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Mutations in OPA1 are responsible of 32-89% cases of Autosomal Dominant Optic Atrophy (ADOA). OPA1 ADOA usually presents in childhood with bilateral, progressive visual loss due to retinal ganglion cells neurodegeneration, but environmental factors are supposed to influence onset and phenotype. Sixty Italian OPA1 mutations carriers (fifty-two symptomatic), belonging to thirteen families, underwent neuro-ophthalmologic evaluation. Visual acuity (n=60) and Optical Coherence Tomography (OCT) (n=12) were compared in missense mutations (OPA-M) versus haploinsufficiency-inducing mutations (OPA-H) and correlated with age. Presence of plus phenotypes was investigated. We found four known mutations, the most common being missense c.1034G>A, and a new missense mutation, c1193A>C, the latter in a 54-yrs old female with late-onset phenotype. Visual acuity, colour sensitivity, and optic disc atrophy were sensitive indicators of disease. OCT RNFL thickness was reduced in OPA1 compared to controls. OPA-M showed worst visual acuity than OPA-H, but not more frequent plus-phenotype, observed only in four OPA-H patients. In both groups, visual acuity worsened with age. Our data confirm worst vision in OPA-M, but not increased plus-phenotype. Since most patients belonged to nine families from south-eastern Sicily (a famous region for the cult of St. Lucy, patron of the blinds) local genetic and environmental factors might have accounted for the low occurrence of plus-phenotypes.

Our aim was to prospectively investigate the impact of Behcet's disease (BD), disease activity, and clinical and demographic characteristics on different aspects of quality of life (QoL) measured by the short-form (SF)-36 QoL scale. We administered the SF-36 to 37 consecutive BD patients in different moments of disease activity, and to 23 healthy controls (HC). The eight subcategories of the SF-36 underwent statistical analysis for identifying differences and correlations. Compared to HC, BD patients showed significantly lower mean scores in all SF-36 QoL subscales except mental health and role-emotional. Females showed a poorer QoL compared to males. Disease activity evaluated by the BD Current Activity Form inversely correlated with physical functioning (ρ = -0.68, p

This study aimed to evaluate the role of interleukin (IL)-1 inhibitors anakinra (ANA) and canakinumab (CAN) in the treatment of Behcet’s disease (BD)-related uveitis. Multicenter retrospective observational study includes 19 consecutive BD patients (31 affected eyes) received treatment with anti-IL-1 agents. Data were analyzed at baseline and at 3 and 12 months. The primary endpoint is the reduction of ocular inflammatory flares (OIF). The secondary endpoints are improvement of best corrected visual acuity (BCVA); reduction of macular thickness defined by optical coherence tomography (OCT) and of vasculitis identified with fluorescein angiography (FA); evaluation of statistically significant differences between patients treated with IL-1 inhibitors as monotherapy, subjects also administered with disease modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids as well as between patients administered with IL-1 inhibitors as first line biologic treatment and those previously treated with TNF-α inhibitors. At 12 months, OIF significantly decreased from 200 episodes/100 patients/year to 48.87 episodes/100 patients/year (p

Background To date, a few studies have reported the long-term efficacy of Infliximab (IFX) in Behcet’s disease (BD)-related uveitis.1,2 Nevertheless, it is known that TNF-α inhibitor drugs may lose their efficacy over time due to the formation of anti-drug antibodies, causing secondary failure and influencing the retention rate of these agents.3 In this regard no previous study has specifically investigated IFX retention-rate in BD-related uveitis. Objectives To evaluate the 10 year drug retention rate of IFX in 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 corticosteroids-sparing effect was observed (p Conclusions IFX retention rate in BD-uveitis is excellent and is not affected by concomitant DMARDs References [1] Keino H, Okada AA, Watanabe T, et al. Long-term efficacy of infliximab on background vascular leakage in patients with Behcet’s disease. Eye (Lond)2014;28(9):1100–6. [2] Keino H, Okada AA, Watanabe T, et al. Efficacy of Infliximab for Early Remission Induction in Refractory Uveoretinitis Associated with Behcet Disease: A 2-year Follow-up Study. Ocul Immunol Inflamm2017;25(1):46–51. [3] Fabbroni M, Cantarini L, Caso F, et al. Drug retention rates and treatment discontinuation among anti-TNF-α agents in psoriatic arthritis and ankylosing spondylitis in clinical practice. Mediators Inflamm2014;2014:862969. Disclosure of Interest None declared

Background In recent times IL-1 inhibition has been proposed as an intriguing therapeutic option in Behcet disease (BD) patients with multi-drug resistant manifestations.1 However, despite the good clinical results obtained during the last years, cases of BD nonresponsive to anakinra (ANA) and canakinumab (CAN) have also been identified. This evidence has induced to suspect the existence of specific subsets of patients characterised by a more pronounced IL-1 driven pathogenesis.2,3 Objectives To identify predictive factors of response to interleukin (IL)−1 inhibition among demographic, clinical and therapeutic data in patients with (BD). Methods BD patients treated with ANA or CAN were enrolled. Patients were divided into 2 groups according to the clinical response: group 1 included subjects showing a treatment duration of at least 52 weeks and no secondary inefficacy during the first follow-up year; the remaining patients were included in the group 2. Demographic, clinical and therapeutic data were analysed to identify significant differences between groups. Results Eighteen patients (50%) were included in group 1 and 18 (50%) in group 2. A better response to IL-1 inhibitors was significantly more common among patients with BD-related uveitis (p=0.006) and patients with a longer disease duration (p=0.03). Conclusions IL-1 blockade is effective in BD, especially in the subset of patients presenting ocular involvement and in those with long-lasting disease. References [1] Vitale A, Rigante D, Lopalco G, Selmi C, Galeazzi M, Iannone F, Cantarini L. Interleukin-1 inhibition in Behcet’s disease. Isr Med Assoc J2016;18(3–4):171–6. [2] Vitale A, Rigante D, Caso F, Brizi MG, Galeazzi M, Costa L, et al. Inhibition of interleukin-1 by canakinumab as a successful mono-drug strategy for the treatment of refractory Behcet’s disease: a case series. Dermatology2014;228(3):211–4. doi:10.1159/000358125 [3] Cantarini L, Vitale A, Scalini P, Dinarello CA, Rigante D, Franceschini R, et al. Anakinra treatment in drug-resistant Behcet’s disease: a case series. Clin Rheumatol2015;34(7):1293–301. doi:10.1007/s10067-013-2443-8 Disclosure of Interest None declared

Background Behcet’s disease (BD) is an inflammatory disorder potentially leading to life- and sight-threatening complications: no laboratory marker correlating with disease activity or predicting the occurrence of disease manifestations is currently available in the clinical practice. Objectives To search for a correlation between serum amyloid-A (SAA) levels and disease activity evaluated via BD current activity form (BDCAF), to assess disease activity in relationship with different SAA thresholds, to examine the association between single organ involvements and the overall major organ involvement with different SAA thresholds, and to assess the influence of biologic therapy on SAA levels. Methods Ninety-five serum samples were collected from 64 BD patients, and their related demographic, clinical and therapeutic data were retrospectively collected. Results No correlation was identified between SAA levels and BD disease activity (Spearman rho=0.085; p=0.411), while a significant difference was found in the mean BDCAF score between patients presenting SAA levels 200 mg/L (p=0.027). SAA levels higher than 200 mg/L were significantly associated with major organ involvement (p=0.008). A significant association was found between SAA levels>150 mg/dl and ocular (p=0.008), skin (p=0.002) and mucosal manifestations (p=0.012). Patients undergoing biologic therapies were significantly associated with SAA levels Conclusions SAA level does not represent per se a biomarker of disease activity, but might be useful as a predictor of major organ involvement and ocular disease relapse at certain thresholds in patients with BD. Disclosure of Interest None declared

The primary aim of the study was to evaluate the efficacy of tumor necrosis factor (TNF)-α blockers adalimumab (ADA) and infliximab (IFX) in refractory sight-threatening retinal vasculitis (RV) during a 12-month follow-up period. Secondary aims were to evaluate (i) any impact of concomitant conventional disease-modifying anti-rheumatic drugs (cDMARDs) and different lines of biologic therapy; (ii) any difference in terms of efficacy between ADA and IFX; (iii) consequences of biotherapies on the best-corrected visual acuity (BCVA); (iv) corticosteroid-sparing effect; and (vi) ocular complications during anti-TNF-α treatment. Demographic, clinical, and therapeutic data were retrospectively collected from the medical records and statistically analyzed. Forty-eight patients (82 eyes) were recruited, 22 (45.8%) of which received IFX and 26 (54.2%) ADA. The percentages of patients achieving RV remission within 3 and 12 months were 54 and 86%, respectively. A significant decrease in RV detection was identified from baseline to 3-month (p 0.0001) and 12-month (p 0.0001) assessments and between 3-month and 12-month visits (p = 0.004). No differences were identified in terms of RV resolution between (i) patients undergoing monotherapy and those co-administered with cDMARDs at 3-month (p = 0.560) and 12-month (p = 0.611) follow-up; (ii) biologic-naïve patients and those already exposed to other biologics at 3-month (p = 0.497) and 12-month (p 0.99) visits; and (iii) patients treated with ADA and those treated with IFX (p = 0.357). During the study period, a statistically significant corticosteroid-sparing effect was observed (p = 0.0002), while BCVA values did not significantly change (p = 0.950). Anti-TNF-α monoclonal antibodies have proved excellent results in patients with recalcitrant sight-threatening RV.

To identify clinical variables capable of predicting long-term treatment duration of TNF-α inhibition in patients with Behcet's disease (BD)-related uveitis. Demographic, clinical, and therapeutic data were retrospectively collected from BD patients treated with the tumor necrosis factor (TNF)-α blockers infliximab and adalimumab. Patients still continuing TNF-α inhibitors at 48-month follow-up visits were classified as long-term responders and were statistically compared to patients discontinuing treatment before the 48-month visit. Forty-five patients (75 eyes) were enrolled. Thirty-two patients continued anti-TNF-α treatment for more than 48 months; 13 patients discontinued the treatment after a mean time of 12.3 ± 10.44 months due to lack (61.5%) or loss (38.5%) of efficacy. Baseline value of BD current activity form was the only variable discriminating long- and short-term responsive patients (p = 0.048, OR = 0.656, C.I. 95% 0.433-0.996). Disease activity levels at the start of treatment predict duration of response to monoclonal TNF antagonists in ocular BD.

Background/aimsAdalimumab (ADA) has been shown to be an effective treatment for Behçet’s disease (BD)-related uveitis. We aimed at evaluating the cumulative retention rate of ADA during a 48-month follow-up period in patients with BD-related uveitis, the impact of a concomitant use of disease modifying anti-rheumatic drugs (DMARDs) on ADA retention rate, and differences according to the various lines of biologic therapy (ie, first- vs second-line or more). Predictive factors of response to ADA were also investigated.MethodsWe enrolled patients diagnosed with BD-related uveitis and treated with ADA between January 2009 and December 2016. Cumulative survival rates were studied using the Kaplan-Meier plot, while the log-rank (Mantel-Cox) test was used to compare survival curves. Statistical analysis was performed to identify differences according to the response to ADA.Results54 consecutive patients (82 eyes) were eligible for analysis. The drug retention rate at 12- and 48-month follow-up was 76.9% and 63.5%, respectively. No statistically significant differences were identified according to the use of concomitant DMARDs (p=0.27) and to the different lines of ADA treatment (p=0.37). No significant differences were found between patients continuing and discontinuing ADA in terms of age (p=0.24), age at BD onset (p=0.81), age at uveitis onset (p=0.56), overall BD duration (p=0.055), uveitis duration (p=0.46), human leucocyte antigen-B51 positivity (p=0.51), and gender (p=0.47).ConclusionsADA retention rate in BD-related uveitis is excellent and is not affected by the concomitant use of DMARDs or by the different lines of biological therapy. Negative prognostic factors for BD uveitis do not impact ADA efficacy.

Purpose: To identify factors associated with sustained response to interleukin (IL)-1 inhibition among demographic, clinical and therapeutic data in patients with Behcet disease (BD).Method...

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.

Aim The primary aim of this study was to explore the safety profile of biologic treatments in Behcet's disease (BD), based on their mechanism of action; the secondary aim was to study any potential variation in terms of retention rate according to each single drug. Method We studied a total of 85 treatment regimens with biologic agents from 64 patients. The total follow-up was calculated as 8640 patient-years (anti-tumor necrosis factor [TNF]-alpha 7.020, anti-interleukin [IL]-beta 1.368). Cumulative rates of drug retention were studied using the Kaplan–Meier plot and covariates in the regression model included the mechanism of action of the biologic agent, other concomitant therapies, disease duration, sex, age at start of drug therapy; for each confounding factor hazard ratios (HR) were calculated. Results The most frequently prescribed biologic treatments were anti-TNF-alpha agents (79%), while anti-IL1-beta was used in the remaining regimens. Concomitant disease-modifying antirheumatic drugs were prescribed in 36% of patients, mainly cyclosporine and methotrexate, while in 35/85 regimens low-dose glucocorticoids were associated. During the follow-up, in all but one regimen the safety profile was free of any adverse events or serious adverse events; we observed only one case of endocarditis, reported during the 10th month of etanercept. Conclusion Data from a large multicenter cohort suggest that anti-TNF-alpha and anti-IL1-beta agents are characterized by an excellent safety profile in BD.

Ocular involvement is frequent in the monogenic autoinflammatory disorders and generally occurs as spontaneously recurring inflammatory events at different ocular sites caused by the aberrant release of proinflammatory cytokines, mainly IL-1β. Over the past decade, we witnessed a significant growth of eye abnormalities associated with idiopathic granulomatous disorders, familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and cryopyrin-associated periodic syndrome. The pathogenetic mechanisms of these disorders have shown the evidence of disrupted cytokine signaling, but the explanation for the heterogeneous ocular involvement remains to be elucidated. We herein review the monogenic autoinflammatory disorders affecting the eye, describing their main clinical features with specific regard to the ocular involvement, which can lead to decreased visual acuity and even blindness, if the primary disorder is undetected or left untreated.

Purpose: To evaluate the 10-year drug retention rate of infliximab (IFX) in Behcet’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

To evaluate golimumab (GOL) efficacy in the management of Behçet's disease (BD)-related uveitis.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.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.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.

Background Current information on the use of adalimumab (ADA) in the treatment of ocular Behcet9s disease (BD) is still based mainly on small series or case reports; nonetheless preliminary evidence is promising. Objectives The study aim was to evaluate the efficacy of ADA in a large series of BD-related uveitis. Methods We performed a multicenter retrospective observational study including 40 selected patients (66 eyes) receiving ADA. Clinical data were retrospectively analyzed at baseline, at 3 and 12 months of treatment. Primary end-point was: reduction of ocular inflammatory flares. Secondary end-points were: improvement of Best Corrected Visual Acuity (BCVA), reduction of macular thickness measured by optical coherence tomography (OCT), reduction in the occurrence of vasculitis assessed by fluorescein angiography (FA), evaluation of statistically significant differences between patients treated with ADA monotherapy and those undergoing ADA plus DMARDs and in patients firstly treated with ADA compared to patients previously administered with other biologics; ADA steroid sparing effect was also evaluated. Results During the first 12 months of ADA therapy the number of flares significantly decreased from 200 flares/100 patients/year to 8.5 flares/100 patients/year (p Conclusions ADA is highly effective and safe for the treatment of BD-related uveitis, providing a long-term control of ocular inflammation. Disclosure of Interest None declared

Objectives To evaluate the role of interleukin (IL)-1 inhibitors anakinra (ANA) and canakinumab (CAN) in the treatment of Behcet disease (BD)-related uveitis Methods multicenter retrospective observational study including 19 consecutive BD patients (31 affected eyes) receiving treatment with anti-IL-1 agents. Data were analyzed at baseline, at 3 and 12 months. Primary end-point: reduction of ocular inflammatory flares (OIF). Secondary end-points: improvement of Best Corrected Visual Acuity (BCVA); reduction of macular thickness defined by optical coherence tomography (OCT) and of vasculitis identified with fluorescein angiography (FA); evaluation of statistically significant differences between patients treated with IL-1 inhibitors as monotherapy, subjects also administered with disease modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids as well as between patients administered with IL-1 inhibitors as first line biologic treatment and those previously treated with TNF-α inhibitors Results at 12 months OIF significantly decreased from 200/100 patients/year to 48.87/100 patients/year (p p p =0.001, respectively). OIF rate was significantly higher in patients co-administered with DMARDs (81.8/100 patients/year) than in patients undergoing IL-1 inhibitors as monotherapy (0.0/100 patients/year) ( p =0.03). No differences were identified on the basis of corticosteroid use and between patients administered with IL-1 inhibitors as first-line biologic approach or second-line. Steroid dosage was significantly decreased at 12-month visit compared to baseline ( p =0.02). Conclusions treatment with IL-1 inhibitors is effective in the management of BD-related uveitis and provides a long-term control of ocular inflammation in refractory and long-lasting cases. Disclosure of Interest None declared

Several pathogenetic studies have paved the way for a newer more rational therapeutic approach to non-infectious uveitis, and treatment of different forms of immune-driven uveitis has drastically evolved in recent years after the advent of biotechnological drugs. Tumor necrosis factor-α targeted therapies, the first-line recommended biologics in uveitis, have certainly led to remarkable results in patients with non-infectious uveitis. Nevertheless, the decision-making process turns out to be extremely difficult in anti-tumor necrosis factor or multidrug-resistant cases. Interleukin (IL)-6 holds a critical role in the pathogenic pathways of uveitis, due to its extended and protean range of effects. On this background, manipulation of IL-6 inflammatory cascade has unraveled encouraging outcomes. For instance, rising evidence has been achieved regarding the successful use of tocilizumab, the humanized monoclonal antibody targeted against the IL-6 receptor, in treating uveitis related to juvenile idiopathic arthritis or Behcet's disease. Similar findings have also been reported for uveitis associated with systemic disorders, such as rheumatoid arthritis or multicentric Castleman disease, but also for idiopathic uveitis, the rare birdshot chorioretinopathy, and even in cases complicated by macular edema. This work provides a digest of all current experiences and evidences concerning IL-6 blockade, as suggested by the medical literature, proving its potential role in the management of non-infectious uveitis.

To evaluate the effectiveness and the systemic corticosteroid sparing effect of a single intravitreal dexamethasone (DEX) implant in patients with chronic noninfectious uveitic macular edema (UME).Data from 22 eyes treated with DEX implant for UME related to systemic or ocular-confined noninfectious diseases were retrospectively analyzed.The mean systemic prednisone (or equivalent) dosage significantly decreased at 3- and 6-month follow-up evaluations compared to baseline (P = 0.002 and P = 0.01, respectively). Compared to baseline, central macular thickness values significantly decreased at 1-, 3-, and 6-month evaluations after the implantation (P 0.0001). The mean best corrected visual acuity (BCVA) value gradually improved at 1-, 3-, and 6-month visits compared to baseline (P = 0.009, P = 0.0004, and P = 0.0001, respectively). At fluorescein angiography, active retinal vasculitis was identified in 11 (50%) eyes at baseline, 3 (13.6%) eyes at 1- and 3-month follow-up, and in 2 (9.1%) eyes at the last visit. Regarding side effects, 3/22 (13.6%) eyes presented a newly recognized intraocular hypertension at 1-month follow-up; however, intraocular pressure reverted to normal values within the 6-month follow-up in all cases.Treatment with intravitreal DEX implant in noninfectious uveitis allowed a significant corticosteroid sparing effect, a significant improvement in BCVA, and a prompt resolution of UME and vasculitis. No safety issues were observed.

The study aim was to evaluate the efficacy of adalimumab (ADA) in a large series of Behcet's disease (BD)-related uveitis. We performed a multicenter retrospective observational study including 40 selected patients (66 eyes) receiving ADA. Clinical data were retrospectively analyzed at baseline, at 3 and 12 months of treatment. Primary end point was reduction of ocular inflammatory flares. Secondary end points were improvement of best corrected visual acuity (BCVA), reduction of macular thickness measured by optical coherence tomography (OCT), reduction in the occurrence of vasculitis assessed by fluorescein angiography (FA), and evaluation of statistically significant differences between patients treated with ADA monotherapy and those undergoing ADA plus DMARDs and in patients firstly treated with ADA compared to patients previously administered with other biologics; ADA steroid sparing effect was also evaluated. During the first 12 months of ADA therapy, the number of flares significantly decreased from 200 flares/100 patients/year to 8.5 flares/100 patients/year (p

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 Behcet'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.

Behçet’s disease (BD) is a multisystemic disorder of unknown etiology mainly defined by recurrent oral aphthosis, genital ulcers, and chronic relapsing bilateral uveitis, all of which represent the “stigmata” of disease. However, many other organs including the vascular, neurological, musculoskeletal, and gastrointestinal systems can be affected. The gastrointestinal involvement in Behçet’s disease (GIBD), along with the neurological and vascular ones, represents the most feared clinical manifestation of BD and shares many symptoms with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. Consequently, the differential diagnosis is often a daunting task, albeit the presence of typical endoscopic and pathologic findings may be a valuable aid to the exact diagnosis. To date, there are no standardized medical treatments for GIBD; therefore therapy should be tailored to the single patient and based on the severity of the clinical features and their complications. This work provides a digest of all current experience and evidence about pharmacological agents suggested by the medical literature as having a potential role for managing the dreadful features of GIBD.

Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis variably combined with T cell-mediated neurologic and cutaneous manifestations. Early and aggressive treatment with systemic corticosteroids is the mainstay of treatment for VKHD. Additional use of immunosuppressants, intravenous immunoglobulins, and tumor necrosis factor-alpha inhibitors can help the most severely affected patients and work as corticosteroid-sparing agents. We report the case of a young woman with relapsing and multiresistant VKHD who demonstrated a stable remission of both uveitis and high-frequency hearing loss following rituximab intravenous administration (1 g. twice, 2 weeks apart, and 6 months later). A complete clinical response was observed 1 month since the first infusion, and no ocular relapses were recorded during the following year; in addition, audiometry showed a high-frequency hearing recovery in the right ear. Further observational studies are required to define the role of CD20 inhibition in the management of VKHD.

The P2×7 receptor (P2×7r) is expressed in innate immune cells (e.g. monocyte/macrophages), playing a key role in IL-1β release. Since innate immune activation and IL-1β release seem to be implicated in Behcet's disease (BD), a systemic immune-inflammatory disorder of unknown origin, we hypothesized that P2×7r is involved in the pathogenesis of the disease. Monocytes were isolated from 18 BD patients and 17 healthy matched controls. In BD monocytes, an increased P2×7r expression and Ca(2+) permeability induced by the selective P2×7r agonist 2'-3'-O-(4-benzoylbenzoyl)ATP (BzATP) was observed. Moreover, IL-1β release from LPS-primed monocytes stimulated with BzATP was markedly higher in BD patients than in controls. TNF-α-incubated monocytes from healthy subjects almost reproduced the findings observed in BD patients, as demonstrated by the increase in P2×7r expression and BzATP-induced Ca(2+) intake. Our results provide evidence that in BD monocytes both the expression and function of the P2×7r are increased compared with healthy controls, as the possible result, at least in part, of a positive modulating effect of TNF-α on the receptor. These data indicate P2×7r as a new potential therapeutic target for the control of BD, further supporting the rationale for the use of anti-TNF-α drugs in the treatment of the disease.

Interleukin (IL)-1 plays a key role in the pathogenesis and thereafter in the search for specific treatments of different inflammatory and degenerative eye diseases. Indeed, an overactivity of IL-1 might be an initiating factor for many immunopathologic sceneries in the eye, as proven by the efficacy of the specific IL-1 blockade in different ocular diseases. For instance, the uveitis in monogenic autoinflammatory disorders, such as Blau syndrome and cryopyrin-associated periodic syndrome, or in complex polygenic autoinflammatory disorders, such as Behcet's disease, has been successfully treated with IL-1 blockers. Similarly, therapy with the IL-1 receptor antagonist anakinra has proven successful also in scleritis and episcleritis in the context of different rheumatic conditions. Moreover, interesting findings deriving from animal models of ocular disease have set a rational basis from a therapeutic viewpoint to manage patients also with dry eye disease and a broadening number of ocular inflammatory and degenerative conditions, which start from an imbalance between IL-1 and its receptor antagonist.

Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy characterized by bilateral symmetrical visual loss, decrease in retinal ganglion cells and a loss of myelin within the optic nerve. ADOA is associated to mutations in Optic atrophy 1 gene (OPA1), which encodes a mitochondrial protein involved in cristae remodeling, maintenance of mitochondrial membrane integrity, mitochondrial fusion and apoptosis regulation. We thus evaluated the rate of apoptosis and the expression levels of OPA1 isoforms in ADOA and control cells. Peripheral blood lymphocytes from eight patients with OPA1 mutation and age matched controls were cultivated both in basal conditions or with 2-deoxy-D-ribose, a reducing sugar that induces apoptosis through oxidative stress. Apoptosis was analyzed by flow cytometry, phosphatidylserine translocation, mitochondrial membrane depolarization and caspase 3 activation. We also analyzed the expression levels of OPA1 isoforms in ADOA and control cells cultured with and without 2-deoxy-D-ribose. We showed an increased percentage of apoptotic cells in ADOA patients compared to controls, both in basal culture conditions and after 2-deoxy-D-ribose treatment. This suggested a great susceptibility of ADOA cells to oxidative stress and a strong correlation between OPA1 protein dysfunctions and morphological-functional alterations to mitochondria. Moreover OPA1 protein expression was significantly decreased in lymphocytes from the ADOA patients after 2-deoxy-D-ribose treatment, implying a great sensitivity of the mutated protein to free radical damage. Concluding, we could confirm that oxidative stress-induced apoptosis may play a key role in the pathophysiological process bringing to retinal ganglion cells degeneration in ADOA.

Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. Although the primum movens of this condition remains unknown, a tangled plot combining autoimmune and autoinflammatory pathways has been hypothesized to explain its start and recurrence. In-depth analysis of BD pathogenetic mechanisms, involving dysfunction of multiple proinflammatory molecules, has opened new modalities of treatment: different agents targeting interleukin-1 have been studied in recent years to manage the most difficult and multi-resistant cases of BD. Growing experience with anakinra, canakinumab and gevokizumab is discussed in this review, highlighting the relative efficacy of each drug upon the protean BD clinical manifestations. Safety and tolerability of interleukin-1 antagonists in different doses have been confirmed by numerous observational studies on both large and small cohorts of patients with BD. In particular, the potential for Mycobacterium tuberculosis reactivation and tuberculosis development appears to be significantly lower with interleukin-1 blockers compared to tumor necrosis factor-α inhibitors, thus increasing the beneficial profile of this approach.

Serum amyloid-A (SAA) is an acute phase protein, synthesized by the liver and previously investigated as a marker of disease activity in many rheumatologic disorders. Its significance in Behcet’s disease (BD), a chronic inflammatory disorder at the crossroad between autoimmune and autoinflammatory syndromes, is still unraveled. Our aim was to assess the role of SAA levels as a potential marker of disease activity in patients with BD. According to our findings, the occurrence of oral aphthosis, neurological impairment, and ocular disease is significantly associated with SAA serum levels higher than 30, 50, and 150 mg/L, respectively. We also suggest that increased SAA levels might identify a thrombotic risk in BD with previous or concurrent vascular involvement.

Background: Optic perineuritis is a rare form of orbital inflammatory pseudotumor in which the specific target tissue is the optic nerve sheath. Patients are mainly represented by adult women. Differential diagnosis with demyelinating optic neuritis is essential in terms of prognosis and treatment. Case presentation: An 8-year-old Caucasian girl presented with bilateral loss of vision, disc edema, eye movement impairment, and diplopia. Brain MRI findings were suggestive of optic perineuritis. The patient received steroid pulse therapy followed by prolonged course of oral steroid therapy. The visual acuity recovered dramatically within 2days. Two months later, a new MRI investigation was normal. No clinical relapse was observed at the follow-up. Discussion: We first report on a child affected by optic perineuritis. Our observation suggests that optic perineurits should be considered in the differential diagnosis of children presenting with visual loss and disc edema. An early and correct diagnosis may lead to an appropriate therapeutic approach with very good outcome.

Recommendations related to ocular, mucosal and cutaneous involvement of Behçet's disease (BD) are mainly evidence-based, but in cases of vascular, neurological and gastrointestinal involvement there are no guidelines to define the best treatment strategy. We report three adult patients with BD, who received an interleukin-1β inhibitor by subcutaneous injections, canakinumab (at the dosage of 150 mg every 6 weeks), after failure shown by corticosteroids and different combinations of immunosuppressant agents. The prompt and sustained clinical efficacy demonstrated by canakinumab as a monotherapy supports the opportunity of using this specific anti-interleukin-1β agent as a valid therapeutic option for resistant or refractory BD. Open trials and observational studies should be performed to test canakinumab efficacy on a larger number of patients. The most appropriate dosage and intervals between administrations should be decided according to the individual patient, severity or recurrence of clinical manifestations and major organ involvement.

Item does not contain fulltext The study objective was to report treatment with an interleukin (IL)-1 receptor antagonist, anakinra, in patients with multiorgan Behcet's disease (BD). Comparison of clinical manifestations, previous treatments, markers of inflammation, concomitant medications, treatment regimen modifications, relapses, and adverse events before and during anakinra administration among patients with BD were evaluated. Nine BD patients (mean age 34.55 +/- 16.30 years) refractory to tumor necrosis factor blockers and standardized therapies are reported in our survey. Their mean age at disease onset was 25 +/- 13.88 years and their overall disease duration was 9.55 +/- 5.33 years. All patients were positive for the HLA-B51 allele. Within 1 or 2 weeks following the initiation of anakinra, eight out of nine patients promptly responded, and most of them were maintained on 100 mg of daily anakinra with low doses of prednisone. However, most patients experienced a relapse in one or more clinical manifestations over time (mean time to relapse 29 +/- 21.65 weeks), and only one patient remained completely under control on anakinra monotherapy. Despite a relapse in one or more disease manifestations, treatment was continued in most patients for a mean period of 13.75 +/- 6.49 months. No serious adverse events occurred. Eight out of nine refractory BD patients showed a prompt improvement after starting anakinra, supporting the concept that IL-1 plays a pathological role in this disease. Nevertheless, after several months, most patients experienced a relapse. It remains unclear whether increasing the dose of anakinra would have prevented the reoccurrence of disease activity.

Our purpose was to increase the knowledge about subcortical low-intensity images on long repetition time by describing brain magnetic resonance images of a young boy after his first spontaneous seizure. Evident in the epileptogenic area were transient images of reversible subcortical low intensity on long-repetition time, T2*-weighted, and b = 0 s/mm2 diffusion, isointense signal on b = 1000 s/mm2 diffusion, and restricted diffusion. Most likely, mechanism was axonal flow disruption with iron accumulation and free radicals production induced during seizure.

PURPOSE To report a case of Alternaria alternata keratitis analyzed with in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (OCT). METHODS A 68-year-old man with unilateral keratitis was evaluated using IVCM (Heidelberg Retina Tomograph II; Heidelberg, Germany) and anterior segment OCT (Visante OCT; Carl Zeiss Meditec, Dublin, CA). RESULTS IVCM demonstrated the presence of small, round, hyperreflective cells surrounded by hyporeflective irregular areas and highly reflective dendritic shaped cells at the level of the epithelium. Stromal examination revealed many hypereflective filamentous structures, and some hyporeflective perpendicular lines and hyperreflective oval bodies were clearly visible along the filaments. Anterior segment OCT examination demonstrated a thickened cornea due to diffuse edema and an irregular corneal surface corresponding to the ulcer. There were hyperreflective areas beneath the epithelium representing the infiltrate. Microbiological examination of corneal scrapings demonstrated the presence of Alternaria alternata. After 1 month of antifungal treatment, IVCM demonstrated a significant reduction of the inflammatory cells and a hyperreflective scar-like tissue. Branching hyphal infiltrates were no longer present. OCT also documented the healing process and the complete recovery of the central and peripheral stromal thickness. CONCLUSIONS IVCM and anterior segment OCT could be useful for the early diagnosis and treatment of fungal keratitis.

Previous studies indicate that extinguished stimuli can still be unconsciously processed, leading to implicit priming effects. Here we investigated whether these implicit effects might be modulated by the semantic nature of the stimuli. Five neglect patients and ten controls performed an identification task of items belonging to living and non-living categories. In the study phase photographs of animals and artifacts were presented either to the left visual field (LVF) or to the right visual field (RVF). In the identification phase, each stimulus was displayed centrally and was revealed in a sequence of frames where the item was represented by an increasingly less and less filtered image up to a complete version. The results showed that lateralized stimuli differentially affected controls’ and neglect patients’ memory retrieval. In controls memory traces from the study phase served as efficient primes, thereby reducing the amount of information necessary for the identification of both stimulus categories. Moreover, hemispheric differences emerged with an advantage of the RVF/left hemisphere for artifact items, while no difference was found for living things. Neglect patients showed a priming effect for artifact items presented either to the RVF/left hemisphere or LVF/right hemisphere, as well as for living items presented to the RVF/left hemisphere, but not for living items presented to the LVF/right hemisphere. The priming effect observed for extinguished artifacts is consistent with the evidence of the existence of a specific mechanism destined to analyze, in an automatic and implicit fashion, motor-relevant information of manipulable objects and tools, which are important for identification process. Results are discussed in relation to current models of organization of conceptual knowledge within the framework of different processes performed by the two hemispheres.

A 30-year-old woman developed acute visual loss and optic disc elevation in the left eye after breastfeeding her second son. The initial diagnosis was optic neuritis. However, MRI showed a lesion in left intraorbital and intracanalicular optic nerve and several cerebral lesions with imaging features of cerebral cavernous malformations (CCMs). Genetic testing was positive for abnormalities known to predispose to CCMs in the patient and her father, who also showed MRI evidence of CCMs. During a 44-month follow-up period in which no intervention took place, the patient's vision in the affected eye fluctuated but eventually became extinguished. Serial MRIs did not always show lesion changes that explained the visual deterioration. In familial CCM, pregnancy might be a "second hit" to genetically predisposed tissue.

Sirs: Autosomal dominant optic atrophy (ADOA) (MIM #165500) is the most prevalent dominantly inherited optic neuropathy, typically presenting in the first decade of life with progressive loss of visual acuity, abnormal colour discrimination, centrocaecal scotoma and optic nerve pallor. ADOA has variable expression ranging from asymptomatic carriers to legally blind patients, so a high degree of phenotype variation is observed within and between families (Delettre et al. 2002; Pesch et al. 2001; Thiselton et al. 2002; Votruba et al. 1998). Intriguing clinical and morphological overlaps between ADOA and other optic neuropathies caused by retinal ganglion cell degeneration, such as Leber’s optic neuropathy (LHON) (Carelli et al. 2004) and normal-tension glaucoma (NTG) (Alward et al. 2003; Votruba et al. 2003), have recently been reported. ADOA is therefore a genetic disorder that provides insights into common mitochondrial pathophysiological mechanisms leading to optic nerve damage. Mutations in the OPA1 gene were recently identified in families that manifest ADOA in an autosomal dominant pattern. The OPA1 gene contains 30 exons (Delettre et al. 2001), 28 of which encode a 960-amino-acid dynamin-related GTPase. A total of 83 different mutations, mainly family specific, have been reported so far (http://lbbma.univ-angers.fr/ eOPA1/). Almost 50 % of the mutations cause premature truncation of the OPA1 protein. Most mutations are in exons 8, 9, 12 and 27, primarily affecting the GTPase domain and the C-terminal coiledcoil domain (Baris et al. 2003). In particular, four mutations are present in exon 9, three being missense mutations and one being a nucleotide deletion. We recently examined two siblings with bilateral optic neuropathy. The first, a 38-year-old Italian male, had experienced progressive loss of visual acuity since the age of 6 years with a residual bilateral visual acuity of 20/30. Colour vision showed generalized dyschromatopsia. Ophthalmoscopy showed normal cupping and appearance of emerging vessels with slight temporal pallor of both optic nerves. Intra-ocular pressure (IOP) was 21 mm Hg (normal value: 18–20 mmHg) (applanation) in both eyes. Goldmann’s visual field charts showed paracentral scotoma. Patternreversal visual evoked potentials (VEPs) showed abnormally high P100 latency bilaterally (RE 112 ms, LE 109 ms). Onset of the disease in the second patient, the 33-year-old sister of the first patient, occurred at 16 years of age. Visual acuity was 20/40 and colour vision (Ishihara) showed red-green dyschromatopsia. Fundoscopy showed a normal cup to disk ratio with normal vessels and bilateral temporal pallor. IOP was 19 mmHg bilaterally (applanation). Goldmann visual field examination showed centrocaecal scotoma. VEPs had abnormally high P100 latency (RE 115 ms, LE 117 ms). The patients’ mother (aged 55 years) was without eye disease (visual acuity, fundoscopy and VEPs were normal). Conversely, maternal aunts (65 and 67 years) were reported to have had dyschromatopsia and poor vision since an early age. After informed consent was obtained, genomic DNA was extracted from peripheral blood leucocytes. A genetic screen of “Leber” mutations at positions 11778, 3460 and 14484 of mtDNA was negative. Exons 8, 9, 12 and 27 of OPA1 gene, including exon-intron junctions, were amplified and sequenced directly using specific primers, as already described (Delettre et al. 2001; Shimizu et al. 2002). The two patients, their mother and two aunts showed one novel heterozygous nonsense mutation in exon 9, R312X, resulting from a C > T transition at position c.934, i. e. 934 bp from the start codon (cDNA) (Fig. 1), while the father was negative for the mutation. This LETTER TO THE EDITORS