Appraisal of vitreous syphilis antibody as a novel biomarker for the diagnosis of syphilitic uveitis: a prospective case-control study.

PURPOSE: To determine the sensitivity and specificity of syphilis antibody tests in vitreous samples and to propose an algorithm using vitreous syphilis antibody as a supplementary test to confirm syphilitic uveitis (SU). METHODS: A prospective case-control study was conducted at the Retina and Uveitis Clinic from May 2017 to January 2020. Initially, patients were classified based on syphilis serology into group 1 (positive testing) and group 2 (negative testing). Group 1 was further divided into 2 subgroups (group 1A and 1B) depending on their relevant clinical manifestations and clinical improvement. Group 2 served as a control group. RESULTS: Thirty-eight patients were enrolled in the study: 14 in group 1A, 5 in group 1B, and 19 in group 2B. No patient was assigned to group 2A. All patients in group 1A, representing definite SU, completed syphilis test (rapid plasma reagin [RPR], enzyme immunoassay [EIA], and fluorescent treponemal antibody-absorption [FTA-ABS]) for vitreous, and all vitreous samples yielded positive results. Of the 5 subjects in group 1B, 3 cases were considered to be not SU with different conditions, and 2 were indeterminate for SU. They presented with different features not typical of SU, and they had variable and fewer positive syphilis antibody responses. The most sensitive test for detecting syphilis antibodies in vitreous was EIA (90.9%), followed by RPR (80.0%) and FTA-ABS IgG (78.9%). EIA and FTA-ABS had the highest specificity, detecting 100% of the syphilis antibody. CONCLUSIONS: Vitreous analysis of syphilis antibody can serve as a supplementary test to confirm SU in selected cases as the proposed algorithm.

Widefield Fundus Fluorescein Angiography Features of Uveitis Associated with Juvenile Idiopathic Arthritis.

PURPOSE: To evaluate the wide-field fundus fluorescein angiography (WFA) characteristics of uveitis associated with juvenile idiopathic arthritis (JIA-uveitis). METHODS: Retrospective review of records. WFA with Spectralis (Heidelberg) of JIA-uveitis patients were analyzed using the scoring system by Angiography Scoring for Uveitis Nomenclature. RESULTS: Thirty-seven eyes of 20 patients were studied. A total score of at least 1 was noted in 27 eyes (72.97%). WFA features included optic disc hyperfluorescence (51.35%), macular leakage (27.03%), retinal vascular staining/leakage at posterior pole (27.03%) and peripheral retina (64.86%), capillary leakage at the posterior pole (37.84%), and peripheral retina (59.46%). A decision to change the management plan was made in 8 of 9 patients with bilateral quiet anterior chambers after WFA results. CONCLUSION: More than 70% of JIA-uveitis eyes showed some WFA-evidence of posterior segment inflammation, which changed the course of therapy for a major proportion of patients with no clinically active anterior chamber inflammation.

Response to the Second TNF-α Inhibitor (Adalimumab or Infliximab) after Failing the First One in Refractory Idiopathic Inflammatory Retinal Vascular Leakage.

PURPOSE: To determine the response to the second TNF-α inhibitor (adalimumab and infliximab) after failing the first agent in idiopathic inflammatory retinal vascular leakage. MATERIALS AND METHODS: This was a retrospective observational case series. Patients with the diagnosis of idiopathic inflammatory retinal vascular leakage who had received both infliximab and adalimumab were included in the study. RESULTS: Twelve and 15 patients received adalimumab (Group one) and infliximab (Group two) as the first treatment, respectively. The remission rates between Group one (58.3%) and Group two (66.7%) were not statistically significant. (P = .4) As the second agent, adalimumab was more effective in younger patients (27.5 ± 20.6) compared to older patients (48.75 ± 10.2). (P = .03). Moreover, patients with lower vision responded marginally better to infliximab as the second treatment (P = .06). CONCLUSION: Either TNF-α inhibitor, adalimumab and infliximab, can be employed in the treatment of the patients with idiopathic inflammatory retinal vascular leakage who fail one of these agents.

Repository Corticotropin Injection as an Alternative Treatment for Refractory Ocular Mucous Membrane Pemphigoid.

PURPOSE: The purpose of this study was to report the clinical course and outcome of patients with refractory ocular mucous membrane pemphigoid (MMP) treated by repository corticotropin injection (RCI). METHODS: Patients with biopsy-proven ocular MMP treated with RCI from 3 tertiary medical centers were evaluated. Medical records between January 2013 and January 2021 were reviewed and deidentified to retrieve relevant disease-related data. Primary outcome measures included conjunctival inflammatory activity, change in Foster clinical conjunctival scarring staging after RCI treatment, and the development of ocular and systemic complications. RESULTS: Included were 15 patients (10 women and 5 men; 36-95 yrs of age) with a mean follow-up of 4.5 years. Most of the patients (80%) had Foster stage 3 at presentation, and all patients had active MMP. Each patient had failed to respond to at least 1 immunomodulatory drug during the follow-up, and 9 (60%) patients had treatment failure of at least 2 other agents before the use of RCI. The mean duration of RCI treatment was 21 months (range, 3-54 mo). Foster stage did not change in any of the 15 patients at the last follow-up. Nine patients continued RCI therapy at the last follow-up, and in all of them, the disease activity of MMP was well controlled. No serious adverse events because of RCI were documented during the follow-up in any treated patient. CONCLUSIONS: RCI may serve as an alternative or an adjunctive treatment in patients with severe and refractory ocular MMP. Treatment with RCI seems to be safe and well-tolerated.

Management of repository corticotropin injection therapy for non-infectious uveitis: a Delphi study.

PURPOSE: Diagnosis and management of non-infectious uveitis (NIU), a major cause of blindness worldwide, are challenging. Corticosteroids, the cornerstone of therapy, are not appropriate for long-term use, and while non-biologic and biologic immunomodulators may be used for some patients, data on their efficacy and safety in this population are limited. Repository corticotropin injection (RCI), believed to affect uveitis by multiple mechanisms, has received regulatory approval for treatment of ophthalmic diseases including posterior uveitis, but is not widely used or discussed in guidelines for the management of uveitis and ocular inflammatory diseases. METHODS: The index study employed a modified Delphi process with a panel of 14 US-based ophthalmologists. Consensus recommendations were developed through a series of three questionnaires. Panellists rated statements on a Likert scale from -5 (strongly disagree) to +5 (strongly agree). RESULTS: The Delphi panel provided consensus recommendations on examinations and testing needed for diagnosis, treatment goals, and the use of corticosteroids, as well as the use of non-biologic and biologic immunomodulators. The panel reached consensus that RCI may be considered for posterior and pan-uveitis, and dosing should be individualized for each patient. Dose reduction/discontinuation should be considered for excessive RCI-related toxicity, hyperglycaemia and/or diabetic complications, excessive costs, or remission ≥ 2 years. Patients should be weaned from RCI if uveitis is stable and well controlled. Adverse events during RCI therapy can be managed by appropriate interventions, with dose reduction/discontinuation considered if events are severe or recurrent. CONCLUSIONS: Expert consensus suggests RCI may be an appropriate treatment option for some patients with uveitis when other therapies are ineffective or intolerable.

Combination of Intravenous Methotrexate and Methylprednisolone Therapy in the Treatment of Severe Ocular Inflammatory Diseases.

Purpose: To evaluate the efficacy of intravenous methotrexate and methylprednisolone in severe, sight-threatening ocular inflammatory conditions.Methods: This was a retrospective observational case series. Patients who had received intravenous methotrexate for ocular inflammation with at least 24 months of follow-up were included in the study.Results: Ten patients (20 eyes) were included in this study. Mean age of the patients was 47.2 ± 17.7 (range:19-74). At 1-month follow-up visit, nine patients showed improvement and one patient failed treatment. At 12-month follow-up visit, all patients were in remission. Two patients were only on intravenous methotrexate infusions. At twenty-four-month follow-up visit, only one patient, in remission, was on intravenous methotrexate therapy. Leukopenia was the only adverse effect observed.Conclusion: Intravenous methotrexate and methylprednisolone infusions can be an effective method of treatment in patients with severe, sight-threatening ocular inflammatory conditions.

Atypical Perinuclear Anti-Neutrophil Cytoplasmic Antibodies in Ocular Inflammatory Diseases.

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.

Outcome of tocilizumab treatment in refractory ocular inflammatory diseases.

PURPOSE: To report the outcomes of tocilizumab treatment for refractory ocular inflammatory diseases. METHODS: A retrospective case series of 17 patients (28 eyes) diagnosed with recalcitrant ocular inflammatory diseases including uveitis (10 cases), scleritis (six cases) and orbital pseudotumour (one case), who received tocilizumab between April 2010 and March 2015. All patients were initiated with treatment of 4 mg/kg or 8 mg/kg tocilizumab. The primary outcome was absence of inflammation and achievement of steroid sparing at 6 and 9 months. Secondary outcomes were change in visual acuity and major adverse effects of tocilizumab causing discontinuation of the treatment. RESULTS: Mean age at initiation of tocilizumab was 41 ± 16 years. Prior to tocilizumab treatment, all patients underwent unsuccessful conventional immunosuppressive therapy while 94% of patients (16/17) failed treatment with various biological agents. After tocilizumab administration, control of inflammation and steroid sparing were achieved in 63% and 71% of uveitis patients at 6 and 9 months, while 50% of scleritis patients achieved the primary outcome at 6 and 9 months. Mean duration of tocilizumab therapy was 12.6 ± 10.0 (range, 2-35) months. Three of four patients who had a follow-up of at least 18 (range, 18-35) months experienced quiescent inflammation for up to 32 months of tocilizumab use until last visit. Four patients (24%) discontinued tocilizumab due to serious side effects including neutropenia, unacceptable dizziness and nausea, severe angioedema and severe abdominal pain. CONCLUSION: Our series demonstrated moderate efficacy of tocilizumab in recalcitrant uveitis and scleritis. Serious adverse effects were not uncommon.

Update on ocular cicatricial pemphigoid and emerging treatments.

Mucous membrane pemphigoid is a systemic disorder that primarily affects mucous membranes. When localized to the conjunctiva, it is known as ocular cicatricial pemphigoid, a potentially blinding disease. Ocular cicatricial pemphigoid is an indication for systemic immunosuppressive treatment to achieve adequate remission. Immunosuppressive agents are selected with a "stepladder" approach, commencing with medications having the fewest side effects. We provide an update of the literature on immunomodulatory agents since 2011 as additional treatment modalities have been explored in the last 4 years.

Vitreous evaluation: a diagnostic challenge.

PURPOSE: To categorize vitrectomy cytologic diagnoses and ancillary tests to address appropriate processing of low-volume vitreous samples. DESIGN: Retrospective case series. PARTICIPANTS: Five thousand seven hundred thirty-six vitreous samples. METHODS: Cytologic diagnoses of therapeutic and diagnostic vitrectomy samples and their processing protocols from 3 teaching institutions were reviewed. MAIN OUTCOME MEASURES: Diagnostic results were categorized as negative for malignancy, suspicious for malignancy, and positive for malignancy. All ancillary studies performed were documented, including special stains, immunohistochemistry analysis, cytokine levels, and polymerase chain reaction (PCR) analysis. RESULTS: Of the 5736 vitreous samples analyzed, 4683 (81.64%) were from Tufts Medical Center (TMC), 955 (16.65%) were from Boston Medical Center (BMC), and 98 (1.70%) were from Massachusetts Eye Research and Surgery Institution (MERSI). Cases from TMC and BMC were therapeutic and diagnostic vitrectomies, and MERSI cases were diagnostic vitrectomies. Most vitrectomies showed negative results for malignancy: 99.47% of TMC cases, 99.89% of BMC cases, and 79.6% of MERSI cases. These included vitreous hemorrhage and inflammatory or infectious findings. Ancillary studies performed in this category included Periodic Acid-Schiff staining for fungi, PCR analysis for toxoplasmosis, cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex virus I and II, and vitreous cultures for infections (coagulase-negative Staphylococcus, Candida, Fusarium, and Propionibacterium species). Interleukin (IL) 10-to-IL-6 ratios were performed on 38.7% of cases from MERSI. Fourteen cases from TMC were suspicious for malignancy based on cytologic evaluation. Eleven cases from TMC, 1 case from BMC, and 20 cases from MERSI showed positive results for malignancy and included B-cell lymphoma, retinoblastoma, melanoma, and metastatic adenocarcinoma. The ancillary testing included PCR for heavy chain immunoglobulin gene rearrangements, immunohistochemistry for EBV, in situ hybridization for κ and λ light chains, and cytogenetics. CONCLUSIONS: This is the largest data pool of reported cytologic diagnoses of diagnostic and therapeutic vitrectomy samples. Cytologic evaluation of therapeutic vitrectomy samples provides a valuable baseline of nonpathologic findings that assist in differentiation between malignancy, infections, and inflammatory conditions. Allocation of small-volume vitreous samples to select ancillary testing from the plethora of available diagnostic tests requires preoperative communication between surgeons and pathologists to ensure appropriate and timely treatment methods.

Road to remission: a comprehensive review of therapy in uveitis.

INTRODUCTION: Although uveitis remains the third leading cause of preventable blindness in the US, the care and management of patients with uveitis and ocular inflammatory disease sit poised to make evolutionary if not revolutionary changes in the years ahead. This review serves to highlight important advances in the pharmacologic options available for the treatment of uveitis and ocular inflammation. AREAS COVERED: Advances in steroid therapy (both topical and extended delivery), updates in the clinical safety of systemic immune modulation, and the emerging therapies for uveitis and ocular inflammatory disease are some of the areas covered in this review. EXPERT OPINION: Corticosteroids have been the mainstay in the care of patients with ocular inflammatory disorders for many years. Indeed, some physicians still use only steroids for treating inflamed eyes. However, the mission is remission of all corticosteroids in order to prevent the complications associated with long-term corticosteroid use. The goal is to achieve quiescence through aggressive use of corticosteroids to extinguish the fire and then move along to achieve steroid-free remission through immunosuppressant agents.

Immunohistochemical differences between normal and chronically inflamed conjunctiva: diagnostic features.

PURPOSE: There is widespread misinterpretation of normal conjunctival fibrinogen. In differentiating between normal conjunctiva and cicatrizing conjunctivitis, including ocular cicatricial pemphigoid, atopic keratoconjunctivitis, and lichen planus, it is important to properly evaluate and characterize the histologic appearance of the structures seen and not base a diagnosis on just the presence or absence of certain features. One feature of conjunctival histology prone to misinterpretation and misdiagnosis is the presence of subepithelial fibrinogen, particularly when the diagnosis of lichen planus is being considered. Although the presence of subepithelial fibrinogen in oral mucous membranes and in skin can be indicative of lichen planus, such is not the case for conjunctiva. An erroneous diagnosis of lichen planus based on the presence of conjunctival subepithelial fibrinogen can initiate prolonged treatment with topical steroids leading to avoidable, blinding, complication, and further, delay therapy for the real cause of the conjunctivitis. We conducted a cross sectional, controlled, blinded and prospective Institutional Review Board-approved study on the occurrence and pattern of fibrinogen at the epithelial basement membrane zone (BMZ) of normal and inflamed conjunctiva. METHODS: Bulbar conjunctiva was obtained from 10 cases of undiagnosed chronic conjunctivitis of at least 6 months duration and 8 patients with normal conjunctiva. Immunofluorescent staining with antifibrinogen antibodies, periodic acid-schiff stain (PAS), and Giemsa staining were performed. RESULTS: BMZ fibrinogen was found in all cases. This layer was linear, smooth, and continuous in normal conjunctiva and 7 cases of chronic conjunctivitis. It was fragmented and lumpy in 1 case of ocular cicatricial pemphigoid (OCP) and showed spikes and spurs in 2 cases of lichen planus. CONCLUSIONS: BMZ fibrinogen is a normal component of the conjunctiva and its morphological features rather than its mere presence should be assessed as a diagnostic tool.

Pharmacotherapy of uveitis.

IMPORTANCE OF THE FIELD: The term 'uveitis' covers a broad spectrum of ocular inflammation affecting the iris, ciliary body, and/or the choroid, all of which comprise the uveal tract. Severe cases of uveitis need be treated aggressively to prevent damage caused by chronic inflammation. Untreated or poorly managed cases can lead to ciliary body dysfunction, inadequate aqueous production, chorioretinal damage, and possibly blindness. AREAS COVERED IN THIS REVIEW: There are many medications that can be used to treat uveitis. Corticosteroids are available in several formulations: topical drops, regional injections, oral and intravenous. Immunomodulatory agents that can be used for uveitis are antimetabolites, T-cell inhibitors, alkylating agents, and biologic response modifiers. These medications, their appropriate uses, and side effect monitoring will be detailed. WHAT THE READER WILL GAIN: There is a stepladder approach to treatment of ocular inflammation. Corticosteroids are the treatment of choice for treating acute flares. Steroid free remission is the goal of therapy and can be achieved with the use of chemotherapeutic agents. Which medications are appropriate and how to escalate therapy will be reviewed. TAKE HOME MESSAGE: Chronic systemic corticosteroid therapy is not an acceptable long treatment plan for uveitis, unless all other medications have failed. Steroid sparing immunosuppressive therapy should be pursued as soon as acute flares of uveitis have been controlled.

Dry eye evaluation and immunohistochemical study of the conjunctiva and lacrimal gland of patients submitted to bone marrow transplantation

Purpose: The primary ocular targets of chronic graft-versus-host disease (GVHD) are the lacrimal gland (LG) and the conjunctiva, and their involvement results in keratoconjunctivitis sicca (KCS). The purpose of the present study was to evaluate the frequancy of signs and symptoms of KCS present in patients submitted to BMT, to identify the cellular phenotype of the conjunctival and lacrimal gland biopsies of these patients by immunohistochemistry and to correlate the findings with the present of dry eye due to GVHD. Methods: Forty-Seven patients were clinically classified into two groups: group I, with ocular GVHD, submitted to allogeneic BMT and Group II, without ocular GVHD, submitted to autologous and allogeneic BMT. Thorough eye examination, including clinical lacrimal function tests and biopsies of the conjunctiva and of the LG were performed in the pre- and posttransplantation period, The biopsies were submitted to imunohistochemical analysis using a panel of monoclonal antibodies. Results: Of the 28 (84,4 percent) patients with chronic GVHD, 13 (46,4 percent) presented ocular GVHD. Of the six patients without GVHD, one (16,7 percent) presented ocular GVHD. None of those submitted to autologous BMT presented ocular GVHD and 14 (41,2 percent) of 34 patients with allogeneic BMT presented ocular GVHD. All patients with ocular GVHD (Group I) has symptoms and the most frequent were burning, foreign body sensation, blurred vision and dryness. the rose bengal test was one of the most sensitive in this study and slit lamp examination was very useful in the evaluation of corneal and conjunctival alterations, since these alterations were always present in patients with dry eye in our study. neither symptoms and signs of dry eye nor significant immunologic reaction was observed in the conjunctiva and in the LG of patients without ocular GVHD (Group II). There was as increase in the T Lymphocyte population, Of the helper lymphocyte (Th/i) and the supressor-cytotoxic lymphocyte (Ts/c) subpopulaton in the conjunctiva and in the LG of patients with ocular GVHD after the transplantation. Conclusions: Patients submitted to allogeneic BMT may develop ocular GHVD characterized by KCS. The immunohistochemical study of the conjunctiva and lacrimal gland biopsies of these patients suggested that these tissue are the target of the T cell mediated immunological reaction.

Management of coincident cataract and uveitis.

Cataract surgery in a patient with uveitis is more complex than senile cataract extraction, because it involves multiple considerations related to the cause of uveitis, prospects of visual rehabilitation, appropriate surgical timing and technique, and the type and material of the intraocular lens used. Establishing the diagnosis, thorough eye examination, careful patient selection and meticulous control of perioperative inflammation are key elements to a successful visual outcome. Our aims in this article are to review the literature on this subject over the past year and highlight the behavior of intraocular lenses of various biomaterials in the uveitic eye. In addition, we also reemphasize the idea of a model of zero tolerance to intraocular inflammation to minimize the incidence of irreversible damage to ocular structures essential to good vision.