Background Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. Methods Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. Results The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). Conclusion Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA—associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.

Objective: To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA).Methods: In this multinational, multicenter study, pediatric rheumatologists and hemato‐oncologists entered patient data collected retrospectively into a web‐based database.Results: A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d‐dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre‐MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one‐third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%.Conclusion: This study provides information on the clinical spectrum and current management of systemic JIA–associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.

Objective: To determine cutoff values for defining the states of inactive disease (ID), low disease activity (LDA; or minimal disease activity), moderate disease activity (MDA), and high disease activity (HDA) using the clinical (3‐variable) Juvenile Arthritis Disease Activity Score (cJADAS).Methods: For selection of cutoffs, data from a clinical database including 609 children with juvenile idiopathic arthritis (JIA) were used. Optimal cutoffs were determined against external criteria by calculating the 75th and 90th percentile (for ID and LDA) and 10th and 25th percentile (for HDA) of cumulative score distribution and through receiver operating characteristic curve analysis. External criteria included definitions for ID and LDA cutoffs and therapeutic decisions for HDA cutoffs. MDA cutoffs were set at the score interval in‐between LDA and HDA cutoffs. Crossvalidation was performed using 2 JIA patient samples (n = 485) and was based on assessment of construct and discriminant validity.Results: The selected cutoffs were as follows: ≤1 for ID in both oligoarthritis and polyarthritis; ≤1.5 and ≤2.5 for LDA in oligoarthritis and polyarthritis, respectively; 1.51–4 and 2.51–8.5 for MDA in oligoarthritis and polyarthritis, respectively; and >4 and >8.5 for HDA in oligoarthritis and polyarthritis, respectively. In crossvalidation analyses, the cutoffs showed a strong ability to discriminate between disease activity states defined subjectively by physicians and parents, levels of pain, and presence/absence of functional impairment and disease damage.Conclusion: Cutoff values for classifying various disease states in nonsystemic JIA using the cJADAS were developed. The cutoffs revealed good measurement characteristics in crossvalidation analyses and are suited for application in clinical practice and research.