Long-term Outcomes of Rituximab Therapy in Ocular Granulomatosis with Polyangiitis: Impact on Localized and Nonlocalized Disease.

PURPOSE: To evaluate the long-term outcomes of rituximab (RTX) treatment in patients with ocular granulomatosis with polyangiitis (GPA) with localized or generalized disease. DESIGN: Retrospective cohort. PARTICIPANTS: Thirty-seven patients with ocular GPA receiving RTX in a multidisciplinary vasculitis clinic between 2004 and 2013. METHODS: A total of 100 patients who received a course of RTX were identified, and notes were reviewed. Baseline demographic details, clinical characteristics (including organ involvement), drugs used, and outcome measures were recorded. MAIN OUTCOME MEASURES: The percentage in remission (inactive disease with prednisolone ≤7.5 mg with or without maintenance treatment) at 6 months, time to remission, percentage relapsing, side effects, B-cell count, antineutrophil cytoplasm antibody titers, induction, and maintenance regimens. RESULTS: The median follow-up time after the first RTX course was 36.5 months. Twenty patients had scleritis, and 17 patients had orbital disease; 86% achieved remission at 6 months. The percentage in remission versus partial remission was not statistically significant between patients with scleritis and patients with orbital disease (85% vs. 15% with scleritis and 82% vs. 18% with orbital disease; P = 1.00). The percentage relapsing was not statistically significant (P = 0.33) between scleritis (60%) and orbital disease (41%). Localized disease (ocular ± ear-nose-throat/lung) was observed in 57%, and generalized disease (ocular plus other organs) was observed in 43%, the former having a median duration of disease of 40 months. There was no statistically significant difference (P = 0.37) in the percentage in remission between localized and generalized ocular disease. Relapses occurred in 51%, with localized disease being a significant risk factor for relapse. Fifty percent of patients with generalized disease versus none with localized disease received cyclophosphamide (CYP) as part of the induction regimen. Patients who received CYP during induction had significantly (P = 0.027) lower ratios of baseline 12-month proteinase 3 titers than patients who did not have CYP. Infections were observed in 16% of patients, with 8% requiring hospital admission. CONCLUSIONS: Our long-term data suggest that RTX is effective for inducing disease remission in localized and generalized ocular GPA. Localized disease is a significant risk factor for relapse, which may be related to less use of CYP in the induction regimen.

Long-term clinical outcome and causes of vision loss in patients with uveitis.

PURPOSE: To evaluate the long-term clinical and functional outcome, risks, and causes of vision loss and burden of disease among patients with uveitis. DESIGN: Cross-sectional study. PARTICIPANTS: The study included 1076 patients diagnosed with uveitis who attended the uveitis clinic at Moorfields Eye Hospital, London, United Kingdom, between 2011 and 2013. METHODS: Information was gathered from the notes of all patients who were examined in the clinic. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), causes of moderate vision loss (MVL; 20/50-20/120), and severe vision loss (SVL; ≤ 20/200). RESULTS: The study included 1799 eyes of 1076 patients with an average follow-up of 7.97 ± 0.17 years (median, 5.6 years; range, 1 month-54 years; 8159 patient-years; 14 226 eye-years). Average BCVA remained stable for patients with anterior uveitis (20/30 at baseline to 20/33 at 10 years), as well as for those with nonanterior uveitis (20/50 at baseline to 20/47 at 10 years). Vision loss was noted in 19.2% of eyes, with an incidence for MVL of 0.01 per eye-year or 0.02 per patient-year and for SVL of 0.01 per eye-year or 0.02 per patient-year. Patients were more at risk of vision loss if they had non-anterior uveitis disease, vitreous opacities, retinal detachment, cystoid macular edema (CME), macular scarring, macular hole, optic neuropathy, or macular ischemia. Chronic CME was the most common cause of MVL (3.55%), and macular scarring was the most common cause for irreversible SVL (4%). Among 525 patients (48.7%) who received oral prednisolone, 320 (61%) required a dose of more than 40 mg/day and 130 (24.8%) also required 1 or more second-line agents. Patients were reviewed on average 33.7 ± 0.7 times or 5.9 ± 0.46 times/year. CONCLUSIONS: Long-term functional outcome among uveitis patients is good, with BCVA remaining stable for more than 10 years of follow-up. In cases when vision loss occurs, it is related mainly to retinal changes. The burden on clinical services is similar regardless of the severity of disease or the risk of vision loss.

Outcomes of changing immunosuppressive therapy after treatment failure in patients with noninfectious uveitis.

PURPOSE: To evaluate the outcomes of changing immunosuppressive therapy for noninfectious uveitis after failure. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with noninfectious uveitis managed at 2 tertiary uveitis clinics in the United Kingdom and Australia. METHODS: Participants with a history of using immunosuppressive therapy were identified in clinics, and notes were reviewed by doctors trained in uveitis therapy. Each treatment episode/course (starting or changing a therapy) was identified, and demographic details, clinical characteristics, drug used (second-line immunosuppressive agent [ISA] or biologicals), and drug doses were obtained. MAIN OUTCOME MEASURES: For each treatment episode, the reasons for changing therapy, corticosteroid-sparing effects, and control of inflammation were determined. RESULTS: A total of 147 patients were identified who underwent 309 different treatment episodes. Fifty-five percent of patients eventually required a change in treatment after their first treatment episode/course. Forty-five episodes involved switching from one ISA to another, with 50% to 100% of these patients achieving "success" (prednisolone ≤10 mg and sustained control) with the new ISA. A combination of ISAs were used in 53 episodes, with "success" being achieved in 50% to 71% of these patients. Biological agents were used in 45 episodes, the most common one being infliximab, which achieved success in 80% of patients. CONCLUSIONS: Our data suggest that control of inflammation can be achieved after switching or combining ISAs.

SIRT1 activation protects against autoimmune T cell-driven retinal disease in mice via inhibition of IL-2/Stat5 signaling.

Sirtuins are a mammalian family of NAD(+)-dependent histone deacetylases that regulate cell function and survival as well as regulating cell responses under inflammatory conditions. SIRT1 activator treatment in vitro using mouse pLN cells, normal human and ocular Behçet's disease donor PBMC resulted in suppressed T cell proliferation and pro-inflammatory cytokine production. Our data suggest a novel mechanism by which SIRT1 activators contribute to suppression of T cell proliferation by both down regulating STAT5A/B expression and suppression of pSTAT5A/B signaling in response to IL-2. Experimental autoimmune uveoretinitis (EAU) in B10.RIII mice is an antigen-specific cell-mediated model of human intra-ocular inflammatory disease. Infiltrating CD4(+) T cells in the retina secrete both IFN-γ and IL-17 and are accompanied by inflammatory granulocytes and macrophages which together result in retinal destruction. Oral SIRT1 activator treatment administered to EAU mice suppressed disease with an accompanying reduction in retinal leukocytic infiltrate, suppressed antigen-specific T cell responses and marked suppression of innate and adaptive pro-inflammatory cytokine production in the eye including IL-6, IL-17A and IFN-γ. In vivo SIRT1 activator treatment also suppressed production of IL-17A, IL-17F, IL-6, TGFß and IL-22 by pLN cells. Oral SIRT1 activator treatment administered to mice during the efferent phase (days7-14) of EAU was effective at suppressing disease. These observations demonstrate that SIRT1 activation is anti-inflammatory in nature and future targeted activation of SIRT1 shows promise as a potential treatment for non-infectious intra-ocular disorders such as uveitis associated with Behçets disease.

Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis.

PURPOSE: To assess the outcomes of the intravitreal administration of methotrexate in uveitis. METHODS: Multicenter, retrospective interventional case series of patients with noninfectious uveitis. Thirty-eight eyes of 30 patients were enrolled, including a total of 54 intravitreal injections of methotrexate at a dose of 400 µg in 0.1 mL. The primary outcome measure was visual acuity. Secondary outcome measures included control of intraocular inflammation and cystoid macular edema, time to relapse, development of adverse events, and levels of systemic corticosteroid and immunosuppressive therapy. RESULTS: Methotrexate proved effective in controlling intraocular inflammation and improving vision in 30 of 38 eyes (79%). The side effect profile was good, with no reported serious ocular adverse events and only one patient having an intraocular pressure of >21 mmHg. Of the 30 eyes that responded to treatment, 8 relapsed, but 22 (73%) entered an extended period of remission, with the Kaplan-Meier estimate of median time to relapse for the whole group being 17 months. The eight eyes that relapsed were reinjected and all responded to treatment. One eye relapsed at 3 months, but 7 eyes again entered extended remission. Of the 14 patients on systemic therapy at the start of the study, 8 (57%) were able to significantly reduce this following intravitreal methotrexate injection. CONCLUSION: In patients with uveitis and uveitic cystoid macular edema, intravitreal MTX can effectively improve visual acuity and reduce cystoid macular edema and, in some patients, allows the reduction of immunosuppressive therapy. Some patients relapse at 3 to 4 months, but a large proportion (73%) enter an extended period of remission of up to 18 months. This larger study extends the results obtained from previous smaller studies suggesting the viability of intravitreal methotrexate as a treatment option in uveitis.

Survey of policy for MRSA screening in English cataract surgical units and changes to practice after updated National guidelines.

BACKGROUND: National guidelines on MRSA (methicillin-resistant Staphylococcus aureus) screening policy in England have changed on a number of occasions, but there is limited data on its influence at a local level. The aim of this study was to determine if changes in National policy influenced preoperative screening of cataract patients for MRSA. METHODS: A structured telephone survey was conducted on all 133 ophthalmology units in England in 2004 and again in 2007 for the initial responders, after a change in national policy. RESULTS: A total of 74 units (56%) responded in 2004 and 71 units (96% of initial respondents) in 2007. In 2004, 57% of units screened for MRSA. They screened groups at high risk of carriage, including patients with previous MRSA (93%) and patients from Nursing homes (21%). Swab sites included the nose (100%), eyes (31%) and perineum (62%). In 2007, there was no significant change in the number of units that screened for MRSA (57% vs 66%; p = 0.118; McNemar test). However, more units screened for MRSA in patients from nursing/residential homes (21% vs 51%; p = 0.004, McNemar test), and in patients who had recent admission to hospital (12% vs 36%; p = 0.003). In the second survey, 3 units (6%) now screened patients who were close relatives of MRSA carriers. CONCLUSION: This survey has highlighted inconsistences in MRSA screening practice of day-case cataract surgery patients across England after 2 major national policy changes. A change in DoH policy only led to more units screening patients for MRSA from high risk groups.

Local therapies for inflammatory eye disease in translation: past, present and future.

Despite their side-effects and the advent of systemic immunosuppressives and biologics, the use of corticosteroids remains in the management of patients with uveitis, particularly when inflammation is associated with systemic disease or when bilateral ocular disease is present. The use of topical corticosteroids as local therapy for anterior uveitis is well-established, but periocular injections of corticosteroid can also be used to control mild or moderate intraocular inflammation. More recently, intraocular corticosteroids such as triamcinolone and steroid-loaded vitreal inserts and implants have been found to be effective, including in refractory cases. Additional benefits are noted when ocular inflammation is unilateral or asymmetric, when local therapy may preclude the need to increase the systemic medication.Implants in particular have gained prominence with evidence of efficacy including both dexamethasone and fluocinolone loaded devices. However, an appealing avenue of research lies in the development of non-corticosteroid drugs in order to avoid the side-effects that limit the appeal of injected corticosteroids. Several existing drugs are being assessed, including anti-VEGF compounds such as ranibizumab and bevacizumab, anti-tumour necrosis factor alpha antibodies such as infliximab, as well as older cytotoxic medications such as methotrexate and cyclosporine, with varying degrees of success. Intravitreal sirolimus is currently undergoing phase 3 trials in uveitis and other inflammatory pathways have also been proposed as suitable therapeutic targets. Furthermore, the advent of biotechnology is seeing advances in generation of new therapeutic molecules such as high affinity binding peptides or modified high affinity or bivalent single chain Fab fragments, offering higher specificity and possibility of topical delivery.

Valacyclovir in the treatment of acute retinal necrosis.

BACKGROUND: To report the outcome of oral valacyclovir as the sole antiviral therapy for patients with acute retinal necrosis (ARN). METHODS: This study reports a retrospective, interventional case series of nine consecutive patients with ten eyes with newly diagnosed ARN treated with oral valacyclovir as the sole antiviral agent. Eight patients received oral valacyclovir 2 g tid (Valtrex, GlaxoSmithKline) and one patient with impaired renal function received oral 1 g tid. The main outcome measures were response to treatment, time to initial response to treatment, time to complete resolution of retinitis, best corrected visual acuity (BCVA) at final follow-up, retinal detachment and development of recurrent or second eye disease. RESULTS: Retinitis resolved in ten of ten (100%) affected eyes. The median time to initial detectable response was seven days and the median time to complete resolution was 21 days. A final BCVA of 20/40 or better was achieved in 6/10 (60%) of eyes. 3/10 eyes (30%) developed a retinal detachment. No patients developed either disease reactivation or second eye involvement over the course of the study (mean follow up 31 weeks, range 7 to 104 weeks). CONCLUSIONS: Treatment with oral valacyclovir as the sole antiviral therapy resulted in complete resolution of retinitis. Final BCVA and retinal detachment rate were comparable with previously reported outcomes for intravenous acyclovir.

Rituximab in refractory ophthalmic Wegener's granulomatosis: PR3 titers may predict relapse, but repeat treatment can be effective.

OBJECTIVE: To report the long-term outcome of the treatment of refractory ophthalmic Wegener's granulomatosis (WG) with rituximab (RIT), including rates of relapse, predictors of relapse, and results of repeat treatment. DESIGN: Retrospective case series. PARTICIPANTS: We included 20 consecutive patients with refractory ophthalmic WG treated with RIT. INTERVENTION: Intravenous RIT infusion, 2 doses of 1 g given 2 weeks apart. MAIN OUTCOME MEASURES: Regular clinical, serologic, and immunologic examinations for disease activity and extent, and for treatment-related side effects. RESULTS: All 20 patients entered remission, the median time to remission being 2 months (range, 1-6). Seven patients (35%) relapsed at a median of 13 months (range, 9-18). Five of these patients took a second course of RIT, and all achieved remission without further relapse. In the 16 patients with positive anti-proteinase-3 (PR3) titers at baseline, rising anti-PR3 titer was a statistically significant predictor of relapse. There were 4 severe adverse events during the study, of which one was directly attributed to treatment with RIT. CONCLUSIONS: In this series of 20 patients with refractory ophthalmic WG, RIT was effective in inducing remission. Relapse occurred in one third of patients within 18 months and seemed to be predictable by rising anti-PR3 titers, but retreatment with RIT was effective in this group. In patients with ophthalmic WG, RIT may be capable of inducing extended remission, in contrast with other biologic and conventional treatments in common use. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

New developments in corticosteroid therapy for uveitis.

Corticosteroids remain the mainstay of the management of patients with uveitis. Topical corticosteroids are effective in the control of anterior uveitis, but vary in strength, ocular penetration and side effect profile. Systemic corticosteroids are widely used for the management of posterior segment inflammation which requires treatment, particularly when it is associated with systemic disease or when bilateral ocular disease is present. However, when ocular inflammation is unilateral, or is active in one eye only, local therapy has considerable advantages, and periocular injections of corticosteroid are a useful alternative to systemic medication and are very effective in controlling mild or moderate intraocular inflammation. More recently, the injection of intraocular corticosteroids such as triamcinolone have been found to be effective in reducing macular oedema and improving vision in uveitic eyes which have proved refractory to systemic or periocular corticosteroids. The effect is usually transient, lasting around 3 months, but can be repeated although the side effects of cataract and raised intraocular pressure are increased in frequency with intraocular versus periocular corticosteroid injections. This has led to the development of new intraocular corticosteroid devices which are designed to deliver sustained-release drugs and obviate the need for systemic immunosuppressive treatment. The first such implant was Retisert, which is surgically implanted (in the operating theatre) and is designed to release fluocinolone over a period of about 30 months. More recently, Ozurdex, a 'bioerodible' dexamethasone implant which can be inserted in an office setting, has completed phase III clinical trials in patients with intermediate and posterior uveitis. This implant lasts approximately 6 months, and has been found to be effective with a much better side effect profile than Retisert or intravitreal triamcinolone injection, at least for one injection.

A case of optic neuropathy after short-term linezolid use in a patient with acute lymphocytic leukemia.

A patient undergoing chemotherapy for treatment of acute lymphocytic leukemia developed septicemia that was treated with linezolid for 16 days. The patient subsequently reported reduced vision in both eyes and was found to have bilateral optic neuropathy. After the discontinuation of linezolid treatment, both the optic neuropathy and visual impairment resolved without sequelae.

Pain Associated With a Subconjunctival Cefazolin-Lidocaine Mixture in Retinal Surgery:A Randomized Control Trial.

BACKGROUND AND OBJECTIVE: The purpose of this randomized, single-masked clinical trial is to explore whether cefazolin mixed with 2% lidocaine can reduce pain. PATIENTS AND METHODS: Patients naïve to ophthalmic surgery were randomized to subconjunctival injection of either a 0.5 mL cefazolin-balanced salt solution (0.3 mL cefazolin and 0.2 mL balanced salt solution) or 0.5 mL cefazolin-lidocaine solution (0.3 mL cefazolin and 0.2 mL 2% lidocaine) during retinal surgery with a retrobulbar block. Pain scores were obtained at the start of surgery, middle of surgery, before and after cefazolin administration, and postoperatively. RESULTS: A total of 54 patients were recruited; 44.6% were male, and the mean age was 60.1 years ± 13.5 years. There were no statistically significant differences between the groups' operative characteristics or pain scores at each study time point. CONCLUSION: In pars plana vitrectomy with or without phacoemulsification and intraocular lens insertion, subconjunctival cefazolin mixed with lidocaine conferred no added analgesic benefit. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:881-886.].

Intravitreal bevacizumab injections for diabetic macular edema - predictors of response: a retrospective study.

BACKGROUND: Outcomes of intravitreal antivascular endothelial growth factor injections are variable among patients with diabetic macular edema (DME). The aim of this study was to determine the ocular and systemic predictors of DME response to intravitreal bevacizumab (IVB). METHODS: Retrospective review over 2 years of 78 eyes from 54 patients. An anatomical response to IVB was defined as a 20% reduction in central macula thickness after the first course (three injections) of IVB. RESULTS: Twenty-eight percent of patients had an anatomical response after the first course of IVB. Systemic hypertension (odds ratio, 95% confidence interval: 12.1, 0.7-21) was a statistically significant predictor (P=0.025) of a good response to IVB, whereas previous macular laser was a statistically significant (P=0.0005) predictor of a poor response (0.07, 0.01-0.32). Sixty-eight percent of eyes underwent subsequent treatment for DME after the first course of IVB. The visual acuity gain at 24 months in hypertensive (0.7±3.6 letters) and nonhypertensive (5.2±3.7 letters) patients was not significantly different (P=0.41). CONCLUSION: Hypertension and previous macular laser were positive and negative predictors of response to IVB, respectively. However, long-term visual acuity changes were not significantly different between eyes with and without systemic hypertension.

Uveitis as a Result of MAP Kinase Pathway Inhibition.

We report the case of a patient treated with dabrafenib and trametinib (mitogen-activated protein kinase pathway inhibitors) for stage 3b cutaneous melanoma who developed bilateral uveitis. Although there have been reports of ocular side effects with this class of drugs, uveitis has not been previously reported to the best of our knowledge. This case indicates the wide range of side effects that can be seen with the newer targeted biological therapies.

Dexamethasone implants in retinal vein occlusion: 12-month clinical effectiveness using repeat injections as-needed.

OBJECTIVE: To report the 12-month outcomes of the dexamethasone intravitreal implant in retinal vein occlusion (RVO), using an as-needed repeat injection protocol. DESIGN: Retrospective consecutive case series of 51 eyes of 49 patients with macular oedema as a result of RVO that received an intravitreal dexamethasone implant and were followed up for at least 12 months. RESULTS: 70% of patients responded to dexamethasone implant injection with an improvement in visual acuity (VA) and macular oedema within 3 months of injection, but only 30% of eyes gained ≥15 letters. The mean change in VA letter score at 12 months compared with baseline for branch RVO (BRVO) and central RVO (CRVO) was 5.7±2.3 and 11.5±11.0 EDTRS letters, respectively. 56% of patients relapsed, with the median time to relapse being 17 weeks for patients with branch RVO and 18 weeks for patients with CRVO. Repeat injections achieved similar VA gains, but the duration of effect of repeat dexamethasone implants was much shorter at 10 weeks. 14 eyes (27%) developed a significant rise in intraocular pressure, and three of these required treatment with oral acetazolamide. Four eyes with CRVO developed neovascular glaucoma during the study. CONCLUSIONS: The intravitreal dexamethasone implant does not last the 6 months implied by the retreatment protocol in the GENEVA trial, and improved results can be achieved with an as-needed retreatment protocol, particularly in CRVO. However, visual outcomes remain similar to those previously seen with triamcinolone in the SCORE study and neovascular complications remain a feature of CRVO.

Rhizobium radiobacter Endophthalmitis following Intravitreal Ranibizumab Injection.

We present the first reported case of acute endophthalmitis due to Rhizobium radiobacter after an intravitreal injection of ranibizumab for neovascular age-related macular degeneration.

Combined infliximab and rituximab in necrotising scleritis.

We report a patient with necrotising scleritis in whom infliximab was used for short-term steroid-sparing while rituximab took effect. This enabled disease control without requiring an extended period of high-dose corticosteroid administration or the concurrent use of cyclophosphamide.

The eye and phacomatoses.

This article reviews the ocular and neuro-opthalmic manifestations of phacomatoses, while emphasizing important differential diagnoses that exist based on their clinical features. Variations in the definition of phacomatoses do exist, but conditions not meeting the classical definition are also presented.