Ocular Sarcoidosis.

Sarcoidosis frequently affects the eye and can do so in many different ways. Sarcoidosis causing uveitis can have distinctive features that facilitate identifying sarcoidosis as the cause of the uveitis. Progress is being made in elucidating ocular sarcoidosis, as for example, by transcriptomics, genetics, therapy, and imaging.

Characterization of autoimmune eye disease in association with Down's syndrome.

BACKGROUND: Autoimmunity and deficiency of the transcription factor autoimmune regulator protein (AIRE) are known associations with Down syndrome (DS). Lack of AIRE abrogates thymic tolerance. The autoimmune eye disease associated with DS has not been characterized. We identified a series of subjects with DS (n = 8) and uveitis. In three consecutive subjects, we tested the hypothesis that autoimmunity to retinal antigens might be a contributing factor. SUBJECTS/METHODS: This was a multicentred, retrospective case series. Deidentified clinical data of subjects with both DS and uveitis were collected via questionnaire by uveitis-trained ophthalmologists. Anti-retinal autoantibodies (AAbs) were detected using an Autoimmune Retinopathy Panel tested in the OHSU Ocular Immunology Laboratory. RESULTS: We characterized eight subjects (mean age 29 [range, 19-37] years). The mean age of detected uveitis onset was 23.5 [range, 11-33] years. All eight subjects had bilateral uveitis (p < 0.001 based on comparison to published university referral patterns), with anterior and intermediate uveitis found in six and five subjects respectively. Each of three subjects tested for anti-retinal AAbs was positive. Detected AAbs included anti-carbonic anhydrase II, anti-enolase, anti-arrestin, and anti-aldolase. DISCUSSION: A partial deficiency in the AIRE on chromosome 21 has been described in DS. The similarities in the uveitis presentations within this patient group, the known autoimmune disease predisposition in DS, the recognized association of DS and AIRE deficiency, the reported detection of anti-retinal antibodies in patients with DS in general, and the presence of anti-retinal AAbs in three subjects in our series supports a causal association between DS and autoimmune eye disease.

A Vascularized Iris Mass in Ocular Syphilis: A Case Report and Review of Literature.

PURPOSE: To describe features of a syphilitic vascularized iris mass on multimodal imaging and its resolution after penicillin treatment. METHODS: Observational case report and literature review of syphilitic iris masses. RESULTS: A 43-year-old woman presented with a unilateral vascularized tan iris mass in the setting of bilateral panuveitis that occurred along with bilateral papillitis, cystoid macular edema and retinal vasculitis. Laboratory work-up confirmed a diagnosis of syphilis. Ultrasound biomicroscopy (UBM) of the iris mass showed parapupillary hyperechoic full-thickness iris stromal thickening with small intrinsic circular lumens without cyst or ciliary body extension, while the anterior segment optical coherence tomography (AS-OCT) demonstrated a hyperreflective mass with deep iris extension and partial hyporeflective rim. Following treatment, the mass fully resolved without residual sequela. A review of literature identified 11 additional cases of syphilitic iris masses in the English literature from 1915 to present. Their presentations and clinical courses were reviewed herein. CONCLUSIONS: This report characterizes a syphilitic iris mass on slit-lamp photography, iris fluorescein angiography, UBM and AS-OCT; depicts key characteristics of syphilitic iris masses; and highlights the need for close inspection of the iris mass as an uncommon sign of ocular syphilis.

Multimodal Imaging Study of Patients With Vitamin A Deficiency Retinopathy.

OBJECTIVES: To describe multimodal imaging findings of vitamin A deficiency retinopathy. METHODS: A retrospective study of patients with serum retinol < 0.3 mg/L. Fundus color photos, spectral domain-optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were reviewed and, when available, electrophysiological tests were analyzed. RESULTS: Forty-five eyes (63.9 ± 15.7 years) were included. Ultra-widefield fundus photography showed drusen-like deposits (53.3%) and macular retinal pigment epithelium (RPE) mottling (40%). The deposits were hypoautofluorescent, and a perifoveal hyperautofluorescent ring was present in 8.9%. By SD-OCT, the ellipsoid zone had an irregular appearance (100%) and conical deposits anterior to the RPE (33.3%). Electroretinogram (ERG) (66.7%) showed a decrease in b-wave in the scotopic registers, and microperimetry (4.4%) showed decreased foveal sensitivity. After vitamin A supplementation, SD-OCT and FAF showed resolution of all findings. Forty percent of eyes had restoration of the scotopic registers in ERG and improved macular sensitivity by microperimetry (4.4%). CONCLUSIONS: Vitamin A deficiency causes a mild cone dysfunction in addition to the more severe absent rod response. [Ophthalmic Surg Lasers Imaging Retina 2023;54:330-336.].

Characterization of autoimmune eye disease in association with Down's Syndrome.

Background Autoimmunity and deficiency of the transcription factor autoimmune regulator protein (AIRE) are known associations with Down Syndrome (DS). Lack of AIRE abrogates thymic tolerance. The autoimmune eye disease associated with DS has not been characterized. We identified a series of subjects with DS (n = 8) and uveitis. In 3 consecutive subjects, we tested the hypothesis that autoimmunity to retinal antigens might be a contributing factor. Subjects/Methods: This was a multicentered, retrospective case series. De-identified clinical data of subjects with both DS and uveitis were collected via questionnaire by uveitis-trained ophthalmologists. Anti-retinal autoantibodies (AAbs) were detected using an Autoimmune Retinopathy Panel tested in the OHSU Ocular Immunology Laboratory. Results We characterized 8 subjects (mean age 29 [range, 19-37] years). The mean age of uveitis onset was 23.5 [range, 11-33] years. All 8 subjects had bilateral uveitis (p < 0.001 based on comparison to published university referral patterns), with anterior and intermediate uveitis found in 6 and 5 subjects respectively. Each of three subjects tested for anti-retinal AAbs was positive. Detected AAbs included anti-carbonic anhydrase II, anti-enolase, anti-arrestin, and anti-aldolase. Discussion A partial deficiency in the AIRE on chromosome 21 has been described in DS. The similarities in the uveitis presentations within this patient group, the known autoimmune disease predisposition in DS, the recognized association of DS and AIRE deficiency, the reported detection of anti-retinal antibodies in patients with DS in general, and the presence of anti-retinal AAbs in 3 subjects in our series supports a causal association between DS and autoimmune eye disease.

Degenerative Peripheral Retinoschisis: Observations From Ultra-Widefield Fundus Imaging.

BACKGROUND AND OBJECTIVE: To describe the ultra-widefield (UWF) imaging characteristics of patients with degenerative peripheral retinoschisis (DPR) using Optomap technology. PATIENTS AND METHODS: In this multicenter, retrospective, noncomparative, consecutive case series, eligible patients underwent detailed retinal examination including indirect ophthalmoscopy. UWF fundus imaging, including color fundus photography, autofluorescence, and angiography, was performed using standardized protocols and findings were recorded and reviewed and analyzed. RESULTS: A total of 35 patients (58 eyes) with DPR were identified who underwent 55 sessions of UWF imaging. Mean age was 65 years, and the inferotemporal quadrant was most commonly affected (74% of eyes). Of these patients, 31 underwent fluorescein angiography and 90% of these studies illustrated abnormalities in the area affected by the schisis. The most common finding was retinal vascular leakage originating from the deep capillary plexus observed in 29 eyes (93.5%). CONCLUSIONS: UWF imaging enables a more detailed identification of the clinical features associated with DPR and provides simple, practical, and noninvasive tools to monitor progression of disease. The breadth of retinal vascular complications identified with fluorescein angiography may suggest an important vascular component associated with the pathogenesis of this entity. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:557-564.].

Ocular Sarcoidosis.

Sarcoidosis is one of the leading causes of inflammatory eye disease. Ocular sarcoidosis can involve any part of the eye and its adnexal tissues and may cause uveitis, episcleritis/scleritis, eyelid abnormalities, conjunctival granuloma, optic neuropathy, lacrimal gland enlargement, and orbital inflammation. Glaucoma and cataract can be complications from inflammation itself or adverse effects from therapy. Ophthalmic manifestations can be isolated or associated with other organ involvement. Patients with ocular sarcoidosis can present with a wide range of clinical presentations and severity. Multidisciplinary approaches are required to achieve the best treatment outcomes for both ocular and systemic manifestations.

Rituximab therapy for refractory scleritis: results of a phase I/II dose-ranging, randomized, clinical trial.

OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory noninfectious scleritis. DESIGN: Prospective, dose-ranging, randomized, double-masked phase I/II clinical trial. PARTICIPANTS: Twelve patients with noninfectious scleritis refractory to systemic corticosteroid and ≥1 other systemic immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTION: Subjects were randomly assigned to 500 (n = 5) or 1000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1000 mg infusions. MAIN OUTCOME MEASURES: Primary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by ≥50%. Patients were characterized as responders to study therapy if ≥1 of these endpoints showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician-reported global health assessment. RESULTS: Of 12 enrolled patients, 9 met the SGS endpoint at or before week 24, and 4 additionally were able to reduce corticosteroid dose by ≥50%. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS: Rituximab was effective treatment for 9 of 12 enrolled patients with refractory, noninfectious scleritis at 24 weeks, although 7 required reinfusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. Further long-term studies are warranted to determine the safety and efficacy of rituximab in treating noninfectious scleritis and other ocular inflammatory diseases.

Rituximab therapy for refractory orbital inflammation: results of a phase 1/2, dose-ranging, randomized clinical trial.

IMPORTANCE: Orbital inflammation is a potentially blinding and disfiguring disease process that is often treated with systemic corticosteroids and immunosuppression; better treatments are needed. OBJECTIVE: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory orbital inflammation. DESIGN, SETTING, AND PARTICIPANTS: A dose-ranging, randomized, double-masked phase 1/2 clinical trial was conducted at a tertiary referral ophthalmology clinic. Ten individuals with orbital inflammation refractory to systemic corticosteroids and at least 1 other immunosuppressive agent were enrolled from January 2007 to March 2010. INTERVENTIONS: Rituximab infusions were administered on study days 1 and 15 at doses of either 500 mg or 1000 mg. Initial responders with recurrent inflammation after week 24 were permitted reinfusion with an additional cycle of 2 open-label 1000-mg rituximab infusions. MAIN OUTCOMES AND MEASURES: The primary outcomes were reduction of inflammation measured with a validated orbital disease grading scale and corticosteroid dose reduction by at least 50%. The secondary outcomes were visual acuity, reduction in pain, and participant- and physician-reported global health assessment. RESULTS: Of 10 enrolled patients, 7 demonstrated improvement on the orbital disease grading scale at the 24-week end point with rituximab therapy. Of these 7 individuals, 4 were receiving corticosteroids at study inception and all achieved successful dose reduction. For the secondary outcome measures in the 10 participants, 7 patients and 8 patients improved in self-rated and physician global health scores, respectively, and 7 patients had reduction in pain by 25% or more at 24 weeks. Four patients who were positive responders at the week 24 end point experienced breakthrough inflammation after week 24 and received reinfusions between 24 and 48 weeks. Vision remained stable in all participants. Three of 10 patients had short-term objective or subjective worsening 2 to 8 weeks after receiving rituximab infusions, which was averted in subsequent patients with oral corticosteroids administered during the infusion and did not affect the eventual positive treatment outcome. No significant differences with regard to efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms. CONCLUSIONS AND RELEVANCE: Rituximab was safe and effective in 7 of 10 patients with noninfectious orbital disease, although 4 required reinfusion with rituximab to maintain control of orbital inflammation. Substantial toxicity was not noted. Rituximab should be considered in the treatment of refractory orbital inflammation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00415506.

Update on the use of systemic biologic agents in the treatment of noninfectious uveitis.

Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet's disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet's disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis.

Adalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trial.

OBJECTIVE: Tumour necrosis factor (TNF) blockers have been demonstrated to be effective in the treatment of systemic and ocular inflammatory diseases. We conducted a prospective, multicentre, open-label Phase II clinical trial to assess the effectiveness and safety of adalimumab, a fully human anti-TNF monoclonal antibody, in treating refractory uveitis. METHODS: Subjects with non-infectious uveitis refractory to corticosteroids and at least one other immunosuppressive medication were enrolled. Treatment outcome was ascertained by a composite endpoint comprised of visual acuity, intraocular inflammation, ability to taper immunosuppressives, and posterior segment imaging. Clinical response was defined by improvement in at least one parameter, worsening in none, and well controlled intraocular inflammation. Week 10 responders were permitted to continue receiving adalimumab for the study duration of 50 weeks. RESULTS: Twenty-one of 31 patients (68%) were characterised as clinical responders at 10 weeks, of whom 12 patients (39%) exhibited durable response after 50 weeks. The most common reason for study termination was primary or secondary inefficacy. No patients experienced treatment-limiting toxicity clearly related to study therapy. CONCLUSIONS: Adalimumab was safe and effective in 68% of refractory uveitis patients 10 weeks after study enrolment, and maintained in 39% after 1 year. Ongoing study is required to determine the place of adalimumab and other TNF blockers in the treatment of uveitis.

Triamcinolone-induced cataract in eyes with diabetic macular oedema: 3-year prospective data from a randomized clinical trial.

PURPOSE: To describe the 3-year risk of cataract after intravitreal triamcinolone (IVTA) injections for diabetic macular oedema and the outcomes of cataract surgery. METHODS: Prospective data from a randomized clinical trial were analysed. At baseline, 27 phakic eyes with diabetic macular oedema were randomized to receive IVTA and 25 to receive sham injection. After 2 years, initial sham-treated eyes were eligible to receive IVTA as the study became open label for the third year. The cumulative incidence of cataract surgery was the primary outcome of the study. Other outcomes assessed included progression of cataract, best-corrected logarithm of the minimal angle of resolution visual acuity before and after surgery and central macular thickness. RESULTS: Over the 3 years of the study, 15/27 (56%) phakic eyes in the IVTA treated group underwent cataract surgery as compared with 2/25 (8%) initial sham-treated eyes (P < 0.001). Mean visual acuity 6 months after cataract surgery was better than at entry into the trial. Two (15%) of the eyes in the IVTA-treated group undergoing cataract surgery had a loss of >15 letters. In the IVTA-treated group, 10/15 (67%) eyes that had three or more injections had progression of posterior subcapsular cataract by > or = 2 grades as compared with only 2/12 (17%) eyes that had fewer than three injections (P = 0.009). CONCLUSIONS: Over half of the eyes receiving IVTA injections for diabetic macular oedema required cataract surgery within 3 years. In eyes with three or more IVTA injections, two-thirds had progression of posterior subcapsular cataract. Visual outcomes after cataract surgery were generally good, although a small proportion of eyes lost greater than 15 letters over the course of the study.

Posterior uveal cleft and hypotony complicating insertion of a fluocinolone acetonide implant.

PURPOSE: To describe posterior uveal cleft and chronic hypotony occurring in association with a fluocinolone acetonide implant (Retisert) that was successfully treated by vitrectomy, removal of the implant, and cryotherapy. METHODS: A 57-year-old female patient with idiopathic uveitis, well-controlled with cyclosporine, developed chronic hypotony with maculopathy after insertion of a fluocinolone acetonide implant. Visual acuity in the affected eye was counting fingers, and intraocular pressure was 0 mmHg. Wound leakage, cyclodialysis cleft, and cyclitic membrane were excluded. Ultrasound biomicroscopy demonstrated a posterior uveal cleft at the site of implant, which was presumed to have created a channel for passage of intraocular fluid to the suprachoroidal space. The patient was treated with pars plana vitrectomy, removal of the implant, cryotherapy at the implant site, and intravitreal triamcinolone acetonide injection. RESULTS: The procedure was well tolerated. Intraoperative appearance suggested incarceration of the implant, which did not show on ultrasound biomicroscopy. Intraocular pressure was normalized 5 days after the surgery. Postoperative visual acuity improved to 20/200 at 2 weeks after the surgery and remained stable through 1 year of follow-up. Uveitis remains well controlled with cyclosporine at 1 year after the procedure. CONCLUSION: Posterior uveal cleft may cause hypotony as a complication of insertion of a fluocinolone acetonide implant. The ultrasound biomicroscopy is a crucial investigation to establish the diagnosis and to exclude other pathologies including cyclodialysis cleft and cyclitic membrane. It may fail to demonstrate incarceration of an implant, however. Proper surgical technique may prevent this complication.

Differential macular morphology in patients with RPE65-, CEP290-, GUCY2D-, and AIPL1-related Leber congenital amaurosis.

PURPOSE: To evaluate genotypic and macular morphologic correlations in patients with RPE65-, CEP290-, GUCY2D-, or AIPL1-related Leber congenital amaurosis (LCA) using spectral-domain optical coherence tomography (SD-OCT). METHODS: SD-OCT macular scans were performed in 21 patients, including 10 with RPE65, 7 with CEP290, 3 with GUCY2D, and 1 with AIPL1 mutations. An image processing software was used to manually draw segmentation lines by three observers. Lamellar structure was evaluated based on the number of retinal layers on segmented images. Total retinal thickness was measured at the central macular and perifoveal areas by using an automated algorithm. RESULTS: All three patients with GUCY2D mutations (age range, 20-53 years) retained six retinal layers with visible photoreceptor inner/outer segment juncture (PSJ). However, the preservation of lamellar structures did not parallel better visual acuity. Patients with other mutations had poorly defined PSJ and disorganized retinal lamellar structures, where only one to three retinal layers could be observed. Patients with CEP290 mutations trended to have retention of the outer nuclear layer at the fovea and macular thickening, especially at younger ages. In patients with RPE65 (age range, 20-71 years) and AIPL1 mutations (age, 22 years), macular thickness was markedly decreased. Disorganization of retinal lamellar structures in the RPE65 group trended toward a worsening with increasing age. CONCLUSIONS: Variations of macular microstructures were observed among LCA patients with different genotypes. Disorganization of retinal lamellar structure was generally age related. Preservation of retinal microanatomic structures may not be associated with better visual acuity.

Application of Biostatistics and Bioinformatics Tools to Identify Putative Transcription Factor-Gene Regulatory Network of Ankylosing Spondylitis and Sarcoidosis.

Transcription factors and corresponding cis-regulatory elements are considered key components in gene regulation. We combined biostatistics and bioinformatics tools to streamline identification of putative transcription factor-gene regulatory networks unique for two immune-mediated diseases, ankylosing spondylitis and sarcoidosis. After identifying differentially expressed genes from microarrays, we employed tightCluster to find tight clusters of potentially co-regulated genes. By subsequently applying bioinformatics tools to search for common cis-regulatory elements, putative transcription factor-gene regulatory networks were found. Recognition of these networks by applying this methodology could pave the way for new insights into disease pathogenesis.

Azathioprine for ocular inflammatory diseases.

PURPOSE: To evaluate treatment outcomes of azathioprine for noninfectious ocular inflammatory diseases. DESIGN: Retrospective cohort study. METHODS: Medical records of 145 patients starting azathioprine as a sole noncorticosteroid immunosuppressant at 4 tertiary uveitis services were reviewed. Main outcome measures included control of ocular inflammation, sustained control after tapering prednisone to

Hypothesis: sarcoidosis is a STAT1-mediated disease.

Immunologic pathways involved in sarcoidosis pathogenesis are largely unknown. We hypothesized that patients with sarcoidosis have characteristic mRNA profiles. Microarray analysis of gene expression was done on peripheral blood (12 patients, 12 controls), lung (6 patients, 6 controls) and lymph node (8 patients, 5 controls). Comparing peripheral blood from patients with sarcoidosis to controls, 872 transcripts were upregulated and 1039 were downregulated at >1.5-fold change and a significant q value. Several transcripts associated with interferon and STAT1 were upregulated. Lung and lymph node analyses also showed dramatic increases in STAT1 and STAT1-regulated chemokines. Granulomas in lymph nodes of patients with sarcoidosis expressed abundant STAT1 and phosphorylated STAT1. STAT1 might play an important role in sarcoidosis. This novel hypothesis unites seemingly disparate observations with regard to sarcoidosis including implication of a casual role for interferons, a suspected infectious trigger, T(H)1 predominating lymphocytes in bronchoalveolar lavage, and the association with hypercalcemia.