Real-world insights and outcomes related to ciclosporin A 0.1% cationic emulsion for the long-term treatment of dry eye disease in Germany: Country-level sub-analysis of the PERSPECTIVE study.

PURPOSE: The PERSPECTIVE study was a real-world European, non-interventional, multicenter, observational study that evaluated the effectiveness, tolerability, and safety of ciclosporin A (CsA) 0.1% cationic emulsion (CE) in routine clinical practice as a treatment for adults with severe keratitis and dry eye disease (DED) that remained insufficiently controlled with artificial tears. This sub-analysis examined data from ophthalmology clinics in Germany to provide more precise insights into treatment patterns, outcomes, and clinical decision-making related to CsA 0.1% CE. METHODS: Study data were collected from adults starting CsA 0.1% CE (one drop in both eyes at bedtime) and followed up at Week 4, 12, and 24, and Month 12. The primary endpoint was mean change from baseline in corneal fluorescein staining (CFS) score (Oxford Grade Scale) at Month 12. Secondary endpoints examined the severity of ocular signs and symptoms, and adverse events (AEs). RESULTS: A total of 236 patients from 20 ophthalmology clinics in Germany participated in the PERSPECTIVE study (69.9% female; mean age 60.8 years). Following treatment with CsA 0.1% CE, patients experienced significant reductions in CFS score from Week 4, which were maintained through to Month 12 (P < 0.0001). From baseline, 81.6% of patients experienced an improvement in CFS score at Month 12. CsA 0.1% CE provided significant reductions in the severity of eyelid and conjunctival erythema at Month 12 compared with baseline (P < 0.001), as well as significant reductions in the severity of subjective ocular symptoms (all P ≤ 0.015). Safety data were consistent with the known safety profile of CsA 0.1% CE. Tolerability was rated as "satisfactory," "good," or "very good" by 97.2% of physicians and 95.7% of patients. CONCLUSION: Outcomes in Germany were similar to those reported for the overall European study population and are indicative of the treatment results that ophthalmologists may expect to see with CsA 0.1% CE treatment in real-life clinical practice. Treatment with CsA 0.1% CE provided long-term improvements over 12 months and was generally well tolerated.

Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care.

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.

[Clinical aspects, diagnostics and differential diagnostics of uveitis for rheumatologists]. / Klinik, Diagnostik und Differenzialdiagnostik der Uveitis für Rheumatologen.

This review article presents the different forms of uveitis and their clinical manifestations. The exact type and localization of the ocular inflammation is crucial for the probability of the underlying rheumatological disease and thus for a correct differential diagnosis. In this first part, in addition to the anatomy of the eye, the different forms of uveitis including the associated nomenclature, typical symptoms, diagnostics and possible complications are presented. In a following second part ("Association of the different forms of uveitis with inflammatory rheumatic diseases and their treatment"), the associations with rheumatological and other systemic diseases are explained and highlighted from an ophthalmological and rheumatological perspective.

[Association of the different forms of uveitis with inflammatory rheumatic diseases and their treatment]. / Assoziation der verschiedenen Uveitisformen mit entzündlich rheumatischen Erkrankungen und ihre Therapie.

The etiology of uveitis greatly varies worldwide, whereby in industrial nations noninfectious causes occur relatively more frequently. In Germany, 44% of all cases of uveitis are due to systemic diseases. In rheumatology, uveitis or other kinds of ocular inflammation, such as scleritis or retinal vasculitis, most commonly occur in spondylarthritis, vasculitis and sarcoidosis. Vice versa, ophthalmologists often ask rheumatologists about an underlying rheumatic disease in patients with uveitis. It is of utmost importance to differentiate between the different forms of uveitis. This review article presents the associations with inflammatory rheumatic diseases as well as treatment options from the point of view of both ophthalmologists and rheumatologists.

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.

New pharmacotherapy options for noninfectious posterior uveitis.

INTRODUCTION: Noninfectious inflammation of the posterior eye segment represents an important cause of visual impairment. It often affects relatively young people and causes a significant personal and social impact. Although steroids and nonbiologic- Disease-Modifying Antirheumatic Drugs (nbDMARDs) are effective both in acute and long- lasting diseases, however they are increasingly being replaced by biologic (DMARDs). bDMARD. This article therefore aims to identify recent advances in the therapy of noninfectious posterior segment uveitis. METHODS: A Medline-search was conducted using the terms: nbDMARD, bDMARD, posterior uveitis, intermediate uveitis, treatment, corticosteroid. In addition, clinical studies were included as registered at ClinicalTrials.gov. RESULTS: Currently two major lines of treatments can be identified: (1) the intraocular application of anti-inflammatory agents and (2) the introduction of new agents, e.g., (bDMARDs) and small-molecule-inhibitors. Whereas intravitreal treatments have the advantage to avoid systemic side effects, new systemic agents are progressively earning credit on the basis of their therapeutic effects. CONCLUSION: Even when current treatment strategies are still hampered by the limited number of randomized controlled trials, promising progress and continuous efforts are seen.

[Macular Oedema in Uveitis: Pathogenesis, Diagnosis, and Treatment]. / Makulaödem bei Uveitis: Pathogenese, Diagnostik und Therapie.

Macular oedema is the most common cause of irreversible visual loss in patients with uveitis. The pathogenesis is caused by pro-inflammatory cytokines that lead to the breakdown of the blood-retina barrier. For the diagnosis of inflammatory macular oedema, optical coherence tomography is now mainly used, but cannot always replace fluorescein angiography. The therapy is mainly performed with intravitreally applied corticosteroids as well as systemic immunomodulators and should start as early as possible to prevent chronification of macular oedema.

[Uveitis in Behçet's Syndrome in Germany - Prognosis During Current Therapy]. / Uveitis bei Behçet-Syndrom in Deutschland ­ Prognose unter aktueller Therapie.

Behçet's syndrome (BS) is an inflammatory systemic disease associated with multiple organ manifestations. Major symptoms include oral and genital ulcerations, skin lesions and uveitis. Diagnosis of Behçet's syndrome is based on clinical findings. A typical for ocular Behçet's syndrome is recurrent non-granulomatous panuveitis with occlusive retinal vasculitis. Treatment used to be based only on the use of systemic corticosteroids and conventional immunosuppressives, but most often this treatment did not appear to be sufficient. In consequence, prognosis of ocular BS was very poor over a long period of time - especially if occlusive retinal vasculitis was present. In recent years, the introduction of biologicals has revolutionised the therapeutic regime and consecutively visual prognosis of ocular Behçet's syndrome has dramatically improved.

[Topical Corticosteroids and Non-steroidal Anti-inflammatory Drugs in the Therapy of Non-infectious Uveitis]. / Topische Kortikosteroide und nicht steroidale Antiphlogistika zur Behandlung der nicht infektiösen Uveitis.

Topical corticosteroids are effective anti-inflammatory drugs in the treatment of anterior uveitis. The intraocular efficacy of topical corticosteroids mostly depends on their intraocular permeability through the cornea. Lipophile derivatives such as dexamethasone and prednisolone acetate penetrate better into the anterior chamber than hydrophilic derivatives. Prednisolone acetate 1% is the first choice in the therapy of patients with anterior uveitis. Loteprednole and fluorometholone have a slightly weaker anti-inflammatory effect, but they induce less elevation of intraocular pressure and might be helpful in the treatment of patients with steroid response. Topical corticosteroid therapy has to be individually adapted, depending on the clinical course and severity of uveitis. The most common side effects of topical corticosteroids are corticosteroid-induced glaucoma and corticosteroid-induced cataracts. Non-steroidal anti-inflammatory drugs inhibit the enzyme cyclooxygenase that is responsible for the formation of pro-inflammatory prostaglandins. These have an adjunctive role in the treatment and prevention of post-operative inflammation after cataract surgery. A therapeutic role of topical NSAID to treat uveitis and cystoid macular oedema secondary to uveitis has not yet been established.

High frequency of MYD88 mutations in vitreoretinal B-cell lymphoma: a valuable tool to improve diagnostic yield of vitreous aspirates.

Vitreoretinal diffuse large B-cell lymphoma is a rare disorder, occurring as primary ocular disease or as secondary involvement by primary central nervous system lymphoma. It is usually diagnosed by cytologic, immunocytochemical, and molecular examination of vitreous aspirates. However, distinguishing vitreoretinal diffuse large B-cell lymphoma from uveitis remains difficult, and clonality analysis may be either unsuccessful or misleading. Diffuse large B-cell lymphoma arising in immune-privileged sites (eg, the central nervous system) shows a high frequency of MYD88 mutations. Therefore, we retrospectively assessed the frequency of MYD88 mutations in vitreoretinal lymphoma (VRL) and their diagnostic potential in 75 vitrectomy samples of 69 patients, and validated our results in a separate cohort (n = 21). MYD88 mutations were identified in 20 of 29 (69%) clinically, histologically, and molecularly confirmed VRL, including 6 cases of the test cohort initially diagnosed as reactive (3/6) or suspicious (3/6) for lymphoma. MYD88 mutations, especially L265P, are very frequent in VRL and their detection significantly improves the diagnostic yield of vitrectomy specimens.

Ophthalmic Rosacea: Case Report in a Child and Treatment Recommendations.

We report a rare case of rosacea with ocular involvement in a child that remitted with prolonged anti-inflammatory oral tetracycline therapy and provide general expert recommendations. A 14-year-old girl presented with discrete papules and pustules on both cheeks with blepharitis and conjunctivitis. Ophthalmologic examination confirmed bilateral severe blepharitis, as well as a corneal infiltrate in the right eye with additional neovascularization. The diagnosis of rosacea with ocular involvement was made. In addition to the existing antibiotic and anti-inflammatory topical eye therapy, systemic treatment with minocycline 50 mg twice a day was started. After marked improvement, the dose was reduced to 50 mg once a day. After further amelioration, treatment was switched to maintenance therapy with 40 mg of prolonged-release doxycycline. Three years after a 12-month course of anti-inflammatory therapy, the patient remained recurrence free.

Diagnostic relevance of direct immunofluorescence in ocular mucous membrane pemphigoid.

BACKGROUND AND OBJECTIVES: The objective was to determine the diagnostic value of direct immunofluorescence (DIF) in ocular mucous membrane pemphigoid (ocular MMP), taking into account immunofluorescence patterns and biopsy sites. PATIENTS AND METHODS: DIF results and medical records of 54 patients with a suspected diagnosis of ocular MMP were reviewed. RESULTS: There was an overall prevalence of ocular MMP in 70.4 % of cases. Linear deposition of IgA, IgG, or C3 showed a high positive predictive value (84-100 %). Sensitivity and negative predictive value of IgG, IgM, IgG, and C3 in DIF were higher in cutaneous samples than in conjunctival biopsies, thus yielding a higher diagnostic accuracy. The sensitivity of DIF in ocular MMP seems to be lower than in bullous pemphigoid. CONCLUSIONS: The diagnostic value of DIF in the workup of ocular MMP was confirmed. However, biopsies taken from non-conjunctival, cutaneous tissue appear to yield more accurate results.

Is cyclophotocoagulation an option in the management of glaucoma secondary to Fuchs' uveitis syndrome?

BACKGROUND: Glaucoma is one of the sight-threatening complications of Fuchs' uveitis syndrome (FUS) and the most difficult to manage. The goal of this study was to assess the efficacy and safety of cyclophotocoagulation (CPC) in the management of glaucoma secondary to FUS. METHODS: In a retrospective analysis, the charts of all patients with FUS referred to our clinic from January 2002 to December 2012 were reviewed. In patients with glaucoma or ocular hypertension, controlled eye pressure was defined using two alternative upper limits of 6 ≤ IOP ≤ 21 mmHg and 6 ≤ IOP ≤ 18 mmHg at 1 year follow-up. RESULTS: One hundred and seventy-six patients with FUS were included in this study. Of those, 28 had ocular hypertension (OHT) or glaucoma. Mean maximal intraocular pressure (IOP) of patients with glaucoma/OHT was 40.8 mmHg. Twenty-three patients (82.1 %) had maximal IOP levels of 35 mmHg or higher. Sixteen patients with glaucoma/OHT underwent CPC alone (ten patients) or in combination with other surgical procedures (six patients). After 1 year, control of IOP for both upper limits (6 ≤ IOP ≤ 18 mmHg) and (6 ≤ IOP ≤ 21 mmHg) was achieved in six of ten patients (60 %) who received CPC alone, and in five of six patients (83.3 %) who required additional surgery after CPC. The mean number of cycloablative procedures was 1.3 (range 1-2) in the CPC alone group and 1.2 (range 1-2) in patients for whom CPC was used as adjunct therapy. There was no exacerbation of intraocular inflammation, no postoperative hypotony and no phthisis bulbi in the 16 patients who underwent CPC. CONCLUSIONS: CPC is a safe and effective procedure that should be considered if medical treatment has failed to control glaucoma in FUS.

Treatment exit options for non-infectious uveitis registry: participant characteristics at 3 years.

PURPOSE: The Treatment exit Options For non-infectious Uveitis (TOFU) registry documents disease courses for non-anterior non-infectious uveitis entities with and without treatment to generate more evidence for clinical management recommendations including treatment exit strategies. In this article, we present the participants' baseline characteristics after the first 3 years. METHODS: TOFU is an observational, prospective registry and recruits patients ≥18 years of age with non-anterior non-infectious uveitis with or without a history of previous disease-modifying antirheumatic drugs (DMARDs) treatment. The data are collected in the electronic data capture software REDCap and include ophthalmological and general medical history as well as clinical findings. RESULTS: Between 24.10.2019 and 27.12.2022, 628 patients were enrolled at 25 clinical sites in Germany and Austria. Patients with intermediate uveitis were most frequently included (n=252; 40.1%) followed by posterior uveitis (181; 28.8%), panuveitis (n=154; 24.5%) and retinal vasculitis (n=41, 6.5%). At baseline, 39.6% were treated with systemic corticosteroids, 22.3% with conventional synthetic (cs) DMARDs, 20.5% with biological (b) DMARDs and 3.6% with other systemic treatments. Average best corrected visual acuity (BCVA) was 0.69 decimal. Patients with panuveitis had the worst BCVA with 0.63 decimal. Overall, only 8 patients (1.3%) suffered from severe visual impairment. CONCLUSIONS: Less than half of participants required DMARD treatment at baseline, with csDMARDs used more frequently than bDMARDs. The presence of severe visual impairment was low, mostly affecting patients with panuveitis. These findings are in line with comparable monocentric cross-sectional studies of tertiary uveitis centres in Germany and will allow us to generate generalisable evidence in TOFU.

[Association of the different forms of uveitis with inflammatory rheumatic diseases and their treatment]. / Assoziation der verschiedenen Uveitisformen mit entzündlich rheumatischen Erkrankungen und ihre Therapie.

The etiology of uveitis greatly varies worldwide, whereby in industrial nations noninfectious causes occur relatively more frequently. In Germany, 44% of all cases of uveitis are due to systemic diseases. In rheumatology, uveitis or other kinds of ocular inflammation, such as scleritis or retinal vasculitis, most commonly occur in spondylarthritis, vasculitis and sarcoidosis. Vice versa, ophthalmologists often ask rheumatologists about an underlying rheumatic disease in patients with uveitis. It is of utmost importance to differentiate between the different forms of uveitis. This review article presents the associations with inflammatory rheumatic diseases as well as treatment options from the point of view of both ophthalmologists and rheumatologists.

Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome.

OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. METHODS: A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. RESULTS: A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5-14 months). The median followup was 11 months (range 5-14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. CONCLUSION: Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

Identification of immunodominant epitopes of alpha-crystallins recognized by antibodies in sera of patients with uveitis.

BACKGROUND: A high incidence of autoantibodies to lens proteins has been found in sera of patients with uveitis. We showed previously that the anti-lens antibodies reacted predominantly with α-crystallins. The aim of the present study was to identify immunodominant epitopes within the protein chains of human αA- and αB-crystallin. METHODS: Epitope specificities of antibodies to αA- and αB-crystallin were examined by ELISA using synthetic overlapping peptides, spanning the entire length of both α-crystallins. The peptides consisted of 25 amino acid residues, with an overlap of at least eight amino acids each. The synthetic peptides were tested against sera of 110 patients with different uveitis forms, classified according to anatomical location of intraocular inflammation. RESULTS: Four immunodominant regions within the protein chains of αA- and αB-crystallin could be identified. These regions were recognized by antibodies in sera of 56% of uveitis patients. Anti-lens antibodies of IgG-type reacted preferentially with regions located at amino acid (aa) residues aa:69-93 and aa:137-161 of αA-crystallin as well as aa:69-110 and aa:137-161 of αB-crystallin. IgM antibodies recognized predominantly region aa:149-173 of αA-crystallin, and aa:69-110 and aa:151-175 of αB-crystallin. IgM antibodies directed to peptide aa:69-93 of αB-crystallin were found in sera of 30% of patients with intermediate uveitis. CONCLUSIONS: Four immunodominant B-cell epitopes within the protein chains of αA- and αB-crystallin have been identified; however, no clear correlation with the anatomically defined uveitis subtypes has been found except for intermediate uveitis. Whether there may be a correlation with uveitis forms with similar etiopathogenesis has to be evaluated in further studies.

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].

Long-term remission after cessation of interferon-α treatment in patients with severe uveitis due to Behçet's disease.

OBJECTIVE: To retrospectively assess the development of visual acuity and the frequency and duration of relapse-free periods in patients who were treated with interferon-α (IFNα) for severe uveitis due to Behçet's disease (BD) and who completed a followup period of ≥2 years. METHODS: IFN alfa-2a was administered at an initial dosage of 6 million IU per day, then tapered to a maintenance dosage of 3 million IU twice per week, and finally discontinued, if possible. In case of a relapse, IFN treatment was repeated. Visual acuity at the end of followup was compared with visual acuity when ocular disease was in remission. RESULTS: Of 53 patients (96 eyes), 52 (98.1%) responded to IFN. In 47 patients (88.7%), IFN could be discontinued when the disease was in remission. Twenty of these 47 (42.6%) needed a second treatment course during a median followup of 6.0 years (range 2.0-12.6 years). Visual acuity improved or remained unchanged in 91 eyes (94.8%). Ocular disease was still in remission in 50% of the patients 45.9 months after cessation of the first IFN course. The relapse rate tended to be lower in women than in men. The BD activity score decreased significantly during followup, but long-term remission of nonocular BD manifestations was not achieved. However, since local treatments were sufficient, no systemic treatment was administered. CONCLUSION: Our findings indicate that IFNα induces long-lasting remission in patients with severe ocular BD, resulting in a notable improvement in visual prognosis.

Risk factors for severe Muckle-Wells syndrome.

OBJECTIVE: Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease resulting in excessive interleukin-1 release. It is unknown whether demographic, clinical, or laboratory characteristics at the time of diagnosis may identify patients who are at high risk for severe disease activity. This study was undertaken to analyze clinical and laboratory features of MWS, compare genetically defined subcohorts, and identify risk factors for severe MWS. METHODS: A multicenter cohort study of consecutive MWS patients was performed. Parameters assessed included clinical features, MWS Disease Activity Score (MWS-DAS), inflammation markers, and cytokine levels. E311K mutation-positive patients were compared with E311K mutation-negative patients. Putative risk factors for severe MWS (defined as an MWS-DAS score of ≥10) were assessed in univariate analyses, and significant predictors were entered into a multivariate model. RESULTS: Thirty-two patients (15 male and 17 female) were studied. The most frequent organ manifestations were musculoskeletal symptoms and eye and skin disorders. Renal disease and hearing loss were seen in >50% of the patients. Genetically defined subcohorts had distinct phenotypes. Severe disease activity was documented in 19 patients (59%). Predictors of severe MWS identified at the time of diagnosis were female sex, hearing loss, musculoskeletal disease, increased erythrocyte sedimentation rate, and low hemoglobin level. Female sex and hearing loss remained significant after adjustment for age in a multivariate model (relative risk 1.8 and 2.6, respectively). CONCLUSION: MWS patients at high risk for severe disease can be identified at the time of diagnosis. Female patients presenting with hearing loss have the highest likelihood of manifesting severe MWS and should be considered a high-risk group.