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Behçet's disease (BD) associated uveitis occurs in approximately 50–70% of the patients. Ocular involvement in BD may induce a severe affection of visual function, leading to a considerable decrease in patients' quality of life. The risk for severe visual loss increases when the ocular posterior segment is involved and in patients with no adequate treatment. Monoclonal tumor necrosis factor (TNF) biotechnological inhibitors represent a relatively recent milestone for the treatment of non-infectious uveitis (NIU) also in BD patients. In addition to TNF inhibitors, further biologic agents have been increasingly proposed for multi-recalcitrant cases, as for interleukin (IL)-1 and IL-6 inhibitors. However, evidence on these new opportunities requires to be widened in the next future. Joining the forces for scientific efforts is essential to quickly obtain solid acquisitions useful for the everyday clinical practice. To this end, the Auto-Inflammatory Disease Alliance (AIDA) Network has recently supported the development of an international registry dedicated to NIU and other inflammatory ocular involvement observed in BD patients. This will be essential to resolve current and future unmet needs burdening the everyday clinical practice. [ABSTRACT FROM AUTHOR]

Posterior idiopathic scleritis is the most common type of scleritis observed in childhood. Nevertheless, anterior and even necrotizing inflammatory scleritis may occur as well. Although less frequently than in the adult population, scleral inflammation can be associated with systemic disorders, which should be promptly recognized and treated to avoid both ocular and systemic complications. Hence, a multidisciplinary diagnostic work-up should be performed to rule out primarily infectious and autoimmune causes, such as viral and bacterial infections, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, pediatric sarcoidosis, Behçet's disease and HLA-B27-associated diseases. Treatment of scleritis should aim to control ocular inflammation, relieve symptoms and prevent relapses, to avoid complications, preserve visual acuity and improve the child's quality of life. It should be tailored to the patient, considering the type and severity of scleritis, the possible identification of an infectious cause or the presence of an associated rheumatologic condition. [ABSTRACT FROM AUTHOR]

Behçet's syndrome (BS) is a multisystemic disorder displaying a marked variability across different geographic areas. The main aim of this study was to analyze demographic and clinical features of a cohort of BS patients diagnosed in three tertiary referral centers in Italy and detect potential associations between the different manifestations. Medical records of 396 patients (218 females, 178 males) were retrospectively analyzed. Mean age at onset was 30.00 ± 18.75 years with a female-to-male ratio of 1.22:1. Mucocutaneous features were the most frequent starting manifestations of BS, followed by eye inflammation. Erythema nodosum (p = 0.007), arthritis/arthralgias (p = 0.0115), and central nervous system (CNS) signs (p = 0.014) were significantly over-represented in female patients, whereas male gender was associated with lower mean age at onset (p = 0.031), higher frequency of pseudofollicular lesions, and uveitis (p = 0.00134 and p < 0.0001 respectively), particularly for posterior segment involvement and panuveitis (p < 0.0001). Regarding the association between disease features, genital ulcers were negatively associated with uveitis (p < 0.0001) and vascular involvement (p < 0.0001). Other negative associations were detected between uveitis and gastrointestinal involvement (p = 0.008), pseudofolliculitis and CNS signs (p = 0.031), vascular involvement (p = 0.002) and erythema nodosum (p = 0.013). Logistic regression identified male gender and genital ulcers, respectively, with a higher (OR 2.199 [1.397-3.461], p < 0.001) and lower risk (OR 0.157 [0.090-0.273], p < 0.0001) of developing major organ involvement. Our evaluations found that the disease had started mostly in the second and third decade with most severe features in the male gender, and that patients presenting with mucocutaneous manifestations were less prone to develop major organ involvement. [ABSTRACT FROM AUTHOR]

To compare the efficacy of adalimumab (ADA) and infliximab (IFX) in patients with non-infectious intermediate uveitis, posterior uveitis, and panuveitis. Demographic, clinical, instrumental, and therapeutic data from patients enrolled were collected at the start of treatment, at 12-month follow-up, and at the last follow-up assessment. One hundred seven patients (46 females, 187 eyes) were enrolled, 66 (61.7%) treated with ADA and 41 (38.3%) with IFX. Bilateral involvement was observed in 80 cases. The mean follow-up was 26.45 ± 21.71 months for ADA patients and 56.60 ± 56.04 months for IFX patients. The overall decrease of uveitis frequency during the first 12 months of treatment was 66.7% in the IFX group and 84.2% in the ADA group, compared to the previous 12 months (p = 0.09). A significantly higher corticosteroid dosage was found among patients treated with ADA at the last follow-up visit (p = 0.008). The percentage of patients co-administered with corticosteroids was significantly higher among ADA patients both at the 12-month visit (p = 0.03) and at the last visit (p = 0.0004). The frequency of uveitic macular edema (UME) was significantly higher among patients treated with ADA compared to those treated with IFX at the 12-month assessment (p = 0.015) and at the last follow-up visit (p = 0.011); central macular thickness was significantly higher in ADA group compared to the IFX group at the last follow-up assessment (p = 0.04). ADA and IFX have shown a similar efficacy in controlling uveitis relapses, but IFX showed a more pronounced corticosteroid sparing effect and a significantly higher capacity in resolving UME compared to ADA. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the 10-year drug retention rate of infliximab (IFX) in Behçet's disease (BD)-related uveitis, the effect of a concomitant use of disease modifying anti-rheumatic drugs (DMARDs) on drug survival and differences according to the lines of biologic treatment.Methods: Cumulative survival rates were studied using the Kaplan-Meier plot, while the Log-rank (Mantel-Cox) test was used to compare survival curves.Results: Forty patients (70 eyes) were eligible for analysis. The drug retention rates at 12-, 24-, 60- and 120-month follow-up were 89.03%, 86.16%, 75.66% and 47.11% respectively. No differences were identified according to the use of concomitant DMARDs (p = 0.20), while a statistically significant difference was observed in relation to the different lines of IFX treatment (p = 0.014). Visual acuity improved from baseline to the last follow-up visit (p = 0.047) and a corticosteroid-sparing effect was observed (p < 0.0001).Conclusions: IFX retention rate in BD-uveitis is excellent and is not affected by concomitant DMARDs. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate golimumab (GOL) efficacy in the management of Behçet's disease (BD)-related uveitis.Methods: We retrospectively collected data from 5 patients (8 eyes) with at least two recent relapses of uveitis, treated with GOL at the standard dose of 50 mg every 4 weeks.Results: A complete control of intraocular inflammation was observed in 7/8 eyes (87.5%) at 12-month follow-up. The number of relapses 12 months before and after GOL initiation was 11 and 1, respectively. At baseline, four eyes had active retinal vasculitis (RV). At 3-month follow-up evaluation RV resolved in all eyes. Mean Best Corrected Visual Acuity was 6.93 ± 4.34 at baseline and 7.32 ± 3.87 at 12-months follow-up.Conclusion: We confirm GOL efficacy in reducing intraocular inflammation in BD, both in term of reduction in the number of uveitis relapses and in achieving a prompt resolution of active RV. [ABSTRACT FROM AUTHOR]

Objective: Since Behçet's syndrome (BS) is the prototype of inflammation‐induced thrombosis, immunosuppressants are recommended in place of anticoagulants. We undertook this study to assess the clinical efficacy and the corticosteroid‐sparing effect of adalimumab (ADA)–based treatment versus disease‐modifying antirheumatic drug (DMARD) therapy in a large retrospective cohort of patients with BS‐related venous thrombosis. Methods: We retrospectively collected data on 70 BS patients treated with DMARDs or ADA‐based regimens (ADA with or without DMARDs) because of venous complications. Clinical and imaging evaluations were performed to define vascular response. We explored differences in outcomes between ADA‐based regimens and DMARDs with respect to efficacy, corticosteroid‐sparing role, and time on treatment. We also evaluated the role of anticoagulants as concomitant treatment. Results: After a mean ± SD follow‐up period of 25.7 ± 23.2 months, ADA‐based regimens induced clinical and imaging improvement of venous thrombosis more frequently (P = 0.001) and rapidly (P < 0.0001) than did DMARDs. The mean dose of corticosteroids administered at the last follow‐up visit was significantly lower with ADA‐based regimens than with DMARDs (P < 0.0001). The time on treatment was significantly longer with ADA plus DMARDs than with DMARDs alone (P = 0.002). No differences were found in terms of efficacy and time on treatment between DMARDs or ADA‐based regimens among patients who received anticoagulants and those who did not. Conclusion: In this large retrospective study, we have shown that ADA‐based regimens are more effective and rapid than DMARDs in inducing resolution of venous thrombosis in BS patients, allowing reduction of steroid exposure. Moreover, our findings suggest that anticoagulation does not modify the efficacy of either ADA‐based regimens or DMARDs for venous complications. [ABSTRACT FROM AUTHOR]

Intraocular inflammation is one of the more relevant complications of Behçet's disease (BD), which tends to respond poorly to different medications. The ocular histopathologic changes are basically identical to those occurring in other organs and consist in a necrotizing leukocytoclastic obliterative vasculitis, which is probably immune complex-mediated and affects both arteries and veins of all sizes. There are growing evidences showing the potential role of biologic agents other than anti-tumor necrosis factor (TNF)-α agents in the management of ocular-BD, which have been collected in this review, including interleukin-1 and interleukin-6 blockade, secukinumab, ustekinumab, daclizumab, rituximab, and alemtuzumab. Further large studies are needed to fully elucidate and establish the clinical efficacy of these different tools in the refractory ocular manifestations of BD. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of the present study was to describe our experience with the recombinant Fab' antibody fragment against TNF-a Certolizumab Pegol (CZP) in patients with Behc,et's disease (BD) refractory to standardized therapies and previous biologic agents. Methods: Retrieved data including demographic characteristics, clinical manifestations, and previous treatments were collected in three different specialized Rheumatologic Units in Italy. In order to evaluate disease activity, the BD current activity form (BDCAF) has been used before starting CZP therapy and at each visit during treatment. Results: Thirteen BD patients (mean age 42.6 ± 8.8 years) with a disease duration of 8.80 ± 6.9 years, underwent CZP treatment for 6.92 ± 3.52 months. Six patients (46.15%) experienced a worsening of symptoms after 4.16 ± 1.21 months, whereas a satisfactory response was achieved in seven patients (53.84%) who were still on CZP therapy at the last follow-up visit (after 9.28 ± 3.03 months of treatment). The mean decrease of BDCAF between the first and last visit was 0.308 ± 1.84 without reaching significant difference (mean 8.3 ± 1.3 and 8 ± 2.08, respectively; p= .51). During the whole study period, CZP was well tolerated in all patients except one who developed a generalized cutaneous reaction after the third administration. Conclusions: These results suggest that despite an improvement of clinical manifestations has been observed in more than half of the patients, it is not possible to draw firm conclusions about the effectiveness of CZP in BD and further studies with larger cohorts of patients are warranted. Whether the increase of CZP dosage may ensure a better clinical response remains an unsolved issue that needs to be considered. [ABSTRACT FROM AUTHOR]

Behçet's disease (BD) is a multi-systemic inflammatory disorder consisting of recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis; however, many other organs may be affected. Several pro-inflammatory cytokines, mainly derived from Th1 and Th17 lymphocytes, seem to be involved in different pathogenic pathways leading to development of the clinical manifestations. On this basis, the primary aim of our study was to compare a core set of pro-inflammatory cytokines between patients with BD and healthy control (HC). The secondary goal was to evaluate potential correlations between these putative circulating biomarkers, the status of disease activity, and the specific organ involvement at the time of sample collection. Fifty-four serum samples were collected from 46 BD patients (17 males, 29 females, mean age 45.5 ± 11.3 years), and 19 HC (10 males, 9 females, mean age 43 ± 8.3 years). Twenty-five serum cytokines (APRIL/TNFS13, BAFF/TNFSF13B, sCD30/TNFRSF8, sCD163, Chitinase3-like1, gp130/sIL-6Rb, IFNb, sIL-6Ra, IL-10, IL-11, IL-19, IL-20, IL-26, IL-27 (p28), IL-28A/ IFN-lambda2, IL-29/IFN-lambda1, IL-32, IL-34, IL-35, LIGHT/TNFSF-14, Pentraxin-3, sTNF-R1, sTNF-R2, TSLP, and TWEAK/TNFSF-12) were simultaneously quantified using a Bio-Rad cytokine bead arrays. Serum concentration of sTNF-R1 (p < 0.01) and sTNF-R2 (p < 0.01) resulted higher in both active and inactive BD than HC, while Chitinase3-like1 (p < 0.05) and gp130/sIL-6Rb (p < 0.01) serum levels were significantly higher in inactive BD, and IL-26 (p < 0.01) in active BD than HC. No differences were observed between inactive and active BD group. In addition, we observed that gp130/ sIL-6Rb, sIL-6Ra, IL-35, and TSLP serum levels were significantly enhanced in patients with mucocutaneous manifestations plus ocular involvement (MO-BD) compared to subgroup with only mucocutaneous involvement (M-BD). Our findings may suggest a signature of IL-6, tumor necrosis factor-αas well as of Th17 response in BD patients due to increased levels of gp130/sIL-6Rb, sTNF-R1, sTNF-R2, IL-26, respectively. This evidence could contribute to improve the knowledge regarding the role of these citokines in the induction of specific BD clinical features. [ABSTRACT FROM AUTHOR]

The study objective was to evaluate the occurrence of sensorineural hearing loss (SNHL) in patients with Behcet's disease (BD), looking at potential correlations with specific demographic, clinical, and therapeutic features. Forty-four consecutive patients (15 males, 29 females) fulfilling the International Study Group (ISG) and/or the International Criteria for Behçet's Disease (ICBD) were enrolled. The endpoints of the study consisted in identifying a deflection of at least 25 dB on pure-tone audiometry and performing statistical analysis to evaluate demographic, clinical, or therapeutic differences between patients with and without SNHL. Our patients showed a mean age ± SD of 45.43 ± 14.05 years; a mean age at disease onset ± SD of 31.54 ± 15.53 years; a disease duration ± SD of 13.89 ± 9.15 years. SNHL was highlighted in 28 (63 %) patients representing the fourth most frequent clinical manifestation in our group of patients. Otologic involvement was significantly more frequent among subjects fulfilling ISG criteria than in patients fulfilling ICBD criteria ( p = 0.04). Regarding correlations with BD manifestations, SNHL was significantly associated with cutaneous plus articular involvement ( p = 0.013). Conversely, detached analysis of articular and skin manifestations led to no significant differences ( p = 0.085 and p = 0.067). No further significant correlations were found between SNHL and BD clinical features or previous or concomitant treatments. Hearing loss was the fourth most common clinical feature in our patients and probably represents an underrated aspect of BD. Hearing impairment was significantly associated with cutaneous plus articular involvement, suggesting the importance of an otologic evaluation in such patients. [ABSTRACT FROM AUTHOR]

Behçet's disease (BD) is universally recognized as a multisystemic inflammatory disease of unknown etiology with chronic course and unpredictable exacerbations: its clinical spectrum varies frompure vasculitic manifestations with thrombotic complications to protean inflammatory involvement ofmultiple organs and tissues. Treatment has been revolutionized by the progressed knowledge in the pathogenetic mechanisms of BD, involving dysfunction and oversecretion of multiple proinflammatory molecules, chiefly tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, and IL-6. However, although biological treatment with anti-TNF-α agents has been largely demonstrated to be effective in BD, not all patients are definite responders, and this beneficial response might drop off over time. Therefore, additional therapies for a subset of refractory patients with BD are inevitably needed. Different agents targeting various cytokines and their receptors or cell surface molecules have been studied: the IL-1 receptor has been targeted by anakinra, the IL-1 by canakinumab and gevokizumab, the IL-6 receptor by tocilizumab, the IL12/23 receptor by ustekinumab, and the B-lymphocyte antigen CD-20 by rituximab.The aim of this review is to summarize all current experiences and the most recent evidence regarding these novel approaches with biological drugs other than TNF-α blockers in BD, providing a valuable addition to the actually available therapeutic armamentarium. [ABSTRACT FROM AUTHOR]

In the original version of this article the author name Gerardo Di Scala was originally presented incorrectly as 'Di Scala Gerardo'; this has been corrected in this article. [ABSTRACT FROM AUTHOR]

• Spondyloarthritis has been associated with several auto-inflammatory conditions, including familial Mediterranean fever, Behçet's disease, undifferentiated systemic auto-inflammatory disease and, more recently, Still's disease. • This research offers a detailed characterization of a cohort diagnosed with "systemic spondyloarthritis" leveraging patients with non-systemic spondyloarthritis and Still's disease as benchmarks for comparing articular and systemic presentations. • A possible relationship between Still's disease and spondyloarthritis has been suggested, based on the analysis of new cases and those reported in the literature, hypothesizing a role for uncontrolled inflammation in the shift towards the spondyloarthritis phenotype. • These findings advocate for the inclusion of sacroiliitis in the diagnostic work-up of pediatric and adult patients exhibiting unexplained systemic auto-inflammatory manifestations. Also, this study prompts further investigative efforts aimed to elucidate the pathophysiological mechanisms connecting the systemic and axial manifestations of systemic spondyloarthritis. (1) characterizing a group of spondyloarthritis (SpA) patients with systemic auto-inflammatory symptoms (S-SpA); (2) comparing SpA features with and without auto-inflammatory symptoms; (3) comparing the auto-inflammatory features of S-SpA and Still's disease (SD). Retrospective observational study. Clinical data of adult and pediatric patients with S-SpA, SD or SpA were collected retrospectively and analyzed. Forty-one subjects with S-SpA, 39 with SD and 42 with SpA were enrolled. The median latency between systemic and articular manifestations in S-SpA was 4.4 (IQR: 7.2) years. S-SpA and SpA had similar frequency of peripheral arthritis and enthesitis (N.S.), while tenosynovitis was more frequent (P = 0.01) and uveitis less frequent (P < 0.01) in S-SpA. MRI showed signs of sacroiliac inflammation and damage in both S-SpA and SpA equally (N.S.). S-SpA patients had less corner inflammatory lesions (P < 0.05) and inflammation at the facet joints (P < 0.01), more interspinous enthesitis (P = 0.01) and inter-apophyseal capsulitis (P < 0.01). Compared to SD, S-SpA patients had lower-grade fever (P < 0.01), less rash (P < 0.01) and weight loss (P < 0.05), but more pharyngitis (P < 0.01), gastrointestinal symptoms (P < 0.01) and chest pain (P < 0.05). ESR, CRP, WBC, ANC, LDH tested higher in SD (P < 0.01). Resolution of systemic symptoms was less frequent in S-SpA than SD on corticosteroid (P < 0.01) and methotrexate (P < 0.05) treatment. When considering all SD patients, a complete response to corticosteroids in the systemic phase significantly reduced the likelihood of developing SpA (OR = 0.06, coefficient −2.87 [CI: −5.0 to −0.8]). SpA should be actively investigated in patients with auto-inflammatory manifestations, including undifferentiated auto-inflammatory disease and SD. [ABSTRACT FROM AUTHOR]

Vasculitis are severe systemic autoimmune diseases which may involve different organs and systems. Conversely, muscles do not represent an organ commonly involved by systemic vasculitis and myositis is not include among any classification or diagnostic criterion of vasculitis. In this regard, we aimed to review the literature in order to report all the available evidence concerning the inflammatory involvement of muscle in patients affected by systemic vasculitis. We collected a total of 108 papers, for a sum of 395 patients affected by muscle vasculitis. Most of them suffered from medium and small vessels vasculitis (mainly polyarteritis nodosa and ANCA-associated vasculitis) or from vasculitis secondary to rheumatoid arthritis. Conversely, muscle involvement in case of large vessel vasculitis occurred seldom, while only few papers reported such occurrence in Kawasaki or Behçet's disease. Histological findings may differ, but the most common ones displayed a necrotizing vasculitis of perimysium vessels, while granulomatous vasculitis was assessed only in case of ANCA-associated vasculitis patients. Creatine kinase were usually within normal range, seldom elevated, while imaging findings were generally undistinguishable from the ones found in idiopathic inflammatory myopathies: magnetic resonance imaging displays signal hyperintensity in T2 and STIR scans, while few data exist for positron emission tomography. The presentation of the disease may be fearsome and severe, sometimes life-threatening, but an overall good response to conventional immunosuppressants and/or glucocorticoids has been reported. • Inflammatory involvement of striate muscle is an uncommon, but not exceedingly rare, manifestation of systemic vasculitis. • In our systematic review, we collected 395 patients affected by muscle vasculitis. • The majority of patients are affected by polyarteritis nodosa or ANCA-associated vasculitis. • The presentation may be severe, but rarely life-threatening, showing an overall good response to treatment. [ABSTRACT FROM AUTHOR]