol 2020; 47:223.
  33. Pivetti-Pezzi P, Accorinti M, Pirraglia MP, et al. Interferon alpha for ocular Behçet's disease. Acta Ophthalmol Scand 1997; 75:720.
  34. Mochizuki M. Immunotherapy for Behçet's disease. Int Rev Immunol 1997; 14:49.
  35. Nichols JC, Ince A, Akduman L, Mann ES. Interferon-alpha 2a treatment of neuro-Behcet disease. J Neuroophthalmol 2001; 21:109.
  36. Zouboulis CC, Orfanos CE. Treatment of Adamantiades-Behçet disease with systemic interferon alfa. Arch Dermatol 1998; 134:1010.
  37. Hamuryudan V, Moral F, Yurdakul S, et al. Systemic interferon alpha 2b treatment in Behçet's syndrome. J Rheumatol 1994; 21:1098.
  38. Deuter CM, Kötter I, Günaydin I, et al. [Ocular involvement in Behçet's disease: first 5-year-results for visual development after treatment with interferon alfa-2a]. Ophthalmologe 2004; 101:129.
  39. Kötter I, Zierhut M, Eckstein AK, et al. Human recombinant interferon alfa-2a for the treatment of Behçet's disease with sight threatening posterior or panuveitis. Br J Ophthalmol 2003; 87:423.
  40. Alpsoy E, Yilmaz E, Başaran E. Interferon therapy for Behçet's disease. J Am Acad Dermatol 1994; 31:617.
  41. O'Duffy JD, Calamia K, Cohen S, et al. Interferon-alpha treatment of Behçet's disease. J Rheumatol 1998; 25:1938.
  42. Kuemmerle-Deschner JB, Tzaribachev N, Deuter C, et al. Interferon-alpha--a new therapeutic option in refractory juvenile Behçet's disease with CNS involvement. Rheumatology (Oxford) 2008; 47:1051.
  43. Yalçindağ FN, Uzun A. Results of interferon alpha-2a therapy in patients with Behcet's disease. J Ocul Pharmacol Ther 2012; 28:439.
  44. Kötter I, Vonthein R, Zierhut M, et al. Differential efficacy of human recombinant interferon-alpha2a on ocular and extraocular manifestations of Behçet disease: results of an open 4-center trial. Semin Arthritis Rheum 2004; 33:311.
  45. Deuter CM, Zierhut M, Möhle A, et al. Long-term remission after cessation of interferon-α treatment in patients with severe uveitis due to Behçet's disease. Arthritis Rheum 2010; 62:2796.
  46. Onal S, Kazokoglu H, Koc A, et al. Long-term efficacy and safety of low-dose and dose-escalating interferon alfa-2a therapy in refractory Behçet uveitis. Arch Ophthalmol 2011; 129:288.
  47. Sobaci G, Erdem U, Durukan AH, et al. Safety and effectiveness of interferon alpha-2a in treatment of patients with Behçet's uveitis refractory to conventional treatments. Ophthalmology 2010; 117:1430.
  48. Vieira M, Buffier S, Vautier M, et al. Apremilast in Refractory Behçet's Syndrome: A Multicenter Observational Study. Front Immunol 2020; 11:626792.
  49. Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine in Behcet's syndrome: effects on long-term prognosis. Arthritis Rheum 1997; 40:769.
  50. Pipitone N, Olivieri I, Cantini F, et al. New approaches in the treatment of Adamantiades-Behçet's disease. Curr Opin Rheumatol 2006; 18:3.
  51. Barnes CG. Treatment of Behcet's syndrome. Rheumatology (Oxford) 2006; 45:245.
  52. Reed JB, Morse LS, Schwab IR. High-dose intravenous pulse methylprednisolone hemisuccinate in acute Behçet retinitis. Am J Ophthalmol 1998; 125:409.
  53. Mohammadi M, Shahram F, Shams H, et al. High-dose intravenous steroid pulse therapy in ocular involvement of Behcet's disease: a pilot double-blind controlled study. Int J Rheum Dis 2017; 20:1269.
  54. Tuncer S, Yilmaz S, Urgancioglu M, Tugal-Tutkun I. Results of intravitreal triamcinolone acetonide (IVTA) injection for the treatment of panuveitis attacks in patients with Behçet disease. J Ocul Pharmacol Ther 2007; 23:395.
  55. Saadoun D, Wechsler B, Terrada C, et al. Azathioprine in severe uveitis of Behçet's disease. Arthritis Care Res (Hoboken) 2010; 62:1733.
  56. Yamada Y, Sugita S, Tanaka H, et al. Comparison of infliximab versus ciclosporin during the initial 6-month treatment period in Behçet disease. Br J Ophthalmol 2010; 94:284.
  57. Tabbara KF, Al-Hemidan AI. Infliximab effects compared to conventional therapy in the management of retinal vasculitis in Behçet disease. Am J Ophthalmol 2008; 146:845.
  58. Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2014; 121:785.
  59. Sfikakis PP, Markomichelakis N, Alpsoy E, et al. Anti-TNF therapy in the management of Behcet's disease--review and basis for recommendations. Rheumatology (Oxford) 2007; 46:736.
  60. Fabiani C, Vitale A, Emmi G, et al. Long-term retention rates of adalimumab and infliximab in non-infectious intermediate, posterior, and panuveitis. Clin Rheumatol 2019; 38:63.
  61. Vallet H, Seve P, Biard L, et al. Infliximab Versus Adalimumab in the Treatment of Refractory Inflammatory Uveitis: A Multicenter Study From the French Uveitis Network. Arthritis Rheumatol 2016; 68:1522.
  62. Lopalco G, Emmi G, Gentileschi S, et al. Certolizumab Pegol treatment in Behcet's disease with different organ involvement: A multicenter retrospective observational study. Mod Rheumatol 2017; 27:1031.
  63. Vitale A, Emmi G, Lopalco G, et al. Long-term efficacy and safety of golimumab in the treatment of multirefractory Behçet's disease. Clin Rheumatol 2017; 36:2063.
  64. Fabiani C, Sota J, Rigante D, et al. Rapid and Sustained Efficacy of Golimumab in the Treatment of Multirefractory Uveitis Associated with Behçet's Disease. Ocul Immunol Inflamm 2019; 27:58.
  65. Sfikakis PP, Kaklamanis PH, Elezoglou A, et al. Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behçet disease. Ann Intern Med 2004; 140:404.
  66. Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. Effect of infliximab on sight-threatening panuveitis in Behçet's disease. Lancet 2001; 358:295.
  67. Hassard PV, Binder SW, Nelson V, Vasiliauskas EA. Anti-tumor necrosis factor monoclonal antibody therapy for gastrointestinal Behçet's disease: a case report. Gastroenterology 2001; 120:995.
  68. Rozenbaum M, Rosner I, Portnoy E. Remission of Behçet's syndrome with TNFalpha blocking treatment. Ann Rheum Dis 2002; 61:283.
  69. Wechsler B, Sablé-Fourtassou R, Bodaghi B, et al. Infliximab in refractory uveitis due to Behçet's disease. Clin Exp Rheumatol 2004; 22:S14.
  70. Sarwar H, McGrath H Jr, Espinoza LR. Successful treatment of long-standing neuro-Behçet's disease with infliximab. J Rheumatol 2005; 32:181.
  71. Benitez-del-Castillo JM, Martinez-de-la-Casa JM, Pato-Cour E, et al. Long-term treatment of refractory posterior uveitis with anti-TNFalpha (infliximab). Eye (Lond) 2005; 19:841.
  72. Lanthier N, Parc C, Scavennec R, et al. Infliximab in the treatment of posterior uveitis in Behçet's disease. Long term follow up in four patients. Presse Med 2005; 34:916.
  73. Ohno S, Nakamura S, Hori S, et al. Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis. J Rheumatol 2004; 31:1362.
  74. Rosenbaum JT. Blind insight: eyeing anti-tumor necrosis factor treatment in uveitis associated with Behçet's disease. J Rheumatol 2004; 31:1241.
  75. Giardina A, Ferrante A, Ciccia F, et al. One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet's disease refractory to standard immunosuppressive drugs. Rheumatol Int 2011; 31:33.
  76. Iwata S, Saito K, Yamaoka K, et al. Efficacy of combination therapy of anti-TNF-α antibody infliximab and methotrexate in refractory entero-Behçet's disease. Mod Rheumatol 2011; 21:184.
  77. Pipitone N, Olivieri I, Padula A, et al. Infliximab for the treatment of Neuro-Behçet's disease: a case series and review of the literature. Arthritis Rheum 2008; 59:285.
  78. Lindstedt EW, Baarsma GS, Kuijpers RW, van Hagen PM. Anti-TNF-alpha therapy for sight threatening uveitis. Br J Ophthalmol 2005; 89:533.
  79. Capella MJ, Foster CS. Long-term efficacy and safety of infliximab in the treatment of Behçet's disease. Ocul Immunol Inflamm 2012; 20:198.
  80. Takeuchi M, Asukata Y, Kawagoe T, et al. Infliximab monotherapy versus infliximab and colchicine combination therapy in patients with Behçet's disease. Ocul Immunol Inflamm 2012; 20:193.
  81. Cantini F, Niccoli L, Nannini C, et al. Efficacy of infliximab in refractory Behçet's disease-associated and idiopathic posterior segment uveitis: a prospective, follow-up study of 50 patients. Biologics 2012; 6:5.
  82. Lee JH, Cheon JH, Jeon SW, et al. Efficacy of infliximab in intestinal Behçet's disease: a Korean multicenter retrospective study. Inflamm Bowel Dis 2013; 19:1833.
  83. Takeuchi M, Kezuka T, Sugita S, et al. Evaluation of the long-term efficacy and safety of infliximab treatment for uveitis in Behçet's disease: a multicenter study. Ophthalmology 2014; 121:1877.
  84. Yalçindag N, Köse HC. Comparison of the Treatment Results for Behçet Uveitis in Patients Treated with Infliximab and Interferon. Ocul Immunol Inflamm 2020; 28:305.
  85. Ohno S, Umebayashi I, Matsukawa M, et al. Safety and efficacy of infliximab in the treatment of refractory uveoretinitis in Behçet's disease: a large-scale, long-term postmarketing surveillance in Japan. Arthritis Res Ther 2019; 21:2.
  86. Perra D, Alba MA, Callejas JL, et al. Adalimumab for the treatment of Behçet's disease: experience in 19 patients. Rheumatology (Oxford) 2012; 51:1825.
  87. Leccese P, Latanza L, D'Angelo S, et al. Efficacy of switching to adalimumab in a patient with refractory uveitis of Behçet's disease to infliximab. Clin Exp Rheumatol 2011; 29:S93.
  88. Mushtaq B, Saeed T, Situnayake RD, Murray PI. Adalimumab for sight-threatening uveitis in Behçet's disease. Eye (Lond) 2007; 21:824.
  89. Calvo-Río V, Blanco R, Beltrán E, et al. Anti-TNF-α therapy in patients with refractory uveitis due to Behçet's disease: a 1-year follow-up study of 124 patients. Rheumatology (Oxford) 2014; 53:2223.
  90. Fabiani C, Vitale A, Emmi G, et al. Efficacy and safety of adalimumab in Behçet's disease-related uveitis: a multicenter retrospective observational study. Clin Rheumatol 2017; 36:183.
  91. Atienza-Mateo B, Martín-Varillas JL, Calvo-Río V, et al. Comparative Study of Infliximab Versus Adalimumab in Refractory Uveitis due to Behçet's Disease: National Multicenter Study of 177 Cases. Arthritis Rheumatol 2019; 71:2081.
  92. Martín-Varillas JL, Atienza-Mateo B, Calvo-Rio V, et al. Long-term Follow-up and Optimization of Infliximab in Refractory Uveitis Due to Behçet Disease: National Study of 103 White Patients. J Rheumatol 2021; 48:741.
  93. Bawazeer A, Raffa LH, Nizamuddin SH. Clinical experience with adalimumab in the treatment of ocular Behçet disease. Ocul Immunol Inflamm 2010; 18:226.
  94. Olivieri I, Leccese P, D'Angelo S, et al. Efficacy of adalimumab in patients with Behçet's disease unsuccessfully treated with infliximab. Clin Exp Rheumatol 2011; 29:S54.
  95. Yang S, Huang Z, Hu Y, et al. The Efficacy of Adalimumab as an Initial Treatment in Patients with Behçet's Retinal Vasculitis. Front Pharmacol 2021; 12:609148.
  96. Yang S, Huang Z, Liu X, et al. Comparative study of adalimumab versus conventional therapy in sight-threatening refractory Behçet's uveitis with vasculitis. Int Immunopharmacol 2021; 93:107430.
  97. Calvo Catalá J, Campos Fernández C, Rueda Cid A, et al. [Efficacy of adalimumab in Behçet's disease. Description of 6 cases]. Reumatol Clin 2011; 7:258.
  98. Díaz-Llopis M, Salom D, Garcia-de-Vicuña C, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology 2012; 119:1575.
  99. Fabiani C, Vitale A, Rigante D, et al. Efficacy of anti-tumour necrosis factor-α monoclonal antibodies in patients with non-infectious anterior uveitis. Clin Exp Rheumatol 2019; 37:301.
  100. Ozyazgan Y, Yurdakul S, Yazici H, et al. Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet's syndrome: a single masked trial. Br J Ophthalmol 1992; 76:241.
  101. Atmaca LS, Batioğlu F. The efficacy of cyclosporin-a in the treatment of Behçet's disease. Ophthalmic Surg 1994; 25:321.
  102. Whitcup SM, Salvo EC Jr, Nussenblatt RB. Combined cyclosporine and corticosteroid therapy for sight-threatening uveitis in Behçet's disease. Am J Ophthalmol 1994; 118:39.
  103. BenEzra D, Cohen E, Chajek T, et al. Evaluation of conventional therapy versus cyclosporine A in Behçet's syndrome. Transplant Proc 1988; 20:136.
  104. Saenz A, Ausejo M, Shea B, et al. Pharmacotherapy for Behcet's syndrome. Cochrane Database Syst Rev 2000; :CD001084.
  105. Hamuryudan V, Ozyazgan Y, Fresko Y, et al. Interferon alfa combined with azathioprine for the uveitis of Behçet's disease: an open study. Isr Med Assoc J 2002; 4:928.
  106. Deuter CM, Kötter I, Günaydin I, et al. Efficacy and tolerability of interferon alpha treatment in patients with chronic cystoid macular oedema due to non-infectious uveitis. Br J Ophthalmol 2009; 93:906.
  107. Eser-Ozturk H, Sullu Y. The Results of Interferon-Alpha Treatment in Behçet Uveitis. Ocul Immunol Inflamm 2020; 28:498.
  108. Qian Y, Qu Y, Gao F, et al. Comparison of the Safety and Efficacy of Interferon Alpha-2a and Cyclosporine-A When Combined With Glucocorticoid in the Treatment of Refractory Behçet's Uveitis: A Randomized Controlled Prospective Study. Front Pharmacol 2021; 12:699903.
  109. Davatchi F, Sadeghi Abdollahi B, Shams H, et al. Combination of pulse cyclophosphamide and azathioprine in ocular manifestations of Behcet's disease: longitudinal study of up to 10 years. Int J Rheum Dis 2014; 17:444.
  110. Hamza M, Meddeb S, Mili I, Ouertani A. [Bolus of cyclophosphamide and methylprednisolone in uveitis in Behçet's disease. Preliminary results with the use of new criteria of evaluation]. Ann Med Interne (Paris) 1992; 143:438.
  111. Du LT, Fain O, Wechsler B, et al. [Value of "bolus" cyclophosphamide injections in Behçet's disease. Experience of 17 cases]. Presse Med 1990; 19:1355.
  112. Davatchi F, Shams H, Shahram F, et al. Methotrexate in ocular manifestations of Behcet's disease: a longitudinal study up to 15 years. Int J Rheum Dis 2013; 16:568.
  113. Jap A, Chee SP. Immunosuppressive therapy for ocular diseases. Curr Opin Ophthalmol 2008; 19:535.
  114. Davatchi F, Shams H, Rezaipoor M, et al. Rituximab in intractable ocular lesions of Behcet's disease; randomized single-blind control study (pilot study). Int J Rheum Dis 2010; 13:246.
  115. Coşkun E, Celemler P, Kimyon G, et al. Intravitreal Dexamethasone Implant for Treatment of Refractory Behçet Posterior Uveitis: One-year Follow-up Results. Ocul Immunol Inflamm 2015; 23:437.
  116. Fabiani C, Emmi G, Lopalco G, et al. Intravitreal Dexamethasone Implant as an Adjunct Weapon for Severe and Refractory Uveitis in Behçet's Disease. Isr Med Assoc J 2017; 19:415.
  117. Yalcinbayir O, Caliskan E, Ucan Gunduz G, et al. Efficacy of Dexamethasone Implants in Uveitic Macular Edema in Cases with Behçet Disease. Ophthalmologica 2019; 241:190.
  118. Watanabe K, Tanida S, Inoue N, et al. Evidence-based diagnosis and clinical practice guidelines for intestinal Behçet's disease 2020 edited by Intractable Diseases, the Health and Labour Sciences Research Grants. J Gastroenterol 2020; 55:679.
  119. Ward EM, Woodward TA, Mazlumzadeh M, Calamia KT. Gastrointestinal disease in Behçet's disease. Adv Exp Med Biol 2003; 528:459.
  120. Hatemi I, Esatoglu SN, Hatemi G, et al. Characteristics, Treatment, and Long-Term Outcome of Gastrointestinal Involvement in Behcet's Syndrome: A Strobe-Compliant Observational Study From a Dedicated Multidisciplinary Center. Medicine (Baltimore) 2016; 95:e3348.
  121. Travis SP, Czajkowski M, McGovern DP, et al. Treatment of intestinal Behçet's syndrome with chimeric tumour necrosis factor alpha antibody. Gut 2001; 49:725.
  122. Kram MT, May LD, Goodman S, Molinas S. Behçet's ileocolitis: successful treatment with tumor necrosis factor-alpha antibody (infliximab) therapy: report of a case. Dis Colon Rectum 2003; 46:118.
  123. Kinoshita H, Kunisaki R, Yamamoto H, et al. Efficacy of infliximab in patients with intestinal Behçet's disease refractory to conventional medication. Intern Med 2013; 52:1855.
  124. Hisamatsu T, Ueno F, Matsumoto T, et al. The 2nd edition of consensus statements for the diagnosis and management of intestinal Behçet's disease: indication of anti-TNFα monoclonal antibodies. J Gastroenterol 2014; 49:156.
  125. Zhang Q, Ma C, Dong R, et al. Efficacy and Safety of Anti-Tumor Necrosis Factor-Alpha Agents for Patients with Intestinal Behcet's Disease: A Systematic Review and Meta-Analysis. Yonsei Med J 2022; 63:148.
  126. Suzuki Y, Hagiwara T, Kobayashi M, et al. Long-term safety and effectiveness of adalimumab in 462 patients with intestinal Behçet’s disease: results from a large real-world observational study. Intest Res 2021; 19:301.
  127. Kinoshita H, Nishioka H, Ikeda A, et al. Remission induction, maintenance, and endoscopic outcome with oral 5-aminosalicylic acid in intestinal Behçet's disease. J Gastroenterol Hepatol 2019; 34:1929.
  128. Yurdakul S, Tüzüner N, Yurdakul I, et al. Amyloidosis in Behçet's syndrome. Arthritis Rheum 1990; 33:1586.
  129. Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behçet disease. Curr Opin Rheumatol 2005; 17:1.
  130. Hamuryudan V, Er T, Seyahi E, et al. Pulmonary artery aneurysms in Behçet syndrome. Am J Med 2004; 117:867.
  131. Adler S, Baumgartner I, Villiger PM. Behçet's disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis. Arthritis Care Res (Hoboken) 2012; 64:607.
  132. Desbois AC, Biard L, Addimanda O, et al. Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients. Clin Immunol 2018; 197:54.
  133. Emmi G, Vitale A, Silvestri E, et al. Adalimumab-Based Treatment Versus Disease-Modifying Antirheumatic Drugs for Venous Thrombosis in Behçet's Syndrome: A Retrospective Study of Seventy Patients With Vascular Involvement. Arthritis Rheumatol 2018; 70:1500.
  134. Kehribar DY, Ozgen M. Infliximab treatment in refractory vascular Behcet's disease: A single-center experience. Vascular 2020; 28:829.
  135. Zhong H, Liu T, Liu Y, et al. Efficacy and safety of tocilizumab in Behçet's syndrome with refractory arterial lesions: a single-centre observational cohort study in China. Rheumatology (Oxford) 2022; 61:2923.
  136. Iscan ZH, Vural KM, Bayazit M. Compelling nature of arterial manifestations in Behcet disease. J Vasc Surg 2005; 41:53.
  137. Lê Thi Huong D, Wechsler B, Papo T, et al. Arterial lesions in Behçet's disease. A study in 25 patients. J Rheumatol 1995; 22:2103.
  138. Tuzun H, Seyahi E, Arslan C, et al. Management and prognosis of nonpulmonary large arterial disease in patients with Behçet disease. J Vasc Surg 2012; 55:157.
  139. Ma WG, Zheng J, Zhu JM, et al. Aortic regurgitation caused by Behçet's disease: surgical experience during an 11-year period. J Card Surg 2012; 27:39.
  140. Liu Q, Ye W, Liu C, et al. Outcomes of vascular intervention and use of perioperative medications for nonpulmonary aneurysms in Behçet disease. Surgery 2016; 159:1422.
  141. Gaudric J, Jayet J, Saadoun D, et al. Factors influencing the recurrence of arterial involvement after surgical repair in Behçet disease. J Vasc Surg 2020; 72:1761.
  142. Hosaka A, Miyata T, Shigematsu H, et al. Long-term outcome after surgical treatment of arterial lesions in Behçet disease. J Vasc Surg 2005; 42:116.
  143. Park JH, Chung JW, Joh JH, et al. Aortic and arterial aneurysms in behçet disease: management with stent-grafts--initial experience. Radiology 2001; 220:745.
  144. Nitecki SS, Ofer A, Karram T, et al. Abdominal aortic aneurysm in Behçet's disease: new treatment options for an old and challenging problem. Isr Med Assoc J 2004; 6:152.
  145. Eleshra A, Abdelgawwad M, Regal S, et al. Short-term outcome of primary stent graft for peripheral artery aneurysm in patients with Behçet disease. J Vasc Surg 2021; 73:279.
  146. Voiriot G, Parrot A, Antoine M, et al. Transcatheter embolotherapy of pulmonary artery aneurysms as emergency treatment of hemoptysis in Behcet patients: experience of a referral center and a review of the literature. Intern Emerg Med 2018; 13:491.
  147. Sun L, Liu J, Jin X, et al. Perioperative management with biologics on severe aortic valve regurgitation caused by Behçet syndrome: the experience from a single center. Ther Adv Chronic Dis 2021; 12:20406223211026753.
  148. Mader R, Ziv M, Adawi M, et al. Thrombophilic factors and their relation to thromboembolic and other clinical manifestations in Behçet's disease. J Rheumatol 1999; 26:2404.
  149. Desbois AC, Wechsler B, Resche-Rigon M, et al. Immunosuppressants reduce venous thrombosis relapse in Behçet's disease. Arthritis Rheum 2012; 64:2753.
  150. Saadoun D, Wechsler B, Resche-Rigon M, et al. Cerebral venous thrombosis in Behçet's disease. Arthritis Rheum 2009; 61:518.
  151. Kalra S, Silman A, Akman-Demir G, et al. Diagnosis and management of Neuro-Behçet's disease: international consensus recommendations. J Neurol 2014; 261:1662.
  152. Tayer-Shifman OE, Seyahi E, Nowatzky J, Ben-Chetrit E. Major vessel thrombosis in Behçet's disease: the dilemma of anticoagulant therapy - the approach of rheumatologists from different countries. Clin Exp Rheumatol 2012; 30:735.
  153. Arif S, Arif S, Liaqat J, et al. Transvenous Catheter-Based Thrombolysis With Continuous Tissue Plasminogen Activator Infusion for Refractory Thrombosis in a Patient With Behcet's Disease. Cureus 2020; 12:e10049.
  154. Xu Y, Qiu M. Case Report: Catheter-Directed Endovascular Thrombolysis for Refractory Cerebral Venous Sinus Thrombosis in a Patient With Behçet Disease. Front Neurol 2021; 12:642088.
  155. Yalcin Kehribar D, Gunaydin S, Ozgen M. Infliximab therapy in parenchymal neuro-Behçet's disease: A single-center experience. Int J Rheum Dis 2021; 24:1302.
  156. Kötter I, Günaydin I, Batra M, et al. CNS involvement occurs more frequently in patients with Behçet's disease under cyclosporin A (CSA) than under other medications--results of a retrospective analysis of 117 cases. Clin Rheumatol 2006; 25:482.
  157. Hirohata S, Kikuchi H, Sawada T, et al. Recommendations for the Management of Neuro-Behçet's Disease by the Japanese National Research Committee for Behçet's Disease. Intern Med 2020; 59:2359.
  158. Shugaiv E, Tüzün E, Mutlu M, et al. Mycophenolate mofetil as a novel immunosuppressant in the treatment of neuro-Behçet's disease with parenchymal involvement: presentation of four cases. Clin Exp Rheumatol 2011; 29:S64.
  159. Liu J, Yan D, Wang Z, et al. Tocilizumab in the treatment of severe and refractory parenchymal neuro-Behçet's syndrome: case series and literature review. Ther Adv Musculoskelet Dis 2020; 12:1759720X20971908.
  160. Sfikakis PP, Arida A, Panopoulos S, et al. Brief Report: Drug-Free Long-Term Remission in Severe Behçet's Disease Following Withdrawal of Successful Anti-Tumor Necrosis Factor Treatment. Arthritis Rheumatol 2017; 69:2380.
  161. Martín-Varillas JL, Calvo-Río V, Beltrán E, et al. Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease. Ophthalmology 2018; 125:1444.
  162. Mirouse A, Barete S, Desbois AC, et al. Long-Term Outcome of Ustekinumab Therapy for Behçet's Disease. Arthritis Rheumatol 2019; 71:1727.
  163. Seider N, Beiran I, Scharf J, Miller B. Intravenous immunoglobulin therapy for resistant ocular Behçet's disease. Br J Ophthalmol 2001; 85:1287.
  164. Russell AI, Lawson WA, Haskard DO. Potential new therapeutic options in Behçet's syndrome. BioDrugs 2001; 15:25.
  165. Boyvat A, Sişman-Solak C, Gürler A. Long-term effects of interferon alpha 2A treatment in Behçet's disease. Dermatology 2000; 201:40.
  166. Lockwood CM, Hale G, Waldman H, Jayne DR. Remission induction in Behçet's disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H. Rheumatology (Oxford) 2003; 42:1539.
  167. Sharquie KE, Najim RA, Abu-Raghif AR. Dapsone in Behçet's disease: a double-blind, placebo-controlled, cross-over study. J Dermatol 2002; 29:267.
  168. Matsuda T, Ohno S, Hirohata S, et al. Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behçet's disease: a randomised, double-blind, placebo-controlled study. Drugs R D 2003; 4:19.
  169. Hensel M, Breitbart A, Ho AD. Autologous hematopoietic stem-cell transplantation for Behçet's disease with pulmonary involvement. N Engl J Med 2001; 344:69.
  170. Rossi G, Moretta A, Locatelli F. Autologous hematopoietic stem cell transplantation for severe/refractory intestinal Behcet disease. Blood 2004; 103:748.
  171. Tomonari A, Tojo A, Takahashi T, et al. Resolution of Behçet's disease after HLA-mismatched unrelated cord blood transplantation for myelodysplastic syndrome. Ann Hematol 2004; 83:464.
  172. Stanford M, Whittall T, Bergmeier LA, et al. Oral tolerization with peptide 336-351 linked to cholera toxin B subunit in preventing relapses of uveitis in Behcet's disease. Clin Exp Immunol 2004; 137:201.
  173. Tellier Z. Intravenous immunoglobulin in eye involvement. Clin Rev Allergy Immunol 2005; 29:295.
  174. Namba K, Sonoda KH, Kitamei H, et al. Granulocytapheresis in patients with refractory ocular Behcet's disease. J Clin Apher 2006; 21:121.
  175. Cantarini L, Vitale A, Scalini P, et al. Anakinra treatment in drug-resistant Behcet's disease: a case series. Clin Rheumatol 2015; 34:1293.
  176. Mohammad AJ, Smith RM, Chow YW, et al. Alemtuzumab as Remission Induction Therapy in Behçet Disease: A 20-year Experience. J Rheumatol 2015; 42:1906.
  177. Emmi G, Talarico R, Lopalco G, et al. Efficacy and safety profile of anti-interleukin-1 treatment in Behçet's disease: a multicenter retrospective study. Clin Rheumatol 2016; 35:1281.
  178. Atienza-Mateo B, Calvo-Río V, Beltrán E, et al. Anti-interleukin 6 receptor tocilizumab in refractory uveitis associated with Behçet's disease: multicentre retrospective study. Rheumatology (Oxford) 2018; 57:856.
  179. Mirouse A, Barete S, Monfort JB, et al. Ustekinumab for Behçet's disease. J Autoimmun 2017; 82:41.
  180. Di Scala G, Bettiol A, Cojan RD, et al. Efficacy of the anti-IL 17 secukinumab in refractory Behçet's syndrome: A preliminary study. J Autoimmun 2019; 97:108.
  181. Bettiol A, Silvestri E, Di Scala G, et al. The right place of interleukin-1 inhibitors in the treatment of Behçet's syndrome: a systematic review. Rheumatol Int 2019; 39:971.
  182. Fabiani C, Vitale A, Rigante D, et al. The Presence of Uveitis Is Associated with a Sustained Response to the Interleukin (IL)-1 Inhibitors Anakinra and Canakinumab in Behçet's Disease. Ocul Immunol Inflamm 2020; 28:298.
  183. Ding Y, Li C, Liu J, et al. Tocilizumab in the treatment of severe and/or refractory vasculo-Behçet's disease: a single-centre experience in China. Rheumatology (Oxford) 2018; 57:2057.
  184. Fagni F, Bettiol A, Talarico R, et al. Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre study. Ann Rheum Dis 2020; 79:1098.
  185. Akiyama M, Kaneko Y, Takeuchi T. Effectiveness of tocilizumab in Behcet's disease: A systematic literature review. Semin Arthritis Rheum 2020; 50:797.
  186. Puyade M, Patel A, Lim YJ, et al. Autologous Hematopoietic Stem Cell Transplantation for Behçet's Disease: A Retrospective Survey of Patients Treated in Europe, on Behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation. Front Immunol 2021; 12:638709.
  187. Zhao C, Li C, Duan FJ, et al. Case Report: Repeated Low-Dose Rituximab Treatment Is Effective in Relapsing Neuro Behçet's Disease. Front Neurol 2021; 12:595984.
  188. Atienza-Mateo B, Beltrán E, Hernández-Garfella M, et al. Tocilizumab in Behçet's disease with refractory ocular and/or neurological involvement: response according to different clinical phenotypes. Clin Exp Rheumatol 2021; 39 Suppl 132:37.
  189. Nagieb CS, Harhash TA, Fayed HL, Ali S. Evaluation of diode laser versus topical corticosteroid in management of Behcet's disease-associated oral ulcers: a randomized clinical trial. Clin Oral Investig 2022; 26:697.
  190. Zand N, Ataie-Fashtami L, Mansouri P, et al. Clinical Effect of Non-Thermal CO2 Laser Therapy (NTCLT) on Pain Relief of Oral Aphthous Ulcers of Behçet's Disease. J Lasers Med Sci 2021; 12:e72.
  191. Kural-Seyahi E, Fresko I, Seyahi N, et al. The long-term mortality and morbidity of Behçet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 2003; 82:60.
  192. Yazici H, Başaran G, Hamuryudan V, et al. The ten-year mortality in Behçet's syndrome. Br J Rheumatol 1996; 35:139.
  193. Park KD, Bang D, Lee ES, et al. Clinical study on death in Behçet's disease. J Korean Med Sci 1993; 8:241.
  194. Saadoun D, Wechsler B, Desseaux K, et al. Mortality in Behçet's disease. Arthritis Rheum 2010; 62:2806.
  195. Noel N, Bernard R, Wechsler B, et al. Long-term outcome of neuro-Behçet's disease. Arthritis Rheumatol 2014; 66:1306.
  196. Akman-Demir G, Serdaroglu P, Tasçi B. Clinical patterns of neurological involvement in Behçet's disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain 1999; 122 ( Pt 11):2171.
  197. Kidd D, Steuer A, Denman AM, Rudge P. Neurological complications in Behçet's syndrome. Brain 1999; 122 ( Pt 11):2183.
  198. Farahangiz S, Sarhadi S, Safari A, Borhani-Haghighi A. Magnetic resonance imaging findings and outcome of neuro-Behçet's disease: the predictive factors. Int J Rheum Dis 2012; 15:e142.
  199. Sahin Eroglu D, Torgutalp M, Yucesan C, et al. Prognostic factors for relapse and poor outcome in neuro-Behçet's syndrome: results from a clinical long-term follow-up of a single centre. J Neurol 2022; 269:2046.
  200. Khabbazi A, Ebrahimzadeh Attari V, Asghari Jafarabadi M, Malek Mahdavi A. Quality of Life in Patients With Behçet Disease and Its Relation With Clinical Symptoms and Disease Activity. Reumatol Clin (Engl Ed) 2021; 17:1.
Topic 8239 Version 39.0

References