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Introduction: Ibrutinib is a small-molecule drug approved for the treatment of haematological disorders and is known to be associated with visual disturbances, but uveitis has not yet been reported as an adverse effect of this medication. We present two cases of ibrutinib-associated severe uveitis in patients with chronic lymphocytic leukaemia., Case Description: Our first case is a 65-year-old woman who presented with acute onset of bilateral fibrinous anterior uveitis 1 day after starting ibrutinib. Her vision was hand movements in the right eye and 20/120 in the left with hyperaemic discs and subretinal fluid. Ibrutinib was stopped and she experienced a significant improvement under local and oral steroid treatment. The second case is a 64-year-old male with subacute onset of bilateral hypertensive anterior uveitis with pupillary seclusion and right eye hyphaema. He was on ibrutinib for the past 9 months. His vision at presentation was 20/80 and 20/60 for the right and left eye, respectively. He responded poorly to local steroid treatment until ibrutinib was stopped due to cardiac side-effects, after which his uveitis resolved and treatment was stopped., Conclusion: The temporal association between changes in ibrutinib treatment and our patients' ocular inflammation suggests a causative link. Ibrutinib increases Th1-based immune responses which is proposed as a mechanism for drug-induced uveitis. Its antiplatelet effect may explain the fibrinous nature of the inflammation and hyphaema.

CD4 + T cell mediated uveitis is conventionally treated with systemic immunosuppressive agents, including corticosteroids and biologics targeting key inflammatory cytokines. However, their long-term utility is limited due to various side effects. Here, we investigated whether DNA methylation inhibitor zebularine can target CD4 + T cells and control intraocular inflammation. Our results showed that zebularine restrained the expression of inflammatory cytokines IFN-γ and IL-17 in both human and murine CD4 + T cells in vitro . Importantly, it also significantly alleviated intraocular inflammation and retinal tissue damage in the murine experimental autoimmune uveitis (EAU) model in vivo , suggesting that the DNA methylation inhibitor zebularine is a candidate new therapeutic agent for uveitis.

Purpose: The purpose of the study was to report a case of multiple sclerosis (MS)-associated uveitis refractory to conventional immunosuppressants, with subsequent remission following treatment with alemtuzumab., Methods: Case report Patient was treated with intravenous alemtuzumab, a lymphocyte depleting anti-CD52 monoclonal antibody that has recently been approved for use in relapsing MS., Results: A 17-year-old female presented with bilateral optic neuritis and subsequently bilateral intermediate uveitis and secondary macular oedema. She was diagnosed with active relapsing MS for which she received treatment with alemtuzumab. The intraocular inflammation previously refractory to conventional immunosuppressants responded to alemtuzumab, inducing remission., Conclusions: To our knowledge, this is the first such report of alemtuzumab treatment in MS-associated ocular inflammatory disease and may demonstrate a potential utility for this drug in related conditions.

Aim: To assess the efficacy of intravitreal ranibizumab for the treatment of new onset inflammatory choroidal neovascularisation (iCNV), including both uveitic and idiopathic CNVs., Methods: Single-centre, open-label, non-randomised Phase IIb clinical trial. Patients fulfilling strict entry criteria of new onset iCNV were given monthly intravitreal ranibizumab injections for 3 months. Thereafter, re-treatment was based on evidence of persisting activity. All patients completed trial follow-up. Optical coherence tomography (OCT) and best-corrected visual acuity (BCVA) were performed at every visit. Fluorescein angiography was performed at baseline, months 4 and 12. Descriptive analysis and Wilcoxon non-parametric test were performed for analysis., Results: 15 patients, 10 women with a mean age of 48.8 years (range 24-85 years) were included in the study. The mean number of injections was 4.33 (range 3-7). There was a statistically significant difference in the BCVA at month 4 (p=0.001) and at month 12 (p=0.001) compared with baseline. The mean gain in BCVA at month 4 compared with baseline was 20±15.36 letters (mean±SD), and at month 12 was 21±16.97 letters. There was a statistically significant difference in the mean central subfield thickness (CST) at baseline versus month 4 (p=0.003) and month 12 (p=0.001)., Conclusion: Patients gained vision (mean of 21 letters at 12 months) and showed reduced CST. These results support the continued use of ranibizumab in the treatment of iCNV., Trial Registration Number: 2008-007476-19, results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: To investigate the relationships between peripheral vasculitis, ischemia, and vascular leakage in uveitis using ultra-widefield fluorescein angiography (FA)., Design: Cross-sectional, consecutive case series., Methods: Consecutive ultra-widefield FA images were collected from 82 uveitis patients (82 eyes) in a single center. The extent of peripheral vasculitis, capillary nonperfusion, and vessel leakage were quantified. Parameters included: (1) foveal avascular zone area and macular leakage, (2) peripheral diffuse capillary leakage and ischemia, (3) peripheral vasculitis, and (4) leakage from neovascularization. Central macular thickness measurements were derived with optical coherence tomography. Main outcome measures were correlations between central and peripheral fluorangiographic changes as well as associations between visual function, ultra-widefield FA-derived metrics, and central macular thickness., Results: Although central leakage was associated with peripheral leakage (r = 0.553, P = .001), there was no association between foveal avascular zone size and peripheral ischemia (r = 0.114, P = .324), regardless of the underlying uveitic diagnosis. Peripheral ischemia was, however, correlated to neovascularization-related leakage (r = 0.462, P = .001) and focal vasculitis (r = 0.441, P = .001). Stepwise multiple regression analysis revealed that a poor visual acuity was independently associated with foveal avascular zone size and central macular thickness (R(2)-adjusted = 0.45, P = .001)., Conclusions: We present a large cohort of patients with uveitis imaged with ultra-widefield FA and further describe novel methods for quantification of peripheral vascular pathology, in an attempt to identify visually significant parameters. Although we observed that relationships exist between peripheral vessel leakage, vasculitis, and ischemia, it was only macular ischemia and increased macular thickness that were independently associated with a reduced visual acuity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To determine whether patients with juvenile systemic granulomatous disease (JSGD) (Blau syndrome) and uveitis have a characteristic ocular phenotype., Methods: Clinical and imaging data were collected retrospectively from patients attending the Regional Combined Paediatric Rheumatology and Ocular Inflammatory Service, Bristol Eye Hospital. General demographic information, laterality of the uveitis, age at onset, anatomical classification and course of the uveitis, clinical phenotype and specific NOD2 mutation were recorded for each patient., Results: Seventeen eyes from nine patients (five males; four females) were included in the study. Mean age at the disease onset was 15 months, range 1-84 months. Eight patients had bilateral uveitis. Anterior uveitis was present in five eyes, intermediate uveitis in two eyes, and there were 10 eyes with panuveitis, manifesting as multifocal choroiditis. Appearance of optic disc included indistinct disc margins in six eyes, optic nerve head pallor in six eyes, optic disc vessel sheathing in four eyes, and there was peripapillary hypo/hyperpigmentation in 13 eyes accompanied with characteristic peripapillary nodular excrescences. Among NOD2 mutations, the p.R334W was the most commonly detected (n: four cases), and three patients carried novel variants, the p.E338D and p.D390V variants in one patient, and the p.H520Y and p.Q809K variants in two different patients., Conclusions: Chronic bilateral panuveitis and a nodular peripapillary appearance in childhood onset uveitis are characteristic features of JSGD, which support the need for an appropriate genetic NOD2 analysis., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

In this study we investigated the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1), a key mDC subtype, in patients with autoimmune uveitis. We observed a significant increase of blood CD1c(+) mDC1 in uveitis patients. The increased CD1c(+) mDC1 exhibited high HLADR expression and less antigen uptake. CD1c(+) mDC1 were divided into two subpopulations. CD1c(hi) mDC1 subpopulation showed less antigen uptake and higher HLADR expression compared to CD1c(lo) mDC1 subpopulation. Importantly, the CD1c(hi) mDC1 subpopulation was increased in uveitis patients. In vitro, mature monocyte-derived dendritic cells (MoDCs), characterized by lower levels of antigen uptake, induced more CD4(+)CD62L(-) T helper cell proliferation. The mature phenotype and function of CD1c(+) mDC1 were regulated by TNFα via a p38 MAPK-dependent pathway. These data show that alterations in the systemic immune response are involved in the pathogenesis of autoimmune uveitis and invite the therapeutic possibility of attenuating uveitis by manipulating blood CD1c(+) mDC1., (Published by Elsevier Inc.)

Annexin-A1 (Anx-A1) is an endogenous anti-inflammatory molecule and while described as a repressor of innate immune responses, the role of Anx-A1 in adaptive immunity, and in particular in T helper (Th) cell responses, remains controversial. We have used a T-cell mediated mouse model of retinal autoimmune disease to unravel the role of Anx-A1 in the development of autoreactive Th cell responses and pathology. RBP1-20-immunized C57BL/6 Anx-A1(-/-) mice exhibit significantly enhanced retinal inflammation and pathology as a result of an uncontrolled proliferation and activation of Th17 cells. This is associated with a limited capacity to induce SOCS3, resulting in un-restricted phosphorylation of STAT3. RBP1-20-specific CD4(+) cells from immunized Anx-A1(-/-) animals generated high levels of Th17 cells-associated cytokines. Following disease induction, daily systemic administration of human recombinant Anx-A1 (hrAnx-A1), during the afferent phase of disease, restrained autoreactive CD4(+) cell proliferation, reduced expression of pro-inflammatory cytokines IL-17, IFN-γ and IL-6 and attenuated autoimmune retinal inflammatory disease. Furthermore, in man, Anx-A1 serum levels when measured in active uveitis patient sera were low and associated with the detection of IgM and IgG anti-Anx-A1 antibodies when compared to healthy individuals. This data supports Anx-A1 as an early and critical regulator of Th17 cell driven autoimmune diseases such as uveitis., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Myeloid dendritic cells (mDCs) play an important role in autoimmune diseases. However, the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1s), the subset of human blood mDCs, is not well understood in noninfectious uveitis., Methods: Fresh peripheral blood samples from human noninfectious uveitis patients (n = 32) and healthy controls (HCs) (n = 64) were stained with FITC-Lineage 1 (Lin1), PERCP-HLADR, and PE-CD1c antibodies. The levels of mDC1 were quantified by using flow cytometric analysis. Longitudinal data from patients (n = 16) were analyzed to correlate the levels of mDC1 with disease activity., Results: Blood CD1c(+) mDC1 and its subpopulation, CD1c(hi) mDC1, were increased in uveitis patients compared with HCs. Longitudinal data demonstrated that both the CD1c(+) mDC1 and CD1c(hi) mDC1 subpopulation reflected a dynamic change in clinical uveitis activity: CD1c expression was increased in active uveitis but decreased when uveitis became inactive., Conclusions: Given these observations, an alteration in blood CD1c(+) mDC1 and the CD1c(hi) mDC1 subpopulation could be a potential biomarker to monitor clinical uveitis activity within patients., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Objective: To assess the safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious childhood uveitis., Methods: Subjects were retrospectively selected from a database. Patients were included if they were diagnosed with chronic, noninfectious uveitis at 16 years of age or under and treated with triple immunosuppressive therapy for at least 6 months (following failure of a combination of 2 immunosuppressants). Patient demographics, diagnoses, duration of uveitis, drug dosages, active joint inflammation, and ophthalmologic data were recorded. Efficacy outcomes for triple therapy were recorded at 6 months., Results: Thirteen patients with bilateral uveitis were included. Using Standardized Uveitis Nomenclature (SUN) criteria, at 6 months only 11 eyes (42%) had a 2-step improvement in anterior chamber cell inflammation (n = 26). In addition, 2 patients required additional oral corticosteroid treatment. There were 4 significant infectious adverse events during a total of 21.9 patient-years (PY) on triple therapy (0.18 events per PY)., Conclusion: In this group of children with refractory uveitis, addition of a third immunosuppressive agent did not confer substantial benefit in redressing ocular inflammation and was associated with significant infections in a minority of patients.

Purpose: To compare tacrolimus monotherapy with tacrolimus and prednisone therapy for the maintenance of disease remission in subjects with noninfectious posterior segment intraocular inflammation (PSII)., Design: Randomized, controlled, phase 2b, open-label, dual-center noninferiority trial., Participants: Fifty-eight patients with sight-threatening PSII., Methods: Patients requiring a second-line systemic immunosuppressive agent to control their PSII were treated with therapeutic doses of oral tacrolimus. Those subjects who subsequently were able to taper their prednisone dose to 10 mg daily without disease reactivation were assigned randomly either to stop prednisone or to continue 7.5 to 10 mg prednisone daily for 9 months., Main Outcome Measures: Change in logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) and rate of patient withdrawal resulting from treatment inefficacy or intolerance., Results: Thirty-five patients successfully tapered their prednisone to 10 mg daily. Of these, 16 were allocated randomly to receive tacrolimus monotherapy and 19 to continue taking prednisone and tacrolimus dual therapy. The difference in the mean change in VA for monotherapy compared with the dual therapy group was less than 1 logMAR letter (logMAR, -0.008; 95% confidence interval, -0.108 to 0.092; P = 0.870). The proportion of patients who tolerated treatment and maintained disease remission for 9 months after randomization also was similar in both groups (monotherapy, 62.5%; dual therapy, 68.4%; P = 0.694). All monotherapy treatment failures were the result of disease reactivation, whereas 50% of dual-therapy failures were the result of drug intolerance., Conclusions: This study provides preliminary evidence that corticosteroids can be withdrawn in tacrolimus-treated patients who are able to achieve control of PSII with 10 mg prednisone daily, and any advantage of dual therapy in the prevention of disease reactivation was offset by its greater treatment intolerance. These findings support the further evaluation of corticosteroid-free treatment in future phase 3 trials (International Standard Randomised Controlled Trial Number Register identification, ISRCTN46576063)., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Despite a lack of robust evidence, anti-TNF therapies are in wide use for the treatment of noninfectious ocular inflammatory diseases. There is a clear rationale, based on mechanistic and preclinical efficacy data, for their use in posterior segment intraocular inflammation. However, their increasing use for other indications has been largely extrapolated from the benefit observed in autoinflammatory and autoimmune systemic diseases. Given their cost and the potential for significant adverse events, this review highlights the evidence for their continued use, possibilities for switching anti-TNF agents, and ways of reducing the risk of therapy.

Purpose: A discrete subpopulation of steroid refractory (SR) CD4(+) T cells has recently been identified in patients with SR ulcerative colitis (UC). The purpose of this study was to test whether this subpopulation is also present in patients with clinically defined SR uveitis. As interleukin (IL)-2 experimentally mediates the SR phenotype, the combined effects of dexamethasone (Dex) and a range of IL-2 targeting immunosuppressive agents were also investigated., Methods: Peripheral blood mononuclear cells (PBMCs) from 27 patients with uveitis and 4 normal volunteers were cultured for 5 days with CD3-CD28 beads. In vitro steroid refractivity or responsiveness was determined by the presence or absence of a subpopulation of SR CD4(+) cells (as previously reported for UC) that continued to proliferate or not in the presence of Dex. The patients were concurrently classified by a masked investigator as having clinically SR (threshold for disease reactivation, >or=10 mg prednisone daily) or steroid sensitive (SS) disease., Results: There was 78% (21/27) agreement between the in vitro and clinical classifications of SR and SS disease (kappa coefficient = 0.56, P = 0.002). This finding corresponds to a positive predictive value of 90% and a negative predictive value of 71%. In normal volunteers, basiliximab, daclizumab, and AG490 achieved an equivalent augmentation of CD4(+) cell suppression in combination with Dex., Conclusions: As in UC, patients with SR uveitis have a subpopulation of SR CD4(+) cells that are a potential target for intervention with anti-IL-2 therapies, including inhibitors of JAK/STAT signaling. The identification of SR T cells also has potential clinical application as a biomarker for SR disease.

Purpose: To evaluate the efficacy and tolerance of mycophenolate mofetil (MMF) for the treatment of noninfectious uveitis using the methods of analysis advocated by the Standardization of Uveitis Nomenclature (SUN) Working Group, and to compare this with other SUN-compliant reports of immunosuppression in ocular inflammation., Design: Retrospective case series. MEDHODS: A predefined data set was retrospectively obtained from the case notes of 100 consecutive uveitis patients treated with MMF at a single academic referral center between April 1, 2000 and August 1, 2006. These data were then analyzed in accordance with SUN recommendations. The main outcome measures were: 1) rate of tapering oral prednisone to 10 mg daily, 2) requirement for alternative second-line immunosuppressive therapy, and 3) rate of MMF dose discontinuation because of side effects., Results: In this large cohort with noninfectious persistent, chronic, or recurrent uveitis, there was an 84.6% probability of achieving a prednisone dose of < or =10 mg daily after one year of MMF treatment. Alternative second-line immunosuppressive therapy was introduced at a rate of 0.18 per patient-year (PY) and MMF was discontinued because of intolerance at a rate of 0.09/PY, predominantly because of gastrointestinal upset. This corroborates the findings of the only previous SUN-compliant study of MMF in ocular inflammation and is comparable to the rates of treatment success and intolerance we have recently reported for tacrolimus., Conclusion: This data generates concordant evidence with other SUN-compliant studies supporting the use of MMF in uveitis.

Purpose: To evaluate the long-term efficacy and tolerance of tacrolimus for the treatment of uveitis., Design: Retrospective case series., Participants: Sixty-two consecutive patients with noninfectious uveitis treated with tacrolimus at a single academic referral center between April 2000 and April 2004., Methods: A standard data set was obtained from patients' medical records and analyzed according to the recommendations of the Standardization of Uveitis Nomenclature Working Group., Main Outcome Measures: (1) Rate of tapering oral prednisone to 10 mg daily, (2) requirement for alternative second-line immunosuppressive therapy, and (3) rate of tacrolimus dose reduction or discontinuation due to side effects., Results: In this cohort with well-established ocular inflammation, patients successfully tapered their oral prednisone to 10 mg daily at an average rate of 1.62 per patient-year (PY), with an 85% probability of achieving < or =10 mg after 1 year 2 months of treatment. Tacrolimus was discontinued due to intolerance at a rate of 0.13/PY. This was predominantly due to noncardiovascular adverse events, and rates of introducing or increasing concomitant treatment for hypertension, hypercholesterolemia, and diabetes mellitus were all below 0.05/PY. Creatinine rises of > or =30% were also notably uncommon (0.05/PY)., Conclusion: Tacrolimus's efficacy for the treatment of uveitis is maintained long-term, and its cardiovascular risk profile is excellent.

CD4+ T cell mediated uveitis is conventionally treated with systemic immunosuppressive agents, including corticosteroids and biologics targeting key inflammatory cytokines. However, their long-term utility is limited due to various side effects. Here, we investigated whether DNA methylation inhibitor zebularine can target CD4+ T cells and control intraocular inflammation. Our results showed that zebularine restrained the expression of inflammatory cytokines IFN-γ and IL-17 in both human and murine CD4+ T cells in vitro. Importantly, it also significantly alleviated intraocular inflammation and retinal tissue damage in the murine experimental autoimmune uveitis (EAU) model in vivo , suggesting that the DNA methylation inhibitor zebularine is a candidate new therapeutic agent for uveitis. [ABSTRACT FROM AUTHOR]

Understanding immune mechanisms of noninfectious intraocular inflammation via animal models, and the relatively more restricted insights that can be achieved through studies in humans, continues to generate successful immunotherapies. This translational conduit elaborates immunopathogenic mechanisms, and illuminates further prospects of tailored therapies and biomarkers of disease activity and prognosis. More recently, our increased understanding has moved on from the success of previous biologic therapies, such as anti-TNF and IFN-α treatments, revealing other possible avenues to target; for example, Th17 cells, immune cell migration and the use of T-regulatory and dendritic cells to induce immunological tolerance. We now recognize that the ocular environment is endowed with many regulatory mechanisms but is hardly privileged in as much as ocular inflammation remains prevalent. Nevertheless, future therapeutic and diagnostic developments will harness our understanding of the local immunoregulatory networks to not only restrain immune-mediated damage, but also to restore homeostasis and neuronal function. This article attempts to crystallize our understanding of local immune regulation and immune mechanisms leading to intraocular inflammation. [ABSTRACT FROM AUTHOR]