Unravelling the clinical heterogeneity of undefined recurrent fever over time in the European registries on Autoinflammation.

BACKGROUND: Systemic autoinflammatory disorders (SAIDs) represent a growing spectrum of diseases characterized by dysregulation of the innate immune system. The most common pediatric autoinflammatory fever syndrome, Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA), has well defined clinical diagnostic criteria, but there is a subset of patients who do not meet these criteria and are classified as undefined autoinflammatory diseases (uAID). This project, endorsed by PRES, supported by the EMERGE fellowship program, aimed to analyze the evolution of symptoms in recurrent fevers without molecular diagnosis in the context of undifferentiated AIDs, focusing on PFAPA and syndrome of undifferentiated recurrent fever (SURF), using data from European AID registries. METHODS: Data of patients with PFAPA, SURF and uSAID were collected from 3 registries including detailed epidemiological, demographic and clinical data, results of the genetic testing and additional laboratory investigations with retrospective application of the modified Marshall and PRINTO/Eurofever classification criteria on the cohort of PFAPA patients and preliminary SURF criteria on uSAID/SURF patients. RESULTS: Clinical presentation of PFAPA is variable and some patients did not fit the conventional PFAPA criteria and exhibit different symptoms. Some patients did not meet the criteria for either PFAPA or SURF, highlighting the heterogeneity within these groups. The study also explored potential overlaps between PFAPA and SURF/uAID, revealing that some patients exhibited symptoms characteristic of both conditions, emphasizing the need for more precise classification criteria. CONCLUSIONS: Patients with recurrent fevers without molecular diagnoses represent a clinically heterogeneous group. Improved classification criteria are needed for both PFAPA and SURF/uAID to accurately identify and manage these patients, ultimately improving clinical outcomes.

[Arthritis and osteomyelitis in childhood and adolescence-Bacterial and nonbacterial]. / Arthritis und Osteomyelitis im Kindes- und Jugendalter ­ bakteriell und nichtbakteriell.

Bacterial arthritis and osteomyelitis are usually acute diseases, which in this way differ from the often insidious course of nonbacterial osteomyelitis; however, there is often an overlap both in less acute courses of bacterial illnesses and also in nonbacterial osteitis. The overlapping clinical phenomena can be explained by similar pathophysiological processes. In bacteria-related illnesses the identification of the pathogen and empirical or targeted anti-infectious treatment are prioritized, whereas no triggering agent is known for nonbacterial diseases. The diagnostics are based on the exclusion of differential diagnoses, clinical scores and magnetic resonance imaging (MRI). An activity-adapted anti-inflammatory treatment is indicated.

Manifestation and staging of arthropathy in cystic fibrosis. Defining different stages of cystic fibrosis arthropathy using ultrasound imaging and clinical scoring.

BACKGROUND: The true prevalence of cystic fibrosis arthropathy (CFA) remains unclear and may be significantly higher than previously reported. In recent studies, joint symptoms have been reported in up to 30% of adults with CF. This underlines the importance of CFA as a rising and clinically relevant co-morbidity. A clear definition of CFA is yet missing and its pathogenesis remains unclear. We investigated the clinical manifestation of CFA particularly via ultrasound (US) examination to define and implement a staging for clinical assessment. METHODS: In a prospective cohort study between March 2018 and February 2020 a total of 98 consecutively recruited, adult cystic fibrosis (CF) patients underwent joint-US examination according to a newly developed ultrasound score (US-CFA). A clinical assessment including rheumatological scores (DAS28, HAQ) has been conducted as well as a specially designed questionnaire. Investigation on clinical and microbiological data, as well as a comprehensive laboratory analysis, were carried out. Cluster analysis has been performed to detect patterns defining different CFA stages based on disease activity. RESULTS: US imaging has shown a considerable incidence of mild to moderate effusion as sign of joint inflammation/(teno-)synovitis. K-means clustering was used to distinguish 3 different stages of CFA based on the intensity of the detected effusion. These stages showed a significant association with disease activity (DAS28, p = 0.0004) as well as with patient-reported symptoms such as total weeks of CFA per year (p = 0.004), acute CFA (p = 0.015), chronic CFA (p = 0.016), disease burden (p = 0.04). Based on the US-CFA, 16% of patients suffered from severe CFA (II), 51% from intermediate CFA (I) and 33% did not present detectable arthritis. Positive serology for Chlamydophilia pneumoniae (IgA, IgG) and Chlamydia trachomatis (IgA, IgG) significantly correlated with the US-CFA. CONCLUSIONS: The results of this study show that a definition and categorization for the clinical manifestation of CFA can be described through US examination, which is able to detect disease activity concordant with the DAS28 as a validated clinical score on arthritis. Defining these stages will lead to a better understanding of the clinical phenotype of the disease and will optimize diagnosis, therapy and research on CFA in the future.

Hemolytic anemia following intravenous immunoglobulins in children with PIMS-TS: Two case reports.

This is the first case report on two children presenting with immediate and severe hemolytic anemia following the administration of high-dose intravenous immunoglobulins (IVIGs) in the context of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Hemolytic anemia was described as a significant decrease in hemoglobin and an increase in lactate dehydrogenase after the second administration of high-dose IVIGs was performed. Both patients were found to have AB blood group. One of our patients showed massive pallor, weakness, and inability to walk in association with hemolysis. However, in both cases, the anemia was self-limiting and transfusion of red blood cells was not required: both patients recovered without persistent impact. Nonetheless, we aim to draw attention to this widely unknown adverse effect of IVIG, especially in the context of PIMS-TS. We suggest determining the patient's blood group prior to high-dose IVIG infusion and replacing the second IVIG through high-dose steroids or anticytokine therapy. Using IVIGs containing lower titers of specifically anti-A or anti-B antibodies to avoid isoagglutinin-caused hemolytic anemia is desirable; however, the information is not routinely available.

Outcome of children with oligoarticular juvenile idiopathic arthritis compared to polyarthritis on methotrexate- data of the German BIKER registry.

BACKGROUND: Oligoarticular juvenile idiopathic arthritis (oligoJIA) is the most commonly diagnosed category of chronic arthritis in children. Nevertheless, there are no evidence- based guidelines for its treatment, in particular for the use of methotrexate (MTX). The primary objective of this analysis is to evaluate the outcomes in patients with persistent oligoJIA compared to those with extended oligoJIA and rheumatoid factor (RF) negative polyarthritis treated with methotrexate. METHODS: Patients with persistent or extended oligoJIA or RF negative PA recorded in the Biologics in Pediatric Rheumatology Registry (BiKeR), receiving methotrexate for the first time were included in the analyses. Efficacy was determined using the Juvenile Arthritis Disease Activity Score 10 (JADAS 10). Safety assessment included the documentation of adverse and serious adverse events. RESULTS: From 2005 through 2011, 1056 patients were included: 370 patients with persistent oligoJIA, 221 patients with extended oligoJIA and 467 patients with RF negative PA. Therapeutic efficacy was observed following the start of methotrexate. Over a period of 24 months JADAS-minimal disease activity (JADAS ≤2) was reached in 44% of patients with persistent oligoJIA, 38% with extended oligoJIA, 46% with RF negative PA, JADAS-remission defined as JADAS ≤1 was reached in 33% of patients with persistent oligoJIA, 29% with extended oligoJIA and 35% (RF negative PA). Patients with extended oligoJIA achieved JADAS remission significantly later and received additional biologic disease-modifying drugs significantly more often than patients with persistent oligoJIA or RF negative PA (p < 0.001). Tolerability was comparable. New onset uveitis occurred in 0.3 to 2.2 per 100 patient years. CONCLUSIONS: Patients with persistent oligoJIA taking methotrexate are at least as likely to enter remission as patients with extended oligo JIA or polyarticular JIA. Patients with extended oligoJIA achieved JADAS remission significantly later. Within 2 years, almost half of the patients with persistent oligoJIA achieved JADAS-minimal disease activity.

[Results of the systematic literature search as basis for the "Evidence-based treatment recommendations for familial Mediterranean fever patients with insufficient response or intolerability to colchicine" of the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Ergebnisse der systematischen Literatursuche als Grundlage für die "evidenzbasierten Therapieempfehlungen für FMF-Patienten mit unzureichendem Ansprechen bzw. Unverträglichkeit auf Kolchizin" der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) is a genetic disease of childhood and adulthood which is relatively rare in Germany. It is characterized by recurrent febrile attacks, peritonitis, pleuritis and arthritis. The established treatment with colchicine is effective and well-tolerated by most patients; however, some patients do not adequately respond or do not tolerate this treatment. Biologics can be considered for some of these patients. The Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) have agreed to develop joint recommendations for this specific clinical situation. AIM: Implementation of a systematic literature search (SLR) on the basis of the EULAR recommendations published in 2016 as the foundation for the development of evidence-based treatment recommendations for FMF patients with insufficient response or intolerance to colchicine. METHODS: The SLR was performed using references from various databases as an update of the SLR carried out by EULAR up to 2014, whereby all articles must have been published between 1 January 2015 and 31 December 2017. The Rayyan abstract tool for the preselection and the classification of the Oxford Centre for Evidence Based Medicine 2009 were used for the preparation of the evidence tables. RESULTS: The search yielded 360 hits and after duplicate matching 263. A total of 88 publications were included (34%) and 102 excluded (39%), a review of the full publication was necessary for a further 73 (28%) and 43 were discussed more intensively. Finally, 64 publications (24%) remained. A total of 4 case-control studies, 31 cohort studies, 8 case series, 7 controlled studies (including 5 abstracts), 10 reviews, 4 meta-analyses and systematic reviews were accepted. DISCUSSION: The SLR was carried out in a scientifically accurate and transparent manner according to international standards. The SLR proved to be a good basis for a consensus on the 5 overarching principles and the 10 recommendations, so that the joint activity of the GKJR and DGRh was successfully and even promptly concluded. The recommendations are a solid basis for treating patients of all ages with FMF. The explanations on the problem of colchicine resistance play an important role here.

[COVID-19: treatment strategies of German-speaking pediatric rheumatologists : Results of an online survey]. / COVID-19: Behandlungsstrategien der deutschsprachigen Kinderrheumatologen : Ergebnisse einer Online-Umfrage.

BACKGROUND: Reliable data on the course and treatment of pediatric COVID-19 ("corona virus disease 2019") in immunosuppressed patients with rheumatic diseases are missing. AIM: Delineation of individual strategies of the members of the Society for Pediatric Rheumatology (GKJR) in cases of COVID-19. METHODS: In May 2020 all GKJR members were invited to take part in an online survey. Opinion data regarding an approach using disease-modifying anti-rheumatic drugs (DMARD) in cases of COVID-19 as well as the readiness to use new therapeutic agents in patients in different stages of the disease were collected. RESULTS: A total of 71 respondents (27.3% of all contacted pediatric rheumatologists) took part in the survey. Of these 28.2% had treated patients with COVID-19. Over 95% of the respondents did not support a preventive adaptation of the anti-rheumatic treatment during the SARS-CoV­2 pandemic. In the case of outpatients under immunosuppression with proven COVID-19 more than 50% of the respondents would refrain from administering intravenous high-dose steroids, cyclophosphamide, anti-CD20 antibodies as well as BAFF, CTLA­4 and TNF-alpha blockades. Conversely, >70% of the respondents would continue the treatment with nonsteroidal anti-inflammatory drugs, hydroxychloroquine (HCQ), oral steroids, mycophenolate, IL­1 blockade and immunoglobulins (Ig). In the case of inpatients 74.6% of respondents would consider targeted COVID-19 treatment. In stable patients with oxygen treatment (stage I) HCQ (18.3%), azithromycin (16.9%) and Ig (9.9%) were most frequently used. In cases of early signs (stage II) or a manifest cytokine storm (stage III) anakinra (40.8% for stage II and 46.5% for stage III), tocilizumab (26.8% and 40.8%, respectively), steroids (25.4% and 33.8%, respectively) and remdesivir (29.6% and 38.0%, respectively) were most frequently used. The need for a personalized approach based on the current clinical situation was emphasized by many respondents. CONCLUSION: The currently low prevalence of COVID-19 in Germany limits the general clinical experience. Therefore, the presented results have to be interpreted with caution and mostly as hypothetical treatment considerations. It is to be expected that there will always be a limited amount of evidence on pediatric COVID-19; therefore, a continuous and critical exchange of expert opinions on the treatment strategies is important.

[Classification of autoinflammatory diseases based on pathophysiological mechanisms]. / Klassifikation autoinflammatorischer Erkrankungen anhand pathophysiologischer Mechanismen.

Monogenic autoinflammatory diseases present with systemic inflammation with the involvement of multiple organs. With the help of modern molecular genetic techniques a large number of diseases with previously unknown pathomechanisms have been described in recent years. This knowledge can be utilized to group autoinflammatory diseases according to the signalling pathways involved and thus provide a better understanding of these entities.

[Clinical symptoms of autoinflammatory diseases]. / Klinische Symptomatik autoinflammatorischer Erkrankungen.

Systemic autoinflammatory diseases are characterized by a spontaneous chronic inflammatory reaction mediated by the innate immunity. The inflammatory processes involve many organs including the skin. Diagnosis remains a challenge despite new molecular genetic methods, but early diagnosis is crucial for the prevention of long-term complications such as amyloidosis. Skin manifestations are often observed early in the course of the disease and can be decisive in the diagnosis.

[Evidence-based treatment recommendations for familial Mediterranean fever : A joint statement by the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Evidenzbasierte Therapieempfehlungen für das familiäre Mittelmeerfieber : Eine gemeinsame Stellungnahme der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) in Germany is a rare, genetically linked disease of childhood and adolescence, which is characterized by recurrent febrile episodes and clinical signs of peritonitis, pleuritis and arthritis. Treatment with colchicine is effective and well-tolerated in the majority of patients; however, some patients do not sufficiently respond to this treatment or are intolerant to colchicine. For these patients first-line treatment with biologics which block interleukin-1 can be used. OBJECTIVE: The aim was to formulate evidence-based treatment recommendations for patients with an insufficient response and intolerance to colchicine treatment. METHODS: Based on a literature search and the European League Against Rheumatism (EULAR) recommendations on FMF from 2016 the appointed members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) convened to work out and form a consensus in a joint statement on evidence-based treatment recommendations on FMF. RESULTS: After intensive discussions all decisions were in concordance. A total of 5 superordinate principles and 10 recommendations were agreed upon. DISCUSSION: The joint activities of the GKJR and the DGRh were successfully concluded in a timely manner. The recommendations form a good basis for optimal treatment of all age groups of patients with FMF.

IL-6 blockade in systemic juvenile idiopathic arthritis - achievement of inactive disease and remission (data from the German AID-registry).

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. METHODS: In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid-register.de ). Data for this retrospective TCZ study were documented by 13 centers. RESULTS: From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. CONCLUSION: Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. TRIAL REGISTRATION: The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

[Role of genetics in familial Mediterranean fever]. / Rolle der Genetik beim familiären Mittelmeerfieber.

Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with a subsequent disproportional proinflammatory reaction. Classically, in FMF patients two pathogenic mutations affecting both alleles are found in the molecular genetic analysis; however, it is well known that the phenotype can also be caused either by mutations with lower penetrance or unknown significance. Furthermore, in a significant number of patients only one or even no MEFV mutations can be detected. Heterozygous mutation carriers who do not suffer from classical FMF, can also present with other signs of inflammation, e. g. subclinical increased inflammation markers, associated inflammatory diseases or unclassified symptoms. Thus, FMF does not follow a classical autosomal recessive inheritance and a variable gene dose effect has to be considered, which is furthermore modulated by other mostly unknown genetic variants and environmental factors. This article summarizes the broad spectrum of clinical presentations associated with MEFV mutations and analyzes the effect of the gene dose on the phenotypical expression. Furthermore, the impact of the molecular genetic analysis on the diagnostics of a patient and on the individualized management of the disease is discussed.

[Clinical aspects and genetics of proteasome-associated autoinflammatory syndromes (PRAAS)]. / Klinik und Genetik bei Proteasomen-assoziierten autoinflammatorischen Syndromen (PRAAS).

Functional disorders of the proteasome can have a severe impact on the innate immune system. Characterized by an autosomal recessive mode of inheritance, this novel type of interferonopathy is considered to be a spectrum of diseases of proteasome-associated autoinflammatory syndromes (PRAAS). Accumulation of ubiquitinated proteins and the induction of type I interferon (IFN) genes seem to play a role in the pathogenesis. The typical clinical manifestations are lipodystrophy, skin, joint and muscle involvement accompanied by a remarkable variability of other associated symptoms. This article provides an overview on currently known molecular alterations as well as clinical similarities and differences of PRAAS. Furthermore, the reported effects of the immunosuppressive therapy approaches used so far are summarized.

Survey about tolerance of the AS03-adjuvanted H1N1 influenza vaccine in children with rheumatic diseases.

The objective of this study is to evaluate complications and changes in health status (disease activity and flare) in response to the AS03-adjuvanted H1N1 vaccine in children with rheumatic diseases. We conducted a nationwide survey addressing paediatric rheumatology sites who participated in the national paediatric rheumatology database. Ninety patients were documented-38 % under treatment with biologicals-of whom 18 % suffered from complications (10 % local and 8 % systemic) with no relevant changes in median disease activity or flare rate during 4 weeks following the vaccination. The adjuvanted H1N1 influenza vaccine seems to be adequately tolerated in children with rheumatic diseases.

Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study.

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

[Genetic fever syndromes. Hereditary recurrent (periodic) fever syndromes]. / Genetische Fiebersyndrome. Hereditäre rekurrierende (periodische) Fiebersyndrome.

Genetic fever syndromes or hereditary recurrent fever syndromes (HRF) are considered to be part of the autoinflammatory diseases (AID) which result from errors in the innate immune system. Patients typically have self-limiting episodes of fever and high levels of inflammation markers. The mode of inheritance is autosomal recessive or autosomal dominant. The diseases of the HRF include familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndrome, hyper-IgD syndrome and cryopyrin-associated periodic fever syndromes. The disease known as deficiency of interleukin 1 (IL1) receptor antagonist does not fully belong to this group because fever is not a typical symptom. The therapy depends on the type and severity of the disease. Effective prophylaxis is possible for FMF. Biologicals, especially IL1 blocking agents are highly effective in very severe fever syndromes. In order to collect more information on AID, to establish a biobank and coordinate research in this field the AID-Net project was founded. Currently 606 patients with AID are registered of whom 381 have HRF.

Unexplained recurrent fever: when is autoinflammation the explanation?

Recurrent fever can be the sole or leading manifestation of a variety of diseases including malignancies, autoimmune diseases and infections. Because the differential diagnoses are manifold, no formal guidelines for the approach of patients with recurrent fever exists. The newly recognized group of autoinflammatory diseases are often accompanied by repetitive fever attacks. As these episodes are frequently associated by a variety of divergent presentations, the differentiation of other causes for febrile illnesses can be difficult. In this article, we first review disease entities, which frequently present with the symptom of recurrent fever. In a next step, we summarize their characteristic pattern of disease presentation. Finally, we analyse key features of autoinflammatory diseases, which are helpful to distinguish this group of diseases from the other causes of recurrent fever. Recognizing these symptom patterns can provide the crucial clues and, thus, lead to the initiation of targeted specific diagnostic tests and therapies.

How not to miss autoinflammatory diseases masquerading as urticaria.

Urticarial skin reactions are one of the most frequent problems seen by allergists and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common diseases that present with urticarial rash, such as urticarial vasculitis and autoinflammatory disorders. The latter include cryopyrin-associated periodic syndrome and Schnitzler's syndrome, both rare and disabling conditions mediated by increased interleukin-1 secretion. Apart from the urticarial rash, patients are suffering from a variety of systemic symptoms including recurrent fever attacks, arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated with a diagnostic delay of many years and do not respond to antihistamines and other treatments of urticaria. Also, the chronic inflammation may lead to long-term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urticarial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash and discuss their clinical picture and management.