Description of the condition
Behçet's Syndrome (BS) is a chronic, relapsing, inflammatory vascular disease characterised by ulcers in the mouth and on the genitals, and inflammation in parts of the eye (uveitis) as well as arthritis (swollen, painful, stiff joints), skin problems, and inflammation of the digestive tract, brain, and spinal cord. Onset most commonly occurs in adults, but paediatric cases have been reported. Both genders are affected equally, but the disease runs a more severe course in males (Yazici 2012). The disease course is characterised by exacerbations and remission ending in a total remission in at least 60% of patients at 20 years of follow-up (Kural-Seyahi 2003).
The disease is of unknown origin. There is no evidence of an infectious cause. A correlation between genetic predisposition and triggering extrinsic factors has been suggested, because more than 60% of BS patients are associated with HLA-B 51 (Yazici 1980; Gül 2012; Kose 2012). Some clinical features show distinct geographical differences. The prevalence is high in Turkey (> 1/1000 people). Fewer cases of intestinal disease are reported in the Mediterranean area; eye disease causes considerable morbidity in Turkish patients (Kural-Seyahi 2003; Tugal-Tutkun 2004) but is rarely a severe problem among Italian (Salvarani 2007) or American patients (Calamia 2009). A positive skin pathergy test is less frequent among patients from northern Europe, America or Japan (Hatemi 2012; Yazici 2012).
The diagnostic criteria for BS were defined by the International Study Group (ISG) for Behçet's Disease in 1990, and include the presence of recurrent oral ulceration, with at least 3 episodes over 12 months, in addition to 2 of the following features: recurrent genital ulcers, eye lesions, skin lesions and a positive pathergy test (ISG 1990). An international team (from 27 countries) has recently proposed a revision of the ISG criteria, in which eye lesions, oral ulcers and genital ulcers are each assigned two points, while skin lesions, Central Nervous System (CNS) involvement and vascular manifestations are assigned one point each. The pathergy test, when used, was assigned one point. A patient scoring four or more points is classified as having BS. These new criteria would have higher sensitivity over the ISG criteria while maintaining reasonable specificity (ICBD 2013).
When the disease involves the CNS it is defined as Neuro-Behçet Syndrome (NBS). Sporadic neurological manifestations are frequent (> 20%), often occurring 1 to 10 years after initial symptoms, but in some cases neurological symptoms are the first manifestation of BS (Akman-Demir 1999; Al-Araji 2009). NBS is more frequent in men than women and it usually occurs at between 20 and 40 years of age ( Al-Araji 2009; Dalvi 2012).
There are two main categories of NBS that should be considered separately: parenchymal and non-parenchymal (Serdaroglu 1998). Parenchymal NBS includes the following four syndromes:
Brainstem involvement that includes ophthalmoparesis, cranial neuropathy, and cerebellar or pyramidal dysfunction.
Cerebral hemispheric involvement that presents with encephalopathy, hemiparesis, hemisensory loss, seizures, dysphasia, cognitive dysfunction and psychosis.
Spinal cord involvement that occurs with pyramidal signs in the limbs, sensory level dysfunction, and, commonly, sphincter dysfunction.
Evidence for cerebral or spinal cord involvement in addition to the brainstem signs and symptoms.
Non-parenchymal NBS occurs as cerebral venous thrombosis or intracranial and extracranial aneurysm (Al-Araji 2009). Patients with non-parenchymal NBS have a significantly better prognosis than those with parenchymal NBS (Siva 2001).
Around a third of NBS patients have single episodes, a third have repeated relapses with remission, and a third undergo a progressive disease course with accrual of multiple functional disability (Akman-Demir 1999; Al-Fahad 1999; Kidd 1999; Siva 2001; Kural-Seyahi 2003). High cellular and/or protein content in the cerebrospinal fluid and parenchymal involvement, especially of the brainstem, are associated with a worse prognosis (Akman-Demir 1999).
Description of the intervention
There is no cure for BS. Treatments focus on relieving the symptoms and preventing worsening or complications.
Treatments for BS include: biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha. Corticosteroids are prescribed for acute exacerbations, to reduce severe joint pain, skin sores, eye disease, or CNS symptoms. Long-term use of corticosteroids in addition to immunosuppressants is also reported. However long-term corticosteroids may cause several side effects such as diabetes, osteoporosis, weight gain, infections, delayed wound healing, persistent heartburn, elevated blood pressure and mental disorders (Mat 2006). Immunosuppressants such as azathioprine, cyclophosphamide, chlorambucil, cyclosporine-A, methotrexate, micophenolate, mitoxantrone, levamisole and tacrolimus are used for patients with BS to reduce inflammation, and prevent exacerbations and complications, but they also cause serious adverse events (Hatemi 2008).
In recent years, there has been considerable interest in evaluating the efficacy of biologics for BS. These compounds have been licensed for use in other conditions, e.g. rheumatoid arthritis, psoriasis, psoriatic arthritis and inﬂammatory bowel disease (Singh 2011). Biologics are a group of medications that suppress the immune system and reduce inﬂammation. Even though suppressing the immune system can increase the risk of infections, it also helps to stabilise an overactive immune system. The following biologics are used off-label for patients with BS: anti-CD20 (rituximab), anti-interleukin (IL)1 (anakinra, canakinumab, gevokizumab, rilonacept), 2 (daclizumab), 6 (tocilizumab), and 17 (secukinumab), and Tumor Necrosis Factor (TNF) inhibitors (adalimumab, etanercept, inﬂiximab). Biologics are administered subcutaneously except for inﬂiximab and rituximab, which are administered as intravenous infusions. Several adverse events such as tuberculosis reactivation with biologics are drug-specific. However, some adverse events such as increased risk of infection are related to a general immunomodulator or immunosuppressive effect and are common to all biologics (Singh 2011).
How the intervention might work
Immunosuppressants are agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others act through activation of T-cells or by inhibiting the activation of helper T-cells, targeting immune mechanisms important in BS pathogenesis (Abbas 2001; Kose 2012).
Biologics are highly specific molecules targeting various immune cells that play a key role in local and systemic inflammation (Singh 2011). Anti-TNF blockers include both soluble receptors that serve as decoy receptors competing with TNF-receptors (etanercept) and monoclonal antibodies targeting the TNF-receptors (adalimumab and infliximab). Rituximab is a monoclonal antibody against CD20, which is found primarily on B-cells. Clinical and laboratory observations suggested an important role of TNF-mediated process in the pathogenesis of BS (Kose 2012). Increased levels of TNF, soluble TNF receptors, and TNF-producing cells were found in the peripheral blood of patients with active disease. Among inﬂammatory cytokine-related genes, TNF blockade reduced expression of IL-1 receptor type 2, interferon γ receptors, IL-6 receptors, and IL-17 receptors (Keino 2011). It was found that inﬂiximab is capable of interfering with gamma delta T cell function in BS characterised by dysregulated cell-mediated immunity (Accardo-Palumbo 2010). Arida analysed published data on 369 patients treated with either adalimumab, etanercept or inﬂiximab, and reported that the majority of patients showed improvement of their mucocutaneous manifestations (Arida 2011). Rituximab was found effective in retinal vasculitis and ocular manifestations in BS (Davatchi 2010). Regeneron and canakinumab are human anti-IL-1β monoclonal antibodies, targeting a cytokine implicated in the pathogenesis of many inﬂammatory diseases. Reports from clinical trials suggest that rilonacept and canakinumab are well tolerated in patients with BS and no serious adverse effects were reported (Dubois 2011).
Why it is important to do this review
A Cochrane review (Saenz 1998) on general management of BS was published in 1998 but it did not consider NBS. A systematic review of all available studies is warranted to evaluate the efficacy and safety of the treatments for NBS.