Ocular Involvement in Selected Rheumatic Diseases - Clinical Manifestation in Adulthood. / Augenbeteiligung bei ausgewählten rheumatischen Erkrankungen ­ Klinik im Erwachsenenalter.

Ocular manifestations of rheumatic diseases are common and contribute significantly to the morbidity and reduced quality of life of affected patients. Knowledge of typical clinical manifestations is important for the rheumatologist in order to support the reference of patients with corresponding symptoms for ophthalmological consultation at an early stage of disease, or to initiate regular screening examinations (e.g. in patients with Behçet's syndrome). Conversely, a (possibly urgent) rheumatological assessment is crucial for certain ophthalmological diseases, in order not to overlook a (possibly fatal) systemic associated disease. Patients with rheumatic or inflammatory ocular diseases should always be informed by the treating physician about possible symptoms of other organ manifestations, in order to avoid a delayed diagnosis. "Classic" associations for uveitis are (HLA-B27-associated) spondyloarthritis and acute anterior uveitis, as well as retinal vasculitis with or without panuveitis and Behçet's syndrome. In patients with rheumatoid arthritis or ANCA-associated vasculitis, however, scleritis (with or without peripheral ulcerative keratitis) typically occurs, but a variety of other findings are also possible. Close interdisciplinary collaboration, particularly regarding therapeutic decisions, is crucial to ensuring a good prognosis for the patient.

Ocular Involvement in Graft-versus-Host Disease. / Augenbeteiligung bei Graft-versus-Host-Erkrankung.

In ocular graft-versus-host disease (GVHD), an inflammatory reaction occurs at the ocular surface after transplantation of allogeneic hematopoietic stem cells. Self-reactive T cells of the donor are particularly responsible for this. This can lead to a pronounced wetting disorder of the ocular surface, conjunctival hyperemia, and corneal ulceration up to perforation. The ocular GVHD is associated with a high degree of suffering, such as pain, photophobia, and reduction in visual acuity. This review provides an overview of typical ophthalmological findings, topical and systemic therapeutic approaches, and concomitant measures (e.g., scleral lenses, punctum plugs) and the appropriate management of complications.

Surgical Glaucoma Treatment in Patients with Juvenile Idiopathic Arthritis-Associated Uveitis: Results after Trabeculectomy or Ahmed Glaucoma Valve Implantation.

PURPOSE: Patients with juvenile idiopathic arthritis (JIA) associated uveitis (JIAU) are at risk for secondary glaucoma, frequently requiring surgical management. We compared the success rates for trabeculectomy (TE) and Ahmed glaucoma valve (AGV) implantation. METHODS: We conducted a retrospective analysis of TE (45 eyes), primary AGV (pAGV) (7 eyes), or secondary AGV (sAGV) implantation after TE (11 eyes) in JIAU at the 2-year follow-up. RESULTS: All groups achieved significant pressure reduction. After 1 year, the overall success rate was higher in the Ahmed groups (p = 0.03). After adjusting the p-value according to Benjamin Hochberg, there is no significant difference between the groups in the Kaplan-Meier, despite a significant logrank test between all groups (p = 0.0194) and a better performance in the Ahmed groups. CONCLUSION: Slightly better success rates were achieved with pAGV in managing JIAU patients with glaucoma refractory to medical treatment.

Challenges and concepts in the diagnosis and management of ocular graft-versus-host disease.

Graft-versus-host disease (GVHD) is characterized by tissue inflammation in the host following an allogeneic hematopoietic cell transplantation (HCT). The pathophysiology is complex and only incompletely understood yet. Donor lymphocyte interaction with the histocompatibility antigens of the host plays a crucial role in the pathogenesis of the disease. Inflammation may affect multiple organs and tissues, e.g., the gastrointestinal tract, liver, lung, fasciae, vaginal mucosa, and the eye. Subsequently, alloreactive donor-derived T and B lymphocytes may lead to severe inflammation of the ocular surface (i.e., cornea and conjunctiva) and the eyelids. Furthermore, fibrosis of the lacrimal gland may lead to severe dry eye. This review focuses on ocular GVHD (oGVHD) and provides an overview of current challenges and concepts in the diagnosis and management of oGVHD. Ophthalmic manifestations, diagnostic procedures, grading of severity and recommendations for ophthalmic examination intervals are provided. Management of ocular surface disease with lubricants, autologous serum eye drops, topical anti-inflammatory agents and systemic treatment options are described based on the current evidence. Ocular surface scarring and corneal perforation are severe complications of oGVHD. Therefore, ophthalmic screening and interdisciplinary treatment approaches are highly relevant to improve the quality of life of patients and to prevent potentially irreversible visual loss.

Comparing the Efficacy of Intravitreal Dexamethasone and Time-displaced Fluocinolone Acetonide on Central Retinal Thickness in Patients with Uveitis.

BACKGROUND: To compare the efficacy of intravitreally administered dexamethasone (Dex) and subsequent time-displaced fluocinolone acetonide (FA) on central subfield thickness (CST) in eyes with noninfectious uveitis. METHODS: Retrospective analysis of twenty-three eyes (18 patients) subsequently receiving intravitreal Dex and FA implants. The main outcome measures were CST, best-corrected visual acuity (BCVA), intraocular pressure (IOP), and status of inflammation. RESULTS: CST (Dex: p < .0001; FA: p = .0008) and BCVA (Dex: p = .0009; FA: p = .0005) improved significantly with both implants. Significantly better effects were noted with Dex for absolute and relative CST reduction (p = .0089 and p = .0051, respectively). Final BCVA did not differ between groups (p = .1893). Dex significantly increased IOP, whereas FA did not. One eye was actively inflamed after Dex and FA injection at follow-up (inflamed eyes before injection: [Dex: 2; FA: 6]). CONCLUSION: Both implants significantly reduced CST and induced a significant gain in visual acuity. Dex might be more effective in reducing CST.

New and Updated Recommendations for the Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis and Idiopathic Chronic Anterior Uveitis.

OBJECTIVE: The Multinational Interdisciplinary Working Group for Uveitis in Childhood identified the need to update the current guidelines, and the objective here was to produce this document to guide clinicians managing children with juvenile idiopathic arthritis-associated uveitis (JIAU) and idiopathic chronic anterior uveitis (CAU). METHODS: The group analyzed the literature published between December 2014 and June 2020 after a systematic literature review conducted by 2 clinicians. Pediatric rheumatologists were paired with ophthalmologists to review the eligible 37 publications. The search criteria were selected to reflect those used for the 2018 Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) recommendations, in order to provide an update, rather than a replacement for that publication. The summary of the current evidence for each SHARE recommendation was presented to the expert committee. These recommendations were then discussed and revised during a video consensus meeting on January 22, 2021, with 14 voting participants, using a nominal group technique to reach consensus. RESULTS: JIAU treatment was extended to include CAU. Fourteen recommendations regarding treatment of JIAU und CAU with >90% agreement were accepted. CONCLUSION: An update to the previous 2018 SHARE recommendations for the treatment of children with JIAU with the addition of CAU was created using an evidence-based consensus process. This guideline should help support clinicians to care for children and young people with CAU.

Beneficial Effect of Upadacitinib in an Adult Patient with Juvenile Idiopathic Arthritis-associated Uveitis after Unsatisfactory Response to Tofacitinib: A Case Report.

OBJECTIVE: Several case reports have been published on the effect of janus kinase inhibitors (JAK-I) on juvenile idiopathic arthritis-associated uveitis (JIAU). Both tofacitinib and baricitinib have been described as therapeutically effective in JIAU. METHODS: We here present a case of a 24-years-old female with refractory course of JIAU receiving upadacitinib therapy. RESULTS: After failing multiple conventional and biologic disease-modifying antirheumatic drugs, the patient finally achieved clinical remission on upadacitinib monotherapy, despite a previously unsatisfactory clinical response of both arthritis and uveitis to tofacitinib monotherapy. CONCLUSION: This case suggests that switching JAK-I might be a successful strategy in the treatment of JIAU, despite previously incomplete response to other preparations.

On the Current Care Situation and Treatment of Ocular Mucous Membrane Pemphigoid in Germany. / Zur Versorgungssituation und konservativen Therapie des okulären vernarbenden Schleimhautpemphigoids in Deutschland.

BACKGROUND: Ocular involvement in mucous membrane pemphigoid (MMP) is relatively rare, with a prevalence of 25 cases per million population, equating to approx. 2,100 patients throughout Germany. Diagnosis can be difficult - especially in cases of isolated ocular involvement - and treatment can be complex and lengthy. Immunosuppressants or immunomodulatory drugs are often used. Due to the complexity of diagnosis and treatment, MMP patients are usually referred to specialized centers. The aim of this project was to evaluate the current care situation of patients with ocular MMP in Germany. METHODS: A paper-based survey was designed and sent to all university eye clinics and other specialized centers in Germany in April 2020. The survey asked about the existence of a specialized outpatient service, the total annual number of patients with MMP, the annual number of newly diagnosed patients, any interdisciplinary collaboration for diagnostic or therapeutic purposes, as well as the local and systemic therapy used. RESULTS: Of a total of 44 clinics, 28 (64%) responded, reporting a total average of 27 ± 42 (0 - 200) patients and 3.6 ± 2.2 (0 - 10) new cases per year. This corresponds to a total of 741 patients. Only nine (32%) of the responding clinics offer specialized MMP clinics. 93% of the centers collaborate with the local dermatology department. 79% perform serological and histological diagnostics in-house. About half of the centers (n = 16) apply a standardized treatment regime. Systemic glucocorticoids (66.7%) are most commonly used, followed by mycophenolate mofetil and dapsone (57.1%), rituximab (33.3%), azathioprine and cyclophosphamide (28.6%), as well as methotrexate (19.0%). The least frequently used treatment is intravenous immunoglobulin (14.3%). CONCLUSION: This survey of German ophthalmology departments obtained data from about one third of the estimated total cohort of all patients with MMP in Germany. These are presumed to be exclusively patients with at least one ocular involvement. The complex care of these patients is usually provided in collaboration with a dermatologist and with the use of systemic anti-inflammatory medication. Currently, an ophthalmological MMP register is being established to better record the epidemiology and care situation of this rare disease in Germany and to improve it in the long term.

The Value of Laser Flare Photometry as a Monitoring Tool for Uveitis. / Der Stellenwert von Laser-Flare-Messungen zur Verlaufsbeurteilung von Uveitiden.

Laser flare (LF) photometry (P) is used to quantify the protein concentration in the aqueous humor, and therefore assess the blood-aqueous humor barrier. LFP is more reliable than the clinical assessment of the Tyndall effect, and is thus especially useful in the follow-up of uveitis patients. In active uveitis, LFP correlates well with the anterior chamber cell grading. Various studies have shown that high LF values are associated with an increased risk of uveitic complications, such as macular edema, glaucoma, and posterior synechiae. LFP can also be used to assess the response to anti-inflammatory treatments as well as the optimal timing and selection of the surgical technique for intraocular surgeries.

Development and External Validation of a Model Predicting New-Onset Chronic Uveitis at Different Disease Durations in Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and externally validate a prediction model for new-onset chronic uveitis in children with juvenile idiopathic arthritis (JIA) for clinical application. METHODS: Data from the international Pharmachild registry were used to develop a multivariable Cox proportional hazards model. Predictors were selected by backward selection, and missing values were handled by multiple imputation. The model was subsequently validated and recalibrated in 2 inception cohorts: the UK Childhood Arthritis Prospective Study (CAPS) study and the German Inception Cohort of Newly diagnosed patients with juvenile idiopathic arthritis (ICON) study. Model performance was evaluated by calibration plots and C statistics for the 2-, 4-, and 7-year risk of uveitis. A diagram and digital risk calculator were created for use in clinical practice. RESULTS: A total of 5,393 patients were included for model development, and predictor variables were age at JIA onset (hazard ratio [HR] 0.83 [95% confidence interval (95% CI) 0.77-0.89]), ANA positivity (HR 1.59 [95% CI 1.06-2.38]), and International League of Associations for Rheumatology category of JIA (HR for oligoarthritis, psoriatic arthritis, and undifferentiated arthritis versus rheumatoid factor-negative polyarthritis 1.40 [95% CI 0.91-2.16]). Performance of the recalibrated prediction model in the validation cohorts was acceptable; calibration plots indicated good calibration and C statistics for the 7-year risk of uveitis (0.75 [95% CI 0.72-0.79] for the ICON cohort and 0.70 [95% CI 0.64-0.76] for the CAPS cohort). CONCLUSION: We present for the first time a validated prognostic tool for easily predicting chronic uveitis risk for individual JIA patients using common clinical parameters. This model could be used by clinicians to inform patients/parents and provide guidance in choice of uveitis screening frequency and arthritis drug therapy.

A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial.

Uveitis is a T cell-mediated, intraocular inflammatory disease and one of the main causes of blindness in industrialized countries. There is a high unmet need for new immunomodulatory, steroid-sparing therapies, since only ciclosporin A and a single TNF-α-blocker are approved for non-infectious uveitis. A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme pivotal for de novo synthesis of pyrimidines, has a high potency for suppressing T and B cells and has already proven highly effective for treating uveitis in experimental rat models. Systemic and intraocular application of KIO-100 (PP-001) (previously called PP-001, now KIO-100) could efficiently suppress rat uveitis in a preventive as well as therapeutic mode. Here we describe the outcome of the first clinical phase 1 trial comparing three different doses of a single intraocular injection of KIO-100 (PP-001) in patients with non-infectious posterior segment uveitis. No toxic side effects on intraocular tissues or other adverse events were observed, while intraocular inflammation decreased, and visual acuity significantly improved. Macular edema, a sight-threatening complication in uveitis, showed regression 2 weeks after intraocular KIO-100 (PP-001) injection in some patients, indicating that this novel small molecule has a high potential as a new intraocular therapy for uveitis. Clinical trial registration: [https://www.clinicaltrials.gov/ct2/show/NCT03634475], identifier [NCT03634475].

Beneficial Effect of Upadacitinib in a Refractory Course of Scleritis: A Case Report.

Noninfectious scleritis typically takes a chronic course, and systemic corticosteroids or disease-modifying anti-rheumatic drug (DMARD) treatment may be inevitable for a prolonged period. Janus kinase (JAK) inhibitors are a relatively new therapeutic option for inflammatory diseases, and three cases of successful treatment of scleritis with tofacitinib, a substance targeting JAK-1 and -3, have been published up to now. We here describe the case of a 51-years-old female patient with bilateral anterior and posterior scleritis who, after treatment failure of multiple DMARDs, finally achieved clinical quiescence of disease under treatment with upadacitinib, a selective JAK-1 inhibitor.

Assessment of angiogenesis-related parameters in juvenile idiopathic arthritis-associated uveitis.

PURPOSE: Juvenile idiopathic arthritis-associated uveitis (JIAU) may run a chronic and treatment-resistant course, and occasionally, alterations of the iris vasculature may be observed clinically. METHODS: Iris tissue (IT), aqueous humor (AH) and serum samples from patients with clinically inactive JIAU (n = 30), acute anterior uveitis (AAU; n = 18), and primary open angle glaucoma (POAG; n = 20) were obtained during trabeculectomy or cataract surgery. Samples were analyzed by RNA-Seq, qRT-PCR, LC-IMS, Western-Blot, and LEGENDplex™ analysis. Pattern of iris vasculature in JIAU patients was assessed qualitatively via fluorescein and indocyanine green angiography (FLA/ICGA). RESULTS: RNA-Seq of IT showed significantly differential expression (DE) of 136 genes between JIAU and POAG, of which 15 were associated with angiogenesis. qRT-PCR, performed to validate RNA-Seq results, showed upregulation of the angiogenesis-related genes Kdr, Angpt-1, Tie-1, Tie-2 and Mmrn2 in IT (JIAU vs POAG, p > 0.05). LC-IMS of IT revealed a total number of 56 DE proteins (JIAU vs POAG), of which Angiopoetin, Lumican and Decorin were associated with angiogenesis and showed increased (p > 0.05) expression on Western-Blot analysis. LEGENDplex™ analysis showed upregulation of ANGPT-2 in AH from JIAU compared to AAU and POAG, whereas VEGF was upregulated in AAU. Iris vascular leakage, hypoperfusion and neovascularization were observed by FLA/ICGA in JIA patients with treatment-refractory complicated course of uveitis. CONCLUSION: Angiogenesis-related factors could play a role in long-standing complicated JIAU, leading to clinically visible alterations in selected cases.

Janus Kinase Inhibitors: Next-Generation Treatment for Uveitis. / Januskinase-Inhibitoren: Next-Generation-Therapie der Uveitis.

A large proportion of patients with visual impairment secondary to non-infectious uveitis may require DMARDs. Although these are highly effective, some patients may require alternatives to the currently available immunomodulators due to an inadequate response or undesirable side effects. Janus Kinase Inhibitors (JAKi) are already approved for several autoimmune diseases in rheumatology, gastroenterology and dermatology. To date, JAKi have been studied in phase 3 trials in various types of uveitis. Mechanism of Action: JAKi work by inhibiting the phosphorylation of Janus kinases, which are transmembrane proteins. This blocks the activation of transcription factors, which in turn downregulates cytokine expression and inflammatory mediators. JAKi represent an extremely effective novel therapeutic approach in rheumatology, gastroenterology and dermatology. They have already been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and atopic eczema. In earlier comparative studies with conventional biologics, a better therapeutic response was reported in some cases. Several published case reports report reduced cortisone levels in patients with uveitis who had responded poorly to conventional and biological DMARDs. Approval studies are under way for JIA-associated and ANA-positive anterior uveitis. In summary, JAKi represent an innovative treatment option for patients with non-infectious uveitis in whom DMARDs are contraindicated or ineffective.

Uveitis in Juvenile Idiopathic Arthritis - Case Reports on Guideline-based Diagnostic Work-up and Treatment. / Uveitis bei juveniler idiopathischer Arthritis ­ leitliniengerechte Diagnostik und Therapie anhand von Kasuistiken.

OBJECTIVES: Case report based presentation of the current German interdisciplinary guideline on the diagnosis and management of juvenile idiopathic arthritis-associated (JIA) uveitis. MATERIAL AND METHODS: Guideline of the German Society of Ophthalmology, the Society of Paediatric and Adolescent Rheumatology, the German Society of Rheumatology, the Professional Association of German Ophthalmologists, with the participation of patient representatives. Recent primary publications were critically graduated for evidence and recommendations; the methodology included consensus building through Delphi rounds and external peer review. The outcomes are presented with typical case studies. OUTCOMES: Once JIA is first diagnosed, periodic ophthalmological check-ups should promptly be instituted ensuring that uveitis is diagnosed before irreversible sequelae become manifest. High-quality patient care can be provided depending on the severity of each uveitis case. At present, anti-inflammatory treatment relies on corticosteroids, conventional synthetic (cs), biological (b) and other disease-modifying anti-rheumatic drugs (DMARDs). CONCLUSIONS: Timely diagnosis and state-of-the-art guideline-based management can significantly improve the long-term outcome of JIA-associated uveitis.

Occurrence and Risk Factors of Uveitis in Juvenile Psoriatic Arthritis: Data From a Population-based Nationwide Study in Germany.

OBJECTIVE: Data on uveitis in juvenile psoriatic arthritis (JPsA), a category of juvenile idiopathic arthritis (JIA), are scarce. We describe prevalence and risk factors for JPsA-associated uveitis (JPsA-U). METHODS: Cross-sectional data from the German National Pediatric Rheumatological Database (2002-2014) were used to characterize JPsA-U and assess risk factors for the development of uveitis. RESULTS: Uveitis developed in 6.6% of 1862 patients with JPsA. Patients with JPsA-U were more frequently female (73.0 vs 62.9%, P = 0.03), antinuclear antibody (ANA) positive (60.3 vs 37.0%, P < 0.001), younger at JPsA onset (5.3 ± 4.1 vs 9.3 ± 4.4 yrs, P < 0.001), and treated with disease-modifying antirheumatic drugs (DMARDs) significantly more frequently compared with JPsA patients without uveitis. On a multivariable analysis of a subgroup of 655 patients enrolled in the study ≤ 1 year after arthritis onset, mean clinical Juvenile Arthritis Disease Activity Score for 10 joints during study documentation was significantly associated with uveitis development. Children with early onset of JPsA (aged < 5 yrs vs ≥ 5 yrs) were significantly more frequently ANA positive (48.4% vs 35.7%, P < 0.001), affected by uveitis (17.3% vs 3.8%, P < 0.001), and treated with DMARDs (52.9% vs 43.8%, P < 0.001), but less often affected by skin disease (55.3% vs 61.0%, P = 0.03). CONCLUSION: The characteristics of patients with JPsA developing uveitis are similar to those of patients with uveitis in other JIA categories, such as oligoarticular JIA. Children with early-onset JPsA are at a higher risk for ocular involvement. Our data support the notion of a major clinical difference between those patients with early vs late onset of JPsA.