Monitoring of Adverse Events and Safety in Autoinflammatory Diseases: Real-Life Data from the Eurofever Registry.

OBJECTIVES: The study is aimed to evaluate the impact of safety events in the Eurofever registry for Autoinflammatory diseases. METHODS: This was a retrospective and longitudinal observational multicentre study. Data were retrieved from the international registry Eurofever, starting patients' enrolment since 2009. All moderate, severe, or very severe AEs reported by treating physician in Eurofever were analyzed regardless of a possible suspected causal relationship to any therapies and according to the latest release of the Medical Dictionary for Regulatory Activities. RESULTS: Complete information on safety were available in 2464 patients enrolled in the registry. In 1499 of them retrospective data encompassing the period from disease onset to enrolment were available, whereas 965 consecutive patients entered in the longitudinal part of the study. A total of 479 AEs have been reported in 275 patients. Eighty-two AEs were reported as serious and 99 were drug-related according to the physicians. Infections or infestations (94; 19.6%), gastrointestinal disorders (66; 13.8%), nervous system disorders (41; 8.6%) and systemic disorders or administration site reactions (35; 7.3%) were the most frequent reported events. The highest absolute number of drug-related AEs were related to biologic DMARDs (40/99 reports, 40,4%) and colchicine (31/99 reports, 31.3%). CONCLUSIONS: Present study shows the importance of a longitudinal and homogeneous registration of the AEs in rare conditions, with a particular focus on the safety profile of the treatments used in these conditions.

Breaking down the fences among registries on autoinflammatory diseases: the E-Merge project.

BACKGROUND: Among the various numbers of different autoinflammatory diseases (AIDs), the absolute majority of them remains rare, with a single representative in large populations. This project, endorsed by PRES, supported by the EMERGE fellowship program, and performed in line with the Metadata registry for the ERN RITA (MeRITA), has the objective of performing a data synchronization attempt of the most relevant research questions regarding clinical features, diagnostic strategies, and optimal management of autoinflammatory diseases. RESULTS: An analysis of three large European registries: Eurofever, JIR-cohort and AID-Net, with a total coverage of 7825 patients from 278 participating centers from different countries, was performed in the context of epidemiological and clinical data merging. The data collected and evaluated in the registries does not cover only pediatric patients, but also adults with newly diagnosed AIDs. General aspects of the existing epidemiological data have been discussed in the context of patient global distribution, potential diagnostic delays, access to genetic testing, and the availability of the treatment. CONCLUSIONS: In general, the results indicate a great potential for upcoming collaborative work using existing data in cohorts that enhance the quality of medical care performed for patients with autoinflammatory diseases.

Clinical characteristics and COVID-19 outcomes in a regional cohort of pediatric patients with rheumatic diseases.

BACKGROUND: This study aimed to assess the baseline characteristics and clinical outcomes of coronavirus disease 2019 (COVID-19) in pediatric patients with rheumatic and musculoskeletal diseases (RMD) and identify the risk factors associated with symptomatic or severe disease defined as hospital admission, intensive care admission or death. METHODS: An observational longitudinal study was conducted during the first year of the SARS-CoV-2 pandemic (March 2020-March 2021). All pediatric patients attended at the rheumatology outpatient clinics of six tertiary referral hospitals in Madrid, Spain, with a diagnosis of RMD and COVID-19 were included. Main outcomes were symptomatic disease and hospital admission. The covariates were sociodemographic and clinical characteristics and treatment regimens. We ran a multivariable logistic regression model to assess associated factors for outcomes. RESULTS: The study population included 77 pediatric patients. Mean age was 11.88 (4.04) years Of these, 30 patients (38.96%) were asymptomatic, 41 (53.25%) had a mild-moderate COVID-19 and 6 patients (7.79%) required hospital admission. The median length of hospital admission was 5 (2-20) days, one patient required intensive care and there were no deaths. Previous comorbidities increased the risk for symptomatic disease and hospital admission. Compared with outpatients, the factor independently associated with hospital admission was previous use of glucocorticoids (OR 3.51; p = 0.00). No statistically significant risk factors for symptomatic COVID-19 were found in the final model. CONCLUSION: No differences in COVID-19 outcomes according to childhood-onset rheumatic disease types were found. Results suggest that associated comorbidities and treatment with glucocorticoids increase the risk of hospital admission.

Experience of Autoimmune and autoinflammatory diseases in a Turkish pediatric cohort with primary immunodeficiencies.

BACKGROUND: Primary immunodeficiency diseases (PID) are the diseases characterized by a dysfunction of the immune system. Affected patients share a different phenotype such as chronic infections, allergy, autoimmunity, and autoinflammation. METHODS: In all, 433 children with PID were enrolled in this study. Clinical, laboratory, and demographic data of patients were reviewed retrospectively to investigate autoimmune and autoinflammatory complications. Autoinflammation in all patients with inflammation was confirmed by genetic analysis after excluding infectious etiology. RESULTS: Clinical features of 433 PID patients were evaluated retrospectively with long-term follow-up. Autoimmune disorders were identified in 69 (15.9%) patients with PID; 31 (45%) patients had a history of autoimmune disease before diagnosis of PID. The frequency of autoimmunity in immune dysregulation subgroup (76.6%) was higher than other forms of PID. The most common autoimmune manifestations were reported to be Addison's disease, hypoparathyroidism, and autoimmune hemolytic anemia. Autoinflammation were identified in 22 of the 433 (5.1%) patients with PID, including hyper immunoglobulin D syndrome (n = 9), Aicardi-Goutieres syndrome 1 (n = 6), adenosine deaminase 2 deficiency (n = 3), Blau syndrome (n = 2), tumor necrosis factor (TNF) receptor-associated periodic syndrome (n = 1), and auto-inflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation syndrome (n = 1). CONCLUSIONS: It is important to recognize association between autoimmunity, autoinflammation, and PID, which in the future could be useful for increased awareness and early diagnosis for these diseases.

Experience of Autoimmune and autoinflammatory diseases in a Turkish pediatric cohort with primary immunodeficiencies

Background Primary immunodeficiency diseases (PID) are the diseases characterized by a dysfunction of the immune system. Affected patients share a different phenotype such as chronic infections, allergy, autoimmunity, and autoinflammation. Methods In all, 433 children with PID were enrolled in this study. Clinical, laboratory, and demographic data of patients were reviewed retrospectively to investigate autoimmune and autoinflammatory complications. Autoinflammation in all patients with inflammation was confirmed by genetic analysis after excluding infectious etiology. Results Clinical features of 433 PID patients were evaluated retrospectively with long-term follow-up. Autoimmune disorders were identified in 69 (15.9%) patients with PID; 31 (45%) patients had a history of autoimmune disease before diagnosis of PID. The frequency of autoimmunity in immune dysregulation subgroup (76.6%) was higher than other forms of PID. The most common autoimmune manifestations were reported to be Addison’s disease, hypoparathyroidism, and autoimmune hemolytic anemia. Autoinflammation were identified in 22 of the 433 (5.1%) patients with PID, including hyper immunoglobulin D syndrome (n = 9), Aicardi–Goutieres syndrome 1 (n = 6), adenosine deaminase 2 deficiency (n = 3), Blau syndrome (n = 2), tumor necrosis factor (TNF) receptor-associated periodic syndrome (n = 1), and auto-inflammation and phospholipase Cγ2-associated antibody deficiency and immune dysregulation syndrome (n = 1). Conclusions It is important to recognize association between autoimmunity, autoinflammation, and PID, which in the future could be useful for increased awareness and early diagnosis for these diseases (AU)

[Transition from pediatric to adult care: Recommendations of the French network for autoimmune and autoinflammatory diseases (FAI2R)]. / La transition de la pédiatrie à l'âge adulte : recommandations de prise en charge de la filière des maladies auto-immunes et auto-inflammatoires rares FAI2R.

Autoimmune and autoinflammatory diseases (AIDs) are a heterogeneous group of diseases. They can occur in childhood and account for significant morbidity and mortality. Transitioning from pediatric to adult healthcare can be difficult for patients and their families. It can interfere with patient follow-up and management, and eventually lead to complications. Although recommendations exist for the successful transition of patients with chronic diseases, few are specifically adapted to children and adults with AIDs (Suris et al., 2015-Solau-Gervais, 2012). The French working group on transition of the rare autoimmune and autoinflammatory diseases presents its reflections and recommendations for a successful transition. Preparation for transition should start early. Its goals are to empower adolescents by providing them with the knowledge to manage their own care, respond appropriately to changes in their condition, and evolve within the adult healthcare system. This requires the active participation of the patient, his or her family, as well as the pediatric and adult medical teams. The transition process involves multidisciplinary care and dedicated therapeutic education programs. Finally, the identification of medical specialists by region, trained in rare AIDs and accompanied by expert patients, may improve the management of patients with rare AIDs from adolescence to adulthood.

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.

Single-Center Overview of Pediatric Monogenic Autoinflammatory Diseases in the Past Decade: A Summary and Beyond.

Objective: Monogenic autoinflammatory diseases (AIDs) are inborn disorders caused by innate immunity dysregulation and characterized by robust autoinflammation. We aimed to present the phenotypes and genotypes of Chinese pediatric monogenic AID patients. Methods: A total of 288 pediatric patients clinically suspected to have monogenic AIDs at the Department of Pediatrics of Peking Union Medical College Hospital between November 2008 and May 2019 were genotyped by Sanger sequencing, and/or gene panel sequencing and/or whole exome sequencing. Final definite diagnoses were made when the phenotypes and genotypes were mutually verified. Results: Of the 288 patients, 79 (27.4%) were diagnosed with 18 kinds of monogenic AIDs, including 33 patients with inflammasomopathies, 38 patients with non-inflammasome related conditions, and eight patients with type 1 interferonopathies. Main clinical features were skin disorders (76%), musculoskeletal problems (66%), fever (62%), growth retardation (33%), gastrointestinal tract abnormalities (25%), central nervous system abnormalities (15%), eye disorders (16%), ear problems (9%), and cardiopulmonary disorders (8%). The causative genes were ACP5, ADA2, ADAR1, IFIH1, LPIN2, MEFV, MVK, NLRC4, NLRP3, NLRP12, NOD2, PLCG2, PSMB8, PSTPIP1, TMEM173, TNFAIP3, TNFRSF1A, and TREX1. Conclusions: The present study summarized both clinical and genetic characteristics of 18 kinds of monogenic AIDs found in the largest pediatric AID center over the past decade, with fever, skin problems, and musculoskeletal system disorders being the most prevalent clinical features. Many of the mutations were newly discovered. This is by far the first and largest monogenic AID report in Chinese pediatric population and also a catalog of the phenotypic and genotypic features among these patients.

Growth Parameters of Turkish Children With an Autoinflammatory Disease Before and After Canakinumab Treatment.

OBJECTIVE: To evaluate the effect of canakinumab on growth parameters of patients with autoinflammatory diseases. METHODS: This retrospective study included Colchicine resistant familial Mediterranean fever (FMF), Mevalonate kinase deficiency (MKD), Tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), Deficiency of adenosine deaminase 2 (DADA2) patients treated with canakinumab for at least six consecutive months. RESULTS: Eleven patients with FMF, 9 with MKD, 3 with TRAPS, and 1 with DADA2 were included. The median age (range) at diagnosis and drug initiation was 6.06 (1.45-16.06) years and 9.72 (1.82-19.11) years, respectively. The mean weight, height, and BMI SD scores significantly increased after canakinumab. There were significant improvements in laboratory parameters and disease activities. However, growth parameters after the drug did not differ according to gender, the duration of diagnostic delay, and age at the diagnosis. CONCLUSIONS: Canakinumab seems to have a positive effect on growth in patients with autoinflammatory diseases by controlling disease activity and inflammation.

Profile of new referrals to a single pediatric rheumatology center in Turkey.

To describe the demographic characteristics and clinical features of patients referred to a pediatric rheumatology outpatient clinic in Turkey and to compare the final diagnoses with the previous literature data. All new patients referred to pediatric rheumatology outpatient clinic of Kanuni Sultan Süleyman Research and Training Hospital between March 2018 and March 2019 were enrolled to the study. Demographic data, referral patterns, disease related features, physical examination findings and final diagnoses of new referrals were collected prospectively. A total of 2982 new referrals were evaluated in 1-year period. Among them 1561 (52%) had a diagnosis of a rheumatic disease. The frequencies of most common rheumatic diseases were; periodic fever syndromes (47.3%), juvenile idiopathic arthritis (18%) and vasculitis (14.4%), respectively. Non-rheumatic conditions were diagnosed in 1243 patients, among them orthopedic/mechanic problems (27.4%) were the most frequent ones followed by vitamin D deficiency (17.5%) and dermatological problems (9.8%). Patients with non-rheumatic conditions comprised a large part of the pediatric rheumatology outpatient clinic. National registries are required to establish the frequencies of pediatric rheumatic diseases in Turkey.

Pattern and diagnostic evaluation of systemic autoinflammatory diseases other than familial Mediterranean fever among Arab children: a multicenter study from the Pediatric Rheumatology Arab Group (PRAG).

To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1-12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1-10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries.

Phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases.

OBJECTIVE: We aimed to characterize the phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases (SAIDs). METHODS: We prospectively evaluated clinical and genetic features of 92 adult patients (≥16 years) suspected of SAIDs in the period from April 2015 to October 2017, at the adult SAIDs center, Peking Union Medical College Hospital. The definite diagnosis of each disease was deemed to be present if both clinical phenotypes and genetic confirmation were met. Clinical manifestations of these patients were compared with those from the pediatric populations and patients from other countries. RESULTS: A final diagnosis of SAIDs was reached in 50 patients, including 13 familial Mediterranean fever (FMF), 10 NLRP12-associated autoinflammtory disease (NLRP12-AID), 7 NLRP3-associated autoinflammatory disease (NLRP3-AID), 5 tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), 3 Blau syndrome, 3 Yao syndrome (YAOS) and 9 periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). First disease onset during adulthood was observed in 30 patients, and the final diagnosis was delayed with a median time of 9 years. Adult monogenic SAIDs patients usually carried low-penetrance mutations and all gene variants were presented as heterozygosis or compound heterozygosis. Frequencies of clinical manifestations in Chinese adult SAIDs patients were similar with adult patients in other countries, but different from pediatric populations. CONCLUSIONS: FMF, NLRP3-AID, and NLRP12-AID are relatively common monogenic SAIDs in Chinese adults. Adult-onset SAIDs may be related to the presence of low-penetrance mutations, characterized by nonspecific, incomplete or atypical disease patterns compared with child-onset SAIDs, leading to a delay of diagnosis.

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' 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.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 2: rheumatoid arthritis, reactive arthritis, Reiter's syndrome, Lyme borreliosis, dermatomyositis and lupus erythematosus.

Syndromes associated with concurrent skin and joint inflammation frequently pose a therapeutic challenge for both dermatologists and rheumatologists. In part 1 of this review, we discussed psoriatic arthritis as well as the autoinflammatory disorders SAPHO syndrome, Still's disease and Behçet's disease. Part 2 will address rheumatoid arthritis, reactive arthritis, Reiter's syndrome and Lyme borreliosis. In addition, we will discuss dermatomyositis and lupus erythematosus, two common autoimmune disorders that frequently present with both cutaneous and joint involvement. For each of the aforementioned disorders, we will highlight aspects of epidemiology, pathogenesis, clinical presentation, diagnosis and treatment.

Autoinflammatory diseases: State of the art.

Autoinflammatory diseases are characterized by innate immunity abnormalities. In autoinflammatory diseases (AID), inflammatory blood biomarkers are elevated during crisis without infection and usually without autoantibodies. The first 4 described AID were familial Mediterranean fever, cryopyrin-associated periodic fever syndrome (CAPS) or NLRP3-associated autoinflammatory disease (NRLP3-AID), mevalonate kinase deficiency (MKD) and TNFRSF1A-receptor associated periodic fever syndrome (TRAPS). Since their description 20 years ago, and with the progresses of genetic analysis, many new diseases have been discovered; some with recurrent fever, others with predominant cutaneous symptoms or even immune deficiency. After describing the 4 historical recurrent fevers, some polygenic inflammatory diseases will also be shortly described such as Still disease and periodic fever with adenitis, pharyngitis and aphtous (PFAPA) syndrome. To better explore AID, some key anamnesis features are crucial such as the family tree, the age at onset, crisis length and organs involved in the clinical symptoms. An acute phase response is mandatory in crisis.

Update on the epidemiology and disease outcome of Familial Mediterranean fever.

Autoinflammatory diseases (AIDs) are diseases of the innate immune system, with clinical and laboratory evidence of attacks of inflammation. The more common AIDs are those associated with periodic fevers: Familial Mediterranean fever (FMF); Mevalonate Kinase Deficiency (MKD)/Hyperimmunoglobulin D Syndrome (HIDS); Cryopyrin-associated Autoinflammatory Syndrome (CAPS); and Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS). Classification criteria have been developed for all these types. FMF is the most common AID worldwide with a particularly high prevalence in the Eastern Mediterranean region. Environmental factors are thought to affect the course of the disease. Outcome measures are being developed for AIDs.

[Periodic fever syndromes].

Periodic fever syndromes (PFS) are characterised by recurrent fever and excessive systemic inflammation. These rare and hereditary syndromes include familial Mediterranean fever, tumour necrosis factor receptor-1 associated periodic syndrome, mevalonate kinase deficiency and cryopyrin-associated periodic syndrome. Each PFS has distinct clinical and genetic features. Availability of improved genetic methods has improved the understanding of the syndromes and diagnostic testing. The main complication is systemic amyloidosis. Targeted biological therapy such as interleukin-1 inhibitors is emerging as an effective treatment.