Conor C. Murphy

Tumor necrosis factor α blockade with infliximab for refractory uveitis and scleritis

Abstract Objective To assess the efficacy and safety of the anti–tumor necrosis factor α agent infliximab in treatment-resistant uveitis and scleritis. Design Retrospective, noncomparative interventional case series. Participants Seven patients with noninfectious ocular inflammatory disease that was refractory to alternative immunosuppression. These included one patient with idiopathic retinal vasculitis and panuveitis, one patient with intermediate uveitis, one patient with chronic juvenile anterior uveitis, three patients with scleritis, and one patient with scleritis and peripheral ulcerative keratitis. Four patients had an underlying systemic disease that was in remission in three cases. Intervention Infusions of infliximab, 200 mg, were given at 4-week to 8-week intervals, depending on the clinical response. Main outcome measures Clinical response, including symptoms, visual acuity, degree of scleral vascular engorgement, corneal thinning, anterior chamber activity, and posterior segment inflammation, reduction in concomitant immunosuppression, and adverse effects. Results The mean patient age was 47 years (range, 24–78), and four patients were female. The mean number of infliximab infusions was seven (range, 2–19), and the mean follow-up period was 12 months (range, 4–22 months). Six patients experienced a clinical improvement, with five achieving remission and significant reduction in immunosuppression. One patient showed an initial response but developed a delayed hypersensitivity response that precluded further treatment. No other adverse effects occurred. Conclusions Infliximab seems to be an effective and safe treatment for noninfectious uveitis and scleritis and may be indicated as rescue therapy for relapses of ocular inflammation or as maintenance therapy when conventional immunosuppression has failed. Further investigation of infliximab for treatment-resistant scleritis and uveitis is warranted.

Minimum Inhibitory Concentrations of Standard and Novel Antimicrobials for Isolates from Bacterial Keratitis

PURPOSE To determine the minimum inhibitory concentrations (MICs) of 12 antimicrobials in current ophthalmic use and 4 potentially new alternatives against isolates from bacterial keratitis. METHODS Bacteria were collected from cases of bacterial keratitis in six centers in the United Kingdom between 2003 and 2006. MICs were measured by using susceptibility strips containing a concentration gradient of the antimicrobials penicillin, cefuroxime, ceftazidime, chloramphenicol, gentamicin, amikacin, vancomycin, teicoplanin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, meropenem, linezolid, tigecycline, and daptomycin. RESULTS Isolates (n = 772) were collected including coagulase negative Staphylococcus (CNS) (30%), Pseudomonas aeruginosa (23%), Staphylococcus aureus (14%), Enterobacteriaceae (14%), and streptococci (13%). Meropenem had low MICs for most isolates. All isolates except P. aeruginosa were susceptible to tigecycline. Linezolid was active against the majority of Gram-positive pathogens. Ten percent of S. aureus and 20% of CNS isolates were methicillin resistant. When systemic breakpoints were used, 84% of S. aureus isolates were susceptible to ciprofloxacin and 98% to moxifloxacin. Of the P. aeruginosa isolates, 99% were susceptible to ceftazidime, 96% to gentamicin, 99% to ciprofloxacin and 100% to moxifloxacin. More than 97% of Enterobacteriaceae isolates were susceptible to ceftazidime, gentamicin, ciprofloxacin, and moxifloxacin. CONCLUSIONS Based on systemic breakpoint data, resistance to commonly used antimicrobials was apparent. Meropenem is a potentially effective agent for ophthalmic use, with low MICs throughout all the bacterial subgroups. Tigecycline and linezolid showed good activity against particular groups and may be useful for treating bacterial keratitis resistant to current antimicrobials. Of the fluoroquinolones, moxifloxacin showed the lowest MICs and resistance for both Gram-positive and -negative bacteria.

Ustekinumab for the treatment of refractory giant cell arteritis

Giant cell arteritis (GCA) is the most common form of systemic vasculitis.1 Glucocorticoids are the mainstay of therapy, required in high doses for prolonged periods, with consequent serious complications in 86% of patients.2 There is a critical unmet need for a proven safe and effective immunosuppressive therapy in GCA, as agents such as methotrexate and infliximab have shown disappointing results in GCA.3 ,4 Interleukins 12 (IL-12) and 23 (IL-23) are implicated in Th1 and Th17 responses, respectively, both inflammatory pathways relevant to GCA pathogenesis.5 ,6 A recent case series reported the use of ustekinumab in three patients with Takayasu arteritis.7 The aim of this study was to evaluate the glucocorticoid-sparing efficacy of ustekinumab, an IL-12/IL-23-blocking monoclonal antibody, in patients with refractory GCA. Patients with GCA attending our centre are enrolled in a prospective registry and managed according to standardised …

A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool)

Background To date, there are no formal guidelines or referral pathways for acute anterior uveitis (AAU) patients developed or endorsed by any international or national societies. The objective of our study was to develop and validate an assessment algorithm for referral from ophthalmologists of appropriate AAU patients to rheumatology that will aid the early diagnosis of the spondyloarthropathy (SpA). Methods All consecutive patients attending the emergency department of local ophthalmology hospital with AAU, but who did not have a known diagnosis of SpA, were eligible to participate in this study. Patients with any other known cause of AAU were excluded. Two independent cohorts were enrolled. Test algorithm and Dublin Uveitis Evaluation Tool (DUET) algorithm (revised form of test algorithm) were used in these cohorts to identify patients as SpA suspects and non-SpA controls, respectively. Results STUDY PHASE-1. ALGORITHM DEVELOPMENT COHORT (n=101): After rheumatologic evaluation of the entire cohort, 41.6% (n=42) had undiagnosed SpA. Our test algorithm was noted to have: sensitivity 100% and specificity 53.5%. Further regression analysis resulted in the development of the DUET algorithm which made the following improvements: sensitivity 95%, specificity 98%, positive likelihood ratio (LR) 56.19, and negative LR 0.04. STUDY PHASE-2. DUET ALGORITHM VALIDATION COHORT (n=72): After rheumatologic evaluation of the cohort, 40% (n=29) were diagnosed with SpA, with the following performance of DUET algorithm—sensitivity 96%, specificity 97%, positive LR 41.5 and negative LR 0.03. Conclusions Approximately 40% of patients presenting with idiopathic AAU have undiagnosed SpA. A simple to apply algorithm is described with excellent sensitivity and specificity.

Quality of life and visual function in patients with intermediate uveitis

Aims: To assess visual function, vision related quality of life (VR-QOL), and general health related quality of life (HR-QOL) in intermediate uveitis (IU). Methods: VR-QOL and HR-QOL were evaluated in 42 patients with IU using the VCM1 and SF-36 questionnaires, respectively. LogMAR visual acuity (VA), Pelli-Robson contrast sensitivity (CS), Farnsworth-Munsell 100 hue colour vision (CV), and Estermann visual field (VF) were recorded monocularly and binocularly. Results: Median (interquartile range) visual acuity (VA) and CS of 72 affected eyes were 0.1 (0.015–0.3) and 1.55 (1.35–1.65), respectively. 9.5% of patients had a VCM1 score of more than 2.0, indicating “more than a little” concern over vision. Worse eye VA (p = 0.045) and CS (p = 0.042) were predictive of a VCM1 score of more than 2.0 independently of age, sex, uveitis duration, laterality and activity, systemic uveitis therapy, and medical co-morbidity. The physical and mental component summary scores of the SF-36 were significantly worse in those who reported significant impairment of vision on the VCM1 than those who did not. Conclusions: The majority of patients with IU maintain good visual function and quality of life. VR-QOL impairment in IU correlates with vision in the worse eye and is associated with impaired HR-QOL.

Systemic CD4+ T cell phenotype and activation status in intermediate uveitis

Aim: To investigate peripheral blood lymphocyte phenotype in patients with intermediate uveitis using CD69, chemokine receptor, and cytokine expression. Methods: Peripheral blood lymphocytes of 18 patients with idiopathic intermediate uveitis and 6 patients with presumed sarcoid intermediate uveitis were evaluated for CD4+ T cell expression of CD69, CCR4, CCR5, CXCR3 and the intracellular cytokines IFNγ, TNFα, and interleukin (IL)-10 by flow cytometry, and for IL-2, IL-4, IL-5, IL-10, IFNγ, and TNFα production following unstimulated and activated culture using cytokine bead array and compared with healthy control subjects. Results: The expression of CD69 and TNFα by peripheral blood CD4+ lymphocytes of patients with idiopathic intermediate uveitis and presumed sarcoid intermediate uveitis was significantly higher than control subjects (p = 0.002 and p<0.05, respectively). The ratios of the concentrations of IL-2:IL-5 and IFNγ:IL-5 in supernatants of activated peripheral blood lymphocyte cultures were significantly higher in patients with presumed sarcoid intermediate uveitis than control subjects. Conclusions: This study implicates TNFα in the pathogenesis of intermediate uveitis, highlighting the potential role of anti-TNF treatments for this disease. Studies of Th1:Th2 cytokine ratios suggested polarisation of the immune response towards Th1 in presumed sarcoid intermediate uveitis despite clinically quiescent systemic disease.

Validity of using vision-related quality of life as a treatment end point in intermediate and posterior uveitis

Aim: To evaluate the responsiveness of the Vision core module 1 (VCM1) vision-related quality of life (VR-QOL) questionnaire to changes in visual acuity in patients with posterior and intermediate uveitis and to validate its use as a clinical end point in uveitis. Methods: Logarithm of the minimum angle of resolution visual acuity and VR-QOL using the VCM1 questionnaire were prospectively recorded in 37 patients with active posterior segment intraocular inflammation before starting systemic immunosuppression with ciclosporin, tacrolimus or the anti-tumour necrosis factor (TNF) agent, p55TNFr-Ig, and again 3 months later. Spearman analysis was used to correlate improvements in visual acuity and VR-QOL between baseline and 3 months. Results: The correlation between changes in visual acuity and VR-QOL was moderate to good for the worse eye (r = 0.47, p = 0.003), but poor for the better eye (r = −0.05, p = 0.91). The responsiveness indices effect size and standardised response mean were 0.57 and 0.59, respectively, showing that the VCM1 questionnaire is moderately responsive to immunsosuppressive therapy for active uveitis. Conclusion: Changes in VR-QOL measured with the VCM1 questionnaire correlated moderately well with changes in the worse eye visual acuity, suggesting that the VCM1 is a valid instrument for monitoring response to treatment in uveitis.

Regulation of Inflammation and Angiogenesis in Giant Cell Arteritis by Acute-Phase Serum Amyloid A

Giant cell arteritis (GCA) is pathologically characterized by dysfunctional angiogenesis and inflammatory cell infiltration. Acute‐phase serum amyloid A (A‐SAA) is an acute‐phase reactant, but is also produced at sites of inflammation and may contribute to vascular inflammation in atherosclerosis. This study was undertaken to examine the effect of A‐SAA on proinflammatory pathways and angiogenesis in GCA, using a novel ex vivo temporal artery tissue explant model.

Corneal inlay implantation complicated by infectious keratitis

Background/aims To report five cases of infectious keratitis following corneal inlay implantation for the surgical correction of presbyopia. Methods This was a retrospective, observational case series. Five eyes of five patients were identified consecutively in two emergency departments during a 1-year period, from November 2013 to November 2014. Patients’ demographics, clinical features, treatment and outcomes are described. Results There were four female patients and one male, aged 52–64 years. Three patients had the KAMRA inlay (AcuFocus) and two had the Flexivue Microlens inlay (Presbia Coöperatief U.A.) inserted for the treatment of presbyopia and they presented from 6 days to 4 months postoperatively. Presenting uncorrected vision ranged from 6/38 to counting fingers. One patients corneal scrapings were positive for a putatively causative organism, Corynebacterium pseudodiphtheriticum, and all patients responded to broad-spectrum fortified topical antibiotics. All patients lost vision with final uncorrected visual acuity ranging from 6/12 to 6/60 and best-corrected vision ranging from 6/7.5 to 6/12. Two patients’ corneal inlays were explanted and three remained in situ at last follow-up. Conclusions Infectious keratitis can occur at an early or late stage following corneal inlay implantation. Final visual acuity can be limited by stromal scarring; in the cases where the infiltrate was small and off the visual axis at the time of presentation, the final visual acuity was better than those patients who presented with larger lesions affecting the visual axis. Though infection may necessitate removal of the inlay, early positive response to treatment may enable the inlay to be left in situ.

Proteomics in uveal melanoma.

Uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence of 5-7 per million per year. It is associated with the development of metastasis in about 50% of cases, and 40% of patients with uveal melanoma die of metastatic disease despite successful treatment of the primary tumour. The survival rates at 5, 10 and 15 years are 65%, 50% and 45% respectively. Unlike progress made in many other areas of cancer, uveal melanoma is still poorly understood and survival rates have remained similar over the past 25 years. Recently, advances made in molecular genetics have improved our understanding of this disease and stratification of patients into low risk and high risk for developing metastasis. However, only a limited number of studies have been performed using proteomic methods. This review will give an overview of various proteomic technologies currently employed in life sciences research, and discuss proteomic studies of uveal melanoma.