Immunology and Uveitis

Immunology and Uveitis Publications

Ebrahimiadib N, Ma L, Modjtahedi BS, Davoudi S, Rahmani S, Syeda S, Stephenson A, Foster CS. Atypical Perinuclear Anti-Neutrophil Cytoplasmic Antibodies in Ocular Inflammatory Diseases. Ocul Immunol Inflamm 2018;:1-5.Abstract
PURPOSE: To characterize the clinical features of patients with ocular inflammatory diseases (OID) who tested positive for atypical perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA). METHODS: Retrospective case series of patients with OID seen at the Massachusetts Eye Research and Surgery Institute (MERSI) from April 2014 to April 2016. RESULTS: 813 patients were tested for ANCA with 34 patients (4%) being positive for atypical P-ANCA. Among those with positive atypical P-ANCA, the most frequent diagnoses were anterior uveitis in 62% (n = 21) followed by scleritis in 20% (n = 7). Only one patient had an episode of recurrent disease flare-up. All but one patient, who had concomitant C-ANCA seropositivity and granulomatosis with polyangiitis, had a favorable disease course with controlled inflammation using topical and/or systemic immunomodulatory therapy. CONCLUSION: In contrast to typical C-ANCA and P-ANCA, atypical P-ANCA seropositivity was not associated with severe vasculitis or poor prognosis in patients with the OID.
Agarwal A, Invernizzi A, Singh RB, Foulsham W, Aggarwal K, Handa S, Agrawal R, Pavesio C, Gupta V. An update on inflammatory choroidal neovascularization: epidemiology, multimodal imaging, and management. J Ophthalmic Inflamm Infect 2018;8(1):13.Abstract
Inflammatory choroidal neovascular membranes are challenging to diagnose and manage. A number of uveitic entities may be complicated by the development of choroidal neovascularization leading to a decrease in central visual acuity. In conditions such as punctate inner choroidopathy, development of choroidal neovascularization is extremely common and must be suspected in all cases. On the other hand, in patients with conditions such as serpiginous choroiditis, and multifocal choroiditis, it may be difficult to differentiate between inflammatory choroiditis lesions and choroidal neovascularization. Multimodal imaging analysis, including the recently introduced technology of optical coherence tomography angiography, greatly aid in the diagnosis and management of inflammatory choroidal neovascularization. Management of these neovascular membranes consists of anti-vascular growth factor agents, with or without concomitant anti-inflammatory and/or corticosteroid therapy.
Agrawal R, Gunasekeran DV, Agarwal A, Carreño E, Aggarwal K, Gupta B, Raje D, Murthy SI, Westcott M, Chee SP, McCluskey P, Ling HS, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Mahajan S, Esposti S, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Lord J, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Kempen J, Cunningham ET, Rousselot A, Nguyen QD, Pavesio C, Gupta V. The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Description of the Spectrum of Choroidal Involvement in 245 Patients with Tubercular Uveitis. Ocul Immunol Inflamm 2018;:1-11.Abstract
PURPOSE: To contribute a global description of the spectrum of choroidal involvement in tubercular uveitis (TBU). METHODS: Retrospective cohort study of TBU patients with choroidal involvement from 25 centers between January 2004 and December 2014. Medical records of patients with a minimum follow-up of 1 year were reviewed. RESULTS: 245 patients were included. The phenotypic variations included serpiginous-like choroiditis (SLC) (46%), tuberculoma (13.5%), multifocal choroiditis (MFC) (9.4%), ampiginous choroiditis (9%), among others. 219 patients were treated with anti-tubercular therapy (ATT) (n = 219/245, 89.38%), 229 patients with steroids (n = 229/245, 93.47%) and 28 patients with immunosuppressive agents (n = 28/245, 11.42%). Treatment failure was noted in 38 patients (n = 38/245, 15.5%). Patients with SLC and ampiginous choroiditis appeared to have superior outcomes on survival analysis (p = 0.06). CONCLUSION: This study provides a comprehensive description of choroidal involvement in TBU. Patients with SLC and ampiginous choroiditis may have better clinical outcomes.
Chen X, Yao X, Chi Y, Guo C, Zhang J, Li J, Zhang S, Rong X, Pasquale LR, Yang L. A Cross-Sectional Observational Study of Nailfold Capillary Morphology in Uveitis. Curr Eye Res 2018;:1-9.Abstract
PURPOSE: We performed nailfold capillary microscopy to explore microvasculature abnormalities in uveitis overall and uveitis stratified in various ways. METHODS: This was a cross-sectional, case-control, observational study. One hundred and seven uveitis patients and 130 control subjects were included. We used a JH-1004 capillaroscope to perform nailfold capillary video microscopy on the fourth and fifth digits of each subject's nondominant hand. Videos were evaluated for hemorrhages, dilated capillary loops > 25 µm, and avascular zones > 200 µm. Univariate analyses were used for the assessment of case-control morphological differences and multivariate analyses were performed to assess the relation between nailfold capillaroscopic findings and uveitis subgroups. RESULTS: In univariate analysis, uveitis patients were more likely to have higher tortuosity ratings and reduced capillary density compared to controls (p < 0.001 for both); furthermore, dilated capillary loops, avascular zone and hemorrhages were more frequent in uveitis versus control subjects (p < 0.001 for all). Among cases, every unit increase in capillary density (vessels/mm) was associated with active uveitis (n = 72 cases) versus inactive disease (n = 35 cases; odds ratio (OR) = 1.7; (95% confidence interval (CI), 1.2-2.5) in multivariate analysis. Furthermore, the presence of any nailfold hemorrhage versus the absence of hemorrhage was more likely to be associated with posterior and panuveitis (n = 41 cases combined) compared to anterior and intermediate uveitis (n = 66 cases combined; OR = 5.8; 95% CI, 2.3-14.2). Moreover, we found a positive correlation between peripheral retinal leakage and nailfold capillaries dilation (r = 0.33; p = 0.015) that was not strictly significant based on the number of comparisons made. CONCLUSIONS: Our study provides support for non-ocular capillary bed abnormalities in uveitis, with interesting correlations based on disease stage and anatomical classification.
Amparo F, Shikari H, Saboo U, Dana R. Corneal fluorescein staining and ocular symptoms but not Schirmer test are useful as indicators of response to treatment in chronic ocular GVHD. Ocul Surf 2018;16(3):377-381.Abstract
PURPOSE: To evaluate long-term ocular surface clinical signs and symptoms response to therapy in patients with chronic ocular GVHD. METHODS: Retrospective review and data modeling. We reviewed the records of post-bone marrow transplantation patients who were newly diagnosed with ocular GVHD and initiated therapy, and analyzed changes in symptoms (Ocular Surface Disease Index [OSDI]; Symptom Assessment in Dry Eye [SANDE]) and signs (corneal fluorescein staining [CFS]; Schirmer test). We used a LOESS technique to fit a model in function of data variations and obtain a predictive value of the scores progression over time. RESULTS: The records of 123 patients who were followed-up for over 2 years (up to 62 months) were reviewed. The median baseline scores recorded were: OSDI 52 units, SANDE 62.2 units, CFS 2.0 Oxford units, and Schirmer 4 mm. After six months of follow up, scores improved for OSDI (-18.6 units, p = 0.007), SANDE (23.7 units, p = 0.01), and CFS (-0.7 Oxford units, p < 0.001). Data analysis showed that after a 2-year follow up the three parameters continued to improve: OSDI -13.67 units (27% reduction), SANDE -17.55 units (28%), CFS -1.1 units (54%), but Schirmer test scores progressively worsened -1.2 mm (22%). CONCLUSION: In patients with ocular GVHD symptoms and corneal fluorescein staining improved after initiation of treatment, meanwhile Schirmer scores declined progressively. This indicates that appropriate treatment in chronic ocular GVHD can lead to mid- and long-term improvements in symptoms and corneal epitheliopathy; however, sustained reduction in Schirmer test scores suggests chronic tear production impairment.
Hua J, Inomata T, Chen Y, Foulsham W, Stevenson W, Shiang T, Bluestone JA, Dana R. Pathological conversion of regulatory T cells is associated with loss of allotolerance. Sci Rep 2018;8(1):7059.Abstract
CD4CD25Foxp3 Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3 Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17 or IFNγ 'exFoxp3' T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1 peripherally-derived Tregs are particularly susceptible to conversion to IL-17/IFNγ exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.
Sobrin L, Stanwyck LK, Pan W, Hubbard RA, Kempen JH, VanderBeek BL. Association of Hypovitaminosis D With Increased Risk of Uveitis in a Large Health Care Claims Database. JAMA Ophthalmol 2018;136(5):548-552.Abstract
Importance: Understanding the role of vitamin D-which regulates inflammatory responses-in noninfectious uveitis (an inflammatory disease) may provide insight into treatment and prevention of this disease. Objective: To investigate whether there is an association between hypovitaminosis D and incident noninfectious uveitis. Design, Setting, and Participants: In a retrospective case-control study, data from a health care claims database containing deidentified medical claims from a large private insurer were used to identify 558 adults enrolled from January 1, 2000, to December 31, 2016, who received a diagnosis of noninfectious uveitis from an eye care clinician (with receipt of a confirmatory diagnosis within 120 days of the initial diagnosis) and who had a vitamin D level measured within 1 year before the first diagnosis. Exclusion criteria included having systemic disease or receiving medication known to lower vitamin D levels, having undergone intraocular surgery, and having infectious uveitis. Each case patient was matched with 5 controls on the basis of age, sex, race/ethnicity, and index date (2790 controls). The controls had vitamin D level determined either within 1 year before or within 6 months after receiving an eye examination with normal findings. Multiple logistic regression models were used to examine the association between hypovitaminosis D and noninfectious uveitis. Main Outcomes and Measures: The primary, prespecified analysis assessed the association of noninfectious uveitis with hypovitaminosis D (vitamin D level ≤20 ng/mL). Results: The 558 cases and 2790 controls were matched on age, and each group had a mean (SD) age of 58.9 (14.7) years. Among the cohort of 3348 patients, 2526 (75.4%) were female, and the racial/ethnic distribution in the matched samples was 2022 (60.4%) white, 552 (16.5%) black, 402 (12.0%) Hispanic, 162 (4.8%) Asian, and 210 (6.3%) unknown. Patients with normal vitamin D levels had 21% lower odds of having noninfectious uveitis than patients with low vitamin D levels (odds ratio [OR], 0.79; 95% CI, 0.62-0.99; P = .04). In a race-stratified analysis, an association between vitamin D and uveitis was found in black patients (OR, 0.49; 95% CI, 0.30-0.80; P = .004) and was qualitatively similar but nonsignificant in white patients (OR, 0.87; 95% CI, 0.62-1.21; P = .40) and Hispanic patients (OR, 0.60; 95% CI, 0.33-1.10; P = .10). Conclusions and Relevance: This and other reports have found an association between hypovitaminosis D and noninfectious uveitis. However, these studies cannot establish a causal relationship. Prospective studies are warranted to evaluate whether hypovitaminosis D causes increased risk of uveitis and the role of vitamin D supplementation in prevention and treatment of uveitis.
Ma L, You C, Hernandez M, Maleki A, Lasave A, Schmidt A, Stephenson A, Zhao T, Anesi S, Foster SC. Management of Ocular Cicatricial Pemphigoid with Intravenous Immunoglobulin Monotherapy. Ocul Immunol Inflamm 2018;:1-7.Abstract
PURPOSE: To assess the long-term efficacy and safety of IVIg monotherapy in patients with recalcitrant ocular cicatricial pemphigoid (OCP). METHODS: A chart review of all OCP patients seen at the Massachusetts Eye Research and Surgery Institution (MERSI) between 2005 and 2015 was completed. Stage was graded by using the Foster grading system. IVIg infusion was 2g/kg/cycle administered in 3 consecutive days monthly. RESULTS: Of 512 OCP patients, 17 patients (34 eyes) treated with IVIg monotherapy were identified. Seven were female and ten were male. The average age at diagnosis was 60.7-year-old. The follow up time ranged from 12 to 140 months. Twenty-six eyes (76.5%) achieved remission. Nine remission eyes received cataract surgeries, and 2 of them had relapse (22.2%). The other 17 eyes did not undergo ocular surgery and remained in remission. IVIg monotherapy showed high efficacy in stage 1 OCP (7/7, 100%). Ocular surgery can be associated with OCP relapse (Table 2). CONCLUSIONS: IVIg monotherapy is an effective and safe therapy in patients with recalcitrant OCP. Ocular surgery can be associated with OCP relapse.
Llop SM, Davoudi S, Stanwyck LK, Sathe S, Tom L, Ahmadi T, Grotting L, Papaliodis GN, Sobrin L. Association of Low Vitamin D Levels with Noninfectious Uveitis and Scleritis. Ocul Immunol Inflamm 2018;:1-8.Abstract
PURPOSE: To determine whether an association between Vitamin D and noninfectious ocular inflammation exists. METHODS: Retrospective case-control study with 765 patients (333 uveitis cases, 103 scleritis cases, 329 controls). Logistic regression models examined the relationship between hypovitaminosis D and ocular inflammation. RESULTS: The odds of having uveitis were 1.92 times higher for patients with hypovitaminosis D compared to patients with normal Vitamin D levels in the multivariate analysis [odds ratio (OR) = 1.92, 95% Confidence Interval (CI) = 1.36-2.72, p = 2.32 × 10]. A secondary analysis demonstrated that the odds of developing uveitis or scleritis were 5% lower and 4% lower, respectively, for every unit increase in Vitamin D level (uveitis: OR = 0.95, 95% CI = 0.94-0.97, p = 9.87 × 10; scleritis: OR = 0.96, 95% CI = 0.93-0.99, p = 0.009). CONCLUSION: Hypovitaminosis D was associated with increased risk of ocular inflammation in this retrospective study.
Ferrara M, Eggenschwiler L, Stephenson A, Montieth A, Nakhoul N, Araùjo-Miranda R, Foster SC. The Challenge of Pediatric Uveitis: Tertiary Referral Center Experience in the United States. Ocul Immunol Inflamm 2018;:1-8.Abstract
PURPOSE: To describe the distribution, clinical findings, visual outcomes, treatment, and complications of children with uveitis at a tertiary referral ophthalmic center. METHODS: Retrospective cohort study. We reviewed the medical records of all patients ≤16 years with uveitis referred to Massachusetts Eye Research and Surgery Institution from March 2005 to July 2016. RESULTS: Of 286 included children, 62.24% were female. Mean age of onset was 8.4 years. The uveitis was mainly anterior (61.9%), recurrent (68.53%), bilateral (81.82%), and noninfectious (96.5%). Idiopathic cases accounted for 51.4%. The most frequent systemic association was juvenile idiopathic arthritis (34.96%). The majority of patients (78.32%) experienced complications. All patients, except one, needed systemic therapy. CONCLUSION: Pediatric uveitis is challenging to diagnose and manage, with frequent and potentially severe complications. Most cases were bilateral, recurrent, and idiopathic. Prompt referral to uveitis-specialized centers and an appropriate systemic therapy are mandatory for good visual outcomes.
Callaway NF, Gonzalez MA, Yonekawa Y, Faia LJ, Mandelcorn ED, Khurana RN, Saleh MGA, Lin P, Sobrin L, Albini TA. OUTCOMES OF PARS PLANA VITRECTOMY FOR MACULAR HOLE IN PATIENTS WITH UVEITIS. Retina 2018;38 Suppl 1:S41-S48.Abstract
PURPOSE: Inflammatory macular hole is a rare complication of uveitis, and data on surgical outcomes of closure are scarce. The purpose of this study is to evaluate the anatomical and visual outcomes of conventional pars plana vitrectomy for patients with uveitis. METHODS: Noncomparative, interventional, and consecutive case series from 6 vitreoretinal surgical centers from 2007 to 2015. Twenty eyes of 19 patients were included with 4 patients separated as viral retinitis. The primary outcome was change in best-corrected visual acuity at Month 3. Secondary outcomes were closure of the macular hole and postoperative optical coherence tomography characteristics. RESULTS: All eyes underwent conventional three-port pars plana vitrectomy with indocyanine green-assisted internal limiting membrane peeling. Mean Snellen best-corrected visual acuity improved from 20/200 to 20/63 (P = 0.01 for a difference in logarithm of the minimum angle of resolution) at Month 3. Twelve (75%) of patients achieved 2 or more lines of visual acuity improvement by postoperative Month 3. Surgery resulted in decreased epiretinal membrane (P = 0.002), intraretinal fluid (P < 0.001), subretinal fluid (P = 0.029), central subfield thickness (P < 0.001), and central cube volume (P = 0.041). Surgical intervention achieved anatomical success, as measured by macular hole closure, in 13 (81%) of patients at postoperative Month 3. CONCLUSION: Patients with inflammatory macular hole respond well to conventional surgery, with good anatomical and visual acuity outcomes.
Lasave AF, You C, Ma L, Abusamra K, Lamba N, Valdes Navarro M, Meese H, Foster SC. LONG-TERM OUTCOMES OF RITUXIMAB THERAPY IN PATIENTS WITH NONINFECTIOUS POSTERIOR UVEITIS REFRACTORY TO CONVENTIONAL IMMUNOSUPPRESSIVE THERAPY. Retina 2018;38(2):395-402.Abstract
PURPOSE: To assess long-term effectiveness of rituximab therapy for refractory noninfectious uveitis affecting the posterior segment. METHODS: Retrospective case series. Patients diagnosed with recalcitrant noninfectious posterior uveitis who were treated with rituximab intravenous infusions between 2010 and 2015 were included. Patients underwent best-corrected visual acuity testing and fluorescein angiography evidence of disk or vascular staining at 6, 12, 18, and 24 months. Patients had at least 24 months of follow-up. RESULTS: Eleven patients (21 eyes) with refractory posterior uveitis treated with intravenous rituximab were included. Nine (81.8%) patients were female. Mean follow-up was 29.3 ± 7.8 months. rituximab was administered as complementary therapy because of previous inefficacy of other therapies in 7 (63.7%) patients, and it was the only treatment in four (36.3%) patients who did not tolerate other drugs. Inflammation signs by fluorescein angiography were controlled in nine (81.8%) patients at the end of follow-up. Baseline best-corrected visual acuity was 20/80 (logarithm of the minimal angle of resolution 0.6 ± 0.4), and final best-corrected visual acuity was 20/40 (0.3 ± 0.5) (P = 0.005). No significant side effects were reported. CONCLUSION: Rituximab therapy was associated with stability and remission of recalcitrant noninfectious posterior uveitis in patients who did not tolerate or did not respond to other therapies.
Sheppard JD, Foster SC, Toyos MM, Markwardt K, Da Vanzo R, Flynn TE, Kempen JH. Difluprednate 0.05% versus Prednisolone Acetate 1% for Endogenous Anterior Uveitis: Pooled Efficacy Analysis of Two Phase 3 Studies. Ocul Immunol Inflamm 2017;:1-13.Abstract
PURPOSE: To analyse pooled data from 2 similar phase 3 noninferiority studies comparing difluprednate 0.05% versus prednisolone acetate 1% in patients with endogenous anterior uveitis. METHODS: Patients received difluprednate alternating with vehicle or prednisolone acetate for 14 days (8 drops/day in both groups), followed by tapering from day 14 to 28. All patients were observed until day 42. RESULTS: More patients on difluprednate than on prednisolone acetate were cleared of anterior chamber cells on day twenty one (71.3% vs 54.7%; p = 0.02); results were similar at the other time points. Treatment withdrawals were higher with prednisolone acetate than difluprednate (19.8% vs 7.4%; log-rank p = 0.02). Study discontinuation due to lack of efficacy was also higher with prednisolone acetate than difluprednate (14.0% vs 0%; p = 0.0002 [pre-specified exploratory analysis]). CONCLUSIONS: More difluprednate-treated eyes were quiet following 21 days of treatment, and difluprednate-treated patients were much less likely to be withdrawn from the study because of treatment failure.
Silpa-Archa S, Preble JM, Foster SC. VITREOUS TREPONEMAL ANTIBODY AS A SUPPLEMENTARY TEST TO SEROLOGY FOR THE CONFIRMATION OF SYPHILITIC CHORIORETINITIS. Retin Cases Brief Rep 2017;Abstract
PURPOSE: To report the novel application of nontreponemal and treponemal antibody to confirm diagnosis of ocular syphilis from vitreous samples. METHODS: Two distinct case reports emphasizing the importance of confirmatory vitreous treponemal antibody. Multimodal imaging of patients was also applied. RESULTS: We report two distinct cases with positive serum treponemal antibody but opposing vitreous treponemal antibody results. One case with a positive vitreous test responded well to antisyphilitic treatment. By contrast, a case with a negative vitreous result was changed to serpiginous choroiditis, eventually cured by immunomodulatory treatment. CONCLUSION: Intraocular fluid analysis of nontreponemal and treponemal antibody may play an important role in ruling out suspected ocular syphilis in settings without a polymerase chain reaction facility, especially immunocompromised patients who are at risk of multiple infections. Further studies are needed to establish the sensitivity and specificity of nontreponemal and treponemal antibody test on vitreous samples.
Sood AB, Pearce WA, Workowski KA, Lockwood J, Yeh S. Combined Intravitreal and Systemic Antibiotic Therapy in a Patient with Syphilitic Uveitis. Ocul Immunol Inflamm 2017;:1-3.Abstract
PURPOSE: To report the novel use of combined intravitreal and systemic antibiotic therapy in a patient with syphilitic panuveitis and discuss the management of ocular syphilis. METHODS: Case report Results: A 45-year old heterosexual male with human immunodeficiency virus (HIV) presented with 1 month of blurry vision in both eyes. Clinical examination revealed a bilateral panuveitis. The patient denied history of genital lesions or rash, but did complain of difficulty hearing bilaterally. Treponemal EIA was positive, the RPR titer greater than 1:512 dilution, and CSF VDRL 1:4. A diagnosis of neurosyphilis and ocular syphilis was made based on the clinical and laboratory findings. The patient was admitted for systemic intravenous antibiotic therapy, but was noted to have a penicillin allergy. Intravitreal ceftazidime was promptly administered bilaterally to achieve treponemacidal levels of antibiotic therapy. After penicillin desensitization protocol, the patient received 14 days of intravenous penicillin with clinical resolution. CONCLUSIONS: There are increasing reports of ocular syphilis in the United States and delay in diagnosis and management can lead to severe visual impairment and blindness. We report the first case of adjunct intravitreal antibiotic therapy in a penicillin allergic patient. As ocular syphilis is a form of bacterial endophthalmitis, combination intravitreal and systemic antibiotics may be considered.

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