Uveitis as predictor of disease flare after the first anti-TNF withdrawal in oligoarticular and polyarticular juvenile idiopathic arthritis: a multicentric Italian experience.

OBJECTIVES: TNF inhibitors (TNFi) have dramatically changed the prognosis of juvenile idiopathic arthritis (JIA), but it is not clear how and when stop therapy. We aim to describe a multicentric cohort of JIA treated with adalimumab or etanercept who discontinued the treatment for persistent inactivity and to identify factors associated with relapse. METHODS: In a multicentric Italian retrospective cohort study, medical records of patients with oligoarticular and polyarticular JIA were evaluated if they stopped therapy for persistent inactivity after the first TNFi. RESULTS: 136 patients were enrolled (102 female, median age at onset 3 years (range 1-15), of whom 55.9% had oligoJIA, 40.4% uveitis and 72.8% ANA positivity. Adalimumab (59.3%) and etanercept (40.7%) were started at a median age of 6 years (range 1-16), TNFi were discontinued after a median time of 30 months (range 6-90), increasing the interval (76.5%), reducing the dose (18.4%) and abrupt discontinuation (16.9%). 79.4% of patients relapsed after a median time of 5 months (range 0.5-66). Patients with uveitis relapsed earlier (log rank χ² 16.4 p<0.0001), while patients who lengthened the interval of administration showed a later relapse (log rank χ² 6.95 p=0.008). Uveitis (HR 2.11 CI 1.34-3.31), age at onset (HR 0.909 CI 0.836-0.987), duration of tapering (HR 0.938 CI 0.893-0.985) and to have a persistent OligoJIA (HR 0.597 CI 0.368-0.968) are significant predictors of disease relapse (Mantel-Cox χ² 34.23 p<0.001). CONCLUSIONS: Younger age at onset, uveitis, duration of tapering, and not-persistent OligoJIA seem to be independent risk factors for earlier relapse after the first TNFi withdrawal.

Convergence and divergence in Kawasaki disease and multisystem inflammatory syndrome in children: results from the COVASAKI survey.

OBJECTIVES: To compare Kawasaki disease (KD) and multisystem inflammatory syndrome (MIS-C) in children. METHODS: Prospective collection of demographics, clinical and treatment data. Assessment of type 1 interferon (IFN) score, CXCL9, CXCL10, Interleukin (IL)18, IFNγ, IL6, IL1b at disease onset and at recovery. RESULTS: 87 patients (43 KD, 44 MIS-C) were included. Age was higher in MIS-C compared to KD group (mean 31±23 vs. 94±50 months, p<0.001). Extremities abnormalities (p=0.027), mucosal involvement (p<0.001), irritability (p<0.001), gallbladder hydrops (p=0.01) and lymphadenopathy (p=0.07) were more often recorded in KD. Neurological findings (p=0.002), gastrointestinal symptoms (p=0.013), respiratory involvement (p=0.019) and splenomegaly (p=0.026) were more frequently observed in MIS-C. Cardiac manifestations were higher in MIS-C (p<0.001), although coronary aneurisms were more frequent in KD (p=0.012). In the MIS-C group, the multiple linear regression analysis revealed that a higher IFN score at onset was related to myocardial disfunction (p<0.001), lymphadenopathy (p=<0.001) and need of ventilation (p=0.024). Both CXCL9 and CXCL10 were related to myocardial disfunction (p<0.001 and p=0.029). IL18 was positively associated to PICU admission (0.030) and ventilation (p=004) and negatively associated to lymphadenopathy (0.004). IFNγ values were related to neurological involvement and lymphadenopathy (p<0.001), IL1b to hearth involvement (0.006). A negative correlation has been observed between IL6 values, heart involvement (p=0.013) and PICU admission (p<0.001). CONCLUSIONS: The demographic and clinical differences between KD e MIS-C cohorts confirm previous reported data. The assessment of biomarkers levels at MIS-C onset could be useful to predict a more severe disease course and the development of cardiac complications.

Management of JIA associated uveitis.

Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease in childhood, and is associated with uveitis in up to 20-25% of cases. Typically, the uveitis is chronic, asymptomatic, non-granulomatous and anterior. For this reason, screening for uveitis is recommended to identify uveitis early and allow treatment to prevent sight-threatening complications. The management of JIA associated uveitis requires a multidisciplinary approach and a close collaboration between paediatric rheumatologist and ophthalmologist. Starting the appropriate treatment to control uveitis activity and prevent ocular complications is crucial. Current international recommendations advise a step-wise approach, starting with methotrexate and moving on to adalimumab if methotrexate alone is not sufficient to control the disease. If the uveitis remains active despite standard treatment other therapeutic options may be considered including anti-IL6 or other anti-TNF agents such as infliximab, although the evidence for these agents is limited.

To switch or to swap? Evidence from a meta-analysis for the best treatment approach in childhood chronic uveitis resistant to the I anti-TNF.

Objective: Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF. Methods: A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed. Results: 23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (χ20.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(χ2 27.5 p < 0.0001). Conclusion: Although non-conclusive, this meta-analysis suggests that, after the first anti-TNF failure, tocilizumab and infliximab are the best available treatment for the management of cNIU.

Ultrawidefield Fluorescein Angiography and OCT Findings in Children and Young Adults with Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy.

PURPOSE: Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare genetic (CAPN5) autoimmune condition typically diagnosed in adulthood and characterized by a triad of inflammation, retinal degeneration, and neovascularization. We report novel multimodal imaging findings in children and young adults with ADNIV, and early treatment response to short-duration local and systemic corticosteroids. DESIGN: Retrospective consecutive case series. PARTICIPANTS: Ten patients aged <25 years with ADNIV and available multimodal imaging. METHODS: The medical records of patients aged <25 years with a diagnosis of ADNIV with ultrawidefield fluorescein angiography (UWFFA) and OCT data were reviewed. MAIN OUTCOME MEASURES: Ultrawidefield fluorescein angiography and OCT findings at baseline and after local corticosteroids. RESULTS: Median age at presentation was 14 years (range, 9-24 years). OCT on presentation demonstrated cystoid macular edema in 8 of 20 eyes and symptomatic vitreoretinal interface disease in 2 of 20 eyes. Initial UWFFA demonstrated retinal vascular leakage (20/20 eyes, 100%), peripheral nonperfusion (13/20 eyes, 65%), and retinal neovascularization (6/20 eyes, 30%). Retinal vascular leakage improved with local corticosteroids, and neovascularization regressed with anti-VEGF therapy. CONCLUSIONS: Ultrawidefield fluorescein angiography findings of prefibrotic ADNIV reported in adults were also present in children and young adults. Early testing for a pathogenic CAPN5 variant in at-risk children and regularly scheduled screening for uveitis and retinal vasculitis with UWFFA and OCT may prompt earlier intervention. Short-duration local steroids are effective at treating retinal vascular leakage and macular edema but are not durable, suggesting a potential role for steroid-sparing immunosuppressive therapy. Early treatment may alter the natural history of disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Childhood mixed connective tissue disease at disease onset: Evidence from a systematic review.

OBJECTIVE: Childhood Mixed Connective Tissue Disease (cMCTD) is the rarest pediatric connective tissue disease that includes features of systemic lupus erythematosus, polymyositis/dermatomyositis, juvenile idiopathic arthritis, and systemic sclerosis, identified by Sharp in 1972 and whose diagnosis remains challenging. This systematic review aims to identify clinical features at the onset of cMCTD and manifestations not currently included into the available diagnostic criteria. METHODS: A systematic literature review was performed in accordance with PRISMA guidelines 2020 using bibliographic databases: MEDLINE via PubMed and EMBASE. ELIGIBILITY CRITERIA: patients diagnosed with MCTD with onset before 18 years. STUDIES INCLUDED: registries, retrospective and prospective cohort studies, case series and reports with analysis of data on signs and symptoms of presentation. RESULTS: 39 articles were included (215 subjects, 82.5% female), mean age of 141 months (± 41 months DS, range 2.5-204). The most used criteria for the diagnosis of MCTD were the Kasukawa criteria (54.5%). The clinical manifestations described at onset were Raynaud's phenomenon (69.7%), arthritis (60.9%), muscular involvement (53.5%), dermatological signs (39.5%), swollen fingers or hands (29.3%), arthralgias (25.6%), fever (22.3%), lung involvement (14.4%), sclerodactily (13.5%), lymphadenopathy (10.7%) serositis (10.2%), esophageal involvement (6.9%), nervous system involvement (6.9%), xeroftalmia (3.7%), xerostomia (3.7%), hepatosplenomegaly (2.8%), cardiac involvement (2.8%), hepatitis (2.3%), parotiditis (2.3%), Hashimoto's thyroiditis (0.9%), ocular involvement (0.9%). CONCLUSIONS: The data from this systematic review suggest great heterogeneity of the clinical presentation of cMCTD for which there are no validated diagnostic criteria that may suggest a new diagnostic approach to allow earlier or more accurate diagnosis in the future.