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.

TACROLIMUS FOR IMMUNOSUPPRESSION IN PATIENTS WITH NONINFECTIOUS INTERMEDIATE, POSTERIOR, OR PANUVEITIDES.

PURPOSE: To evaluate the effectiveness of tacrolimus in patients with noninfectious intermediate, posterior, or panuveitis needing a two-immunosuppressive-agent regimen. METHODS: Design: Retrospective cohort study. Setting: Two tertiary-care uveitis practices at academic medical centers. Patient population: Thirty-two patients with noninfectious intermediate, posterior, or panuveitides in whom single-agent immunosuppression was inadequate to effect successful corticosteroid sparing. Intervention: tacrolimus, added as the second immunosuppressive agent. Main outcome measure: successful corticosteroid sparing, defined as inactive uveitis at a dose of prednisone ≤7.5 mg/day. RESULTS: Active uveitis was present in 65.6% of patients at initiation of tacrolimus, and the median time to inactive uveitis was 1.5 months (95% confidence interval 1.2, 4.08). The median time to successful corticosteroid sparing was 3.9 months (95% confidence interval 1.41, 6.67), and by 6 months of follow-up successful corticosteroid sparing was achieved in 75% of patients. Tacrolimus was discontinued for side effects in five patients, three for tremor, and two for hyperglycemia. All side effects were reversible with tacrolimus discontinuation. CONCLUSION: Tacrolimus seems to have efficacy as a second immunosuppressive agent in two-immunosuppressive drug regimens, when a single agent does not permit successful corticosteroid sparing. Side effects were reversible with tacrolimus discontinuation.

Using the Electronic Medical Record to Increase Laboratory Test Monitoring in Ocular Inflammation Patients: A Quality Improvement Study.

BACKGROUND AND OBJECTIVES: Treatment of chronic, noninfectious ocular inflammation includes corticosteroids, disease-modifying antirheumatic medications, and biologics. To mitigate adverse effects associated with the use of these medications, routine laboratory test monitoring is recommended throughout treatment. We evaluated the effectiveness of an alert added to the electronic medical record (EMR) to aid in laboratory test monitoring for patients prescribed these high-risk medications. METHODS: A prospective, interventional study assessed the effect of the alert within the EMR on laboratory test ordering at the Division of Ocular Immunology at the Wilmer Eye Institute. The primary outcome measure was the change in number of ordered laboratory tests at 3, 6, and 12 months after the alert activation compared with pre-intervention levels and overall through the study period. The laboratory tests that were monitored included complete blood count, comprehensive metabolic panel, dual-energy x-ray absorptiometry (DXA) scanning, fasting lipid panel, and interferon gamma release assays. RESULTS: The laboratory test orders for 153 patients on high risk medications were analyzed. Only the frequency of ordering the DXA and interferon gamma release assays increased significantly, compared with baseline, throughout the study. Conversely, there was a significant decrease in the frequency of ordering of fasting lipid profiles and hemoglobin A 1c at each time point and for complete blood count and comprehensive metabolic panel at the 6-month time point. CONCLUSION: An EMR alert results in increased laboratory test ordering initially for tests drawn on a yearly basis, but the effect on more frequently ordered tests wanes with time if the alert can be silenced by the provider. Nonetheless, it provides a novel mechanism to increase laboratory ordering in patients on high-risk medications that can be adapted for use in other EMR software. Future studies are needed to assess whether physician laboratory test ordering behavior is altered throughout the study period with the use of a non-silencable alert.

Adalimumab-associated Acquired Hemophilia in a Patient with Scleritis.

Acquired hemophilia A (AHA) is a rare condition that may be drug-induced. In this case report, we describe a patient who presented with extensive subcutaneous bleeding three years after beginning treatment with adalimumab for necrotizing scleritis. His workup was compatible with drug-induced AHA. He was treated with high-dose corticosteroids, cyclophosphamide, and rituximab. Adalimumab was discontinued. We present this case as an example of a rare, but potentially life-threatening, complication of adalimumab.

Effectiveness of the Dexamethasone Implant in Lieu of Oral Corticosteroids in Intermediate and Posterior Uveitis Requiring Immunosuppression.

PURPOSE: To evaluate dexamethasone intravitreal implant effectiveness in lieu of high-dose oral prednisone for short-term treatment of noninfectious intermediate and posterior uveitis in patients requiring immunosuppression. METHODS: This is a proof-of-concept, open-label, non-comparative clinical trial with 12-month follow-up. The primary outcome was uveitis control without additional prednisone at 6 and 12 months. Secondary outcomes were need for multiple implants or additional prednisone, and safety data. RESULTS: 20 patients (28 eyes) were enrolled- 16 eyes had control by 6 months; 20 by 12 months. No patients required high-dose prednisone. 6 patients enrolled on prednisone: 2 stopped; 4 tapered to 7.5 mg daily or less by 12 months. 16 eyes required multiple implants; five required cataract surgery; 12 required drops to control IOP; 2 underwent glaucoma surgery. CONCLUSIONS: The dexamethasone implant was effective in lieu of high-dose prednisone although the majority required multiple implants. All patients decreased or discontinued prednisone during follow-up.

Relapsing Thrombotic Thrombocytopenic Purpura (TTP) in a Patient Treated with Infliximab for Chronic Uveitis.

PURPOSE: To report a case of relapsing thrombotic thrombocytopenic purpura (TTP) in a patient treated with infliximab for chronic uveitis. CASE REPORT: A 57-year-old African American woman with chronic anterior and intermediate uveitis, treated with infliximab for more than 1 year, presented with fatigue, dark colored urine, and ecchymosis on her extremities. She was diagnosed with thrombotic thrombocytopenic purpura (TTP) and recovered after treatment. After a remission period of 8 months, she was treated again with infliximab for recurrent intraocular inflammation. She developed a relapse of TTP 4 weeks after reintroducing infliximab. CONCLUSION: Relapsing thrombotic thrombocytopenic purpura can be a rare complication associated with infliximab. To our knowledge, it has not been reported in the literature to date.

Effectiveness of Difluprednate for the Treatment of Anterior Scleritis.

PURPOSE: To describe the effectiveness and side effect profile of difluprednate therapy in a series of patients with anterior scleritis. DESIGN: Retrospective, interventional case series. METHODS: Data collected from all patients with anterior scleritis who used difluprednate as a single treatment agent from January 1, 2018, to January 1, 2020, including demographics, scleritis type, presence of nodules or necrosis, changes in scleritis activity, intraocular pressure (IOP), number of difluprednate drops used, best-corrected visual acuity (BCVA), and lens status. The primary outcome was clinical resolution of scleritis. Secondary outcomes included BCVA loss ≥2 lines, change in lens status or cataract surgery, and IOP ≥24 mm Hg. RESULTS: Twenty-five patients (35 eyes) were analyzed. The median age was 60 years (range 13-78); 60% were female; 64% were White. Forty percent had bilateral disease, and 44% of patients had an associated systemic disease. The majority of eyes (66%) had diffuse anterior scleritis. Eighty-three percent of eyes achieved resolution of scleritis, with a median time of resolution of 6 weeks. Eyes treated with an initial dose of ≥4 times daily were more likely to achieve disease resolution (hazard ratio [HR] = 3.43, 95% confidence interval [CI] 1.19, 9.88, P = .02). Nine eyes had IOP elevation. Four eyes lost ≥2 lines of BCVA, and 1 due to cataract progression. One eye underwent cataract surgery. CONCLUSIONS: Difluprednate alone may effectively treat non-infectious anterior scleritis with a tolerable side effect profile.

Ocular Outcomes after Treatment of Cytomegalovirus Retinitis Using Adoptive Immunotherapy with Cytomegalovirus-Specific Cytotoxic T Lymphocytes.

PURPOSE: To describe ocular outcomes in eyes with cytomegalovirus (CMV) retinitis treated with adoptive immunotherapy using systemic administration of CMV-specific cytotoxic Tlymphocytes (CMV-specific CTLs). DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with active CMV retinitis evaluated at a tertiary care academic center. METHODS: Treatment of CMV retinitis with standard-of-care therapy (systemic or intravitreal antivirals) or CMV-specific CTLs (with or without concurrent standard-of-care therapies). MAIN OUTCOME MEASURES: The electronic medical record was reviewed to determine baseline characteristics, treatment course, and ocular outcomes, including best-corrected visual acuity (BCVA), treatments administered (CMV-specific CTLs, systemic antivirals, intravitreal antivirals), resolution of CMV retinitis, any occurrence of immune recovery uveitis, cystoid macular edema, retinal detachment, or a combination thereof. RESULTS: Seven patients (3 of whom had bilateral disease [n = 10 eyes]) were treated with CMV-specific CTLs, whereas 20 patients (6 of whom had bilateral disease [n = 26 eyes]) received standard-of-care treatment. Indications for CMV-specific CTL therapy included persistent or progressive CMV retinitis (71.4% of patients); CMV UL54 or UL97 antiviral resistance mutations (42.9%); side effects or toxicity from antiviral agents (57.1%); patient intolerance to longstanding, frequent antiviral therapy for persistent retinitis (28.6%); or a combination thereof. Two patients (28.6%; 4 eyes [40%]) received CMV-specific CTL therapy without concurrent systemic or intravitreal antiviral therapy for active CMV retinitis, whereas 5 patients (71.4%; 6 eyes [60%]) continued to receive concurrent antiviral therapies. Resolution of CMV retinitis was achieved in 9 eyes (90%) treated with CMV-specific CTLs, with BCVA stabilizing (4 eyes [40%]) or improving (4 eyes [40%]) in 80% of eyes over an average follow-up of 33.4 months. Rates of immune recovery uveitis, new-onset cystoid macular edema, and retinal detachment were 0%, 10% (1 eye), and 20% (2 eyes), respectively. These outcomes compared favorably with a nonrandomized cohort of eyes treated with standard-of-care therapy alone, despite potentially worse baseline characteristics. CONCLUSIONS: CMV-specific CTL therapy may represent a novel monotherapy or adjunctive therapy, or both, for CMV retinitis, especially in eyes that are resistant, refractory, or intolerant of standard-of-care antiviral therapies. More generally, adoptive cell transfer and adoptive immunotherapy may have a role in refractory CMV retinitis. Larger prospective, randomized trials are necessary.

Uveitis for the non-ophthalmologist.

The uveitides are a heterogeneous group of diseases characterized by inflammation inside the eye. The uveitides are classified as infectious or non-infectious. The non-infectious uveitides, which are presumed to be immune mediated, can be further divided into those that are associated with a known systemic disease and those that are eye limited,-ie, not associated with a systemic disease. The ophthalmologist identifies the specific uveitic entity by medical history, clinical examination, and ocular imaging, as well as supplemental laboratory testing, if indicated. Treatment of the infectious uveitides is tailored to the particular infectious organism and may include regional and/or systemic medication. First line treatment for non-infectious uveitides is corticosteroids that can be administered topically, as regional injections or surgical implants, or systemically. Systemic immunosuppressive therapy is used in patients with severe disease who cannot tolerate corticosteroids, require chronic corticosteroids at >7.5 mg/day prednisone, or in whom the disease is known to respond better to immunosuppression. Management of many of these diseases is optimized by coordination between the ophthalmologist and rheumatologist or internist.

Escalation to Weekly Adalimumab for the Treatment of Ocular Inflammation.

Purpose: To report the outcomes of the escalation of adalimumab (ADA) dose for refractory ocular inflammatory diseases.Methods: A retrospective case series of 15 patients (29 eyes) diagnosed with ocular inflammatory disease, including uveitis and scleritis, which was not adequately controlled with standard, every other week ADA dosing, leading to an escalation to weekly dosing.Results: Ten of fifteen patients escalated to weekly ADA achieved control of their inflammation; neither of the two patients increased for control of cystoid macular edema (CME) had resolution and required regional corticosteroids. One patient discontinued weekly ADA due to serious infection. The median length of follow up was 12 months.Conclusion: Our series suggests that the escalation of ADA can be a useful strategy for treating recalcitrant ocular inflammation, but may not be adequate to treat refractory CME.

Uveitis for Dermatologists: A Review.

Certain dermatologic conditions and drugs used for their treatment are associated with uveitis, a vision-threatening group of inflammatory eye diseases. Dermatologists may therefore be the first healthcare providers to recognize the presence of uveitis in certain patients and can help ensure morbidity is minimized. Posterior uveitis in particular, which may manifest as insidious, painless vision loss, may first be identified by a careful review of systems by a dermatologist. Understanding uveitis and its associations with certain skin findings and drugs will help enable identification and triage of patients in need of ophthalmic care. An overview of uveitis is provided, including its epidemiology, etiologies, classification, presenting signs and symptoms, general management, and complications. Next, dermatologic diseases that may be associated with uveitis are reviewed with a focus on how uveitis is most likely to present. Lastly, drugs used by dermatologists and less common dermatologic diseases associated with uveitis are reviewed. Multidisciplinary management is necessary for patients with both skin disease and ocular complications such as uveitis. Dermatologists’ recognition of uveitis in patients may reduce time to referral and improve patient outcomes. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5165.

Clinical Features and Incidence Rates of Ocular Complications in Patients With Retinal Vasculitis.

PURPOSE: To describe the incidence rates of visual loss and ocular complications in patients with retinal vasculitis (RV). DESIGN: Retrospective cohort study. METHODS: Clinical data were collected for 96 patients (175 eyes) diagnosed with RV from 2003 to 2013. Main outcome measures included rates of visual loss and ocular complications. Comparison of outcomes in patients with a relapsing vs nonrelapsing disease also were analyzed. RESULTS: Over a median follow-up of 44 months (range: 1-153 months), the rate of visual loss to 20/50 or worse was 0.13 per eye-year (/EY, 95% confidence interval [CI], 0.09/EY to 0.18/EY) and to 20/200 or worse was 0.06/EY (95% CI, 0.04/EY to 0.08/EY). The most common complications were cataract (0.31/EY), epiretinal membrane (0.16/EY), and recurrent macular edema (0.09/EY). Patients with a relapsing course (median number of relapses = 1, range: 1-6) appeared to have greater risk for visual loss to 20/50 (odds ratio [OR] = 2.07; 95% CI, 0.88-4.90, P = .09) and 20/200 or worse (OR = 2.49; 95% CI, 0.98-6.30, P = .05). Immunosuppressive drug therapy lowered the risk of visual loss, independent of relapsing disease course (OR = 0.79; 95% CI, 0.66-0.94, P = .01 and OR = 0.73; 95% CI, 0.57-0.93, P = .01 for the 20/50 or worse and 20/200 or worse thresholds, respectively). CONCLUSIONS: Rates of visual loss and complications among patients with RV were similar to reported rates in noninfectious uveitides. Treatment with immunosuppressive drugs lowered the risk of visual loss. A relapsing course suggested an increased risk for visual loss but was not statistically significant, perhaps owing to low numbers of recurrences.

Acute Retinal Necrosis: Presenting Characteristics and Clinical Outcomes in a Cohort of Polymerase Chain Reaction-Positive Patients.

PURPOSE: To identify determinants of adverse outcomes in acute retinal necrosis (ARN), presenting characteristics and incidence rates of vision loss and ocular complications in a cohort of polymerase chain reaction (PCR)-positive eyes were analyzed. DESIGN: Retrospective observational cohort study. METHODS: Forty-one eyes of 36 patients with clinically diagnosed ARN, PCR-positive for herpes simplex virus or varicella zoster virus and evaluated between January 2002 and June 2013, were included. Main outcome measures included incidence rates of vision loss and retinal detachment (RD). RESULTS: Presenting visual acuity was generally poor (20/50 to >20/200 in 27%; 20/200 or worse in 56%). The incidence rate of ≤20/200 was 0.66/eye-year (EY), (95% confidence interval [CI], 0.32/EY to 1.22/EY); the rate of light perception or no light perception vision was 0.07/EY (95% CI, 0.02/EY to 0.16/EY). During follow-up, 59% of eyes developed at least 1 RD (rate = 0.40/EY, 95% CI, 0.19/EY to 0.58/EY). Eyes with retinitis involving ≥25% of the retina at presentation detached at nearly 12 times the rate, as compared to those with <25% retinal involvement (0.70/EY vs 0.06/EY; P = .001). Development of an RD was the greatest determinant of adverse visual outcomes, with 4% of eyes, that had experienced at least 1 RD, achieving a best-corrected visual acuity of ≥20/40 compared to 53% of eyes that never detached (P = .0003). CONCLUSIONS: Poor outcomes in ARN were common in this cohort. RD confers the greatest risk of incident vision loss, and once 25% or more of the retina is involved the risk of RD and visual loss increases significantly.

Occurrence of and Risk Factors for Ocular Hypertension and Secondary Glaucoma in Juvenile Idiopathic Arthritis-associated Uveitis.

PURPOSE: To describe the incidence of ocular hypertension (OHT) and secondary glaucoma (SG) in JIA-associated uveitis, identify risk factors for development of these complications, and describe their effect on visual outcomes. METHODS: A retrospective cohort of 108 patients (196 eyes) with JIA-associated uveitis seen over 30 years at an academic practice. RESULTS: Of examined eyes, 40% had OHT or SG at presentation. These eyes had a nearly three-fold higher incidence of legal blindness during follow-up, compared with eyes without OHT or SG. An additional 41 eyes developed OHT or SG during follow-up. Presenting with anterior uveitis, active inflammation, and using systemic corticosteroids were risk factors for developing OHT, while use of immunosuppressive medication at presentation reduced this risk. Risk factors for developing SG included anterior uveitis and use of systemic corticosteroids. CONCLUSIONS: OHT and SG were common in patients with JIA-associated uveitis. Use of immunosuppressive drugs may decrease the risk of developing OHT.

Risk of Hypotony in Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To describe risk factors for hypotony in patients with juvenile idiopathic arthritis (JIA)-associated uveitis. DESIGN: Retrospective cohort study. METHODS: All patients with JIA-associated uveitis (N = 108; affected eyes = 196) evaluated and followed at the Wilmer Eye Institute from July 1984 through June 2014 were included in this study. Prevalence and incidence of hypotony (intraocular pressure [IOP] <5 mm Hg) and low IOP (5 mm Hg ≤ IOP < 8 mm Hg) and risk factors for developing hypotony were analyzed. RESULTS: At presentation, 9.3% of patients (7.1% of affected eyes) had hypotony. During a median follow-up of 5.3 years, the rate of developing hypotony and low IOP were 0.04 per eye-year (/EY; 95% confidence interval [CI]: 0.02/EY, 0.05/EY) and 0.06/EY (95% CI: 0.04/EY, 0.08/EY), respectively. Risk factors for development of hypotony during follow-up appeared to be associated with more severe uveitic disease, such as the presence of panuveitis (adjusted hazard ratio [aHR], 43.1; P = .004), anterior chamber cells or flare ≥ 3+ (aHR, 25.6, P < .001), posterior synechiae (aHR, 5.9, P = .02), and the use of oral corticosteroid (aHR 28.9; P = .003) at the presenting examination. Receiving immunosuppressive drug therapy at the time of presentation was associated with a lower risk of development of hypotony (aHR, 0.02; P = .002). CONCLUSIONS: Hypotony affects a small but significant proportion of patients with JIA-associated uveitis and is associated with signs of active and severe uveitis. Immunosuppression was associated with significantly lower risk of hypotony, suggesting that aggressive control of the inflammation may reduce risk of hypotony in JIA-associated uveitis.

Peripheral Ulcerative Keratitis following Laser in situ Keratomileusis.

PURPOSE: We report a case of a patient with a history of glomerulonephropathy, not disclosed prior to laser in situ keratomileusis (LASIK), who developed severe postoperative peripheral ulcerative keratitis (PUK) soon after surgery. METHOD: Case report. RESULTS: Within a week of surgery, the patient, who had no blepharitis or ocular surface disease, also developed diffuse lamellar keratitis (DLK) that was not contiguous with the PUK. Microbiologic evaluation of the flap interface disclosed no organisms, and no epithelial ingrowth was found. Both PUK and DLK resolved with topical and oral steroid therapy, and the patient's induced refractive error improved over the 12 months following LASIK. CONCLUSIONS: Necrotizing keratitis has been described after LASIK surgery in patients with or without autoimmune disease. However, to our knowledge, there has been no case of PUK following LASIK. As shown by our patient's clinical course and the typical association of PUK with systemic conditions, patients with a history of atypical postinfectious sequelae may require additional preoperative counseling, vigilant postoperative monitoring, and possibly additional intervention. Because patients do not always divulge medical details, especially if an extraocular site was involved or illness occurred many years prior, this case demonstrates the importance of performing a diligent history that excludes autoimmune disorders or atypical postinfectious sequelae prior to proceeding with keratorefractive intervention.