Welzel T, Wildermuth AL, Deschner N, Benseler SM, Kuemmerle-Deschner JB
Pediatric rheumatology online journal •
Autoinflammatory diseases (AID) are rare chronic conditions with high disease burden, affecting children and adults. Clinically and genetically confirmed, AID can be effectively treated with targeted cytokine inhibition. In contrast, for patients with clinical AID symptoms without pathogenic gene variants, no treatment recommendations are available. Colchicine is approved and established as effective, safe and low-cost first-line therapy in Familial Mediterranean Fever. Up to now, efficacy data for colchicine in children with a clinical AID diagnosis without pathogenic gene variants are rare. This pilot study was performed to evaluate the effectiveness of colchicine in children with a clinical diagnosis of AID without pathogenic gene variants. A pilot cohort study of consecutive children with active clinical AID without pathogenic gene variants treated with colchicine monotherapy was performed between 01/2009 and 12/2018. Demographics, clinical and laboratory characteristics were determined serially. Colchicine dosing and safety were documented. Physician estimate of disease activity was captured on visual analogue scales (VAS). Complete response (PGA ≤2 plus CRP ≤0.5 mg/dL and/or SAA ≤10 mg/L) at last follow-up. partial/no response, flare characteristics and requirement for rescue therapies. Nonparametric comparison of disease activity measures. A total of 33 children were included; 39% were female. Median age at colchicine start was 3.8 years, median follow-up was 14.1 months. Clinical AID diagnoses included CAPS (24%), FMF (27%), PFAPA (43%) and unclassified AID (6%). At baseline, overall disease activity was moderate (PGA 4), inflammatory markers were elevated (CRP 12.1 mg/dL; SAA 289.2 mg/L), and 97% reported febrile flares. 55% achieved complete response, 35% showed partial response and 58% had no febrile flares at last follow-up. Inflammatory markers (SAA: p < 0.0001, CRP: p < 0.005) and disease activity (p < 0.0001) decreased significantly. Overall, 93% of children experienced improvement of flare characteristics. Colchicine was found to be effective and safe in children with a clinical AID diagnosis in the absence of pathogenic gene variants. Colchicine is a low-cost treatment option for non-organ threatening AID.
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F , et al.
Annals of the rheumatic diseases •
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. 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. 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). Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G , et al.
Annals of the rheumatic diseases •
The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be 'gold standard' on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.
Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete •
Hereditary periodic (fever) syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or joint symptoms. Some of these disorders present with organ involvement and serological signs of inflammation without fever. There is a strong serological inflammatory response with an elevation of serum amyloid A (SAA), resulting in an increased risk of secondary amyloidosis. There are monogenic disorders (familial mediterranean fever (FMF), hyper-IgD-syndrome (HIDS), cryopyrin-associated periodic syndromes (CAPS), "pyogenic arthritis, acne, pyoderma gangrenosum" (PAPA), and "pediatric granulomatous arthritis (PGA) where mutations in genes have been described, which in part by influencing the function of the inflammasome, in part by other means, lead to the induction of the production of IL-1β. In "early-onset of enterocolitis (IBD)", a functional IL-10 receptor is lacking. Therapeutically, above all, the IL-1 receptor antagonist anakinra is used. In case of TRAPS and PGA, TNF-antagonists (etanercept) may also be used; in FMF colchicine is first choice. As additional possible autoinflammatory syndromes, PFAPA syndrome (periodic fever with aphthous stomatitis, pharyngitis and adenitis), Schnitzler syndrome, Still's disease of adult and pediatric onset, Behçet disease, gout, chronic recurrent multifocal osteomyelitis (CRMO) and Crohn's disease also are mentioned.
Hereditary periodic fever syndromes (autoinflammatory syndromes) are characterised by relapsing fevers and additional manifestations such as skin rashes, mucosal manifestations, and joint pain. Some of these disorders only present with organ manifestations and serological signs of inflammation without obvious fever (e.g. PAPA and Blau syndrome). There is a strong serological inflammatory response with an elevation of serum amyloid A (risk of secondary amyloidosis). There are monogenic disorders for which the mode of inheritance and gene mutation are known, but probably also polygenic diseases which present with similar symptoms to the classic autoinflammatory syndromes. Gene mutations have been described for the monogenic disorders (FMF, HIDS, CAPS, PAPA and Blau syndrome), which lead to an induction of the production of IL-1ss. Therapeutically, the IL-1-receptor antagonist anakinra is mainly used. In the case of TRAPS and Blau syndrome, TNF antagonists may also be used. PFAPA syndrome, the Schnitzler syndrome, Still's disease of adult and pediatric onset, Behçet's disaese and Crohn's disease also are mentioned as additional possible autoinflammatory syndromes.