Zhao Y, Oliver MS, Schnabel A, Wu EY, Wang Z , et al.
Annals of the rheumatic diseases •
To develop and validate classification criteria for paediatric chronic nonbacterial osteomyelitis (CNO) jointly supported by the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR). This international initiative had 4 phases: (1) candidate items were proposed in a survey of paediatric rheumatologists, (2) criteria definition and reduction by Delphi and nominal group technique exercises, (3) criteria weighting using multicriteria decision analysis, and (4) refinement of weights and threshold score in a development cohort of 441 patients and validation in another cohort of 514 patients. The new EULAR/ACR classification criteria for CNO require typical radiographic or magnetic resonance imaging findings and bone pain as an obligatory entry criterion and exclusion criteria of malignancy, infection, vitamin C deficiency, and hypophosphatasia, followed by additive weighted criteria in 5 clinical (site of bone lesions, pattern of bone lesions, age at onset, coexisting conditions, fever) and 4 pathology/laboratory domains (bone biopsy findings if done, anaemia, C-reactive protein level, and erythrocyte sedimentation rate). A total score ≥55 is required for classification as CNO. The new criteria had a sensitivity of 82% and specificity of 98% in the validation cohort. These new classification criteria for paediatric CNO developed with international input reflect current views about CNO, have high specificity and good sensitivity, and provide a key foundation for future CNO research.
Gerritsma AM, Sutera D, Cantarini L, Cattalini M, Lachmann HJ , et al.
Clinical and experimental rheumatology •
To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly.
Theodoropoulou K, Wittkowski H, Busso N, Von Scheven-Gête A, Moix I , et al.
Frontiers in immunology •
The inflammasome has been recognized as one of the key components of innate immunity. Gain-of-function mutations in the exon 3 of gene have been implicated in inflammatory diseases suggesting the presence of functionally important sites in this region. Q703K (c.2107C>A, p.Gln703Lys, also known in the literature as Q705K) is a common variant of , that has been considered to be both clinically unremarkable or disease-causing with a reduced penetrance. We aimed to investigate the potential genetic impact of the variant Q703K in patients with recurrent fever presenting with two autoinflammatory diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and CAPS (cryopyrin-associated periodic syndrome), as well as with undefined autoinflammatory disease (uAID). This is an international multicentric observational retrospective study characterizing the clinical phenotype of patients presenting with recurrent fever suspected to be of auto-inflammatory origin and where the Q703K variant was found. Monocytes of parents of 6 Q703K+ PFAPA patients were studied and levels of pro-inflammatory cytokines produced by monocytes of Q703K+ and Q703K- parents have been compared by ELISA. We report 42 patients with the Q703K genetic variant: 21 were PFAPA patients, 6 had a CAPS phenotype, and 15 had an uAID. The phenotypes of PFAPA, CAPS and uAID were quite similar between Q703K positive and negative patients with the exception of increased prevalence of pharyngitis in the Q703K positive CAPS population compared to the negative one. The production of IL-1β was not significantly different between Q703K+ and Q703K- monocytes from asymptomatic parents. The evidence we report in our study shows an increased prevalence of Q703K in patients with autoinflammatory diseases, suggesting an association between the Q703K variant and the risk of PFAPA, CAPS and uAID syndromes. However, we did not show a functional effect of this mutation on the inflammasome basal activity.
Vanoni F, Caorsi R, Aeby S, Cochard M, Antón J , et al.
Pediatric rheumatology online journal •
Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far. A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance. The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients. Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG •
Autoinflammatory diseases encompass a group of inflammatory diseases that are non-infectious, non-allergic, non-autoimmune and non-immunodeficient. The term was initially coined for a small group of familial periodic fever syndromes of which familial Mediterranean fever (FMF) is the most common and best known. Genetic and molecular analyses demonstrated for the majority of these diseases an impairment of inflammasomes to cause an increased activity of an interleukin-1-dependent inflammatory response. Over the last years an increasing number of either rare hereditary syndromes or acquired common diseases could be summarized under the designation of autoinflammatory disease, thus creating an emerging new rubric of inflammatory diseases. Many of them display cutaneous manifestations as both concomitant or more rarely main symptoms. To name some of them like erysipelas-like erythema in FMF; urticaria-like rashes in tumor necrosis factor receptor 1- or cryopyrin-associated periodic syndromes (TRAPS, CAPS), hyperimmunoglobulin D syndrome (HIDS) or Schnitzler syndrome; pyoderma gangrenosum and acne in PAPA syndrome; or behçetoid aphthous ulcerations in HIDS and PFAPA syndrome. Based on the new insights into pathogenesis one increasingly realizes the good response of these diseases to IL-1 antagonist therapies.
Proceedings of the National Academy of Sciences of the United States of America •
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
