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Purpose: A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population., Methods: Patients' and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1β were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics., Results: Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1β signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1β resulted in concentration-dependent LRG1 release., Conclusion: Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1β signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD., (© 2022. The Author(s).)

Objectives: Some adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19., Methods: Using the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated., Results: 607 CYP with RMDs <19 years old from 25 different countries with SARS-CoV-2 infection were included, the majority with juvenile idiopathic arthritis (JIA; n=378; 62%). Forty-three (7%) patients were hospitalised; three of these patients died. Compared with JIA, diagnosis of systemic lupus erythematosus, mixed connective tissue disease, vasculitis, or other RMD (OR 4.3; 95% CI 1.7 to 11) or autoinflammatory syndrome (OR 3.0; 95% CI 1.1 to 8.6) was associated with hospitalisation, as was obesity (OR 4.0; 95% CI 1.3 to 12)., Conclusions: This is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised., Competing Interests: Competing interests: RC reports personal AstraZeneca shares, unrelated to this manuscript. IK-P reports personal fees by Novartis, SOBI, Chugai, Pfizer, AbbVie, BMS, all unrelated to this manuscript. FOR reports consulting/speaker’s fees from Abbvie, Novartis, Pfizer and Sobi, all unrelated to this manuscript. NMW reports personal consultant fees from UCB, BMS, all unrelated to this manuscript. AS reports personal fees from lectures for AbbVie, Celltrion, MSD, Janssen, Lilly, Roche, BMS, and Pfizer, all unrelated to this manuscript. EFM reports personal consultant fees from Boehringer Ingelheim Portugal, Lda, all unrelated to this manuscript. LPCDR received support for specific activities: grants from Abbvie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal S.A., MSD, Medac, A. Menarini Portugal - Farmacêutica, S.A., Pfizer, UCB Pharma, Roche Farmacêutica Química, Lda; and non-financial support from Pfizer, and Grünenthal GmbH, all unrelated to this manuscript.PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). MN reports funding from Childhood Arthritis & Rheumatology Research Alliance, Inc (CARRA) to his informatics research and operations group at Boston Children’s Hospital in its capacity as the CARRA Data Warehouse and associated work for CARRA and the CARRA Registry and has sponsored the COVID-19 Global Pediatric Rheumatology Database study, of which he is the Principal Investigator. MN also serves as Director of Informatics for CARRA, for which he receives no direct compensation but do receive research sponsorship for CARRA-related research, development, and operations (see above). He is also a co-investigator of the CARRA Registry and site Principal Investigator at Massachusetts General Hospital. KLH reports non-personal speaker’s fees from Abbvie and grant income from BMS, UCB, and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. All other authors report no disclosures., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Systemic-onset JIA (SJIA) and adult-onset Still's disease (AOSD) are the same sporadic systemic auto-inflammatory disease. SpA is a group of inflammatory non-autoimmune disorders. We report the observations of eight patients with SJIA/AOSD who also presented features of SpA during their disease evolution and estimate the prevalence of SpA in SJIA/AOSD., Methods: This was a retrospective national survey of departments of paediatric and adult rheumatology and internal medicine. To be included, SJIA patients had to fulfil the ILAR criteria, AOSD patients the Yamaguchi or Fautrel criteria, and all patients the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial or peripheral SpA, ESSG criteria for SpA or Classification Criteria for Psoriatic Arthritis (CASPAR) criteria for PsA. The data were collected with a standardized form., Results: Eight patients (five adults) were identified in one paediatric and two adult departments. In all but one patient, SpA manifestations occurred several years after SJIA/AOSD onset [mean (s.d.) delay 6.2 (3.8) years]. Two patients had peripheral and three axial SpA, and four later exhibited PsA and one SAPHO syndrome. The prevalence of SpA in an adult cohort of 76 patients with AOSD was 6.58% (95% CI 2.17, 14.69), greater than the prevalence of SpA in the French general population (0.3%; 95% CI 0.17, 0.46). The prevalence of SpA in an SJIA cohort of 30 patients was 10% (95% CI 2.11, 26.53), more than that reported in the general population of industrialized countries, estimated at 0.016-0.15%., Conclusion: While the temporal disassociation between SpA and AOSD in most cases might suggest a coincidental finding, our work raises the possibility of an SpA/AOSD spectrum overlap that needs further study., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: There is little known about SARS-CoV-2 infection in patients with systemic autoinflammatory disease (SAID). This study aimed to describe epidemiological features associated with severe disease form and death. Mortality between patients with and without SAID hospitalised for SARS-CoV-2 infection was compared., Methods: A national multicentric prospective cohort study was conducted from the French Rheumatic and Musculoskeletal Diseases (RMD) COVID-19 cohort. Patients with SAID were matched with patients with non-SAID on age±7 years, gender and number of comorbidities to consider important confounding factors. Impact of SAID on severity of SARS-CoV-2 infection was analysed using multinomial logistic regression for severity in three classes (mild, moderate and severe with mild status as reference). Fine-Gray regression model for length of hospital stay and binomial logistic regression model for risk of death at 30 days., Results: We identified 117 patients with SAID (sex ratio 0.84, 17 children) and compared them with 1545 patients with non-autoinflammatory immune-mediated inflammatory disorders (non-SAID). 67 patients had a monogenic SAID (64 with familial Mediterranean fever). Other SAIDs were Behçet' disease (n=21), undifferentiated SAID (n=16), adult-onset Still disease (n=9) and systemic-onset juvenile idiopathic arthritis (n=5). Ten adults developed severe form (8.6%). Six patients died. All children had a benign disease. After matching on age±7 years, sex and number of comorbidities, no significant difference between the two groups in length of stay and the severity of infection was noted., Conclusion: As identified in the whole French RMD COVID-19 cohort, patients with SAID on corticosteroids and with multiple comorbidities are prone to develop more severe COVID-19 forms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA)., Methods: Data from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively)., Results: Three hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment., Conclusion: The results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time. [ClinicalTrials.gov: NCT01399281 and NCT03932344]., (Copyright © 2022 by the Journal of Rheumatology.)

Introduction: New Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants., Objectives: To evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort., Methods: Baseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients., Results: Since November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC-). The majority of the EPCC- patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC- patients (69%, p < 0.0001), who were treated in a higher proportion with steroid or NSAID on demand (p = 0.003 and 0.008, respectively). Four percent of patients received Anti-IL-1 treatment., Conclusions: The combination of EPCC and the 2018 INSAID classification of MEFV variants is able to identify two distinct groups of patients, which differ in clinical characteristics, therapeutic approach and response to treatment. EPCC+ patients displayed the typical features of FMF, while EPCC- patients had a more variable phenotype with a lower percentage of response to colchicine., Competing Interests: Declearation of Competing Interest The authors do not declare a competing interest for the present study, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19., Methods: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting., Results: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19., Competing Interests: Competing interests: AA, AN, HB, FC, GDM, RG, CM-C and JRC have nothing to declare. PMM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. G-RRB has received consulting and/or speaker’s fees from Abbvie, Gilead, Lilly, Roche, Sanofi, Pfizer all unrelated to this manuscript. IK-P has received consulting and/or speaker’s fees from Novartis, SOBI, Amgen, CHUGAI, Pfizer, LFB, Novimmune, Abbvie and PAtent for AIDAI score AVR has received speaker fees/Honoraria from Abbvie, Lilly, Roche, UCB, SOBI and Novartis all unrelated to this manuscript. DGM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. XM has received consulting and/or speaker’s fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in paediatric BD and more precisely to look for a regulatory T lymphocyte (Treg)/Th17 imbalance., Methods: T cell subpopulations were analysed by flow cytometry in the peripheral blood of paediatric patients with acute BD (aBD; n = 24), remitting BD (rBD; n = 12) and in healthy controls (HCs; n = 24). Tregs (CD4+CD25hiCD127-/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4 and HLA-DR expression), CD4+ and CD8+ T cells producing IFN-γ (Th1 and Tc1) or IL-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and heat shock protein 60) stimulation were enumerated., Results: Th17 (1.9- and 5.1-fold) and Tc17 (4.0- and 2.0-fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HCs. Th17 frequency under antigenic stimulation was also higher in patients than in HCs. The percentage and number of Tregs and activated Tregs in patients and in HCs were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+ T cells., Conclusion: There is a bias towards Th17 polarization in aBD and rBD in children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+ T cell differentiation into Th1 and Th17 cells. Thus, in paediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the Th cell response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease usually presenting before the age of 10 years. Non-specific clinical features or late-onset presentation may delay its diagnosis until adulthood., Objective: To determine whether DADA2 diagnosed in adulthood is associated with specific characteristics compared to DADA2 diagnosed in childhood., Methods: We pooled a cohort of 12 adult DADA2 patients followed in France with cases identified through a systematic literature review. For each patient, we determined the type of clinical presentation and assessed six key organ involvements., Results: A total of 306 cases were included. Among the 283 patients with available data regarding age at diagnosis, 140 were diagnosed during adulthood and 143 during childhood. The vascular presentation of DADA2 was more frequent in the adult diagnosis group (77.9% vs. 62.9%, p < 0.01), whereas the hematological presentation (bone marrow failure) prevailed in the pediatric diagnosis group (10.0% vs. 20.3% p = 0.02). In patients with vasculopathy, severe skin manifestations developed in 35% and 10% of the adult and pediatric diagnosis groups, respectively. Conversely, fewer strokes occurred in the adult group presenting with systemic vasculopathy (54% vs. 81%). Symptomatic humoral immune deficiency (HID) was rarely a clinical presentation in itself (5% and 2.8%) but accompanied other phenotypes of DADA2, especially the hematological phenotype in the adult group (33% vs. 4%)., Conclusion: DADA2 diagnosed in adulthood presents more often with a vascular phenotype and less often with bone marrow failure than DADA2 diagnosed in childhood. Adults diagnosed with DADA2 vasculopathy display more severe skin involvement but fewer strokes., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest for this study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Interleukin (IL)-1 inhibitors represent the main treatment in patients with colchicine-resistant/intolerant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS). However, the reasons for the use of IL-1 inhibitors in these diseases are still not completely clarified., Objective: Identify real-life situations that led to initiating anakinra or canakinumab treatment in hereditary recurrent fevers (HRFs), combining data from an international registry and an up-to-date literature review., Patients and Methods: Data were extracted from the JIRcohort, in which clinical information (demographic data, treatment, disease activity, and quality of life) on patients with FMF, MKD, and TRAPS was retrospectively collected. A literature search was conducted using Medline, EMBASE, and Cochrane databases., Results: Complete data of 93 patients with HRF (53.8% FMF, 31.2% MKD, and 15.1% TRAPS) were analyzed. Data from both the registry and the literature review confirmed that the main reasons for use of IL-1 blockers were the following: failure of previous treatment (n = 57, 61.3% and n = 964, 75.3%, respectively), persistence of disease activity with frequent attacks (n = 44, 47.3% and n = 1,023, 79.9%) and/or uncontrolled inflammatory syndrome (n = 46, 49.5% and n = 398, 31.1%), severe disease complication or associated comorbidities (n = 38, 40.9% and n = 390, 30.4%), and worsening of patients' quality of life (n = 36, 38.7% and n = 100, 7,8%). No reasons were specified for 12 (16.4%) JIRcohort patients and 154 (12%) patients in the literature., Conclusion: In the absence of standardized indications for IL-1 inhibitors in crFMF, MKD, and TRAPS, these results could serve as a basis for developing a treat-to-target strategy that would help clinicians codify the therapeutic escalation with IL-1 inhibitors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vinit, Georgin-Lavialle, Theodoropoulou, Barbier, Belot, Mejbri, Pillet, Pachlopnik, Poignant, Rebelle, Woerner, Koné-Paut and Hentgen.)

Objective: To better define the clinical distinctions between the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related paediatric inflammatory multisystem syndrome (PIMS) and Kawasaki disease (KD)., Methods: We compared three groups of patients: group 1, cases from our national historic KD database (KD-HIS), before the SARS-CoV-2 pandemic; group 2, patients with KD admitted to an intensive care unit (KD-ICU) from both our original cohort and the literature, before the SARS-CoV-2 pandemic; and group 3, patients with PIMS from the literature., Results: KD-HIS included 425 patients [male:female ratio 1.3, mean age 2.8 years (s.d. 2.4)], KD-ICU 176 patients [male:female ratio 1.3, mean age 3.5 years (s.d. 3.1)] and PIMS 404 patients [male:female ratio 1.4, mean age 8.8 years (s.d. 3.7)]. As compared with KD-HIS patients, KD-ICU and PIMS patients had a higher proportion of cardiac failure, digestive and neurological signs. KD-ICU and PIMS patients also had a lower frequency of typical KD-mucocutaneous signs, lower platelet count, higher CRP and lower sodium level. As compared with KD-HIS and KD-ICU patients, PIMS patients were older and more frequently had myocarditis; they also had fewer coronary abnormalities and lower sodium levels. Unresponsiveness to IVIG was more frequent in KD-ICU than KD-HIS and PIMS patients., Conclusion: On clinical grounds, KD-HIS, KD-ICU and PIMS might belong to a common spectrum of non-specific pathogen-triggered hyperinflammatory states. The causes of increasing inflammation severity within the three entities and the different effects on the heart remain to be determined., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In the context of the current coronavirus disease 2019 (COVID-19) pandemic, cutaneous lesions are being described. Here, we report on a 13-year-old girl with SARS-CoV-2-associated Henoch-Schönlein purpura and Epstein-Barr virus (EBV) infection. She presented without any respiratory symptoms, only a purpuric skin rash, abdominal pain, low-grade fever, and pharyngitis. Virology tests by polymerase chain reaction (PCR) were positive for SARS-CoV-2 and EBV. The potential association of Henoch-Schönlein purpura and SARS-CoV-2 should be kept in mind in order to reduce the spread of the virus, particularly in children with few respiratory symptoms., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2021 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Still's disease and Kawasaki disease (KD) today belong to the group of cytokine storm syndromes, a pathophysiological set related to excessive activation of the innate immune response. We present here a personal vision of what can link these two diseases, taking up their concepts at their beginning. By their many clinical and physiopathological similarities, we conclude that they constitute a common spectrum whose fate is modified by subtle differences in terms of adaptive response that could, in part, be driven by genetic factors.

Objectives: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies., Methods: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting., Results: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates., Conclusions: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19., Competing Interests: Competing interests: AA, AN, HB, FC, GDM, RG, CM-C and JRC have nothing to declare. PMM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. GRB has received consulting and/or speaker’s fees from Abbvie, Gilead, Lilly, Roche, Sanofi, Pfizer all unrelated to this manuscript. IK-P has received consulting and/or speaker’s fees from Novartis, SOBI, Amgen, CHUGAI, Pfizer, LFB, Novimmune, Abbvie and PAtent for AIDAI score AVR has received speaker fees/Honoraria from Abbvie, Lilly, Roche, UCB, SOBI and Novartis all unrelated to this manuscript. DGM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. XM has received consulting and/or speaker’s fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The major role of interleukin (IL)-1 in the pathogenesis of hereditary recurrent fever syndromes favored the employment of targeted therapies modulating IL-1 signaling. However the best use of IL1 inhibitors in terms of dosage is difficult to define at present. Methods: In order to better understand the use of IL1 inhibitors in a real-life setting, our study assessed the dosage regimens of French patients with one of the four main hereditary recurrent fever syndromes (Familial Mediterranean Fever (FMF), TNF receptor associated periodic syndrome (TRAPS), cryopyrin associated periodic fever (CAPS) and mevalonate kinase deficiency). The patients were retrieved retrospectively from the JIR cohort, an international platform gathering data of patients with pediatric inflammatory diseases. Results: Forty five patients of the JIR cohort with a hereditary recurrent fever syndrome had received at least once an IL1 inhibitor (anakinra or canakinumab). Of these, 43% received a lower dosage than the one suggested in the product recommendations, regardless of the type of the IL1 inhibitor. Especially patients with FMF and TRAPS seemed to need lower treatment regimens; in our cohort none of the FMF or TRAPS patients received an intensified dose of IL-inhibitor. On-demand treatment with a short half-life IL-1 inhibitor has also been used successfully for some patients with one of these two conditions The standard dose was given to 42% of the patients; whereas an intensified dose of IL-1 inhibitors was given to 15% of the patients (44% of CAPS patients and 17% of mevalonate kinase deficiency patients). In our cohort each individual patient's need for treatment seemed highly variable, ranging from on demand treatment regimens to intensified dosage maintenance therapies depending on the activity and the severity of the underlying disease. Conclusion: IL-1 inhibitors are a good treatment option for patients with a hereditary recurrent fever syndrome, but the individual need of the dosage of IL-1 inhibitors to control the disease effectively seems highly variable. Severity, activity but also the type of the underlying disease, belong to the parameters underpinning the treat-to-target strategy implemented in an everyday life practice., Competing Interests: VH, IK, GG, MH, and SG-L received personal fees and non-financial support from Novartis and SOBI; CG and AB received non-financial support from Novartis; AP received non-financial support from SOBI. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hentgen, Koné-paut, Belot, Galeotti, Grateau, Carbasse, Pagnier, Pillet, Delord, Hofer and Georgin-Lavialle.)

Objective: Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)- and steroid-resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin-1 in patients with IVIG-resistant KD., Methods: Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient's body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C-reactive protein (CRP) levels., Results: Seventy-five percent of patients in the intention-to-treat group and 87.5% in the per-protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1-99.8%) of physician evaluations and on 100% (95% CI 73.5-100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7-81.3%]) and 6 of 12 patients (50% [95% CI 21.1-78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred., Conclusion: Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG-refractory KD., (© 2020, American College of Rheumatology.)

Objective: To evaluate the long-term efficacy and safety of canakinumab and explore prediction of response in patients with systemic juvenile idiopathic arthritis (JIA) with or without fever at treatment initiation., Methods: At enrollment, patients with active systemic JIA (ages 2 to <20 years) started open-label canakinumab (4 mg/kg every 4 weeks subcutaneously). Efficacy measures included the adapted American College of Rheumatology (ACR) Pediatric 50/70/90 criteria, the Juvenile Arthritis Disease Activity Score (JADAS), and clinically inactive disease and clinical remission on medication, evaluated by either the JADAS or ACR criteria., Results: Of the 123 patients (70 with fever and 52 without fever [fever status was not reported for 1 patient]), 84 (68.3%) completed the study (median duration 1.8 years). Comparable efficacy (adapted ACR Pediatric 50/70/90/100) was observed by day 15 in both subgroups (60.0%/48.6%/37.1%/24.3% in those with fever and 67.3%/48.1%/34.6%/19.2% in those without fever), and further increased thereafter. By month 6, clinical remission according to the JADAS or the ACR criteria was achieved in 17 (24.3%) and 26 (37.1%), respectively, of patients with fever and 9 (17.3%) and 12 (23.1%), respectively, of patients without fever. Median time to onset of clinical remission according to the JADAS or ACR criteria was 57 and 30 days, respectively, in those with fever, and 58 and 142 days, respectively, in those without fever. An adapted ACR Pediatric 50 response by day 15 was the strongest predictor of achieving clinical remission according to the JADAS (odds ratio [OR] 13 [95% confidence interval (95% CI) 4, 42]; P < 0.0001) or glucocorticoid discontinuation (OR 19 [95% CI 3, 114]; P = 0.002). Of the 71 of 123 patients (57.7%) who received glucocorticoids at study entry, 27 (38.0%) discontinued glucocorticoids and 21 (29.6%) reached a dose of <0.2 mg/kg/day, with no difference between those with and those without fever; 13 patients (10.6%) tolerated a sustained canakinumab dose reduction to 2 mg/kg every 4 weeks. No new safety findings were observed., Conclusion: Canakinumab provided rapid and sustained improvement of active systemic JIA irrespective of the presence of fever at treatment initiation., (© 2020, American College of Rheumatology.)

Objective: The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases., Methods: We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician's diagnosis served as the gold standard for the determination of specificity., Results: We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets., Conclusion: This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This article provides an overview of the main drugs to treat autoinflammatory disorders focusing on the four emblematic diseases within this group which represent, to date, the vast majority of patients with monogenic SAID; i.e. familial Mediterranean fever, mevalonate kinase deficiency, TNF receptor 1 deficiency and cryopyrin-associated periodic syndrome. We will therefore resume the evolutionary risks of the four main IL-1 dependent SAID, there treatments and monitoring tools. After having exposed the general principles, we will detail specific guidelines for the management in everyday clinical practice of patients according to the four main pathologies based on both our expertise and international recommendations. We aim herein to guide practitioners in charge of patients with common SAID towards optimal follow-up with appropriate monitoring of anti-inflammatory drugs.

Objectives: To evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study., Methods: Patients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg., Results: Of the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported., Conclusion: crFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported., Competing Interests: Competing interests: SO has been a consultant for Novartis and Speaker’s Bureau for Sobi; EB-C has been a consultant for Novartis; IF has been an Advisor for Novartis; GA has received research grants from Novartis; HO has no potential conflict of interest; SV has no potential conflict of interest; KM has received research grant from Novartis; JMK has been an Advisor for AstraZeneca, Bristol Myers Squibb, Boehringer Ingleheim and Eli Lilly; JMK has received research grants from Bristol Myers Squibb; ED is an employee of Novartis; FDB has received research grants from Novartis, Sobi, Novimmune, Abbvie, Roche and Sanofi; IK-P has been a consultant for Novartis, LBF, Sobi, CHUGAI, Pfizer and Abbvie; IK-P has received research grant (non-financial) from Sobi., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Current data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities., Methods: Multicentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ('Kawa-COVID-19'). A historical cohort of 'classical' KD served as a comparator., Results: Sixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of 'classical' KD by older age at onset 10 vs 2 years (p<0.0001), lower platelet count (188 vs 383 G/L (p<0.0001)), a higher rate of myocarditis 7/16 vs 3/220 (p=0.0001) and resistance to first IVIg treatment 10/16 vs 45/220 (p=0.004)., Conclusion: Kawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19. Trial registration number NCT02377245., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Familial Mediterranean fever (FMF), the most frequent autoinflammatory disease, is caused by mutations in the MEFV gene. It is characterized by recurrent febrile attacks of polyserositis. Liver abnormalities may develop during its course, but they remain poorly defined., Objective: To describe liver involvement in FMF patients., Methods: A systematic search was conducted through PubMed/Medline and Embase from 1946 to January 2020. All articles describing children and adults with FMF and liver involvement were included. Patients with amyloidosis were excluded. The selected full-text articles were independently reviewed by three investigators., Results: Forty-three articles were identified, of which 20 articles with a total of 99 patients were included: 74 adults, 23 children and two patients of unknown age. Ten patients had cryptogenic cirrhosis, 48 had nonalcoholic fatty liver disease (NAFLD), four had Budd-Chiari syndrome (BCS), 12 had isolated hyperbilirubinaemia and 25 had elevated liver enzymes., Conclusion: Despite a low prevalence of metabolic risk factors, FMF may be associated with NAFLD and cryptogenic cirrhosis as a consequence of chronic or recurrent inflammation. FMF patients should be regularly screened for liver injury. The latter may be prevented and treated by daily colchicine intake. The evidence was insufficient to establish an association with BCS, hyperbilirubinaemia or autoimmune hepatitis., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A few weeks after the peak of the global 2019 novel coronavirus disease pandemic, cases of shock, multisystem inflammation and severe myocarditis have occurred in children and adolescents, generating some concerns and above all many questions. An almost immediate association raised with shock syndrome related to Kawasaki disease (KD). However, in light of bo/th experience and literature have taught us about severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, and what already known on the epidemiology of KD, we suggest here the hypothesis of a new 'post-viral' systemic inflammatory disease related to excessive adaptive immune response rather than a form of KD caused by SARS-COV-2. We discuss analogies and differences between the two forms., Competing Interests: Competing interests: IK-P has received consulting fees from AbbVie, Pfizer, Roche, CHUGAI, Novartis, SOBI and Novimmune. RC has no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Castleman disease (CD) is a rare non-malignant lymphoproliferation of undetermined origin. Two major disease phenotypes can be distinguished: unicentric CD (UCD) and multicentric CD (MCD). Diagnosis confirmation is based on histopathological findings in a lymph node. We attempted to survey all cases of paediatric CD identified to date in France to set up a national registry aiming to improve CD early recognition, treatment and follow-up, within the context of a new national reference center (http://www.castleman.fr)., Methods: In 2016, we e-mailed a questionnaire to members of the French paediatric immunohaematology society, the paediatric rheumatology society and the Reference Centre for Castleman Disease to retrospectively collect cases of paediatric CD (first symptoms before age 18 years). Anatomopathological confirmation was mandatory., Results: We identified 23 patients (12 girls) with a diagnosis of UCD (n = 17) and MCD (n = 6) between 1994 and 2018. The mean age at first symptoms was 11.47 ± 4.23 years for UCD and 8.3 ± 3.4 years for MCD. The mean diagnosis delay was 8.16 ± 10.32 months for UCD and 5.16 ± 5.81 years for MCD. In UCD, the initial symptoms were isolated lymph nodes (n = 10) or lymph node associated with other symptoms (n = 7); fever was present in 3 patients. Five patients with MCD presented fever. No patients had HIV or human herpesvirus 8 infection. Autoinflammatory gene mutations were investigated in five patients. One patient with MCD carried a K695R heterozygous mutation in MEFV, another patient with MCD and Duchenne myopathy carried two variants in TNFRSF1A and one patient with UCD and fever episodes carried two heterozygous mutations, in IL10RA and IL36RN, respectively. Treatment of UCD was mainly surgical resection, steroids, and radiotherapy. Treatment of MCD included tocilizumab, rituximab, anakinra, steroids, chemotherapy, and splenectomy. Overall survival after a mean of 6.1 ± 6.4 years of follow-up, was 100% for both forms., Conclusion: Paediatric CD still seems underdiagnosed, with a significant diagnosis delay, especially for MCD, but new international criteria will help in the future. Unlike adult CD, which is strongly associated with HIV and human herpesvirus 8 infection, paediatric CD could be favored by primary activation of innate immunity and may affect life expectancy less.

We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is approximately 50 times higher compared with the general population. Arthritis was refractory to most treatment. Patients with Alagille syndrome should routinely be screened for musculoskeletal symptoms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

About 10-20% of patients with Kawasaki disease (KD) are unresponsive to intravenous immunoglobulin (IVIg) and are at increased risk of coronary artery abnormalities (CAAs). Early identification is critical to initiate aggressive therapies, but available scoring systems lack sensitivity in non-Japanese populations. We investigated the accuracy of 3 Japanese scoring systems and studied factors associated with IVIg unresponsiveness in a large multiethnic French population of children with KD to build a new scoring system. Children admitted for KD between 2011-2014 in 65 centers were enrolled. Factors associated with second line-treatment; i.e. unresponsiveness to initial IVIg treatment, were analyzed by multivariate regression analysis. The performance of our score and the Kobayashi, Egami and Sano scores were compared in our population and in ethnic subgroups. Overall, 465 children were reported by 84 physicians; 425 were classified with KD (55% European Caucasian, 12% North African/Middle Eastern, 10% African/Afro-Caribbean, 3% Asian and 11% mixed). Eighty patients (23%) needed second-line treatment. Japanese scores had poor performance in our whole population (sensitivity 14-61%). On multivariate regression analysis, predictors of secondary treatment after initial IVIG were hepatomegaly, ALT level ≥30 IU/L, lymphocyte count <2400/mm 3 and time to treatment <5 days. The best sensitivity (77%) and specificity (60%) of this model was with 1 point per variable and cut-off ≥2 points. The sensitivity remained good in our 3 main ethnic subgroups (74-88%). We identified predictors of IVIg resistance and built a new score with good sensitivity and acceptable specificity in a non-Asian population.

Objective: To assess long-term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS)., Methods: CAPS patients (ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization., Results: Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy., Conclusion: Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long-term use of canakinumab for CAPS in children ≤5 years of age., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To determine whether neutropenia is associated with increased risk for infection in patients with systemic juvenile idiopathic arthritis (sJIA) and polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ)., Methods: Data up to Week 104 from 2 phase III trials of intravenous TCZ in sJIA (n = 112; ClinicalTrials.gov, NCT00642460) and pcJIA (n = 188; ClinicalTrials.gov, NCT00988221) were pooled. Worst common toxicity criteria grade and lowest observed absolute neutrophil count (ANC) were identified for each patient. Associations between patient characteristics and lowest observed ANC were tested using univariate regression analysis. Infection and serious infection rates per 100 patient-years (PY) in periods associated with grades 1/2 and 3/4 neutrophil counts were compared with rates associated with normal neutrophil counts., Results: ANC decreased to grade ≥ 3 in 25.0% and 5.9% of sJIA and pcJIA patients, respectively, and decreases were transient. Young age (p = 0.047) and methotrexate use (p = 0.012) were positively associated with neutropenia in patients with sJIA but not in patients with pcJIA. The rate of serious infections in patients with sJIA (10.9/100 PY; 95% CI 6.8-16.5) tended to be higher than in patients with pcJIA (5.2/100 PY; 95% CI 3-8.5). No increase in rates of serious or nonserious infections was observed during periods of neutropenia in either trial., Conclusion: Patients with JIA treated with TCZ experienced transient neutropenia that was not associated with an increased number of infections.

Introduction: Conventional immunosuppressive drugs, anti-TNF alpha treatments and biotherapies are increasingly being used in non-infectious uveitis., Areas Covered: The present work was led by a multidisciplinary panel of experts, including internal medicine specialists, rheumatologists and ophthalmologists, and proposes an extensive review on the use of biological agents in non-infectious uveitis., Expert Opinion: In case of dependency to steroids or sight-threatening disease, conventional immunosuppressive drugs (methotrexate, azathioprine and mycophenolate mofetil) and/or biological therapies such as anti-TNF alpha treatments (adalimumab, infliximab) can be used to achieve and maintain disease quiescence. Interferon is an efficient immunomodulatory drug that can be proposed as second-line therapy in specific indications (eg. refractory macular edema, sight-threatening Behçet's uveitis). Other biologics, especially tocilizumab, are showing promising results. Local treatments (steroids, sirolimus etc.) can be used as adjuvant therapies in case of unilateral relapse. Therapeutic response must always be evaluated by clinical examination and appropriate ancillary investigations.

Objective: Provisional evidence-based classification criteria for hereditary periodic fever (HPF) have been recently developed. However, no consensus on how to combine clinical criteria, laboratory tests, and results of molecular analysis has been reached. The objective of this study is to understand which variables physicians consider important for the classification of patients with HPF., Methods: Two Delphi surveys were sent to health professionals in the field of autoinflammation. In the first open survey, 124 researchers could list all the variables they consider useful for the diagnosis of each monogenic periodic fever. The variables could be of any type and each researcher could complete the survey for 1 or more diseases. In the second survey, 162 researchers were asked to select, from a list of items coming from the first survey, the 10 top variables and to rank them by assigning a score from 10 to 1., Results: The response rates to the Delphi surveys were 85% for the first session and 87% for the second. The variables selected for each disease (corresponding to the third quartile, considering the total score obtained by the variables after the second Delphi survey) were 21 for mevalonate kinase deficiency, 22 for cryopyrinopathies, 18 for familial Mediterranean fever, and 20 for tumor necrosis factor receptor-associated periodic fever syndrome. A positive genetic test reached the top rank in all the HPF., Conclusion: Our process led to the identification of those features considered the most important as candidate variables to be included in a new set of evidence-based classification criteria for HPF.

Objectives: Children with Familial Mediterranean fever may suffer from musculoskeletal involvement, somewhat difficult to distinguish from juvenile spondyloarthritis. The association of these two diseases has been scarcely reported in children. Objective of this work was to define the association of familial Mediterranean fever and juvenile spondyloarthritis in France., Methods: Three cohorts of children with familial Mediterranean fever, juvenile spondyloarthritis, familial Mediterranean fever related juvenile spondyloarthritis, were retrospectively identified in the French reference center of auto-inflammatory diseases. Familial Mediterranean fever was defined according to Tel-Hashomer or Turkish pediatric criteria with at least one exon-10 MEFV-gene mutation. Juvenile spondyloarthritis was defined according to ILAR criteria. Patients with familial Mediterranean fever or juvenile spondyloarthritis were respectively compared to familial Mediterranean fever related juvenile spondyloarthritis patients., Results: Sixteen children were identified as having familial Mediterranean fever related juvenile spondyloarthritis. The male/female-ratio was 0.6, with median age at spondyloarthritis onset of 7.5years (3-16years). All carried at least one M694V variant in MEFV gene; 16.7% were HLA-B27-carriers. Compared to 83 familial Mediterranean fever patients, familial Mediterranean fever related juvenile spondyloarthritis patients had less frequently fever (P<0.01) and more frequently arthritis (P<0.05), enthesitis (P<0.001), inflammatory back pain (P<0.001), inadequate response to colchicine (P<0.05). Compared to 20 juvenile spondyloarthritis patients, familial Mediterranean fever related juvenile spondyloarthritis patients less often received non-steroidal anti-inflammatory drugs (P<0.01) and anti-tumor necrosis factor drugs (P<0.001)., Conclusions: Familial Mediterranean fever may be associated with typical pattern of juvenile spondyloarthritis. These patients, with less response to colchicine, should be diagnosed earlier and treated as for jSpA., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusion: 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.

Objectives: To assess the efficacy and safety of adalimumab on uveitis in patients with early onset, chronic, juvenile idiopathic arthritis (JIA)-associated or idiopathic anterior uveitis and an inadequate response to topical steroids and methotrexate (MTX)., Methods: Patients aged 4 years or more with ocular inflammation quantified by laser flare photometry (LFP) ≥30 photon units/ms were double-blindly randomised (1:1) to 2 groups, one treated with placebo and one with adalimumab subcutaneously at a dose of 24 mg/m 2 in patients aged <13 years, 40 mg in the others, every other week. The primary outcome was response at month 2 (M2) defined as a 30% reduction of inflammation on LFP in the assessable eye with more severe baseline inflammation and no worsening on slit lamp examination. From M2 to M12, all patients received adalimumab., Results: At M2, among 31 patients included in intention-to-treat analysis, there were 9/16 responders on adalimumab and 3/15 on placebo (P=0.038, Χ 2 test; relative risk=2.81, 95% CI 0.94 to 8.45; risk difference: 36.3%, 95% CI 2.1 to 60.6); there was no significant difference using the Standardised Uveitis Nomenclature classification criteria of improvement. Thirty patients continued the trial after M2 and received adalimumab (open-label phase), 29 reached M12. There were seven serious adverse events none related to study treatment., Conclusions: This trial is in favour of using adalimumab in patients with early onset, chronic anterior uveitis, which is in most cases associated with JIA, in case of inadequate response to topical therapy and MTX. LFP could be a valuable tool to assess early treatment efficacy., Trial Registration Number: NCT01385826., Competing Interests: Competing interests: PQ has received speakers’s fees (

Objectives: To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA)., Methods: We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors associated with response to tocilizumab (assessed using NIH score)., Results: Forty-six patients with TA were included, with a median age of 43 years [29-54], and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 [2-3] at baseline to 0 [0-1] and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg [8-19] at baseline to 4 mg [5-21] and 5 mg [4.5-9] at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% [CI 95%; 0.7-0.95], 72% [CI 95%; 0.55-0.95] and 48% [CI 95%; 0.2-0.1] at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 [CI 95%; 1.08-29], p = 0.041), and C-reactive protein level (HR 1.16 [CI 95%; 1.01-1.31], P = 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p = 0.02)., Conclusion: This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.

Background: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares., Methods: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab., Results: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years)., Conclusions: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).

Monogenic auto-inflammatory diseases are characterized by genetic abnormalities coding for proteins involved in innate immunity. They were initially described in mirror with auto-immune diseases because of the absence of circulating autoantibodies. Their main feature is the presence of peripheral blood inflammation in crisis without infection. The best-known auto-inflammatory diseases are mediated by interleukines that consisted in the 4 following diseases familial Mediterranean fever, cryopyrinopathies, TNFRSF1A-related intermittent fever, and mevalonate kinase deficiency. Since 10 years, many other diseases have been discovered, especially thanks to the progress in genetics. In this review, we propose the actual panorama of the main known auto-inflammatory diseases. Some of them are recurrent fevers with crisis and remission; some others evaluate more chronically; some are associated with immunodeficiency. From a physiopathological point of view, we can separate diseases mediated by interleukine-1 and diseases mediated by interferon. Then some polygenic inflammatory diseases will be shortly described: Still disease, Schnitzler syndrome, aseptic abscesses syndrome. The diagnosis of auto-inflammatory disease is largely based on anamnesis, the presence of peripheral inflammation during attacks and genetic analysis, which are more and more performant., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Familial Mediterranean Fever (FMF) is the most frequent monogenic auto-inflammatory disease. FMF is an autosomal recessive disease, which affects populations from Mediterranean origin and is associated with MEFV gene mutations encoding for the protein pyrin. Pyrin activation enhances the secretion of interleukin 1 by myelo-monocytic cells. Main features of the disease are acute attacks of serositis mainly located on the abdomen, less frequently on chest and joints, accompanied by fever and biological inflammatory markers elevation. Usually attacks last 1 to 3 days and spontaneously stop. A daily oral colchicine intake of 1 to 2mg/day is able to prevent attack's occurrence, frequency, intensity and duration among most patients. Colchicine is also able to prevent the development of inflammatory amyloidosis, the most severe complication of FMF. This state of the art article will focus on the diagnosis of FMF, the treatment and an update on the pathophysiology including the recent described dominant form of MEFV-associated new auto-inflammatory diseases., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Mevalonate kinase deficiency is a rare, autosomal recessive, auto-inflammatory disease. This results from mutations in the gene MVK coding for the enzyme mevalonate kinase. This enzyme is involved in cholesterol and isoprenoids synthesis. Depending partially of the residual activity of the mevalonate kinase, the clinical spectrum realizes a continuum which extends from the mild phenotype of the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) to a lethal form of mevalonic aciduria. The HIDS is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, abdominal pain, diarrhea, arthralgia, hepatomegaly, splenomegaly and skin rash. The first attack more frequently takes place in the first year of life, even during the neonatal period, where it can be confused with a maternofetal infection. There is furthermore in mevalonate aciduria a psychomotor retardation, a failure to thrive, a cerebellar ataxia, a dysmorphic syndrome and a reduction of the visual acuity. The diagnosis is based on the mevalonic aciduria during febrile attack. Genetics confirm the diagnosis in more than 80 % of the cases. The dosage of IgD, low sensitive and specific, has no interest. There is no reference treatment. The less severe forms can be treated by non-steroidal anti-inflammatory drugs or steroids during febrile attacks. The most severe patients can be treated by biotherapy: antagonists of IL-1, TNF-α and IL-6., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Objective: To assess performance of the 2016 macrophage activation syndrome (MAS) classification criteria for patients with systemic juvenile idiopathic arthritis (JIA) who develop MAS while treated with biologic medications., Methods: A systematic literature review was performed to identify patients with MAS while being treated with interleukin (IL)-1 and IL-6 blocking agents. Clinical and laboratory information was compared to a large previously compiled historical cohort., Results: Eighteen publications were identified, and after removing duplicates, 35 patients treated with canakinumab and 49 patients with tocilizumab were available for analysis; 5 anakinra-treated patients were excluded due to limited numbers. MAS classification criteria were less likely to classify tocilizumab-treated patients as having MAS compared to the historical cohort or canakinumab-treated patients (56.7%, 78.5%, and 84%, respectively; P < 0.01). Patients who developed MAS while treated with canakinumab trended towards lower ferritin at MAS onset than the historical cohort (4,050 versus 5,353 ng/ml; P = 0.18) but had no differences in other cardinal clinical or laboratory features. In comparison, patients who developed MAS while treated with tocilizumab were less likely febrile and had notably lower ferritin levels (1,152 versus 5,353 ng/ml; P < 0.001). Other features of MAS were more pronounced in patients treated with tocilizumab, including lower platelet counts, lower fibrinogen, and higher aspartate aminotransferase levels. Mortality rates for patients with MAS treated with tocilizumab or canakinumab were not significantly different from the historical cohort., Conclusion: These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologic agents., (© 2017, American College of Rheumatology.)

Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)