Behçet's disease (BD) is a chronic, relapsing, and debilitating systemic vasculitis of unknown aetiology with the clinical features of mucocutaneous lesions, ocular, vascular, articular, neurologic, gastrointestinal, urogenital, and pulmonary involvement. The disease is much more frequent along the ancient “Silk Route” extending from Eastern Asia to the Mediterranean basin, compared with Western countries. The disease usually starts around the third or fourth decade of life. Male sex and a younger age of onset are associated with more severe disease. Although the treatment has become much more effective in recent years, BD is still associated with severe morbidity and considerable mortality. The main aim of the treatment should be the prevention of irreversible organ damage. Therefore, close monitoring, early, and appropriate treatment is mandatory to reduce morbidity and mortality. The treatment is mainly based on the suppression of inflammatory attacks of the disease using immunomodulatory and immunosuppressive agents. In this paper, current state of knowledge regarding the therapeutic approaches is outlined. To provide a rational framework for selecting the appropriate therapy along the various treatment choices, a stepwise, symptom-based, evidence-based algorithmic approach was developed.
Behçet's disease (BD) is a chronic, relapsing, and debilitating systemic vasculitis of unknown aetiology with the clinical features of mucocutaneous lesions, ocular, vascular, articular, neurologic, gastrointestinal, urogenital, and pulmonary involvement [
Mucocutaneous lesions figure prominently in the presentation and diagnosis and may be considered the hallmarks of BD. Oral ulcers (OUs), genital ulcers (GUs), and cutaneous lesions together with ocular lesions and arthropathy are the most frequent features of the disease in all countries. Mucocutaneous lesions often precede other manifestations. Therefore, their recognition may permit earlier diagnosis and treatment, with salutary results [
Ocular involvement is a serious complication of BD and is characterized by repeated, explosive inflammatory attacks that may lead to visual loss in almost 15% of eyes. Panuveitis is the most frequent ocular lesion in BD. Anterior uveitis, posterior uveitis, and retinal vasculitis are the other main ocular manifestations. They are bilateral in most of the patients [
BD runs a chronic course with unpredictable exacerbations and remissions. In a recent multicenter study [
Each or any combination of mucocutaneous, articular, and ocular symptoms of the disease may have significant pain or loss in function, or both. Besides considerable morbidity, the disease confers an increased mortality, mainly due to large vessel (especially pulmonary arterial) and neurologic involvement as well as bowel perforation. In general, mortality ratios as well as mucocutaneous and articular manifestations tend to decrease significantly with the passage of time. Both the onset of eye disease and its greatest damage are usually within the first few years of disease onset. A recent study [
Treatment of the disease has become much more effective in recent years because of advances in understanding the pathogenesis the underlying disease and availability of a wide spectrum of therapeutic agents. Although several effective treatments currently exist, none of them result in a cure of the disease and some are associated with significant side effects. The choice of treatment is generally based on the clinical presentation and the site affected. However, the main aim of the treatment should be the prevention of irreversible organ damage, especially, during the early, active phase of the disease. Close monitoring and appropriate treatment may control and change the course of the disease. It is wise to remember that especially male patients and those with early onset disease are associated with more severe presentations including major vessel disease, ocular, gastrointestinal, and neurological involvement and, therefore, require more aggressive treatment [
This paper overviews the current state of knowledge regarding the therapeutic approaches for BD. Based on the mainly controlled studies and personal experience in clinical practice and basic research in this field, a stepwise, symptom-based, evidence-based algorithmic approach for the management of BD was proposed. This approach might enable clinicians to rationalize and further increase the selection of the most appropriate therapy among numerous treatment options [
The majority of experience in the treatment of OUs comes from the studies performed in patients with recurrent aphthous stomatitis (RAS). As we mentioned before, OUs of BD are identical to RAS in appearance. Therefore, therapeutic remedies related with RAS, to some extent, can be applied to OUs of BD.
Although controlled studies are still lacking, the efficacy of topical
In addition to the above-mentioned treatment approaches to OUs, patients should be advised to maintain good daily oral hygiene [
Corticosteroids have been widely used almost for all lesions of the disease. The compound is an effective choice especially in mucocutaneous lesions, acute uveitis, and neurologic disease. They can be given as monotherapy or in combination with other drugs such as colchicine, interferon (IFN)-
Colchicine inhibits the enhanced chemotactic activity of neutrophils. Promising results with colchicine (0.5–2 mg/d p.o.) have been reported especially in mucocutaneous and articular findings. The first placebo-controlled study suggested that the drug is effective only for EN and arthralgia [
Recently, Davatchi et al. [
Calguneri et al. [
In a double-blind, placebo-controlled study of 35 BD patients, having as the main symptom OUs, Matsuda et al. [
In a recent controlled study of 32 patients, Sharquie et al. [
Dapsone also inhibits the enhanced chemotactic activity of neutrophils and can be used as an alternative compound to colchicine. In a double-blind, crossover study of 20 patients, Sharquie et al. reported significant reductions in the number, duration, and frequency of OUs and number of GUs in dapsone-treated patients. This compound also showed a significant decrease in the frequency of EN and PPLs. Arthritis and epididymitis were also significantly supressed by dapsone, but the effect of the compound on arthralgia failed to reach the level of statistical significance [
Despite the encouraging results of the last three studies, a limited number of patients included, and a relatively short follow-up periods were the main limitations.
The drug selectively inhibits TNF-
Azathioprine, an important disease-modifying compound, shows an anti-inflammatory effect by suppressing both cellular and humoral immune responses. In a randomised, double-blind, placebo-controlled study [
Cyclophosphamide is the fast-acting alkylating agent. It has been found as a beneficial therapeutic agent for eye disease and systemic vasculitis (neurologic involvement and arterial aneurysms). In a double-blind crossover study [
Cyclosporin A (CyA) is an immunosuppressant agent which selectively inhibits T lymphocytes. The drug is capable of markedly ameliorating uveitis as well as mucocutaneous lesions. CyA is still one of the most effective agents for the treatment of uveitis which reduces the frequency of ocular exacerbations and improves visual acuity. In a conrolled study of 96 patients with recurrent uveitis, CyA (10 mg/kg/d) has been shown to be superior to colchicine (1 mg/d) in decreasing frequency and severity of ocular attacks [
In recent years, the increasing evidence suggests that interferon (IFN)-
IFN-
The primary side effects of IFN-
Several pieces of evidence indicate that TNF-
The majority of current data related with infliximab comes from the uncontrolled, open studies, small case series, and case reports. The main 3 prospective studies performed by Sfikakis et al. [
Melikoglu et al. [
A recent position paper concluded that infliximab is recommended as an add-on therapy for severe BD, refractory or intolerant to traditional immunosuppressive regimens. Moreover, a single infusion of infliximab (5 mg/kg) can be used as a first-line agent for sight-threatening, bilateral posterior eye segment inflammation, because the fast onset of response is critical to prevent fixed retinal lesions, and therefore, permanent visual loss. In case when ocular relapses are not controlled by azathioprine and/or cyclosporin, maintenance therapy with 5 mg/kg doses of infliximab every 6–8 weeks could be used for 2 years, provided no relapses occur between intervals [
However, the high cost, the need for injections, troublesome toxic side effects, and the inability to cure the disease are the main limitations for widespread acceptance of anti-TNF-
Adverse effects of anti-TNF-
Rituximab is a chimeric monoclonal antibody against CD20, a B-cell differentiation marker. Recently, Davatchi et al. [
Several open studies of
Although various treatment modalities appear, surgical intervention often is indicated for arterial aneurysms. In patients with recurrent or massive hemoptysis, surgery may be necessary. Endovascular treatment for pseudoaneurysms due to BD seems to be an effective choice when the disease activity is strictly controlled with immunosuppressive therapy [
Activity spectrum of systemic therapeutic agents on BD in randomized, controlled studies is summarized in Table
Activity spectrum of systemic therapeutic agents on Behçet’s disease in randomized, controlled studies.
Treatment | Dose | Indication and reference |
---|---|---|
Corticosteroids versus placebo | 40 mg/every 3 w | Decrease the frequency of EN in women [ |
Colchicine versus placebo | 1–2 mg/d | Decreases the frequency of EN and effective on arthralgia [ |
1 mg/d | Decrease in overall disease activity index and significant improvement in OUs, GUs, PPLs, and EN [ | |
Colchicine versus Colchicine + Benzathine penicillin | 1–2 mg/d; 1.2 MU/3 w | Combined treatment more effective in reducing frequency of arthritic episodes, duration and frequency of OUs and EN, and the frequency of GUs [ |
Colchicine versus Benzathine penicillin versus Colchicine + Benzathine penicillin | 1 mg/d; 1.2 MU/mo | Combined use of colchicine and benzathine penicillin treatment more effective than colchicine or penicillin alone [ |
Rebamipide versus placebo | 300 mg/d | Reduces the number of OUs and pain [ |
Zinc sulfate versus placebo | 300 mg/d | Significant improvement in the clinical manifestations index of mucocutaneous lesions [ |
Dapsone versus placebo | 100 mg/d | Effective on the number, healing time and frequency of OUs, number of GUs, and frequency of EN and PPLs. Suppresses arthritis and epididymitis [ |
Thalidomide versus placebo | 100–300 mg/d | Sustained remission of OUs, GUs, and PPLs [ |
Azathioprine versus placebo | 2,5 mg/kg/d | Reduces the occurrence of OUs, GUs, arthritis, and ocular symptoms. Prevents the development of new eye disease [ |
Cyclophosphamide + Corticosteroids versus Corticosteroids | 1 g/m2/mo | Combined treatment of CCP and corticosteroids more effective in eye disease than corticosteroids alone [ |
Cyclosporin A versus Colchicine | 10 mg/kg/d | CyA more effective on the severity and frequency of OUs, GUs, and PPLs. Superior to colchicine in decreasing the frequency and severity of ocular attacks [ |
Cyclosporin A versus conventional treatments (prednisolon, chlorambucil) | 10 mg/kg/d | CsA more effective than conventional therapy in ocular disease, however, conventional therapy superior to CyA in controlling OUs, GUs, and arthritis [ |
Cyclosporin A versus conventional treatments (prednisolon, chlorambucil) | 10 mg/kg/d | Improvement of hearing loss in 25% of patients receiving CyA treatment [ |
Cyclosporin A versus Cyclophosphamide | 5 mg/kg/d | A significant improvement in VA during the first 6 months in CyA group compared with CCP [ |
Cyclosporin A versus conventional treatments (prednisolon, Azathioprine) | 5 mg/kg/d | CyA more effective than conventional therapy in OUs, GUs, cutaneous lesions, thrombophlebitis as well as articular and neurologic symptoms [ |
Interferon- | 6 MU/d-3 x/w | Effective on pain and healing time of OUs and frequency of GUs and PPLs. Also helpful in decreasing frequency and duration of EN, TFB, and articular symptoms [ |
Etanercept versus placebo | 25 mg/d-2 x/w | Reduces the occurrence of OUs, nodular skin lesions, and PPLs [ |
Rituximab versus cytotoxic combination therapy | 2 1000-mg courses (15-day interval) | A significant improvement in total adjusted disease activity index in rituximab group [ |
d: day; EN: erythema nodosum; GUs: genital ulcers; Mo: month; OUs: oral ulcers; PPLs: papulopustular lesions; TFB: thrombophlebitis; VA: visual acuity; w: week.
Summary of evidence-based algorithmic treatment for mucocutaneous Behçet’s disease.
1st line | *Topical: Antimicrobial agents, Sucralfate, Corticosteroids, Pimecrolimus |
Systemic: Colchicine, Colchicine + Benzathine penicillin | |
2nd line | *Topical: Anti-inflammatory agents, Amlexanox |
Systemic: Corticosteroids, Dapsone, Azathioprine, Thalidomide | |
3rd line | *Topical: Anaesthetics, Silver nitrate |
Systemic: Zinc sulfate, Rebamipide, Pentoxifylline, Methotrexate, Cyclosporine-A, IFN- |
*Since the effectiveness of topical treatment is generally limited to the application area, it should almost always be associated with systemic therapy.
Summary of evidence-based algorithmic treatment for articular Behçet’s disease.
1st line | Colchicine, Colchicine + Benzathine penicillin, or anti-inflammatory analgesics |
2nd line | Azathioprine, Corticosteroids |
3rd line | Methotrexate, Salazopyrine, IFN- |
Summary of evidence-based algorithmic treatment for ocular Behçet’s disease.
1st line | *Topical: corticosteroids + mydriatics ± cycloplegic agents |
Systemic: Corticosteroids, Cyclosporine-A, Azathioprine | |
2nd line | IFN- |
3rd line | Methotrexate, Mycophenolate mofetil, Cyclophosphamide, Rituximab |
*Topical treatment as a sole agent should be restricted to those who has mild uveitis (anterior uveitis).
Summary of evidence-based algorithmic treatment for Vasculo-Behçet disease.
1st line | Corticosteroids, Azathioprine, Cyclophosphamide, |
2nd line | Anti-TNF- |
3rd line | Anticoagulation, Antiplatelets |
Summary of evidence-based algorithmic therapy for Neuro-Behçet's disease.
1st line | Corticosteroids |
2nd line | Azathioprine, cyclophosphamide, Anti-TNF- |
3rd line | Methotrexate, Anticoagulation |
Colchicine should be the first choice in the treatment of GUs and/or EN, especially in female patients [
Short-term corticosteroids in combination with other drugs such as colchicine can be used as alternatives in the treatment of acute attacks of mucocutaneous lesions [
Rebamipide [
Antimicrobial agents [
Evidenced based algorithmic treatment approach for mucocutaneous Behçet’s disease is summariezed in Table
Evidenced-based algorithmic treatment approach for articular Behçet’s disease is summariezed in Table
Colchicine should be the first choice [
In unresponsive cases, azathioprine [
Although controlled studies are still lacking, methotrexate and salazopyrine are used successfully in the clinical practice [
Evidenced-based algorithmic treatment approach for ocular Behçet’s disease is summarized in Table
Ocular involvement requires special attention and usually aggressive treatment since it has the highest morbidity. In mild uveitis such as anterior uveitis, topically applied corticosteroid eye drops together with mydriatics or cycloplegic agents can often control the disease [
As we mentioned before, IFN-
Methotrexate, MMF, cyclophosphamide, and rituximab can be used in selected patients as a 3rd-line therapy [
In the most severe cases with retinal vasculitis or macular involvement, CyA or anti-TNF-
Although several promising therapies are evolving, the treatment of severe disease is not entirely satisfactory and treatment of those remains predominantly empirical. Severe disease has relatively lower incidence. Because of the limited number of patients enrolled in studies in this area statistical comparisons were usually not made. These factors make recommendation of individual treatments difficult for these involvements.
Evidenced-based algorithmic treatment approach of Behçet’s disease with large vessel, neurologic, and gastrointestinal involvement is summarized in Tables
Summary of evidence-based algorithmic therapy for gastrointestinal Behçet's disease.
1st line | Sulfasalazine, corticosteroids |
2nd line | Azathioprine |
3rd line | Anti-TNF- |
In the presence of deep vein thromboses, azathioprine can be used. In severer cases with inferior vena cava or superior vena cava syndrome and Budd-Chiairi syndrome cyclophosphamide as monthly pulse treatment should be added to the treatment. It is unclear the effectiveness of additional use of antiplatelets or anticoagulation [
In arterial involvement, corticosteroids together with cyclophosphamide are generally preferred to control the disease. Anticoagulation should not be given in the presence of pulmonary arterial aneurysm because of the danger of bleeding [
Surgery may be necessary in life-threatening conditions such as growing aneurysm, acute rupture [
In parenchymal involvement, corticosteroids (100 mg/d or 1 gx 5 days as pulse treatment) should be the first choice. Azathioprine is usually combined with corticosteroids. In severe or unresponsive cases, cyclophosphamide can be given additionally [
In venous sinus thrombosis corticosteroids with or without immunosuppressives are the main treatment approaches. In this situation additional use of anticoagulation is also suggested [
Sulfasalazine and corticosteroids seem to be the 1st-line treatment options [
In conclusion, treatment of BD has become much more effective in recent years. Due to recent advances in understanding the pathogenesis of the underlying disease and availability of a wide spectrum of therapeutic agents, alleviation of most symptoms, control of the disease, and, even, modification of the course of the disease are now possible.