Current insights in the pathogenesis of scleritis.

Scleritis is a sight-threatening inflammation characterized by severe pain and redness of the eye. It can cause blindness by severe complications like scleral and corneal necrosis, keratitis, and uveitis. The pathogenesis of scleritis is largely unknown due to a combination of the rarity of the disease, the little available human tissue-based research material, and the lack of animal models. The immune system is assumed to play a crucial role in the pathogenesis of scleritis. Multiple clues indicate probable antigenic stimuli in scleritis, and the involvement of matrix metalloproteinases in the destruction of scleral tissue. In this article we review the current insights into the pathogenesis of scleritis, and we suggest new hypotheses by implementing knowledge of systemic autoimmune disease pathogenesis. Understanding the pathogenesis of scleritis is crucial to improve the clinical management, as well as to find novel treatment modalities.

Assessment of conjunctival, episcleral and scleral thickness in healthy individuals using anterior segment optical coherence tomography.

PURPOSE: To determine the thickness of the conjunctiva, episclera and sclera in healthy individuals using anterior segment optical coherence tomography (AS-OCT). METHODS: We prospectively included 107 healthy individuals of different age groups (18-39 years, 40-54 years, 55-69 years and ≥70 years). For each eye, AS-OCT scans of four quadrants (temporal, nasal, superior and inferior) were acquired. The thickness of the conjunctiva, episclera and sclera was measured for each scan. In addition, the axial length of both eyes was measured, and general characteristics, including smoking, allergies and contact lens use, were collected. RESULTS: The mean conjunctival thickness was significantly different between the nasal and superior quadrants (87 ± 30 µm vs. 77 ± 16 µm; p < 0.001), as well as the superior and inferior quadrants (77 ± 16 µm vs. 86 ± 19 µm; p = 0.001). The mean episcleral thickness was larger in the superior (174 ± 54 µm) and inferior (141 ± 43 µm) quadrants, compared to the nasal (83 ± 38 µm) and temporal quadrants (90 ± 44 µm). The mean scleral thickness of the inferior quadrant was the largest (596 ± 64 µm), followed by the nasal (567 ± 76 µm), temporal (516 ± 67 µm) and superior (467 ± 52 µm) quadrants (all p < 0.001). The averaged scleral thickness increased 0.96 µm per age year (0.41-1.47 µm, p < 0.001). CONCLUSIONS: This study provides an assessment of the thickness of scleral and adjacent superficial layers in healthy individuals determined on AS-OCT, which could enable future research into the use of AS-OCT in diseases affecting the anterior eye wall.

Clinical Relevance of Autoantibodies and Inflammatory Parameters in Non-infectious Scleritis.

PURPOSE: Scleritis is a potentially blinding disorder, with highly unpredictable course and outcome. We analyzed the prevalence and clinical relevance of autoantibodies and inflammatory parameters in non-infectious scleritis. METHODS: Retrospective analysis of laboratory findings in all consecutive patients at the department of Ophthalmology of the Erasmus MC with non-infectious scleritis. RESULTS: We included 81 patients with non-infectious scleritis. A systemic autoimmune disease was present in 46%. Positive anti-nuclear antibodies were found in 30%, anti-neutrophil cytoplasmic antibodies were positive in 19%, and the presence of rheumatoid factor was shown in 17%. The aforementioned autoantibodies, as well as inflammatory parameters, failed to show prognostic clinical value. In contrast, anti-citrullinated peptide antibodies (ACPA), found in 9% of scleritis patients, were significantly associated with the development of scleral necrosis (P = .01). CONCLUSIONS: The presence of ACPA in patients with non-infectious scleritis was associated with the development of scleral necrosis.

Subconjunctival Rituximab Administration for the Treatment of Scleritis.

PURPOSE: Scleritis is a sight-threatening inflammation, which is commonly accompanied by severe complications. Aggressive systemic immunosuppressive treatment, which is frequently needed, can be associated with serious complications, and might therefore be (temporarily) contraindicated. METHODS: We report on the outcomes of three patients with severe, active, non-infectious scleritis, refractory or intolerant to systemic treatment, who received subconjunctival rituximab (RTX) injections. A dose of 2.5 to 7.5 mg was administered after topical anesthesia, and follow-up varied from 8 to 10 months. RESULTS: Subconjunctival RTX showed minimal to no effect on subjective symptoms, clinical features and/or ultrasound images. No serious adverse effects occurred. CONCLUSION: Further studies are needed to assess the effect of local administration of RTX in scleritis, but our limited observation is not promising.

The Usefulness of Aqueous Fluid Analysis for Epstein-Barr Virus in Patients with Uveitis.

Purpose: To determine characteristics of patients with laboratory findings indicative of intraocular Epstein-Barr-virus (EBV) infection and to establish the usefulness of the laboratory analysis in patients with uveitis.Methods: Retrospective study of patients who underwent diagnostic aqueous fluid analysis. Diverse demographic data of patients were registered.Results: EBV-PCR tested positive in 3/201 (1%) and EBV-GWC in 22/245 (9%). The prevalence of immunosuppression was similar in EBV positive (by PCR/GWC) and EBV negative patients (7/25; 28% vs. 50/272;18%, P = 0.29). Out of all 22 EBV-GWC positive patients, GWC was between 3 and 10 in 91%. In total, 14 patients had laboratory results indicating only EBV infection. Patients without an alternative explanation for uveitis (6/14; 43%) had a chronic recurrent course and good visual prognosis.Conclusion: Low EBV-GWC values combined with multiple positive GWC and/or PCR for other infectious agents. Intraocular assessment for EBV in the initial examination of uveitis patients has limited value.

Successful Tocilizumab Treatment for Scleritis.

Purpose: To present a rare case of scleritis associated with a prior diagnosis of giant cell arteritis (GCA) that was unresponsive to glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, and azathioprine, but reached and maintained a full remission with tocilizumab.Observations: A 62-year-old Caucasian female presented with scleritis and headache. Four years earlier, the patient was diagnosed with GCA. Treatment with topical and systemic NSAIDs, prednisone and diverse disease-modifying antirheumatic drugsonly had a partial effect on the scleritis whilst the arthralgia and headaches increased. Despite the absence of laboratory evidence of active GCA, tocilizumab was started and the scleritis and headaches disappeared within several days. Prednisone could be fully tapered within 3 months and to date, 12 months after the start of tocilizumab, the patient has maintained a sustained remission.Conclusions: Our patient demonstrates that tocilizumab might represent a therapeutic option for scleritis, and its further evaluation for this severe ocular disease is worthwhile.

An Intraocular Inflammatory Profile of Rubella Associated Uveitis.

Purpose: To analyze intraocular cytokine levels and cell profiles in patients with rubella virus-associated uveitis (RVU). Methods: We collected intraocular fluid samples from patients with RVU (n = 10), uveitis of other causes (n = 27), and cataract (n = 22). Levels of 15 cytokines (IL-1ß, IL-1ra, IL-2, IL-6, IL-6rα, IL-7, IL-8, IL-10, IL-17A, IL-23, TARC, MCP-1, TNF-α, PlGF, and VEGF) were measured using multiplex assay, and intraocular cell populations were determined by multiparameter flowcytometry. Clinical characteristics of RVU patients were collected and compared to laboratory outcomes. Results: RVU patients exhibited high intraocular levels of MCP-1, IL-6rα, and TARC, whilst patients with noninfectious uveitis were characterized by high levels of PlGF. Cataract patients showed high levels of IL-2 and IL-23. Intraocular cell population of RVU patients disclosed mainly T-cells and monocytes/macrophages and B-cells were scarcely detected. Conclusion: RVU patients exhibit a cytokine profile distinct from noninfectious uveitis and cataract.

Tuberculosis and other causes of uveitis in Indonesia.

PurposeThe purpose of this study is to assess the causes of uveitis in Indonesia and determine the importance of tuberculosis (TB) as a cause of uveitis.Patients and methodsProspective cohort study examining 146 consecutive new human immunodeficiency virus-negative patients with active uveitis between June 2014 and May 2015. We assessed the anatomic locations and specific causes of uveitis, as well as associations with infectious and non-infectious systemic diseases. We determined the prevalence of positive QuantiFERON Tb Gold test (QFT) results in Indonesian patients with uveitis and calculated the number of patients with active systemic TB.ResultsPosterior and panuveitis were the most common anatomic entities (38% each). Infections represented the most frequent cause of uveitis (33%); the most prevalent were toxoplasmosis (19%) and active systemic TB (8%). The majority of patients were QFT positive (61%). A specific diagnosis could not be established in 45% of the patients. At first presentation to the ophthalmologist, the majority of patients (66%) had a visual acuity of less than finger counting at 3 m and already exhibited various complications of uveitis. When classifying the QFT-positive patients with unexplained uveitis into a TB-related group, the percentage of 'TB-associated' uveitis cases increased from 8-48%. Highly elevated QFT levels were observed in patients with uveitis of unknown cause and no signs of active systemic TB.ConclusionsIn Indonesia, infectious uveitis was the most common type of uveitis and the leading causes consisted of toxoplasmosis and TB. The association observed between highly elevated QFT results and uveitis of otherwise unexplained origins indicates that a link exists between the latent TB infection and the development of uveitis.

[Relationship between rubella virus and Fuchs heterochromic uveitis; 2 patients]. / Samenhang tussen rubellavirus en fuchs-heterochromie-uveïtis; 2 patiënten.

Two otherwise healthy men, aged 26 and 29 years, were diagnosed with Fuchs heterochromic uveitis (FHU) on the basis of the presence of iris heterochromia or iris atrophy, stellate corneal precipitates, and/or cataract. Microbiological investigation of aqueous humour demonstrated intraocular antibody production against rubella virus, but not against Toxoplasma gondii, herpes simplex virus or varicella zoster virus. Microbial nucleic acid detection was negative for all pathogens. Some time later, both patients underwent cataract surgery, which improved their vision considerably. FHU is a chronic, generally unilateral iridocyclitis, accompanied by the above-mentioned ophthalmologic manifestations in the absence of systemic disease. Little is known about the pathogenesis ofFHU, but recent publications have provided evidence for the possible involvement of the rubella virus.

HLA-B27-associated acute anterior uveitis in the University Referral Centre in North Thailand: clinical presentation and visual prognosis.

BACKGROUND: Acute anterior uveitis (AAU) is the most frequent type of uveitis encountered in the west. Although human leucocyte antigen (HLA)-B27-associated ankylosing spondylitis was reported in South East Asia, it is not known whether HLA-B27-associated ocular disease is prevalent in Thailand. METHODS: A prospective study of 100 unrelated blood donors and 121 consecutive patients with AAU was carried out. All people underwent HLA-B27 typing and full ocular examination. Radiological examination of the sacroiliac joints was conducted in patients with low back pain or arthralgias. RESULTS: The prevalence of HLA-B27 was 10% among the blood donors in contrast with 44% in the AAU group (p<0.001). The clinical characteristics of HLA-B27-associated AAU were similar to those published throughout the world (unilaterality in 74%, hypopyon in 31%, recurrent AAU in 64%). However, the increased intraocular pressure (IOP) was more common in the HLA-B-27-negative group (p = 0.03) than in their HLA-B27-positive counterparts. At least 15% of the HLA B27-positive group had radiological signs of ankylosing spondylitis. CONCLUSION: The prevalence of HLA-B27 in the population without uveitis in Thailand is about 10% and clinical characteristics of HLA-B27-positive AAU are similar to those reported in the west. In contrast with earlier reports, HLA-B27-negative AAU in Thailand was associated with increased IOP and should be further studied.

[Clinical reasoning and decision-making in practice. A patient with loss of vision and painful legs]. / Klinisch denken en beslissen in de praktijk. Een patiënt met visusdaling en pijnlijke benen.

A 69-year-old man was admitted to the Department of Ophthalmology with bilateral loss of vision. For a few months he had also had shooting pains in both legs and instability of gait. Neurological examination showed loss of vision bilaterally and minor sensory disturbances of the legs with diminished tendon reflexes. As extensive further examination showed no specific abnormalities, the tentative diagnosis 'arteriitis temporalis' was made. Despite treatment with corticosteroids his condition deteriorated. Only after a repeat medical history had been taken did it become clear that in the past he had had homosexual contact with a number of partners. This increased the likelihood of a sexually transmitted disease in the differential diagnosis. In the meantime the results from serological tests became known: there were strongly elevated titres for syphilis in both serum and cerebral spinal fluid. Eventually the patient was diagnosed with neurosyphilis with ocular involvement and tabes dorsalis. He recovered almost completely in a few months after treatment with doxycycline.

Visual outcomes and ocular morbidity of patients with uveitis referred to a tertiary center during first year of follow-up.

PURPOSE: To describe the visual outcomes and morbidity of newly referred uveitis patients. METHODS: Retrospective cohort study of 133 newly referred uveitis patients with active uveitis who required care in a tertiary center for at least 1 year. Main outcomes were best-corrected visual acuity (BCVA) at referral and 1 year after referral, duration of visual impairment, systemic medications used, as well as all complications and surgeries during the first year of follow-up. Generalized estimating equation models was used to assess prognosticators for poor BCVA. RESULTS: The mean age at onset of uveitis was 43 years. The proportion of patients with at least one eye with BCVA ≤0.3 decreased from 35% at referral to 26% (P=0.45) at 1-year follow-up. The mean duration of visual impairment in the first year after referral was 4 months per affected eye. At 1-year follow-up, bilateral visual impairment was observed in 4% but at least one ocular complication developed in 66% and 30% of patients required at least one intraocular surgery. Systemic immunosuppressive treatment was required in 35% of patients and the mean number of visits to ophthalmologist was 11 per year, while 8% of patients required hospital admission. Prognosticators for poor visual outcome included surgery undergone before referral (odds ratio (OR), 3; 95% CI, 1-11; P=0.047), visual impairment at referral (OR, 21; 95% CI, 8-54; P<0.001), and glaucoma before referral (OR, 7; 95% CI, 2-28; P=0.007). CONCLUSIONS: Patients with severe uveitis had a favorable BCVA 1 year after referral with only 4% of patients having bilateral visual impairment. This, in contrast to the prolonged duration of visual impairment during the first year of follow-up and the demanding care.

Molecular and Serological Intraocular Fluid Analysis of Coxiella burnetii-seropositive Patients with Concurrent Idiopathic Uveitis.

PURPOSE: Previous studies have suggested a link between Q fever and uveitis. We determined whether Coxiella burnetii causes intraocular infection in C. burnetii-seropositive patients with idiopathic uveitis. METHODS: From a retrospective observational case series, paired aqueous humor and serum samples from 10 C. burnetii-seropositive patients with idiopathic uveitis were examined for intraocular antibody production by using the Goldmann-Witmer coefficient and by polymerase chain reaction (PCR). RESULTS: Although intraocular IgG against C. burnetii was detected, no intraocular antibody production was observed (low Goldmann Wittmer coefficients). All PCR results were negative. CONCLUSIONS: Uveitis due to an intraocular infection with C. burnetii is unlikely.

Photoreceptor function in eyes with macular edema.

PURPOSE: The irreversible loss of visual acuity in macular edema is usually attributed to permanent loss of photoreceptor cells, although there is hardly any information on changes in photoreceptor function in macular edema. The purpose of this study was to assess photoreceptor function in various stages of macular edema and to relate the findings to visual acuity and angiographic changes. METHODS: Directional sensitivity (optical Stiles-Crawford effect) and visual pigment density of foveal cones was measured with a custom-built scanning laser ophthalmoscope (SLO) in 19 eyes of 19 patients. Twelve eyes exhibited macular edema: five of inflammatory origin, and seven of diabetic origin. Seven eyes with an intraocular inflammatory disease without clinical or angiographic evidence of edema were also included (four of which had previous macular edema and one of which had shown development of macular edema at the 1-year follow-up). Results of SLO measurements were related to findings using fluorescein angiography and Snellen visual acuity, both assessed at the time of SLO measurement and 6 months thereafter. RESULTS: Eyes with macular edema exhibited diminished directional sensitivity of photoreceptor cells in the fovea compared with eyes without (P = 0.02). Visual pigment density of eyes with macular edema was decreased and associated with both initial and follow-up visual function and with the angiographic macular edema grade at follow-up. Abnormal directional sensitivity and pigment density were already present in eyes with slight edematous changes and normal visual acuity. CONCLUSIONS: Eyes with inflammatory or diabetic macular edema showed decreased directional sensitivity and visual pigment density in the macular area. These findings may support a role for SLO measurements in detecting retinal damage due to macular edema.

Cell-mediated immunity against human retinal extract, S-antigen, and interphotoreceptor retinoid binding protein in onchocercal chorioretinopathy.

Autoimmune mechanisms are thought to be involved in the pathogenesis of onchocercal chorioretinopathy. Cell-mediated immune responses to human retinal S-antigen, interphotoreceptor retinoid binding protein (IRBP), and crude retinal extract were investigated in patients with onchocerciasis from Sierra Leone, West Africa using a two-step migration-inhibition factor assay. Patients were subdivided into three groups: (1) without ocular involvement (n = 10), (2) with ocular onchocerciasis limited to the anterior segment (n = 19), and (3) with onchocercal chorioretinopathy (n = 21). A group of endemic controls (n = 25) from Sierra Leone were also studied. The cellular immune response to concanavalin A (Con A) was measured to assess the general capacity of lymphocytes to respond to a mitogen. Four of 50 (8%) patients with onchocerciasis and four of 25 (16%) endemic controls reacted with at least one retinal antigen. From the patients with onchocercal chorioretinopathy two of 21 (10%) showed a positive cellular response. The general mitogen response tested with Con A was positive in all these individuals. A role for an antiretinal autoimmune mechanism in the pathogenesis of onchocercal chorioretinopathy, as studied with human S-antigen, IRBP, or crude retinal extract, could not be shown because the cellular response to these antigens did not differ in patients with or without onchocercal chorioretinopathy or in endemic controls.

Immunity to a corneal antigen in Fuchs' heterochromic cyclitis patients.

Immunity to a major corneal antigen was studied in 28 Fuchs' heterochromic cyclitis patients and compared with the response of 44 patients with other types of uveitis and 19 healthy controls. The highest incidence of immune response was found in patients with anterior segment involvement only (anterior uveitis and Fuchs') whereas the frequency of anti-corneal immune response in patients with posterior segment involvement only was low and not significantly different from that of healthy controls. Cellular immunity to corneal antigens was found in the majority of Fuchs' heterochromic cyclitis patients, and in one-third of the anterior uveitis patients. No correlation could be established in these patients between a positive cellular response and the chronicity of the disease or the presence of keratic precipitates. Humoral immunity to the corneal antigen was also the highest in patients with anterior segment involvement, but there was no difference in response between Fuchs' and non-Fuchs' anterior uveitis patients. This study suggests that anti-corneal immunity may be triggered in inflammatory diseases of the anterior segment, especially in Fuchs' heterochromic cyclitis.

The lifetime cumulative incidence of acute anterior uveitis in a normal population and its relation to ankylosing spondylitis and histocompatibility antigen HLA-B27.

The lifetime cumulative incidence of acute anterior uveitis (AAU) was determined in a sample of a large population (n = 10,500). Nine hundred seventeen subjects, who answered the question "Have you ever had a red eye" in the affirmative in 1977, were asked to participate in a follow-up study 10 years later. From the 917 respondents, 539 were studied completely. A questionnaire was used to collect historic data, and confirmation of these data was obtained from the treating ophthalmologists and physicians. From these data, subjects were selected for an ophthalmologic examination. The respondents also underwent a rheumatologic examination. The results revealed that the lifetime cumulative incidence of definite AAU is approximately 0.2% in the general population and 1% in the histocompatibility antigen HLA-B27-positive population. In one third of the definite AAU patients, the cause of the disease was known. The lifetime cumulative incidence of definite AAU of unknown cause was 0.15% in the general population. When possible and probable AAU are included, the lifetime cumulative incidence of AAU in the general population is about 0.4%. The observed frequency of the concurrence of AAU and ankylosing spondylitis (AS) was 0.4% in the HLA-B27-positive population and 0.02% in the HLA-B27-negative population. Comparison with the expected frequency of the concurrence of AAU and AS revealed that AAU and AS probably are related diseases irrespective of the association of both diseases with HLA-B27.

Chemoattractant and neutrophil degranulation activities related to interleukin-8 in vitreous fluid in uveitis and vitreoretinal disorders.

PURPOSE: To investigate whether the cytokine interleukin-8 (IL-8), a strong chemoattractant and activator for neutrophils, is responsible for neutrophil infiltration and degranulation in the eye in uveitis. METHODS: IL-8 and elastase were measured with specific enzyme-linked immunoassays in vitreous fluid samples obtained from 69 patients with various uveitis entities. Vitreous fluid of nonuveitis patients and eye bank eyes served as controls. The chemotactic activity of vitreous fluid was tested with the Boyden chamber technique. RESULTS: IL-8 was detected in 45% of the vitreous fluid samples from uveitis patients and in 26% of vitreous fluid samples from nonuveitis patients. Vitreous fluid samples with IL-8 levels exceeding 100 pg/ml were chemotactic for neutrophils. This chemotactic activity could be blocked by 41% to 79% with a monoclonal anti-IL-8 antibody. Elastase levels in vitreous fluid of uveitis patients with detectable IL-8 were significantly higher than those in vitreous fluid samples with no detectable IL-8. CONCLUSION: These results indicate that IL-8 participates in the inflammatory processes in the eye by attracting and degranulating neutrophils. It is suggested that these processes contribute to the pathogenesis of tissue destruction in uveitis.

Fuchs' heterochromic iridocyclitis is not associated with ocular toxoplasmosis.

To analyze the association between Fuchs' heterochromic iridocyclitis (FHI) and toxoplasmosis, we performed ocular examinations and used various specific laboratory tests to establish a role for Toxoplasma gondii in the pathogenesis of FHI. Results were compared with those for other types of uveitis and healthy controls. Of the 88 patients with FHI, nine (10.2%) had toxoplasmosislike scars, but an association could not be proved by the indirect immunofluorescence antibody test or enzyme-linked immunosorbent assay, or by a test for cellular immunity to Toxoplasma antigen. Analysis of aqueous humor samples for Toxoplasma antibodies in patients with FHI also yielded negative results. On the basis of the negative results of these laboratory tests, we concluded that FHI is not associated with ocular toxoplasmosis.