Approaches to Immunosuppression in Behcet's Disease
Approaches to Immunosuppression in Behcet's Disease
Current treatment of BD is guided by organ involvement (Figure 1) and the severity of the disease, according to The European League Against Rheumatism recommendations from 2008. Although colchicine is sufficient for mucocutaneous and/or articular manifestations, early and aggressive immunosuppresive agents in combination with glucocorticoids are necessary for the more serious manifestations of BD (i.e., ocular, neurologic, gastrointestinal or vascular involvement) (Table 1).
(Enlarge Image)
Figure 1.
Graduated immunosuppressive strategy.
Anti-IL-1: IL-1 inhibitor; Anti-IL-6: IL-6 inhibitor; AZA: Azathioprine.
Oral ulcers are the most frequent and constant symptom of BD. Recurrent oral ulcers and/or genital ulcers, seen in 98 and 77% of patients, respectively, and cutaneous lesions seen in 72% of patients (erythema nodosum, papulopustular lesions, reactivity of the skin to needle prick or injection [pathergy reaction], pseudofolliculitis and acneiform nodules) often precede other manifestations. In a retrospective Japanese study of 412 patients, oral ulcers were the most common initial manifestation, which preceded the diagnosis by 7.5 ± 10.2 years. Genital ulcers and skin involvement were observed 1 or 2 years before BD diagnosis. Most cases can be managed with topical corticosteroids and lidocaine gel. Colchicine has been widely used, although there is no solid evidence to show that it is beneficial for all mucocutaneous lesions.
A 2-year, double-blind, controlled study revealed that colchicine (vs placebo) was effective for genital ulcers and erythema nodosum only in women. Thalidomide has also reported efficacy in treating patients with mucocutaneous lesions refractory to treatment with colchicine. However, teratogenicity, neurotoxicity and constipation restrict usage of this drug. Pentoxifylline, which reduces the production of inflammatory cytokines such as TNF-α, was effective in reducing the frequency and severity of oral and vaginal ulcers. In an open trial, dapsone has been observed to improve severe skin lesions.
Joint involvement affects approximately 50% of patients with BD. Arthralgias and arthritis in BD mainly involve large joints (knees and ankles). Usually, arthritis is not erosive. In two double-blind trials, colchicine was able to control arthralgias and reduced the occurrence of arthritis. For refractory exacerbations, agents such as NSAIDs, methotrexate (MTX), azathioprine (AZA) or in the most refractory cases anti-TNF-α should be tried.
Gastrointestinal manifestations are seen in 6% of patients. Gastrointestinal involvement, characterized by multiple ulcers similar to inflammatory bowel disease, is an important complication of BD that is more prevalent among patients from countries in the Far East. There is no evidence-based treatment that can be recommended for the management of gastrointestinal involvement of BD. Sulfasalazine and 5-aminosalicylate are used empirically but could maintain remission in entero-BD. In a retrospective study this treatment was found to maintain remission in 143 Korean patients with entero-BD. Agents such as corticosteroids, AZA and/or TNF antagonists should be tried first before surgery, except in emergency surgical procedure (perforation).
Neurological manifestations occur in 5–50% of cases in BD, including parenchymal (i.e., meningoencephalitis and pseudotumoral inflammation) and nonparenchymal forms (i.e., dural sinus thrombosis and cerebral arterial aneurysm). In our retrospective study of 64 patients with cerebral venous thrombosis among a cohort of 820, the prevalence of cerebral venous thrombosis among patients with neurological involvement was calculated as 13%. Currently, no controlled data guides the management of CNS involvement in BD. For patients with parenchymal neuro-BD without any poor prognostic factor, AZA and corticosteroids are usually prescribed as first-line treatment. For the more severe patients, intravenous cyclophosphamide (CYC) and corticosteroids are recommended. If these regimens fail, TNF-α-blocking drugs, such as infliximab (IFX), should be added. For dural sinus thrombosis, corticosteroids and anticoagulation are recommended.
Cardiac involvement in BD is rare (approximately 2% of patients). Cardiac abnormalities in patients with BD include pericarditis, myocarditis, endocarditis with valvular regurgitation, intracardiac thrombosis, endomyocardial fibrosis, coronary arteritis with or without myocardial infarction, and aneurysms of the coronary arteries or sinus of Valsalva. Pericarditis is the most common cardiac lesion. The outcome of cardiac involvement in BD is poor. We observed deaths in 15.4% of BD patients with cardiac involvement compared with 5.4% in those without cardiac involvement during a median follow-up of 3 years. Complete remission of cardiac involvement is reported to be associated with anticoagulation, colchicine and use of immunosuppressants, mainly AZA. Even if oral anticoagulation, immunosuppressive agents and colchicine seem to improve the prognosis of cardiac manifestations in BD, data are lacking. Anticoagulation is mainly used for intracardiac thrombosis.
BD can affect both venous and arterial vessels, with venous lesions being more frequent than arterial lesions. Venous thromboses are observed in approximately 20% of patients with BD. In our experience, we found 101 patients with arterial involvement among a cohort of 820 patients with BD followed between 1976 and 2009. Arterial lesions were frequently single (68%), most commonly affecting the aorta, followed by femoral, pulmonary and iliac arteries, and consisted of aneurysms (47%), occlusions (37%) or stenosis (14%). There is no firm evidence to guide us in managing major vessel disease in BD. For the management of acute large deep vein thrombosis in BD, immunosuppressive agents such as corticosteroids, AZA, CYC or ciclosporin are recommended. For the management of arterial aneurysms and/or occlusion, CYC and corticosteroids are recommended. In the case of patients with BD and major vessel thrombosis, there is no consensus on giving anticoagulation, antiplatelet or antifibrinolytic agents, as well as regarding the duration of anticoagulation. Regarding anticoagulation, there are no controlled data or evidence of benefit from uncontrolled studies on anticoagulants in the management of deep vein thrombosis of BD. Some authors recommend anticoagulants for major vein thrombosis, while others suggest they be avoided owing to the increased risk of fatal bleeding from coexisting pulmonary arterial aneurysm and the estimated low risk of pulmonary embolism in BD. In our study, almost all BD patients with deep vein thrombosis received anticoagulation therapy, despite a high number (n = 44, 14.9%) of associated arterial aneurysms, of whom eight had pulmonary arterial aneurysms. The tolerance was satisfactory, with 2% of hemorrhagic complications. In addition, we have previously described that immunosuppressive agents significantly reduce venous thrombosis relapse in BD.
Patients with ocular involvement typically have bilateral nongranulomatous panuveitis and retinal vasculitis. Uveitis is observed in approximately 50% of patients with BD. Uveitis and retinal vasculitis are sight-threatening manifestations of BD with limited treatment options. Despite early treatment with corticosteroids and immunosuppressants, up to 20% of patients become blind. Any patient with BD and inflammatory eye disease affecting the posterior segment should be on a treatment regime that includes AZA and systemic corticosteroids. If the patient has severe eye disease defined as loss of visual acuity (>2 lines) and/or retinal disease (retinal vasculitis or macular involvement), it is recommended that either ciclosporin A (CsA) or IFX be used in combination with AZA and corticosteroids. Alternatively, IFN-α could be used instead. The efficacy of CsA versus IFX has been compared in the early phase of treatments in refractory uveretinitis in BD. In a retrospective study, 17 patients were treated with IFX compared with 20 with CsA, both received in monotherapy. During the 6-month period after the initiation of the treatments, the number of episodes was 0.4 ± 1.0 in the IFX group and 1.2 ± 1.2 in the CsA group. In addition to a lower number of uveitis attacks during the 6 months after the initiation of the treatments in the IFX group compared with the CsA group (p < 0.05), 82% of patients remained relapse-free in the group treated with IFX compared with 45% of patients in the group treated with CsA.
Conventional Immunosuppressive Approach
Current treatment of BD is guided by organ involvement (Figure 1) and the severity of the disease, according to The European League Against Rheumatism recommendations from 2008. Although colchicine is sufficient for mucocutaneous and/or articular manifestations, early and aggressive immunosuppresive agents in combination with glucocorticoids are necessary for the more serious manifestations of BD (i.e., ocular, neurologic, gastrointestinal or vascular involvement) (Table 1).
(Enlarge Image)
Figure 1.
Graduated immunosuppressive strategy.
Anti-IL-1: IL-1 inhibitor; Anti-IL-6: IL-6 inhibitor; AZA: Azathioprine.
Mucocutaneous Involvement
Oral ulcers are the most frequent and constant symptom of BD. Recurrent oral ulcers and/or genital ulcers, seen in 98 and 77% of patients, respectively, and cutaneous lesions seen in 72% of patients (erythema nodosum, papulopustular lesions, reactivity of the skin to needle prick or injection [pathergy reaction], pseudofolliculitis and acneiform nodules) often precede other manifestations. In a retrospective Japanese study of 412 patients, oral ulcers were the most common initial manifestation, which preceded the diagnosis by 7.5 ± 10.2 years. Genital ulcers and skin involvement were observed 1 or 2 years before BD diagnosis. Most cases can be managed with topical corticosteroids and lidocaine gel. Colchicine has been widely used, although there is no solid evidence to show that it is beneficial for all mucocutaneous lesions.
A 2-year, double-blind, controlled study revealed that colchicine (vs placebo) was effective for genital ulcers and erythema nodosum only in women. Thalidomide has also reported efficacy in treating patients with mucocutaneous lesions refractory to treatment with colchicine. However, teratogenicity, neurotoxicity and constipation restrict usage of this drug. Pentoxifylline, which reduces the production of inflammatory cytokines such as TNF-α, was effective in reducing the frequency and severity of oral and vaginal ulcers. In an open trial, dapsone has been observed to improve severe skin lesions.
Joint Involvement
Joint involvement affects approximately 50% of patients with BD. Arthralgias and arthritis in BD mainly involve large joints (knees and ankles). Usually, arthritis is not erosive. In two double-blind trials, colchicine was able to control arthralgias and reduced the occurrence of arthritis. For refractory exacerbations, agents such as NSAIDs, methotrexate (MTX), azathioprine (AZA) or in the most refractory cases anti-TNF-α should be tried.
Gastrointestinal Involvement
Gastrointestinal manifestations are seen in 6% of patients. Gastrointestinal involvement, characterized by multiple ulcers similar to inflammatory bowel disease, is an important complication of BD that is more prevalent among patients from countries in the Far East. There is no evidence-based treatment that can be recommended for the management of gastrointestinal involvement of BD. Sulfasalazine and 5-aminosalicylate are used empirically but could maintain remission in entero-BD. In a retrospective study this treatment was found to maintain remission in 143 Korean patients with entero-BD. Agents such as corticosteroids, AZA and/or TNF antagonists should be tried first before surgery, except in emergency surgical procedure (perforation).
Neurological Involvement
Neurological manifestations occur in 5–50% of cases in BD, including parenchymal (i.e., meningoencephalitis and pseudotumoral inflammation) and nonparenchymal forms (i.e., dural sinus thrombosis and cerebral arterial aneurysm). In our retrospective study of 64 patients with cerebral venous thrombosis among a cohort of 820, the prevalence of cerebral venous thrombosis among patients with neurological involvement was calculated as 13%. Currently, no controlled data guides the management of CNS involvement in BD. For patients with parenchymal neuro-BD without any poor prognostic factor, AZA and corticosteroids are usually prescribed as first-line treatment. For the more severe patients, intravenous cyclophosphamide (CYC) and corticosteroids are recommended. If these regimens fail, TNF-α-blocking drugs, such as infliximab (IFX), should be added. For dural sinus thrombosis, corticosteroids and anticoagulation are recommended.
Cardiac Involvement
Cardiac involvement in BD is rare (approximately 2% of patients). Cardiac abnormalities in patients with BD include pericarditis, myocarditis, endocarditis with valvular regurgitation, intracardiac thrombosis, endomyocardial fibrosis, coronary arteritis with or without myocardial infarction, and aneurysms of the coronary arteries or sinus of Valsalva. Pericarditis is the most common cardiac lesion. The outcome of cardiac involvement in BD is poor. We observed deaths in 15.4% of BD patients with cardiac involvement compared with 5.4% in those without cardiac involvement during a median follow-up of 3 years. Complete remission of cardiac involvement is reported to be associated with anticoagulation, colchicine and use of immunosuppressants, mainly AZA. Even if oral anticoagulation, immunosuppressive agents and colchicine seem to improve the prognosis of cardiac manifestations in BD, data are lacking. Anticoagulation is mainly used for intracardiac thrombosis.
Major Vessel Disease
BD can affect both venous and arterial vessels, with venous lesions being more frequent than arterial lesions. Venous thromboses are observed in approximately 20% of patients with BD. In our experience, we found 101 patients with arterial involvement among a cohort of 820 patients with BD followed between 1976 and 2009. Arterial lesions were frequently single (68%), most commonly affecting the aorta, followed by femoral, pulmonary and iliac arteries, and consisted of aneurysms (47%), occlusions (37%) or stenosis (14%). There is no firm evidence to guide us in managing major vessel disease in BD. For the management of acute large deep vein thrombosis in BD, immunosuppressive agents such as corticosteroids, AZA, CYC or ciclosporin are recommended. For the management of arterial aneurysms and/or occlusion, CYC and corticosteroids are recommended. In the case of patients with BD and major vessel thrombosis, there is no consensus on giving anticoagulation, antiplatelet or antifibrinolytic agents, as well as regarding the duration of anticoagulation. Regarding anticoagulation, there are no controlled data or evidence of benefit from uncontrolled studies on anticoagulants in the management of deep vein thrombosis of BD. Some authors recommend anticoagulants for major vein thrombosis, while others suggest they be avoided owing to the increased risk of fatal bleeding from coexisting pulmonary arterial aneurysm and the estimated low risk of pulmonary embolism in BD. In our study, almost all BD patients with deep vein thrombosis received anticoagulation therapy, despite a high number (n = 44, 14.9%) of associated arterial aneurysms, of whom eight had pulmonary arterial aneurysms. The tolerance was satisfactory, with 2% of hemorrhagic complications. In addition, we have previously described that immunosuppressive agents significantly reduce venous thrombosis relapse in BD.
Eye Involvement
Patients with ocular involvement typically have bilateral nongranulomatous panuveitis and retinal vasculitis. Uveitis is observed in approximately 50% of patients with BD. Uveitis and retinal vasculitis are sight-threatening manifestations of BD with limited treatment options. Despite early treatment with corticosteroids and immunosuppressants, up to 20% of patients become blind. Any patient with BD and inflammatory eye disease affecting the posterior segment should be on a treatment regime that includes AZA and systemic corticosteroids. If the patient has severe eye disease defined as loss of visual acuity (>2 lines) and/or retinal disease (retinal vasculitis or macular involvement), it is recommended that either ciclosporin A (CsA) or IFX be used in combination with AZA and corticosteroids. Alternatively, IFN-α could be used instead. The efficacy of CsA versus IFX has been compared in the early phase of treatments in refractory uveretinitis in BD. In a retrospective study, 17 patients were treated with IFX compared with 20 with CsA, both received in monotherapy. During the 6-month period after the initiation of the treatments, the number of episodes was 0.4 ± 1.0 in the IFX group and 1.2 ± 1.2 in the CsA group. In addition to a lower number of uveitis attacks during the 6 months after the initiation of the treatments in the IFX group compared with the CsA group (p < 0.05), 82% of patients remained relapse-free in the group treated with IFX compared with 45% of patients in the group treated with CsA.