An International Delphi Survey for the Definition of the Variables for the Development of New Classification Criteria for Periodic Fever Aphtous Stomatitis Pharingitis Cervical Adenitis (PFAPA).

BACKGROUND: Diagnosis of Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) is currently based on a set of criteria proposed in 1999 modified from Marshall\u27s criteria. Nevertheless no validated evidence based set of classification criteria for PFAPA has been established so far. The aim of this study was to identify candidate classification criteria PFAPA syndrome using international consensus formation through a Delphi questionnaire survey. METHODS: A first open-ended questionnaire was sent to adult and pediatric clinicians/researchers, asking to identify the variables thought most likely to be helpful and relevant for the diagnosis of PFAPA. In a second survey, respondents were asked to select, from the list of variables coming from the first survey, the 10 features that they felt were most important, and to rank them in descending order from most important to least important. RESULTS: The response rate to the first and second Delphi was respectively 109/124 (88%) and 141/162 (87%). The number of participants that completed the first and second Delphi was 69/124 (56%) and 110/162 (68%). From the first Delphi we obtained a list of 92 variables, of which 62 were selected in the second Delphi. Variables reaching the top five position of the rank were regular periodicity, aphthous stomatitis, response to corticosteroids, cervical adenitis, and well-being between flares. CONCLUSION: Our process led to identification of features that were felt to be the most important as candidate classification criteria for PFAPA by a large sample of international rheumatologists. The performance of these items will be tested further in the next phase of the study, through analysis of real patient data

Recommendations for the management of autoinflammatory diseases.

Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥ 80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD

In silico validation of the autoinflammatory disease damage index

Introduction Autoinflammatory diseases can cause irreversible tissue damage due to systemic inflammation. Recently, the Autoinflammatory Disease Damage Index (ADDI) was developed. The ADDI is the first instrument to quantify damage in familial Mediterranean fever, cryopyrin-associated periodic syndromes, mevalonate kinase deficiency and tumour necrosis factor receptor-associated periodic syndrome. The aim of this study was to validate this tool for its intended use in a clinical/research setting. Methods The ADDI was scored on paper clinical cases by at least three physicians per case, independently of each other. Face and content validity were assessed by requesting comments on the ADDI. Reliability was tested by calculating the intraclass correlation coefficient (ICC) using an â observer-nested-within-subject\u27 design. Construct validity was determined by correlating the ADDI score to the Physician Global Assessment (PGA) of damage and disease activity. Redundancy of individual items was determined with Cronbach\u27s alpha. Results The ADDI was validated on a total of 110 paper clinical cases by 37 experts in autoinflammatory diseases. This yielded an ICC of 0.84 (95% CI 0.78 to 0.89). The ADDI score correlated strongly with PGA-damage (r=0.92, 95% CI 0.88 to 0.95) and was not strongly influenced by disease activity (r=0.395, 95% CI 0.21 to 0.55). After comments from disease experts, some item definitions were refined. The interitem correlation in all different categories was lower than 0.7, indicating that there was no redundancy between individual damage items. Conclusion The ADDI is a reliable and valid instrument to quantify damage in individual patients and can be used to compare disease outcomes in clinical studies

Classification criteria for autoinflammatory recurrent fevers.

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\u27 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

Correspondence on “Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry” by Machado et al

We read with great interest the article by Machado et al who describe safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal disease. 1 The authors observed that vaccine against SARS-CoV-2 is well tolerated with rare report of I-RMD flare and very rare reports of serious adverse events. We observed that the authors included only 27 patients with autoinflammatory diseases. We thus propose to complete their observation with the result of our study about 190 patients with autoinflammatory disease (AID). A web survey assessing adverse effects after COVID-19 vaccination was sent on 7-30 June 2021 to patients with AID followed in the French national adult AID reference centre, and already included in the Juvenile Inflammatory Rheumatism (JIR) cohort. The patients were asked whether they had received a COVID-19 vaccination, the type of vaccine and number of injections. Severe adverse events were defined by the need for hospitalisation. Local reaction, fever, headache, arthralgia, myalgia, allergic reaction, fatigue, nausea, adenopathy, heart disorder, venous thromboembolism and stroke were monitored after the first and the second injection. The survey was sent by email to 445 patients with AID: 225 (50%) patients answered it, 168 aged between 18 and 55 years old and 57 aged above 55 years old. Among the 190 patients who received two doses of COVID-19 vaccines (online supplemental table), most patients had familial Mediterranean fever (FMF) (n=128, 67.4%); other AID were undefined systemic AID (n=20), TNF-α receptor-associated periodic syndrome (n=13), cryopyrin-associated periodic syndrome (n=9), adult-onset still disease (n=9), mevalonate kinase deficiency (n=7) and A20 haploinsufficiency (n=4). Eleven patients declared also having AA amyloidosis (5.7%). Colchicine was the most used treatment (n=138, 72.6%); 37 (19.5%) patients were on biotherapy, mostly interleukin-1 inhibitors (n=33) and 15 patients were not taking any treatment. Forty-six patients had already contracted SARS-CoV-2. Out of the 190 (84.4%) vaccinated patients with AID, BNT162b2 (Pfizer/ BioNTech) (n=157, 82.6%) and ChAdOx1 nCoV-19 (AstraZeneca) (n=22, 11.5%) were the most common vaccines; few patients received CX-024414 (Moderna) (n=11, 5.8%). Eighty-eight patients (46%) developed mild adverse events after the first injection and 70 patients (54%) after the second injection. Among the 153 patients who received BNT162b2, tenderness at the injection site was the most reported event (n=39, 25.5%); others were myalgia (n=28, 18.3%), fever (n=20, 13%) and headache (n=16, 10.5%). Concerning ChAdOx1 nCoV-19, reported events were fever (n=13, 59%), myalgia (n=11, 50%) and intense fatigue (n=2, 9%). Concerning CX-024414, four patients reported fever and myalgia (36%). No severe adverse event requiring hospitalisation has been reported. Twelve patients with FMF (9.3%) reported a mild flare after the first injection, which did not require hospitalisation. No vaccinated patient had developed COVID-19 after the second vaccine injection. Altogether, this study shows that adverse event of COVID-19 vaccination in patients with AID are similar to the expected adverse effects reported in the general population. 2 Especially among patients with FMF on colchicine treatment, the vaccine is very safe and should be highly recommended to patients with risk factors of severe COVID-19, since we previously reported death among such patients with FMF. 3 It also suggests that COVID-19 vaccination does not usually trigger an AID flare; these data were also reported in patients with autoimmune diseases 4 and AID. 5 To our knowledge, this is the largest study describing the effects of COVID-19 vaccination among patients with AID: the vaccine is well tolerated; these data combined with the results from Machado et al 1 could reassure patients displaying immune systemic disorders including AID patients who are still hesitant about COVID-19 vaccination, especially in the actual context of the resurgence of the epidemy

Correspondance on ‘Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases’

International audienc

Infectious adverse events in children with Juvenile Idiopathic Arthritis treated with Biological Agents in a real-life setting: Data from the JIRcohorte

OBJECTIVES: The main objective of our study is to assess the infectious adverse events occurring in juvenile idiopathic arthritis (JIA) children treated with biological agents. METHODS: Patients were selected from the retrospective module of the JIRcohorte, data concerning the period between January 2001 and August 2015. All infectious adverse events (IAE) were retrieved. For every infectious side effect, the date, the severity, the need for a hospitalization, the type of pathogen and the affected organ were noted. Incidence rates were expressed in number of events per 100 person-years (100p-y), and OR were calculated. RESULTS: Six hundred seventy-seven patients with JIA were included in the study. A total of 3075.4 person-years of exposure were analyzed. One hundred eighty-four infectious events were described (6.0 events/100 p-y): 15.5/100 p-y with tocilizumab (TCZ), 9.6/100 p-y with Canakinumab (CAN), 7.4/100 p-y with abatacept (ABA), 6.9/100 p-y with Golimumab (GOL), 6.7/100 p-y with Anakinra (ANA), 6.3/100 p-y with Infliximab, 4.8/100 p-y with Etanercept, and 3.7/100 p-y with Adalimumab. Risk of developing an infection was significantly higher with IL-6 antagonists or IL-1 antagonists than with TNF-inhibitor. Forty point eight percent of the infectious adverse events (IAE) affected the upper respiratory tract or the Ear, nose and throat (ENT) system. Twelve infectious adverse events were described as severe or very severe (0.4/100p-y). No case of tuberculosis or death was reported. CONCLUSION: Infectious complications with biologics occurring in children treated for JIA are rare, and in most of the cases have a mild or moderate severity, affecting mainly the upper respiratory tract or the ENT.status: publishe

Evidence Based Recommendations For Diagnosis And Treatment Of Tumor Necrosis Factor Receptor-1 Associated Periodic Syndrome (Traps)

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Evidence Based Recommendations For Genetic Diagnosis Of Familial Mediterranean Fever

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