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Background The choice of the initial biological therapy for patients with suspected autoinflammatory diseases and not conclusive genetic test remains challenging. Objectives To assess the clinical response to the initial biological therapy in pediatric patients with suspected autoinflammatory disease with no genetic diagnosis. Methods We retrospectively reviewed the clinical charts of patients followed in our clinic who started empirical biological therapy after being diagnosed with suspected autoinflammatory disease(sAID) due to the intensity of their symptoms and no response to colchicin or FAMEs. Next generation sequencing using an immune deficiency/dysregulation(115 genes) and autoinflammatory panel(12 genes) was negative/inconclusive in all patients. Results We identified 9 patients:6/9 were male, median age at fever onset 1.33 years old IQR(0.46-4), age at diagnosis of sAID 3.8 years old IQR(1.75-7). Clinical presentation included fever(9/9), abdominal pain and arthromyalgia(7/9), aphthous(6/9), headache, rash and adenopathy(5/9), delayed growth(4/9), tonsillitis and pericarditis(3/9) as well as diarrhea and pleuritis(2/9). One patient presented with stroke, cutaneous lesions, vasculopathy and haemolytic uraemic syndrome and 1 patient with amyloidosis and secondary hepatosplenomegaly. None of the children suffered from uveitis or meningitis. The flares lasted a median of 14 days(IQR 8-20). Two patients had persistent symptoms. Their mean/median lab values are shown at table. 4/9 patients had homozygous mutations with uncertain significance, heterozygous mutations or polymorphism but their symptoms or familiar study was not suggestive of the corresponding AID. One patient had an heterozygous mutation in MEFv (p.P3696,p.R408q) and also a CECR1 heterozygous mutation with uncertain significance, one patient had pR92Q heterozygous mutation in TNFRSF1A, one patient had MEFv pR202Q homozygous mutation, other patient had a NOD-2 heterozygous mutation and the patient with amyloidosis had INO80 deficiency and a NOD2 mutation (p.A918D). All patients responded to steroid therapy; subsequently 8/9 received anti IL-1Receptor kineret as first biological therapy and 1/9 with suspected vasculopathy received anti-TNF. Response to IL-1R antagonist was complete in 3/8 and partial in 4/8 children;1/8 showed no response. 2/8 patients were switched to anti-TNF: One each to etanercept and Infliximab with good response. The patient with amyloidosis was changed to anti IL-6R with incomplete response but clear improvement compared to anti Il-1R response. The patient with suspected vasculopathy and initial anti-TNF treatment had partial response with no recurrent stroke but persistent skin lesions. Conclusion An important group of patients with sAID lack genetic confirmation. Empirical use of IL-1R antagonist is promising but not effective in all patients as it was observed in our case series,where 5/8 children showed partial or no response,3/5 needing a second biologic treatment in form of anti-TNF due to persistent moderate-severe symptoms. A model to predict the response to different therapeutic strategies, based on clinical features and immunological profile (including inflammatory cytokines) might help to choose the most appropriate immunomodulatory treatment. Disclosure of Interests None declared

IMPORTANCE: Treatment of infantile hemangioma (IH) with topical timolol in the first 2 months of life (early proliferative phase) may prevent further growth and the need for treatment with oral propranolol. To our knowledge, no studies have determined whether beginning early treatment with timolol for IH is better than in other proliferative stages. OBJECTIVE: To evaluate the efficacy and safety of timolol maleate solution, 0.5%, for the early treatment of IH in infants younger than 60 days. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, double-blind, placebo-controlled, phase 2a pilot clinical trial included patients aged 10 to 60 days with focal or segmental hemangiomas (superficial, deep, mixed, or minimal/arrested growth). Patients were randomly assigned to treatment with topical timolol maleate solution, 0.5%, or placebo twice daily for 24 weeks. Changes in lesion size (volume, thickness) and color were evaluated from photographs taken at 2, 4, 8, 12, 24, and 36 weeks. Vital signs and adverse effects were recorded at each visit. The study was carried out from November 2015 to January 2017, and data analyses were completed in September 2019. MAIN OUTCOMES AND MEASURES: The primary outcome of complete or nearly complete IH resolution and the secondary outcomes of changes in lesion thickness, volume, and color were evaluated by a blinded investigator. RESULTS: Of the 69 patients recruited, the mean (SD) age was 48.4 (10.6) days; 55 (80%) were female; and 51 (74%), 11 (16%), 6 (9%), and 1 (1%) had superficial, mixed, abortive, or deep IHs, respectively. The IHs were localized, segmental, or indeterminate in 60 (87%), 7 (10%), and 2 (3%) patients, respectively. The IHs were located on the head and/or neck (n = 23 [33%]) or other body sites (n = 46 [67%]). The study was completed by 26 of 33 (79%) patients receiving timolol and 31 of 36 (86%) receiving placebo. There were no significant differences between timolol and placebo for complete or nearly complete IH resolution at 24 weeks (n = 11 [42%] vs n = 11 [36%]; P = .37). The odds ratio of complete or almost complete response vs no response at week 24 was 1.33 (95% CI, 0.45-3.89). There were no between-group differences in IH size (volume, thickness). An improvement in color was observed at week 4 in the timolol group, and timolol was well tolerated with no systemic adverse effects. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, results demonstrated that topical timolol is well tolerated for the treatment of early proliferative IH but provides limited benefit in lesion resolution when given during the early proliferative stage. TRIAL REGISTRATION: EudraCT Identifier: 2013-005199-17.

BACKGROUND Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P