Publications by authors named "Conor C Murphy"

47 Publications

Behçet's disease presenting as bilateral occlusive retinal vasculitis in a young woman.

BMJ Case Rep 2021 Mar 4;14(3). Epub 2021 Mar 4.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1136/bcr-2021-241794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934770PMC
March 2021

Monocular syphilitic uveitis.

BMJ Case Rep 2021 Feb 9;14(2). Epub 2021 Feb 9.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1136/bcr-2020-241403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875258PMC
February 2021

Beware the quiet eye: primary vitreoretinal lymphoma masquerading as posterior uveitis.

BMJ Case Rep 2020 Dec 31;13(12). Epub 2020 Dec 31.

Royal College of Surgeons in Ireland, RCSI University of Medicine and Health Sciences, Dublin, Ireland.

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http://dx.doi.org/10.1136/bcr-2020-240802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780513PMC
December 2020

Herpes simplex virus 1 targets IRF7 via ICP0 to limit type I IFN induction.

Sci Rep 2020 12 17;10(1):22216. Epub 2020 Dec 17.

Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

Herpes simplex keratitis (HSK), caused by herpes simplex virus type 1 (HSV-1) infection, is the commonest cause of infectious blindness in the developed world. Following infection the virus is initially suspended in the tear film, where it encounters a multi-pronged immune response comprising enzymes, complement, immunoglobulins and crucially, a range of anti-viral and pro-inflammatory cytokines. However, given that HSV-1 can overcome innate immune responses to establish lifelong latency throughout a susceptible individual's lifetime, there is significant interest in understanding the mechanisms employed by HSV-1 to downregulate the anti-viral type I interferon (IFN) mediated immune responses. This study aimed to investigate the interactions between infected cell protein (ICP)0 and key elements of the IFN pathway to identify possible novel targets that contribute to viral immune evasion. Reporter gene assays demonstrated the ability of ICP0 to inhibit type I IFN activity downstream of pathogen recognition receptors (PRRs) which are known to be involved in host antiviral defences. Further experiments identified interferon regulatory factor (IRF)7, a driver of type I IFN, as a potential target for ICP0. These findings increase our understanding of the pathogenesis of HSK and suggest IRF7 as a potential therapeutic target.
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http://dx.doi.org/10.1038/s41598-020-77725-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747705PMC
December 2020

Changing trends in corneal transplantation: a national review of current practices in the Republic of Ireland.

Ir J Med Sci 2020 Sep 4. Epub 2020 Sep 4.

Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland.

Background: First Irish National Corneal Transplant Registry report.

Aim: To report about current corneal transplantation practices in Ireland including patient demographics, indications and types of transplant performed and to compare the findings with other developed countries.

Methods: Nationwide retrospective review of the corneal transplants performed in Ireland between 2016 and 2019.

Results: Overall, 536 keratoplasties were carried out: 256 (47.8%) Penetrating Keratoplasties (PK), 212 (39.6%) Descemet Stripping Automated Endothelial Keratoplasties (DSAEK), 30 (5.6%) Descemet Membrane Endothelial Keratoplasties (DMEK), and 25 (4.7%) Deep Anterior Lamellar Keratoplasties (DALK). The most common indication was Keratoconus (KC, 19%), followed by Fuchs endothelial dystrophy (FED, 18.8%), and Pseudophakic bullous keratopathy (PBK, 17%). KC (34%) and re-grafting (17%) were the leading indications for PK, whereas FED and PBK were the major indications for DSAEK (38% and 33%) and DMEK (67% and 20%), respectively. During the period studied, the number of transplants increased from 11.3 to 14 grafts per month. The number of PKs remained stable, whereas Endothelial Keratoplasties, DSAEK and DMEK, increased (3.8 to 5.6 and 0.2 to 1.6 per month, respectively), becoming the most commonly performed grafts since 2018. Only a small number of DALK were performed.

Conclusions: Corneal transplantation in Ireland is following international trends as endothelial procedures have become the most common approach since 2018. However, a low overall number of transplants is performed in Ireland compared with other countries suggesting that care pathways should be implemented to improve access to corneal transplantation.
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http://dx.doi.org/10.1007/s11845-020-02340-1DOI Listing
September 2020

5-year longitudinal study of clinical and patient-reported outcomes in acute anterior uveitis.

Eye (Lond) 2021 Feb 13;35(2):651-658. Epub 2020 May 13.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Introduction: Acute anterior uveitis (AAU) is a frequently encountered form of uveitis, most commonly an immune-mediated condition associated with the HLA-B27 gene with or without spondyloarthritis, or idiopathic in nature. This study's aim was to measure clinical and patient-reported outcomes 5 years after the first episode of immune-mediated AAU.

Methods: This is a longitudinal observational study. Ninety-six patients who underwent evaluation at the time of presentation with their first episode of AAU were invited to return for evaluation 5 years later. Standardised ocular history, clinical examination and quality of life (QOL) assessment with the Short Form 36 (SF-36) and the Vision Core Measure 1 (VCM 1) questionnaire were completed and analysed.

Results: Fifty-four patients (56%) returned for subsequent assessment. Physical function was the only sub scale domain of the SF-36 that had significantly deteriorated over the 5 years since the first episode of AAU (45.95 vs. 49.37, p = 0.003). Only 7.4% (n = 4) of patients expressed "more than a little concern" regarding their vision, reflected by a VCM1 score of 2.0 or more. At 5 years, the mean best corrected visual acuity (BCVA) of eyes affected by AAU was LogMAR 0.02 and only 3% (n = 2) of eyes had a BCVA of less than Logmar of 0.3. Five affected eyes (8%) had developed cataract and no patients had developed glaucoma by the 5 year review.

Conclusions: This study demonstrates that immune-mediated AAU has an excellent 5 year prognosis with minimal impact on patients' health and vision-related quality of life.
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http://dx.doi.org/10.1038/s41433-020-0937-6DOI Listing
February 2021

miR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome.

Sci Rep 2020 05 4;10(1):7484. Epub 2020 May 4.

Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

In primary Sjögren's syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. Previous investigations have suggested that dysregulated localized and systemic inflammation contributes to the development and pathogenesis of pSS. A miR microarray performed in primary human conjunctival epithelial cells (PECs) demonstrated significant differences in miR expression at the ocular surface between pSS patients and healthy controls. MicroRNA-744-5p (miR-744-5p) was identified as being of particular interest, as its top predicted target is Pellino3 (PELI3), a known negative regulator of inflammation. Validation studies confirmed that miR-744-5p expression is significantly increased in PECs from pSS patients, whilst PELI3 was significantly reduced. We validated the miR-744 binding site in the 3' untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10. These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino3 expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients.
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http://dx.doi.org/10.1038/s41598-020-64422-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198540PMC
May 2020

Vision-related and health-related quality of life in patients with giant cell arteritis.

Eur J Ophthalmol 2020 Jan 20:1120672120901693. Epub 2020 Jan 20.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Objective: To establish if there is a difference in health-related quality of life and vision-related quality of life in patients with a confirmed diagnosis of giant cell arteritis compared with those with clinical features suspicious for the disease at initial presentation but in whom giant cell arteritis is ultimately excluded.

Methods: A cross-sectional study of 116 patients who presented to two tertiary referral hospitals in Ireland with symptoms suspicious for giant cell arteritis was performed between August 2011 and June 2017. The Vision Core Measurement 1 and Short Form-36 questionnaires were used as assessment tools.

Results: The mean (standard deviation) age of all 116 participants was 69.4 (9.3) years of whom 74 (63.8%) were female. In the giant cell arteritis group, 19.7% had permanent loss of vision and 54.7% had non-permanent visual disturbance. Vision Core Measurement 1 score in the giant cell arteritis group correlated with worse eye visual acuity (r = 0.4233, p = 0.0002). The Short Form-36 subscales of role physical (p = 0.0002), role emotional (p = 0.024), and the mental composite score (p = 0.012) were significantly worse in patients with giant cell arteritis. A significant correlation was found between vision-related quality of life scores and all Short Form-36 subscale scores except bodily pain (r = -0.215 to -0.399, p < 0.05 for all), and between social functioning and visual acuity in the better eye (r = -0.242, p = 0.038).

Conclusion: Vision-related quality of life is an important subjective concern for both patients presenting with a suspicion of giant cell arteritis and those with a definite diagnosis of giant cell arteritis. Features of giant cell arteritis impact on patients' physical and emotional states and vision influences global quality of life in giant cell arteritis. A long-term multidisciplinary approach is warranted for clinical, physical, and psychological treatment and support.
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http://dx.doi.org/10.1177/1120672120901693DOI Listing
January 2020

Refractory recurrent ocular graft versus host disease.

BMJ Case Rep 2019 Dec 15;12(12). Epub 2019 Dec 15.

Ophthalmology, Royal College of Surgeons in Ireland, Dublin, Ireland

Ocular graft-versus-host disease (GVHD) is one of the most frequent and long-term complications affecting patients after haematopoietic stem cell transplantation. It is associated with significant morbidity and a marked reduction in quality of life. Although common, currently there are no widely accepted guidelines available for its management, and no suggested regime of treatment that is completely satisfactory. So far, prophylactic treatment strategies for ocular GVHD have yet to be developed and treatment is normally initiated based on symptoms often after permanent ocular tissue changes and surface damage has occurred. Here we describe a case of recurrent ocular GVHD and its associated complications that was highly refractory to treatment.
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http://dx.doi.org/10.1136/bcr-2019-232579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936579PMC
December 2019

PRDX3 is associated with metastasis and poor survival in uveal melanoma.

J Clin Pathol 2020 Jul 26;73(7):408-412. Epub 2019 Nov 26.

National Institute for Cellular Biotechnology, Dublin, Ireland.

Aims: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and 40% develop fatal metastatic disease. Overexpression of thioredoxin-dependent peroxidase reductase (PRDX3) has been implicated in several cancers, including prostate, breast, colorectal and lung cancer. The aim of this study was to compare the immunohistochemical expression of PRDX3 in formalin-fixed, paraffin-embedded (FFPE) primary UM tissues of patients who did and did not develop metastatic disease.

Methods: Immunohistochemical staining of PRDX3 was performed on FFPE tissue microarray samples of 92 primary UM tumours from patients who did and did not develop metastatic disease. The immunohistochemical staining was assessed by two observers who were blinded to all clinicopathological and cytogenetic details including metastatic/non-metastatic information. Based on a scoring system, expression of PRDX3 was graded as high or low.

Results: There were 55 tumours (59.8%) from patients who developed metastatic disease, while 37 (40.2%) were from patients who did not develop metastasis. A statistically significant difference in PRDX3 expression was observed in patients who did and did not develop metastasis (p=0.001). A significant positive correlation between high PRDX3 expression and metastasis was observed (p=0.001). A significant negative correlation between PRDX3 expression and survival was found (p=0.005). Kaplan-Meier survival analysis showed a statistically significant difference in overall survival between tumours that demonstrated low and high expression of PRDX3 (67.61 vs 130.64 months, respectively, p=0.013).

Conclusions: High immunohistochemical expression of PRDX3 in primary UM tissue is associated with metastasis and poor survival.
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http://dx.doi.org/10.1136/jclinpath-2019-206173DOI Listing
July 2020

High-risk Corneal Transplantation: Recent Developments and Future Possibilities.

Transplantation 2019 12;103(12):2468-2478

Department of Ophthalmology, CHU de Nantes, France.

Human corneal transplantation (keratoplasty) is typically considered to have superior short- and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities.
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http://dx.doi.org/10.1097/TP.0000000000002938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867666PMC
December 2019

Reply.

Cornea 2020 02;39(2):e5

Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1097/ICO.0000000000002188DOI Listing
February 2020

Systemic IL-1β production as a consequence of corneal HSV-1 infection-contribution to the development of herpes simplex keratitis.

Int J Ophthalmol 2019 18;12(9):1493-1497. Epub 2019 Sep 18.

Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

This study sought to identify potential therapeutic targets in herpes simplex keratitis (HSK) patients with active and inactive infection by investigating peripheral cytokine production. Peripheral blood mononuclear cells (PBMCs) and serum were prepared from healthy controls and HSK patients during active infection or following treatment (inactive infection). Serum antibody titres were determined by ELISA. Protein expression levels were analysed by Western blot. Cytokine levels were determined by multiplex ELISA. Active corneal herpes simplex virus type 1 (HSV-1) infection resulted in significantly elevated peripheral levels of IL-1β in HSK patients compared to healthy controls, and remained significantly increased following treatment. Elevated production of IL-1β in inactive patients was associated with significantly increased levels of IRF3 and STAT1, key proteins involved in promoting anti-viral immune responses. Our data suggest that inflammation persists beyond the period that it is clinically evident and that enhanced peripheral production of IL-1β may have implications for HSV-1 viral clearance in active and inactive HSK patients.
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http://dx.doi.org/10.18240/ijo.2019.09.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739588PMC
September 2019

Interleukin-6 does not upregulate pro-inflammatory cytokine expression in an model of giant cell arteritis.

Rheumatol Adv Pract 2019 6;3(1):rkz011. Epub 2019 May 6.

Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin Academic Medical Centre, Royal College of Surgeons, Ireland.

Objective: The aim of this study was to examine the pro-inflammatory effects of IL-6 in temporal artery explant cultures.

Methods: Patients meeting 1990 ACR classification criteria for GCA were prospectively recruited. Temporal artery biopsies were obtained and temporal artery explants cultured with IL-6 (10-40 ng/ml) in the presence or absence of its soluble receptor (sIL-6R; 20 ng/ml) for 24 h. Explant supernatants were harvested after 24 h and assayed for IFN-γ, TNF-α, Serum amyloid A, IL-1β, IL-17, IL-8, angiotensin II and VEGF by ELISA. Myofibroblast outgrowths, cytoskeletal rearrangement and wound repair assays were performed.

Results: IL-6 augmented production of VEGF, but not of any of the other pro-inflammatory mediators assayed. No differences were observed in the explants cultured in the presence or absence of the sIL-6R or between those with a positive ( = 11) or negative ( = 17) temporal artery biopsy. IL-6 did not enhance myofibroblast proliferation or migration. Western blot analysis confirmed signalling activation, with increased expression of pSTAT3 in response to IL-6+sIL-6R.

Conclusion: IL-6 stimulation of temporal artery explants from patients with GCA neither increased expression of key pro-inflammatory mediators nor influenced myofibroblast proliferation or migration.
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http://dx.doi.org/10.1093/rap/rkz011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649906PMC
May 2019

Safety and Efficacy of Supratarsal Triamcinolone for Treatment of Vernal Keratoconjunctivitis in Ireland.

Cornea 2019 Aug;38(8):955-958

Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Purpose: To describe the clinical features, risk factors, and treatment outcomes after supratarsal injection of triamcinolone for vernal keratoconjunctivitis (VKC).

Methods: A retrospective review of all patients treated with supratarsal triamcinolone for VKC between February 2002 and May 2017 at the Royal Victoria Eye and Ear Hospital and Our Lady's Children Hospital Crumlin, Dublin, Ireland, was performed.

Results: Twenty-five patients, 46 eyes, and 145 injections were included for analysis. The mean age at first injection was 9.1 ± 5.7 years. Ninety-six percent of the patients were male. A seasonal variation was noted, with 59 injections (41%) of triamcinolone administered for acute and refractive cases of VKC in the summer compared with 35 (24%), 35 (24%), and 16 (11%) in the spring, autumn, and winter months, respectively. The most common presenting complaint was red eye, which was seen in all cases. Hay fever (64%) was the most common associated systemic disease. Each eye required, on average, 3.2 injections (range 1-9 injections), and the mean duration from the onset of symptoms to final treatment was 3.03 years (range 0-7.9 years). The mean presenting and final visual acuities were 0.33 and 0.11 logarithm of the minimum angle of resolution, respectively (P < 0.0001). During our study period, no patient experienced intraocular pressure rise requiring treatment, development of lenticular opacity, or ptosis after supratarsal injection of triamcinolone.

Conclusions: In this case series, supratarsal triamcinolone was used in cases of VKC in which topical medications had failed to control the disease process. All patients reported improvement after treatment. There were no cases of intraocular pressure rise, lenticular opacity, or ptosis development after treatment.
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http://dx.doi.org/10.1097/ICO.0000000000001963DOI Listing
August 2019

Corneal melt secondary to eosinophilic granulomatosis with polyangiitis.

BMJ Case Rep 2019 Jun 21;12(6). Epub 2019 Jun 21.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody-associated vasculitis that can affect any organ system. It is most often characterised by chronic airway inflammation along with prominent peripheral blood eosinophilia, although the disease can affect the cardiovascular, gastrointestinal, renal or central nervous systems. Ocular manifestations are uncommon and when they do occur, are varied in their clinical presentations. To the best of our knowledge, this is the first case of corneal melt secondary to EGPA to have been reported.
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http://dx.doi.org/10.1136/bcr-2019-229859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605890PMC
June 2019

Clinical and microbiological characteristics of Moraxella keratitis.

Br J Ophthalmol 2019 12 1;103(12):1704-1709. Epub 2019 Feb 1.

Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland

Background/aims: To describe the risk factors, clinical features, bacterial subspecies characteristics and treatment outcomes of Moraxella keratitis in a single centre.

Methods: A retrospective review of all patients diagnosed with Moraxella keratitis between November 2012 and December 2017 at the Royal Victoria Eye and Ear Hospital, Dublin, Ireland was performed. Matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry was used to identify subspecies.

Results: Forty-one cases of Moraxella keratitis were identified. Previous ocular surgery and diabetes were the most common local and systemic risk factors. The most common appearance on presentation was an oval-shaped paracentral infiltrate with a mean diameter of 4.2 mm. Mean presenting and final logarithm of minimal angle of resolution visual acuity were 1.307±0.74 and 0.99±1.01, respectively. Surgical procedures, including penetrating keratoplasty, corneal glueing or evisceration, were required to manage nine (22%) patients. Mean time to complete corneal epithelialisation was 32 (range, 7-109) days and mean duration of topical antibiotic therapy was 54 (range, 9-124) days. MALDI-TOF analysis revealed the following subspecies: (16; 39%), (15; 36%), (4; 10%) and (2; 5%). In four cases (10%), subspecies analysis was inconclusive. and . were associated with larger infiltrates on presentation (p<0.05), required more surgical intervention and longer treatment duration (p<0.001).

Conclusion: In this large series of patients from Ireland, Moraxella keratitis was notable for its severity on presentation, slow response to antimicrobial therapy, high risk of surgical intervention and poor visual outcome. We have demonstrated the value of subspecies identification using MALDI-TOF by reporting significant differences in the clinical features and prognosis of and compared with other subspecies.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313557DOI Listing
December 2019

Performance characteristics and predictors of temporal artery ultrasound for the diagnosis of giant cell arteritis in routine clinical practice in a prospective cohort.

Clin Exp Rheumatol 2019 Mar-Apr;37 Suppl 117(2):72-78. Epub 2019 Jan 4.

Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin Academic Medical Centre, Dublin, Ireland.

Objectives: The diagnosis of giant cell arteritis (GCA) is primarily a clinical one. Temporal artery (TA) ultrasound (US) has been proposed as a new diagnostic tool. We aimed to assess the performance characteristics of TA US in routine clinical practice.

Methods: All patients presenting with suspected GCA to our institution are recruited to a prospective registry. Patients who had both a TA US and biopsy (TAB) performed at the time of presentation were included in the current study. The performance characteristics of TA US was compared to physician diagnosis at six months following presentation. Predictive factors for a positive TA US were explored in univariate and multivariable logistic regression analyses.

Results: 162 patients were included, 123 (76%) with GCA. Mean (SD) duration of glucocorticoid therapy was 6.6 days (19.4) at the time of TA US. TA US had a sensitivity of 52.8% (95%CI 43.7, 61.9) and specificity of 71.8% (95%CI 54.9, 84.5) for the diagnosis of GCA. Glucocorticoid duration did not significantly impact the results. A sequential strategy of TA US followed by TAB in the case of a negative US had a sensitivity of 78.9% (95%CI 70.1, 85.5) and specificity of 71.8% (95%CI 54.9, 84.5), equivalent to a simultaneous testing strategy. The only factor independently predictive of a positive TA US was male sex (OR 5.53, 95% CI 2.72 to 11.22, p<0.001).

Conclusions: TA US is potentially useful in the diagnosis of GCA; however, interpretation of its results requires knowledge of the performance characteristics in the target population.
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June 2019

Novel gene targets for miRNA146a and miRNA155 in anterior uveitis.

Br J Ophthalmol 2019 02 8;103(2):279-285. Epub 2018 Oct 8.

Department of Ophthalmology, Royal College of Surgeons in Ireland, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Background/aims: Anterior uveitis (AU) is the most common form of intraocular inflammation. MicroRNAs (miRNA) are small, non-coding RNAs functioning as post-transcriptional repressors of gene expression. Knowledge of miRNAs can implicate specific genes and pathogenic signalling pathways in disease. This study examines miRNA expression, function and target genes in AU pathogenesis.

Methods: AU and healthy control (HC) peripheral blood mononuclear cells (PBMC) were initially screened for expression of five miRNAs by real-time PCR. Regulation of the aberrantly expressed miRNAs by TLR1/2, TLR3, TLR4, IL1β and TNFα was quantified by real-time PCR and paired cytokine outputs measured by ELISA. Functional effects of miRNA overexpression using transfected THP1 cells examined IL6, IL8, IL10 and IL1β cytokine outputs by ELISA. Target genes were identified using TargetScan online computational algorithm and relevant targets verified by cloning of the 3'UTR and luciferase reporter gene assays.

Results: Increased expression of miRNA146a (p<0.01), miRNA155 (p<0.05) and miRNA125a5p (p<0.01) was demonstrated in AU PBMC compared with HC. miRNA155 was increased following TLR1/2 (p<0.05) and TLR4 (p<0.05) stimulation and miRNA146a increased in response to IL1β (p<0.05). In a proinflammatory environment, miRNA155 overexpression in THP1 cells yielded increased cytokine output whereas miRNA146a overexpression showed decreased cytokine output. CD80, PRKCE and VASN were confirmed as novel targets for miRNA146a and SMAD2, TYRP1 and FBXO22 for miRNA155.

Conclusion: This study identifies overexpression of proinflammatory miRNA155, regulatory miRNA146a and miRNA125a-5p in AU. CD80, PRKCE and VASN are novel miRNA146a targets and SMAD2, TYRP1 and FBXO22 are novel targets for miRNA155.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312885DOI Listing
February 2019

Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis.

Ann Rheum Dis 2018 12 10;77(12):1815-1824. Epub 2018 Aug 10.

Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital Dublin, Academic Medical Centre, Dublin 4, Ireland.

Objectives: The pathogenesis of giant cell arteritis (GCA) remains unclear. T1 and T17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis.

Methods: IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture.

Results: Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs.

Conclusion: IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.
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http://dx.doi.org/10.1136/annrheumdis-2018-213488DOI Listing
December 2018

IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation.

JCI Insight 2018 08 9;3(15). Epub 2018 Aug 9.

Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Severe lung inflammation and alveolar hemorrhage can be life-threatening in systemic lupus erythematosus (SLE) patients if not treated early and aggressively. Neutrophil influx is the driver key of this pathology, but little is known regarding the molecular events regulating this recruitment. Here, we uncover a role for IL-16/mir-125a in this pathology and show not only that IL-16 is a target for miR-125a but that reduced miR-125a expression in SLE patients associates with lung involvement. Furthermore, in the pristane model of acute "SLE-like" lung inflammation and alveolar hemorrhage, we observed reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was markedly reduced in the peritoneal lavage of pristane-treated IL-16-deficient mice and elevated following i.n. delivery of IL-16. Moreover, a miR-125a mimic reduced pristane-induced IL-16 expression and neutrophil recruitment and rescued lung pathology. Mechanistically, IL-16 acts directly on the pulmonary epithelium and markedly enhances neutrophil chemoattractant expression both in vitro and in vivo, while the miR-125a mimic can prevent this. Our results reveal a role for miR-125a/IL-16 in regulating lung inflammation and suggest this axis may be a therapeutic target for management of acute lung injury in SLE.
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http://dx.doi.org/10.1172/jci.insight.120798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129123PMC
August 2018

Alcohol delamination of the corneal epithelium for recurrent corneal erosion syndrome.

Int J Ophthalmol 2018 18;11(7):1129-1131. Epub 2018 Jul 18.

Education and Research Centre, Royal Victoria Eye and Ear Hospital, Dublin D02XK51, Ireland.

Aim: To evaluate the outcomes of alcohol delamination (ALD) of the corneal epithelium for the treatment of recurrent corneal erosion syndrome (RCES) and to implement a standardized treatment protocol for this condition utilizing evidence based practice and the findings of an internal audit.

Methods: A retrospective analysis of 42 eyes of 40 patients diagnosed with RCES who were treated with ALD between January 2006 and March 2016 was conducted. Patients had 20% alcohol applied to the cornea with the use of a well for 40s. Patients were reviewed one week later in the Outpatient Department. Outcome criteria were established based on standards from other studies in the medical literature. These included, a treatment success rate of at least 72% (defined as complete resolution of symptoms one month after treatment), a postoperative complication a rate of <5% (mainly infective keratitis, and subepithelial haze), and the absence of any detrimental effect on visual acuity in ≥95% of patients.

Results: The mean age at the time of ALD was 41.17±13.44y. Patients were followed for an average of 12.8±15.65mo. The majority were female (52.5%, =21) and the majority of eyes treated with ALD were left eyes (62.9%, =26). Trauma was the primary aetiology in our study population. Treatment was successful in 73.8% (=31) of eyes and in 75% (=30) of patients. Recurrence occurred in 26.2% of eyes at a mean of 10.41±12.63mo post treatment.

Conclusion: ALD is an efficacious and cost-effective primary surgical intervention for RCES.
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http://dx.doi.org/10.18240/ijo.2018.07.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048330PMC
July 2018

Ustekinumab for refractory giant cell arteritis: A prospective 52-week trial.

Semin Arthritis Rheum 2018 12 22;48(3):523-528. Epub 2018 Apr 22.

Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin Academic Medical Centre, Elm Park, Dublin 4, Ireland.

Objectives: Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Glucocorticoids are an effective treatment but have significant adverse events and relapses are common. Interleukins 12 (IL-12) and 23 (IL-23) stimulate T1 and T17 responses and are implicated in the pathogenesis of GCA. The aim of this study was to evaluate the efficacy and safety of IL-12/23 blockade with ustekinumab in GCA.

Methods: We performed a prospective open label study of ustekinumab in patients with refractory GCA. Ustekinumab 90mg was administered subcutaneously every 12 weeks. The primary outcome was the comparison of the median glucocorticoid dose prior to commencement of ustekinumab and at 52 weeks. Secondary outcomes included physician assessed relapse, acute phase reactants, and imaging assessment of large vessel vasculitis (LVV).

Results: Twenty-five GCA patients received ustekinumab. All patients had failed to taper glucocorticoids despite addition of a median of 1 other immunosuppressive agent. At week 52, median (IQR) daily prednisolone dose decreased from 20 (15, 25)mg to 5 (2.5, 5)mg (p < 0.001). Six patients (24%) stopped prednisolone completely. No patient experienced a relapse of GCA while receiving ustekinumab. Median (IQR) CRP decreased significantly from 12.9 (5.3, 42) to 6 (2.6, 12.5)mg/L (p = 0.006). CT angiography demonstrated improvement of LVV in all patients studied. No unexpected adverse events were observed with ustekinumab.

Conclusions: Ustekinumab may be effective for the treatment of GCA and warrants further assessment in a randomized controlled trial.
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http://dx.doi.org/10.1016/j.semarthrit.2018.04.004DOI Listing
December 2018

The Effect of Anterior Uveitis and Previously Undiagnosed Spondyloarthritis: Results from the DUET Cohort.

J Rheumatol 2017 Sep 1;44(9):1347-1354. Epub 2017 Jul 1.

From the Department of Ophthalmology, Royal Victoria Eye and Ear Hospital; Department of Rheumatology, St. Vincent's University Hospital, Elm Park, Dublin; University Hospital Kerry, Tralee, Kerry, Ireland.

Objective: Anterior uveitis (AU) is an intraocular inflammatory condition closely linked to spondyloarthritis (SpA). Clinical disease variables may often underestimate the true effect of the disease on patient's quality of life. This study examines AU and associated undiagnosed SpA using established quality-of-life tools to inform clinicians of the effect of these diseases.

Methods: The Dublin Uveitis Evaluation Tool (DUET) algorithm was developed and validated in a cohort of consecutive patients with AU who were all screened by a rheumatologist for the presence of SpA. This same cohort completed vision-related [Vision Core Measure 1 (VCM1)] and general health [Medical Outcomes Study Short Form-36 (SF-36)] questionnaires when AU was active and resolved.

Results: VCM1 scores improved with AU resolution. VCM1 did not correlate with vision at baseline, but did on resolution of inflammation. Physical SF-36 scores were reduced during AU episodes and improved on resolution remaining below those of population norms. Subanalysis revealed that SpA scores were more affected than the idiopathic AU group.

Conclusion: AU affects physical aspects of quality of life more than is appreciated by clinical variables, especially in those with pre-existing, undiagnosed SpA. This study is unique in examining the effect of SpA on patients prior to diagnosis. These results highlight the role of the ophthalmologist in identifying patients with SpA who present with AU using the DUET algorithm.
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http://dx.doi.org/10.3899/jrheum.170115DOI Listing
September 2017

Outcomes of penetrating keratoplasty in congenital hereditary endothelial dystrophy.

Br J Ophthalmol 2018 01 6;102(1):19-25. Epub 2017 May 6.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Background/aim: To report the outcome of penetrating keratoplasty (PKP) in Irish patients with congenital hereditary endothelial dystrophy (CHED).

Methods: A retrospective case series review of patients with CHED who underwent PKP was conducted. The outcomes of PKP in 14 patients with CHED at the Royal Victoria Eye and Ear Hospital in Dublin from 1978 to 2013 were described following case note review. The main outcome measures were best-corrected visual acuity (BCVA) and graft survival.

Results: Thirty-three corneal transplants were performed, which included 32 PKPs and one Descemet's stripping endothelial keratoplasty. Twenty-four eyes underwent primary corneal grafts and nine eyes had regrafts. The graft survival rates at final follow-up were 37.5% and 33% in the primary graft and regraft groups, respectively. Preoperative BCVA was 20/200 or worse in all patients. At the final postoperative visit, the BCVA was 20/80 or better in four eyes following primary PKP, 20/160 in one eye following regrafting and was 20/200 or worse in all other eyes. The mean time to graft failure was 16 months (range 0-37 months). The mean follow-up time was 101 months (range 12-252 months). Fifty per cent of the patients continue to attend for follow-up.

Conclusions: This study has demonstrated a poor outcome from PKP for CHED in this Irish cohort. This arises from a combination of dense amblyopia and a high risk of graft failure in the long term.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309565DOI Listing
January 2018

Ustekinumab for the treatment of refractory giant cell arteritis.

Ann Rheum Dis 2016 08 3;75(8):1578-9. Epub 2016 May 3.

Department of Rheumatology, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin Academic Medical Centre, Dublin 4, Ireland.

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http://dx.doi.org/10.1136/annrheumdis-2016-209351DOI Listing
August 2016

Homozygous SLC4A11 mutation in a large Irish CHED2 pedigree.

Ophthalmic Genet 2017 Mar-Apr;38(2):148-151. Epub 2016 Apr 8.

b Department of Ophthalmology , Royal Victoria Eye and Ear Hospital , Dublin , Ireland.

Background: Congenital hereditary endothelial dystrophy (CHED) is a genetic disorder of corneal endothelial cells resulting in corneal clouding and visual impairment. Autosomal dominant (CHED1) and autosomal recessive (CHED2) forms have been reported and map to distinct loci on chromosome 20. CHED2 is caused by mutations in the SLC4A11 gene which encodes a membrane transporter protein.

Materials And Methods: Members of a large CHED2 family were recruited for clinical and genetic studies. Genomic DNA was sequenced for the exons and intron-exon boundaries of the SLC4A11 gene.

Results: Twelve family members were recruited, of which eight were diagnosed with CHED. A homozygous SLC4A11 mutation (Leu843Pro) was detected in the eight patients; a single copy of the mutation was present in three unaffected carriers.

Conclusions: A missense SLC4A11 mutation (Leu843Pro) is responsible for CHED2 in this family; this is the first report of this mutation in a homozygous state.
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http://dx.doi.org/10.3109/13816810.2016.1151901DOI Listing
November 2017

Isolated ocular lichen planus in a child.

J AAPOS 2015 Aug 23;19(4):381-3. Epub 2015 Jul 23.

Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland; Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin, Ireland.

Lichen planus (LP) is an autoimmune inflammatory condition of the skin and mucous membranes, of unknown aetiology, that infrequently involves the eye. Ocular LP has not been described in children. We present the case of an 8-year-old girl with severe, filamentous dry eyes and persistent conjunctival hyperemia with bilateral progressive conjunctival symblepharon. Her conjunctival biopsy showed heavy linear fibrinogen deposits along the basement membrane without IgG, IgA, IgM, or C3 deposition, consistent with LP. No skin or other mucosal lesions were present, suggesting a diagnosis of isolated conjunctival LP. Oral and topical cyclosporine combined with methotrexate and low-dose oral steroids led to sustained disease remission. To our knowledge, this is the first case of isolated ocular LP in a child.
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http://dx.doi.org/10.1016/j.jaapos.2015.03.019DOI Listing
August 2015

Corneal inlay implantation complicated by infectious keratitis.

Br J Ophthalmol 2016 Feb 29;100(2):269-73. Epub 2015 Jun 29.

Royal Victoria Eye and Ear Hospital, Dublin, Ireland Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin, Ireland.

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 patient's 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.
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http://dx.doi.org/10.1136/bjophthalmol-2015-306641DOI Listing
February 2016

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

Arthritis Rheumatol 2015 Sep;67(9):2447-56

St. Vincent's University Hospital and Dublin Academic Medical Centre, Dublin, Ireland.

Objective: 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.

Methods: Serum A-SAA levels were measured by enzyme-linked immunosorbent assay (ELISA). Temporal artery explants and peripheral blood mononuclear cell (PBMC) cultures were established from patients with GCA. Temporal artery explant morphology, viability, and spontaneous release of proinflammatory mediators following 24-hour culture were assessed by hematoxylin and eosin, calcein viability staining, and ELISA. Temporal artery explants and PBMC cultures were stimulated with A-SAA (10 μg/ml), and interleukin-6 (IL-6), IL-8, vascular endothelial growth factor, Ang2, and matrix metalloproteinase 2 (MMP-2)/MMP-9 were quantified by ELISA and gelatin zymography. The effect of conditioned medium from temporal artery explants on angiogenesis was assessed using endothelial cell Matrigel tube-formation assays. Temporal artery explants were also embedded in Matrigel, and myofibroblast outgrowth was assessed.

Results: Serum A-SAA levels were significantly higher in GCA patients versus healthy controls (P < 0.0001). Intact tissue morphology, cell viability, and spontaneous cytokine secretion were demonstrated in temporal artery explants. A-SAA treatment induced a significant increase in the levels of IL-6 and IL-8 from temporal artery explants (P < 0.05) and IL-8 from PBMCs (P < 0.05) compared to basal conditions. Conditioned medium from A-SAA-treated explants significantly induced angiogenic tube formation (P < 0.05 versus basal controls). Finally, A-SAA induced myofibroblast outgrowth and MMP-9 activation.

Conclusion: Our findings demonstrate a functional role for A-SAA in regulating temporal artery inflammation, angiogenesis, and invasion, all key processes in the pathogenesis of GCA.
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http://dx.doi.org/10.1002/art.39217DOI Listing
September 2015