Dear Editor, Neurological involvement in Behçet's disease (BD) occurs in 5–15% of patients and is collectively defined as neuro-BD.1, 2 Diagnosis is usually established when central and/or peripheral nervous systems are involved in the context of BD and in the absence of other demyelinating, degenerative, tumoral or infectious disorders.3 Focal parenchymal central nervous system (CNS) lesions, aseptic meningo-encephalitis, vascular thrombosis and arterial vasculitis are frequently observed. Radiological assessment, in particular brain magnetic resonance imaging (MRI) and/or cerebrospinal fluid (CSF) examination, are useful tools for the overall evaluation of these patients.4 According to European League Against Rheumatism (EULAR) recommendations, BD therapy is tailored on disease phase and severity, and includes corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate or tumor necrosis factor-α (TNF-α) blockers.5 Recently, the novel interleukin (IL)-1β neutralizing agents canakinumab (at a dose of 150 mg subcutaneously injected every 4–8 weeks) and gevokizumab (at a single dose of 0.3 mg/kg intravenously injected, re-administered on day 28 or later as rescue in the case of relapses), as well as the IL-1 receptor antagonist anakinra (at a daily dose of 2–3 mg/kg subcutaneously injected) have been useful in refractory patients with severe ocular involvement.6, 7 We herein report on a patient with BD presenting an isolated neurological relapse, despite an otherwise good disease control, during treatment with azathioprine and canakinumab. A 30-year-old Caucasian woman was referred to our Rheumatology Unit because of recurrent oral and genital aphthosis, erythema nodosum, pseudofolliculitis and severe bilateral panuveitis since she was 21 years old. In addition, she was human leukocyte antigen (HLA)-B51 positive and complained of arthralgia, recurrent fevers and headache. The patient fulfilled the International Criteria for Behçet's Disease (ICBD),8 presenting a score of eight points, and was diagnosed with BD. During the past years the patient had been treated with high-dose corticosteroids (intravenous methylprednisolone at a dosage of 1 g daily for 5 days, followed by oral prednisone up to 1 mg/kg daily) and one application of 700 μg of preservative-free intravitreal dexamethasone. However, no immunosuppressant agent had been previously administered because of the lack of a definite diagnosis. A further ocular severe relapse occurring 8 weeks after the last cycle of intravenous methylprednisolone led the patient to our attention. During the first admission in our hospital she presented acute loss of vision, while ophthalmologic evaluation showed bilateral uveitis with supraciliary effusions, vitritis, keratitic precipitates, edema of the optic nerve and decreased retinal sensitivity at the visual field test. Accordingly, spectral domain-ocular coherence tomography identified central retinal increased thickness, and fluorescein angiography highlighted bilateral disc hyperfluorescence, with optic nerve head leakage and diffuse late staining. A right segmental scleral buckling due to right retinal detachment was also identified. Brain magnetic resonance imaging (MRI) showed widespread gliotic areas, referred as perivascular inflammation mainly involving the temporal lobes, peritrigonal white matter, corona radiata, semioval center and roof of the ventriculi. Cerebrospinal fluid (CSF) examination showed both normal biochemistry and cell count, while oligoclonal immunoglobulin G (IgG) was identified in the alkaline region of isoelectric focusing gels. No pathogens were found in the CSF. The thrombotic risk profile was negative for factor V Leiden, prothrombin gene G20210A mutation, hyperhomocysteinemia, antithrombin III, protein C or S deficiency, and anti-phospholipid antibodies. No echocardiographic abnormalities were found. For these reasons, azathioprine (at a dosage of 2.5 mg/kg/day) and prednisone (up to 25 mg/day) were started, leading to sustained and complete disease control. However, a further uveitis flare combined with severe headache occurred after 36 months; a second brain MRI showed an increase in the number of hyperintense gliotic lesions. Due to the patient's past history of severe recurrent urinary tract infections and based on our recent interest in IL-1 inhibitors for BD patients with refractory eye involvement,6, 7, 9-11 we decided to add anakinra (100 mg/day) soon after BD exacerbation. This new therapy led to complete disease control within a few days. During the following 18 months no BD manifestations were recorded and headache disappeared. Prednisone dosage was slowly tapered to 5 mg/day. In addition, brain MRI showed a stable neurological picture. Unfortunately, bilateral uveitis reoccurred after 18 months, requiring full-dose prednisone (50 mg/day) and anakinra replacement with canakinumab (at a dosage of 150 mg every 4 weeks). No further ocular manifestations were recorded at the 6-month follow-up visit, although a new brain MRI revealed additional gliotic lesions with perivascular inflammatory infiltrate in the periventricular left temporal area and subcortical frontal parasagittal right area (Fig. 1). As a consequence, prednisone was resumed (to 25 mg daily), azathioprine continued and treatment with the anti-TNF-α agent adalimumab started. The main goal in BD therapeutic strategies is prevention of multi-system damage. Although there is no specific guidance for the management of neuro-BD, EULAR recommendations suggest high-dose corticosteroids, azathioprine, interferon, cyclophosphamide, methotrexate and infliximab for parenchymal lesions in the CNS.12 Cyclosporine, which is largely used to treat ocular manifestations of BD, is not indicated due to its potential neurotoxicity. Recently, increasing interest has been paid to blocking proinflammatory cytokines other than tumor necrosis factor-α, such as IL-1, in parallel with the striking success observed in patients with inherited autoinflammatory disorders.13 According to recent medical reports, uveitis and articular manifestations of BD have proven to be highly responsive to IL-1 inhibition, while mucositis and thrombophlebitis have shown refractoriness, requiring either concomitant corticosteroids and immunosuppressant drugs or switching to different biologic agents.14 However, achieving a full remission of all BD disease signs by blocking a single cytokine is debatable; different clinical BD phenotypes are observable and an ideal therapy needs to be tailored on the basis of the individual clinical picture. In the reported case, we introduced biologic agents with the aim of reversing both eye and CNS damage. In particular, we preferred to initially treat our patient with anti-IL-1 agents rather than TNF inhibitors in consideration of a past history of severe recurrent urinary infections. In fact, IL-1 seems to play a less pronounced role in host defense mechanisms, so that IL-1 inhibition may render patients less susceptible to infectious events, in comparison with TNF-α inhibitors.11, 15 Based on the previous rapidly sustained and long-term response to the IL-1 blocker anakinra, we switched treatment to canakinumab, a second IL-1 inhibitor, when a bilateral uveitis recurred. In support of this, previous data reported canakinumab effectiveness also in anakinra-resistant patients.6, 7 However, although we previously suggested that canakinumab given every 6 weeks could represent a suitable mono-drug therapeutic option for BD patients suffering from mucosal, ocular and gastrointestinal involvement.7 In this case the presence of both ocular and CNS involvement led us to lean towards canakinumab administration every 4 weeks. Notably, anakinra administration prevented neurological disease progression for about 18 months; in contrast, canakinumab did not allow a similar result after loss of anakinra efficacy. This could be due to the different canakinumab pharmacodynamics; in particular, canakinumab function is only limited to IL-1β, while anakinra inhibits the action of both IL-1β and IL-1α. Moreover, a compensatory shift in the cytokine expression profile from IL-1 to other proinflammatory cytokines might have occurred in our patient. In conclusion, this case confirms that IL-1 inhibition can have a role as a therapeutic option in BD patients, especially when presenting with severe uveitis. Nevertheless, canakinumab (at a dose of 150 mg every 4 weeks) has not led to brilliant results in the control of neurological BD manifestations in this patient. Further studies are required to better define and evaluate the long-term effects of anti-IL-1 agents in the management of neuro-BD. Luca Cantarini, grant/research support from Novartis, SOBI and consultant to Novartis, SOBI. All other authors have nothing to disclose.