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The work situation is an important dimension of professional life and wellbeing, and a policy lever to strengthen recruitment and retention. This study aims to explore the work situation of physicians and residents in internal medical rheumatology, considering the impact of the coronavirus pandemic COVID-19.A questionnaire-based online survey was conducted in early 2021 at the Hannover Medical School, supported by the German Society of Rheumatology. Target groups were all rheumatology physicians and residents in Germany. The main areas of investigation included work hours, task delegation, and collaboration; workload and mental health issues; discrimination and sexual harassment experiences; and the impact of COVID-19. Descriptive statistical analysis was performed for the standardized items and qualitative content analysis for the free-text information.The respondents (n = 101) expressed positive attitudes towards cooperation and task delegation to medical assistants, especially those specialized in rheumatology, while attitudes towards cooperation with GPs pointed to blockades. There was a strong mismatch between actual and desired work hours both in the group of women and in the group of men. 81% rated their workload as high or very high; every sixth rheumatologist has suffered from stress or burnout syndromes at least once in the past. Experiences of gender discrimination and sexual harassment/violence were frequently reported, mostly by women. COVID-19 was an amplifier of stress, with major stressors being digitalization and increased demand for communication and patient education.There is an urgent need to improve the work situation of rheumatologists and reduce stress and mental health risks.HINTERGRUND UND FRAGESTELLUNG: Die Arbeitssituation ist ein wichtiger Aspekt im Berufsleben und für das Wohlergehen und ein politischer Hebel, um den Verbleib im Beruf sowie die Fachkräfterekrutierung zu verbessern. Ziel dieser Studie war es, die Arbeitsbedingungen internistischer Rheumatolog*innen und Weiterbildungsassistent*innen unter Berücksichtigung der Auswirkungen der Coronavirus-Pandemie COVID-19 zu untersuchen.Eine fragebogenbasierte Online-Erhebung wurde Anfang 2021 an der Medizinischen Hochschule Hannover durchgeführt, unterstützt von der Deutschen Gesellschaft für Rheumatologie. Zielgruppe waren alle Rheumatolog*innen und Weiterbildungsassistent*innen in Deutschland. Thema waren Arbeitszeiten, Kooperation und Delegation, Arbeitsbelastungen und Burnout-Syndrome, Diskriminierung und sexuelle Belästigung sowie Auswirkungen von COVID-19. Standardisierte Items wurden deskriptiv und Freitextinformationen mittels qualitativer Inhaltsanalyse ausgewertet.In der Untersuchungsgruppe (n = 101) zeigten sich positive Einstellungen zu Kooperation und Aufgabendelegation an medizinische Fachangestellte, v. a. Rheumatologische Fachassistenz, während die Einstellungen zur Kooperation mit Hausärzt*innen Blockaden sichtbar machten. Die tatsächliche Arbeitszeit unterschied sich sowohl in der Gruppe der Frauen als auch der Männer sehr deutlich von der Wunscharbeitszeit. Ihre Arbeitsbelastung bewerteten 81 % als hoch oder sehr hoch; jede*r 6. Befragte war mindestens einmal in der Vergangenheit von Stress und Burnout betroffen. Diskriminierungserfahrungen und sexuelle Belästigungen waren weitverbreitet und betrafen Frauen stärker als Männer. COVID-19 erwies sich als Stressverstärker; Digitalisierung, erhöhter Bedarf an Kommunikation und Patientenaufklärung waren wesentliche Stressfaktoren.Die Arbeitssituation von Rheumatolog*innen sollte dringend verbessert werden, um Stress und Gesundheitsrisiken zu verringern.

Background and purpose The phenotype of Sjogren's syndrome-associated neuropathy has been better characterized in recent years. However, Sjogren's syndrome-associated neuropathy remains an underdiagnosed entity with only few insights considering the pathomechanisms of nerve damage. Nerve ultrasound has proven to be a useful and efficient tool in detecting nerve damage of autoimmune origin. We, therefore, aimed to evaluate this method for Sjogren's syndrome-associated neuropathy. Methods Patients with Sjogren's syndrome and clinical signs of neuropathy underwent sonographic examination of both median and ulnar nerves. Nerve thickening was classified for cross-sectional areas of >12 mm² at the median nerve and for >10 mm² at the ulnar nerve. Fascicle thickening was documented for cross-sectional areas ≥5 mm² at the median and ≥3 mm² at the ulnar nerve. Results Forty-three patients were included in the analysis (median age 60 years [interquartile range 53-73 years], female rate 60%). 31/43 patients (72%) showed abnormalities on nerve ultrasound, while nerve thickening was found more frequently than fascicle thickening (90% vs. 52% of patients with sonographic abnormalities, respectively). Abnormal findings were observed more frequently at the median nerve and in proximal localization. Abnormal findings on nerve conduction studies were evident in 36/43 patients (84%). Nerve conduction studies revealed a tendency of demyelinating nerve damage patterns being associated with abnormal findings on nerve ultrasound. Conclusions In addition to nerve conduction studies, nerve ultrasound may have a supporting role in the diagnosis of Sjogren's syndrome-associated neuropathy. Also, our data support an immune-mediated inflammatory demyelinating pathogenesis of Sjogren's syndrome-associated neuropathy.

Rheumatologen waren die Vorreiter in der Bestimmung von Autoantikorpern zur Diagnostik chronisch-entzundlicher Erkrankungen. Rheumafaktoren werden seit 1940 gemessen, antinukleare Antikorper und deren Zielstrukturen seit den 1950er und 1960er Jahren. Trotz der grosen Zahl an Autoantikorpern, die heute in der Routine bestimmt werden konnen, fehlen uns bei vielen chronisch-entzundlichen Erkrankungen noch diagnostische Marker. Autoantikorper konnen heute mit neuen Technologien, die in dem Artikel beschrieben werden, leichter identifiziert werden, so dass in Zukunft mit der Entdeckung neuer diagnostischer Marker zu rechnen ist.

Ein 64-jahriger Patient entwickelte uber 20 Jahre zunehmende sensible und motorische Schadigungen der Arm- und Beinnerven. Histologisch wurde mittels Suralisbiopsie eine schwere axonale Neuropathie gesichert. Die Genese konnte trotz ausfuhrlicher Laboruntersuchungen inklusive immunologischer und metabolischer Tests nicht identifiziert werden. Schlieslich wurde eine reduzierte Tranenproduktion durch einen pathologischen Schirmer-Test nachgewiesen. Eine Speicheldrusenbiopsie aus der Unterlippe zeigte eine lymphozytare Entzundung, Grad III nach Chisholm und Mason, sodass ein Sjogren-Syndrom diagnostiziert wurde.

In order to reduce the prognostically relevant time interval between the initial manifestation of a rheumatic and musculoskeletal disease and diagnosis as well as the consecutive initiation of an appropriate treatment, several rheumatological centers in Germany have improved the access to initial rheumatologic evaluation by establishing early recognition/screening clinics at their respective sites. Corresponding models located at Altoetting·Burghausen, Bad Pyrmont, Berlin Buch, Duesseldorf, Heidelberg, Herne, Mannheim as well as supraregional/multicenter initiatives Rheuma Rapid, RhePort and Rheuma-VOR are presented in this overview along with the respective characteristics, potential advantages and disadvantages, but also first evaluation results of several models. The aim of this publication is to promote early detection of rheumatic and musculoskeletal diseases as one of the most important challenges in current rheumatology by encouraging further rheumatologic centers and practices to launch their own early recognition/screening consultation model on the basis of aspects presented herein.

Die rheumatoide Arthritis, die Psoriasisarthritis und die axiale Spondyloarthritis zahlen zu den haufigsten rheumatischen Erkrankungen. Bei allen 3 Erkrankungsbildern kristallisiert sich eine moglichst fruhe Diagnose und Therapieeinleitung als entscheidend heraus. Die aus ADAPTHERA weiterentwickelte und auf mehrere Bundeslander erweiterte prospektive Proof-of-Concept-Netzwerkstudie „Rheuma-VOR“ verfolgt das Ziel, diese 3 entzundlich-rheumatischen Erkrankungen so fruh wie moglich zu erkennen und die Versorgungsqualitat mithilfe von multidisziplinaren Koordinationsstellen zu verbessern. Bis dato wurden 3710 Screeningbogen mit einer moglichen Verdachtsdiagnose von rheumatoider Arthritis, Psoriasisarthritis oder axialer Spondyloarthritis von 1298 verschiedenen Primarversorgern bei den bundeslandspezifischen Koordinationsstellen gemeldet. Insgesamt wurden 1958 Termine bei 53 teilnehmenden rheumatologischen Spezialisten vergeben. Bei 876 Patienten wurde eine der 3 rheumatischen Erkrankungen im Fruhstadium diagnostiziert. Die Wartezeit liegt in Abhangigkeit des Bundeslandes bei durchschnittlich 42,5 Tagen und somit deutlich unter dem Bundesdurchschnitt. Ebenso ist festzuhalten, dass die Kapazitat der rheumatologischen Spezialisten durch die koordinierte Kooperation und die Risikostratifizierung der Rheuma-VOR-Koordinationsstellen um 1281 Termine (34,5 %) entlastet werden konnte. Daruber hinaus zeigen die 2‑wochige Rheuma-Bus-Tour und die in Rheinland-Pfalz begleitend durchgefuhrten Initiativen (Rheuma-VOR-Screening-App, Sichtungssprechstunde) erste vielversprechende positive Ergebnisse.

„Was ist neu?“ Wirkmechanismen der JAK-Inhibitoren JAK-Inhibitoren wirken intrazellulär und hemmen im Gegensatz zu den Biologika viele Zytokine. Pharmakokinetik JAK-Inhibitoren werden oral eingenommen. Angesichts der Halbwertzeit von einigen Stunden sind sie gut steuerbar. Zulassungslage Die JAK-Inhibitoren Baricitinib und Tofacitinib sind zugelassen für die Therapie der mittelschweren bis schweren aktiven RA bei erwachsenen Patienten nach erfolgloser Therapie mit DMARDs. Tofacitinib ist auch bei Colitis ulcerosa und in der Kombination mit MTX auch bei der Psoriasis-Arthritis (PsA) zugelassen. Wirksamkeit In der Kombination mit Methotrexat (MTX) ist Tofacitinib bei der rheumatoiden Arthritis (RA) so gut wirksam wie Adalimumab mit MTX, Baricitinib war in der Kombination mit MTX sogar bei einigen Endpunkten besser als Adalimumab mit MTX. Die JAK-Inhibitoren sind auch in der Monotherapie wirksam. Nebenwirkungen Das Nebenwirkungsprofil der JAK-Inhibitoren unterscheidet sich nicht wesentlich von dem von TNF- oder IL6-Rezeptor-Inhibitoren. Nur das Auftreten eines Herpes zoster ist während der JAK-Inhibition etwas häufiger. Perspektive JAK-Inhibitoren hemmen zahlreiche Zytokine, die auch bei verschiedenen anderen chronischen Krankheiten eine Rolle spielen. Daher ist mit Zulassungen für weitere Indikationen zu rechnen, z. B. Kollagenosen.

To prevent serious complications such as permanent loss of vision and structural vascular damage, treatment must be initiated quickly in patients with giant-cell arteritis (GCA). So far, usually long-term corticosteroids in cumulative high dosages have been the standard therapy option. However, steroids are often insufficient to achieve adequate disease control and are associated with serious adverse events. Therefore, steroid-sparing therapy options are the focus of interest.

Objective Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA). Methods Patients ages 18-45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA-B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed. Results One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA-B27. A combination of IgA anti-CD74 and HLA-B27 results in a posttest probability of 80.2%. Conclusion IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation.

Aim To calculate the prevalence of human leukocyte antigen (HLA)-B27 in axial spondyloarthritis patients (axSpA) compared to blood donors (BD) in Lebanon, to identify the clinical and radiological findings associated with HLA-B27 and to estimate the proportion of patients fulfilling the clinical arm of the Assessment of the Spondyloarthritis International Association (ASAS) criteria. Method Consecutive Lebanese adult axSpA patients fulfilling the ASAS classification criteria were included from 12 rheumatology clinics across Lebanon. BD served as controls. A binary logistic regression was used to study the association between HLA-B27 and the disease features. Results A total of 247 individuals were included (141 axSpA patients and 106 BD). The prevalence of HLA-B27 was 3.8% in BD and 41.1% in axSpA. Overall, 39.7% of the axSpA patients fulfilled the clinical arm of the ASAS classification criteria. Sensitivity of HLA-B27 for axSpA was 41.1%, specificity was 96.2%, positive predictive value was 93.6%, and negative predictive value was 55.13%. Positive likelihood ratio (LR) was 10.9 and negative LR was 1.63. We found a positive association of HLA-B27 with family history of SpA and psoriasis. Conclusion Our study confirmed a low prevalence of HLA-B27 in axSpA patients and BD in this Lebanese population, However, we found a high specificity and positive LR, as well as the same number of axSpA patients fulfilling the clinical arm of the ASAS criteria as in European studies. HLA-B27 is therefore valuable for identification of axSpA in Lebanese patients despite the overall low prevalence in this population. Our results may guide future evaluations the role of HLA-B27 in planning local referral strategies.

F-18 fluorodeoxyglucose (F-18 FDG) PET/CT plays an increasing role in the diagnostic workup of large vessel vasculitis (LVV); however, information on the relationship between immunosuppressive drugs and vessel wall uptake is limited. In 94 patients with a confirmed diagnosis of LVV, the vessel wall-to-liver ratio (VLR) was assessed in eight vessel segments. Patients were grouped according to intake of immunomodulatory drugs (Group 1, prednisone; Group 2, prednisone + methotrexate; and Group 3, prednisone + others) and compared to treatment-naïve individuals. A total of 54/94 (57.4%) were treated with immunomodulatory drugs (Group 1, 29/49 (53.7%); Group 2, 9/54 (16.7%); Group 3, 11/54 (20.4%); and Group 4, 5/54 (9.3%)), whereas the remainder received no therapy (40/94 (42.6%)). The mean VLR of the arterial segments correlated significantly with the hematopoietic organs (r ≥ 0.22, p ≤ 0.05), c-reactive protein (r ≥ 0.25, p ≤ 0.05), and prednisone dosage (r ≥ −0.4, p ≤ 0.05). Relative to treatment-naïve patients, a significantly lower VLR was recorded in 5/8 (62.5%) of the investigated vessel segments in Group 1 (p ≤ 0.02), in 6/8 of the vessel segments in Group 2 (75.0%, p ≤ 0.006), and in 7/8 of the segments in Group 3 (87.5%, p ≤ 0.05). In LVV, the F-18 FDG uptake in vessel wall as a marker of inflammatory activity was attenuated by immunomodulatory drugs, which provides a foundation for future serial monitoring of treatment efficacy.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases. ispartof: ARTHRITIS & RHEUMATOLOGY vol:73 issue:6 pages:1073-1085 ispartof: location:United States status: published

Health workforce shortage in German rheumatology has been identified as a healthcare service and delivery problem. Health policy has increased staffing targets, yet effective intervention strategies are lacking. This research aimed to systematically map the rheumatology workforce to improve the evidence for interventions and explore possibilities for more effective health workforce management.The WHO National Health Workforce Accounts provided a conceptual framework for the mapping exercise. Four major sets of indicators were selected, comprising staffing levels, health labor market flows, composition and education/training. A comparison of age groups and time series was applied to explore trends. Public statistics and other secondary sources served our analysis using descriptive methodology.In Germany there are 1076 physicians specialized in internal medical rheumatology. Absolute numbers have nearly doubled (91%) since 2000 but with a strong demographic bias. Between 2000 and 2019 numbers markedly increased in the group aged 50 years and older but only by 9% in the younger group under 50 years; since 2010 the group aged 40-50 years even faces a decrease. In 2019, the absolute numbers of rheumatologists in retirement age exceeded those aged 40 years and under. Since 2015 an expanding workforce trend has overall flattened but this was strongest in the hospital sector; the numbers in resident training did not show any relevant growth.Health workforce trends reveal that an available number of rheumatologists cannot meet new health policy planning targets. There is a need for effective health workforce management, focusing on innovation in resident training, improved task delegation and gender equality.HINTERGRUND UND FRAGESTELLUNG: Fachkräftemangel in der Rheumatologie in Deutschland ist als Versorgungsproblem erkannt. Die Gesundheitspolitik hat mit neuen Planungszielen reagiert, aber es fehlen effektive Interventionsstrategien. Ziel dieser Studie ist ein systematischer berufsstruktureller Überblick, um die Grundlage für Interventionen zu verbessern und Möglichkeiten für ein effektives Fachkräftemanagement aufzuzeigen.Die WHO National Health Workforce Accounts (NHWA) dienen als konzeptioneller Rahmen. Ausgewählt werden 4 Indikatoren: Personalbestand, Arbeitsmarktbewegungen, Komposition und Weiterbildung. Die Exploration von Entwicklungstrends stützt sich auf vergleichende Analysen von Altersgruppen und Zeitreihen. Die Erhebung nutzt öffentliche Statistiken und andere Sekundärliteratur; die Auswertung erfolgt deskriptiv.In Deutschland sind 1076 Ärzt*innen mit einer Facharztqualifikation oder Schwerpunktbezeichnung in der internistischen Rheumatologie ärztlich tätig. Die absolute Zahl verdoppelte sich seit 2000 deutlich (91 %), aber mit einem demografischen Bias. Im Zeitraum 2000 bis 2019 stieg die Zahl der über 50-Jährigen deutlich, aber die der unter 50-Jährigen nur um 9 %; seit 2010 sind die Zahlen in der Gruppe 40 bis 50 Jahre rückläufig. Im Jahr 2019 waren mehr Rheumatolog*innen im Rentenalter als unter 40-Jährige ärztlich tätig. Seit 2015 schwächt sich der steigende Trend insgesamt ab, aber am stärksten im Krankenhaussektor; die Weiterbildungen lassen keine konstante Steigerung erkennen.Berufsstrukturelle Trends zeigen, dass die gesundheitspolitischen Planziele mit den verfügbaren Humanressourcen nicht zu erreichen sind. Gefordert ist ein besseres Fachkräftemanagement, insbesondere durch Innovation der Weiterbildung, Aufgabenverschiebung und verbesserte Geschlechtergerechtigkeit.

Real-world data are crucial to continuously improve the management of patients with rheumatic and musculoskeletal diseases (RMDs). The German RheumaDatenRhePort (RHADAR) registry encompasses a network of rheumatologists and researchers in Germany providing pseudonymized real-world patient data and allowing timely and continuous improvement in the care of RMD patients. The RHADAR modules allow automated anamnesis and adaptive coordination of appointments regarding individual urgency levels. Further modules focus on the collection and integration of electronic patient-reported outcomes in between consultations. The digital RHADAR modules ultimately allow a patient-centered adaptive approach to integrated medical care starting as early as possible in the disease course. Such a closed-loop system consisting of various modules along the whole patient pathway enables comprehensive and timely patient management in an unprecedented manner.

Real-world data are crucial to continuously improve the management of patients with rheumatic and musculoskeletal diseases (RMDs). The German RheumaDatenRhePort (RHADAR) registry encompasses a network of rheumatologists and researchers in Germany providing pseudonymized real-world patient data and allowing timely and continuous improvement in the care of RMD patients. The RHADAR modules allow automated anamnesis and adaptive coordination of appointments regarding individual urgency levels. Further modules focus on the collection and integration of electronic patient-reported outcomes in between consultations. The digital RHADAR modules ultimately allow a patient-centered adaptive approach to integrated medical care starting as early as possible in the disease course. Such a closed-loop system consisting of various modules along the whole patient pathway enables comprehensive and timely patient management in an unprecedented manner.

This study addresses the challenging characterisation and differentiation of CIDP versus CIDP in association with Sjögren's syndrome to facilitate the process in clinical routine.Patients with both CIDP and Sjögren's syndrome and CIDP without Sjögren's syndrome were compared concerning relevant differences in clinical, laboratory and electrophysiological findings. 154 patients who fulfilled the diagnostic EFNS/PNS criteria for CIDP were included in the analysis. 54 of these patients additionally fulfilled the ACR/EULAR classification criteria for Sjögren's syndrome.The frequency of female patients was higher in patients with CIDP and Sjögren's syndrome (52%) versus CIDP patients without Sjögren's syndrome (28%). Furthermore, the occurrence of cranial nerve impairment was significantly higher in patients with Sjögren's syndrome (39% versus 14%). There were no significant group differences in the evaluation of initial symptoms, severity of disability judged by INCAT disability scale score, presence or distribution of sensory deficits, limb weakness and the presence of ataxia, pain or dysautonomia, CSF laboratory or electrophysiological findings.In conclusion, our data indicate that cranial nerve impairment and female gender might represent red flags for an additional Sjögren's syndrome in patients with CIDP. The patterns of clinical disabilities and electrophysiological findings due to peripheral nerve damage are similar in both CIDP entities.

Purpose Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. Methods We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. Results We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. Conclusion Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus., INSERM, University of Paris; Rockefeller University; St. Giles Foundation; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R37AI095983]; French National Research Agency (ANR) under the "Investments for the future" programFrench National Research Agency (ANR) [ANR-10-IAHU-01, ANR13-ISV3-0001-01, ANR-16-CE17-0005-01]; ECOS-NORD [C19S01-63407, SRC2017]; ANRHGDIFDFrench National Research Agency (ANR) [ANR-14-CE15-006-01]; ANR-IFNGPHOX [ANR-13-ISV3-0001-01]; GENMSMD [ANR-16-CE17-0005-01]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/11757-2, 2010/51814-0, 2012/51094-2]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)National Council for Scientific and Technological Development (CNPq) [303809/2010-8]; Instituto de Salud Carlos IIIInstituto de Salud Carlos IIIEuropean Commission [PI11/01086, PI14/00405]; European Regional Development Fund (ERDF)European Commission; Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX) [619-2013]; Diana Garcia de Olarte foundation PID; ColcienciasDepartamento Administrativo de Ciencia, Tecnologia e Innovacion Colciencias [713-2016, 111574455633]; "Poste d'accueil" INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm); Imagine Institute, The Laboratory of Human Genetics of Infectious Diseases is supported in part by institutional grants from INSERM, University of Paris, The Rockefeller University and the St. Giles Foundation, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (R37AI095983), and grants from the French National Research Agency (ANR) under the "Investments for the future" program (ANR-10-IAHU-01) and IFNGPHOX (ANR13-ISV3-0001-01 for JB and ACN), GENMSMD (ANR-16-CE17-0005-01 for JB) grants, ECOS-NORD (C19S01-63407 for JB and JFR), and SRC2017 (for JB). CO-Q is supported by ANRHGDIFD (ANR-14-CE15-006-01). AG was supported by the ANR-IFNGPHOX (ANR-13-ISV3-0001-01), GENMSMD (ANR-16-CE17-0005-01), and the Imagine Institute. AC-N and EBO-J are supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP grants 2012/11757-2, 2010/51814-0, and 2012/51094-2) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ grant 303809/2010-8). MMG and RC are supported by Instituto de Salud Carlos III, grants PI11/01086 and PI14/00405, co-financed by the European Regional Development Fund (ERDF). JFR and AAA are supported by Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX; 619-2013, Diana Garcia de Olarte foundation PID and Colciencias grant 713-2016 #111574455633). JR was supported by "Poste d'accueil" INSERM and Imagine Institute.

Einleitung: Die Riesenzellarteriitis (RZA) und Takayasu – Arteriitis (TAK) sind Großgefäßvaskulitiden (GGV), die zu schweren Komplikationen wie Erblindung, Organ- und Extremitätenischämien und bei einem Teil der Erkrankten zum Tod führen können. Glukokortikoid-assoziierte[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Rheumatologiekongress 2020, 48. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 34. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh)

BackgroundSerology testing is explored for epidemiological research and to inform individuals after suspected infection. During the COVID-19 pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test probability exist.MethodsIn a large German university hospital, we performed weekly questionnaire assessments and anti-SARS-CoV-2 IgG measurements with various commercial tests, a novel surrogate virus neutralization test, and a neutralization assay using live SARS-CoV-2.ResultsFrom baseline to week six, n=1,080 screening measurements for anti-SARS CoV-2 (S1) IgG from n=217 frontline HCP (65% female) were performed. Overall, 75.6% of HCP reported at least one symptom of respiratory infection. Self-perceived infection probability declined over time (from mean 20.1% at baseline to 12·4 % in week six, pConclusionWhen assessing anti-SARS-CoV-2 immune status in individuals with low pre-test probability, we suggest confirming positive results from single measurements by alternative serology tests or functional assays. Our data highlight the need for a methodical serology screening approach in regions with low SARS-CoV-2 infection rates.

Uncertain rates of asymptomatic infections have raised concerns about potentially high rates of thus far undiagnosed SARS-CoV-2 infections. Serological testing for SARS-CoV-2 specific IgG can be helpful in identification of asymptomatic infections. We report baseline results of the CVOID-19 Contact (CoCo) Study, which follows 217 frontline healthcare workers at a university hospital and performs weekly SARS-CoV-2 specific serology (IgA/IgG). The majority of participants had direct contact to patients with infectious respiratory diseases. Study participants estimated their personal likelihood of having had a SARS-CoV-2 infection with a mean of 20.9% (range 0 to 90%). In contrast, anti-SARS-CoV-2-IgG prevalence was in the range of 1-2% among health care workers. The CoCo Study is not fully representative for other hospitals and the sensitivity of anti-SARS-CoV-2 serology in low prevalence conditions may require further improvement. Taken together, low rates of SARS-CoV-2 specific IgG in healthcare workers in Northern Germany are in sharp contrast to the high personal risk perception. Regular anti-SARS-CoV-2 IgG testing of health-care workers may aid in monitoring the pandemic, assessing the quality of immune responses, directing resources for protective measures, and assuring CVID-19 care in the long run.

There have been concerns about high rates of thus far undiagnosed SARS-CoV-2 infections in the health-care system. The COVID-19 Contact (CoCo) Study follows 217 frontline health-care professionals at a university hospital with weekly SARS-CoV-2-specific serology (IgA/IgG). Study participants estimated their personal likelihood of having had a SARS-CoV-2 infection with a mean of 21% [median 15%, interquartile range (IQR) 5–30%]. In contrast, anti-SARS-CoV-2 IgG prevalence was about 1–2% at baseline. Regular anti-SARS-CoV-2 IgG testing of health-care professionals may aid in directing resources for protective measures and care of COVID-19 patients in the long run.

The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In this case, distinguishing PID from hypogammaglobulinemia secondary to anti-inflammatory treatment of autoimmunity may become challenging. The aim of this study was to evaluate the diagnostic accuracy of peripheral blood lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Comparison of B and T cell subsets from patients with PID and patients with rheumatic disease, who developed hypogammaglobulinemia as a consequence of anti-inflammatory regimes, revealed significant differences in proportion of na&iuml, ve B cells, class-switched memory B cells and CD21low B cells among B cells as well as in CD4+ memory T cells and CD4+ T follicular cells among CD4+ T cells. Identified differences in B cell and T cell subsets, and especially in the proportion of class-switched memory B cells and CD4+ T follicular cells, display a considerable diagnostic efficacy in distinguishing PID from secondary hypogammaglobulinemia due to anti-inflammatory regimens for rheumatic disease.

Objective Extraglandular neurological manifestations of Sjögren’s syndrome are increasingly recognized, defining the disease entity of Neuro‐Sjögren. Neuropsychological assessment of patients with Sjögren’s syndrome has hitherto been performed on predominantly rheumatological cohorts. These studies revealed a wide variety of prevalence rates for cognitive impairment (22–80%), while variable cut‐off criteria for detection of cognitive impairment were applied. Attentional functions have not yet been thoroughly investigated in these patients, although they clearly represent relevant aspects of cognitive functioning in daily life. Methods We therefore conducted extensive neuropsychological assessment based on two neuropsychological test batteries [i.e., the extended German version of the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery (CERAD‐PLUS), and the test battery for attentional performance (TAP) as a well‐established assessment of attentional functions in the German‐speaking part of Europe]. Results Sixty‐four patients with Neuro‐Sjögren, who were treated at our university hospital between December 2016 and January 2019, were included. Evidence for the presence of cognitive impairment was found in 55% of patients with Neuro‐Sjögren. The degree of cognitive impairment ranged from mild (38%) to severe (17%). Attentional and mnemonic subtests showed pronounced cognitive impairment in patients with Neuro‐Sjögren. Interpretation Our results suggest that a substantial proportion of patients with Neuro‐Sjögren suffer from cognitive impairment, putatively as a corollary of attentional deficits, which might exert adverse effects on occupational abilities, other cognitive functions, and social role functioning.

Background Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification. Methods With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. An inception cohort prospectively followed for 6 and 14 months was studied to validate the results in early cases and analyze if cluster assignment was modified with time. Results Four clusters were identified Three aberrant clusters were ‘acute phase inflammatory’, ‘T cell immunity’, and ‘interferon’, each including all diagnoses, were defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern, to which 74% of healthy controls clustered with patients. The inception cohort showed that most patients were either assigned always to the same cluster or moved from the healthy-like cluster to a single aberrant cluster resembling the relapsing-remitting dynamic of these diseases, showing that single aberrant molecular signatures characterize each individual patient. Conclusions Patients with SADs share molecular signatures and can be therefore stratified into three disease clusters differentiating each patient into a specific molecular disease pathway. Such assignment is stable with time. These results have important implications for understanding disease progression and therapy design marking a paradigm shift in our view of SADs. Acknowledgment This work has been supported through a grant from the Innovative Medicines Initiative Joint Undertaking No. 115565 and in-kind and in-cash contributions from the EFPIA partners. G.B. is supported by the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), through the Sara Borrell subprogram (CD18/00153). The authors would like to particularly express their gratitude to the patients, nurses and many others who helped directly or indirectly in the consecution of this study.

Background: Kappa free light chains (KFLC) are a promising new biomarker to detect neuroinflammation. Still, the impact of pre-analytical effects on KFLC concentrations was not investigated. Methods: KFLC concentrations were measured in serum and cerebrospinal fluid (CSF) of patients with a newly diagnosed multiple sclerosis (MS) or clinically isolated syndrome (CIS) before (n = 42) or after therapy with high-dose methylprednisolone (n = 65). In prospective experiments, KFLC concentrations were analyzed in the same patients in serum before and after treatment with high-dose methylprednisolone (n = 16), plasma exchange (n = 12), immunoadsorption (n = 10), or intravenous immunoglobulins (n = 10). In addition, the influence of storage time, sample method, and contamination of CSF with blood were investigated. Results: Patients diagnosed with MS/CIS and treated with methylprednisolone showed significantly lower KFLC concentrations in serum as untreated patients. Repeated longitudinal investigations revealed that serum KFLC concentrations continuously decreased after each application of methylprednisolone. In contrast, other immune therapies and further pre-analytical conditions did not influence KFLC concentrations. Conclusion: Our results show prominent effects of steroids on KFLC concentrations. In contrast, various other pre-analytical conditions did not influence KFLC concentrations, indicating the stability of this biomarker., publishedVersion

SUMMARYBackgroundClinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.MethodsWith the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.ResultsFour clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient.ConclusionsPatients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in the view of SADs.

Zusammenfassung Hintergrund Die systemische Sklerose (SSc) ist eine fibrosierende Autoimmunerkrankung aus der Gruppe der Kollagenosen. Neben der Hautfibrose zählt eine Beteiligung der Lunge, insbesondere in Form einer interstitiellen Lungenerkrankung (ILD), zu den häufigsten und schwersten Organmanifestationen der SSc. Die Krankheit geht insbesondere bei progressiver ILD mit einer erheblichen Morbidität und Mortalität einher. In den letzten 5 Jahren wurden in zahlreichen klinischen Studien neue Behandlungskonzepte für die SSc-ILD untersucht. Material und Methoden Im Rahmen dieses Reviews erfolgte eine Literaturrecherche mittels PubMed, die sich auf die relevantesten Beiträge der bis Ende 2018 veröffentlichten medizinischen Literatur mit den Schlagwörtern „SSc“ und „Treatment“ konzentrierte. Ergebnisse Die Therapie der SSc-ILD hat sich in den letzten Jahren aufgrund der Ergebnisse zahlreicher klinischer Studien gewandelt. Die aktualisierten Leitlinien der Europäischen Rheumatologengesellschaft (EULAR) empfehlen den Einsatz von Cyclophosphamid oder einer hämatopoetischen Stammzelltransplantation. Daten zur positiven Beeinflussung der SSc-ILD liegen auch für Mycophenolat, Tocilizumab und Anabasum vor. Aufgrund der pathophysiologischen Gemeinsamkeiten zur idiopathischen Lungenfibrose wird derzeit der Einsatz der antifibrotischen Wirkstoffe Nintedanib und Pirfenidon in randomisierten, multizentrischen klinischen Studien getestet und könnte eine zusätzliche, vielversprechende Therapiestrategie sein. Schlussfolgerung Innovative therapeutische Perspektiven für die SSc-ILD sind durch Erfolg versprechende Ansätze aktueller Arzneimittelstudien gegeben und könnten in Zukunft die Prognose von Betroffenen merklich verbessern.

Gout is caused by crystallization of uric acid in the form of monosodium urate (MSU) crystals, which induce a sterile inflammatory response that is hardly distinguishable from microbe-induced inflammatory responses. It is unclear, if MSU crystals (like microbes) are recognized by specific pattern recognition receptors. To identify possible soluble pattern recognition molecules for MSU crystals, we purified MSU-binding proteins from human body fluids. We identified C-reactive protein (CRP) as a major MSU-binding protein. Binding of CRP was strong enough to specifically deplete CRP from human serum. We found that CRP was required for fixation of complement components C1q, C1r, C1s and MASP1. Thus, we have identified a pattern recognition molecule for MSU crystals that links to the activation of complement. Notably, CRP does not show an even binding to the complete surface of the crystals. It rather binds to edges or distinct faces of the crystals.

Background Osteoarticular tuberculosis is rare in Germany. In particular, trochanteric bursitis is an extremely rare manifestation of osteoarticular tuberculosis. We describe a case of tuberculous coxitis with trochanteric bursitis, successfully treated with a fourfold tuberculostatic therapy. Case presentation We report the case of a 43-year-old human immunodeficiency virus-negative Sudanese man with osteoarticular tuberculosis, who was originally admitted with the suspected diagnosis of ankylosing spondylitis. Low grade fever together with the positive result of an interferon-gamma release assay test as well as findings from magnetic resonance imaging provided clues to the diagnosis. A definitive diagnosis could be set after a computed tomography-guided biopsy. Conclusions Apart from a rare involvement pattern of osteoarticular tuberculosis, including trochanteric bursitis, this case highlights the increasing importance of osteoarticular tuberculosis as a differential diagnosis of rheumatic disorders. With the growing migration flows from tuberculosis-endemic African countries, clinicians in central and northern Europe may be more frequently confronted with atypical involvement patterns of osteoarticular tuberculosis.

Die rheumatoide Arthritis (RA) ist mit einer Pravalenz von ca. 1 % die wichtigste chronisch-entzundliche Gelenkerkrankung. Unbehandelt fuhrt sie zu Gelenkzerstorungen und damit zu Behinderungen der Patienten, aber auch zu erhohter Rate an Krebs- und Herz-Kreislauf-Erkrankungen. Nachdem die Pathophysiologie der Erkrankung besser verstanden wurde, konnten in den letzten 20 Jahren mit den Biologika Medikamente entwickelt werden, die sehr gezielt in den Entzundungsprozess bei der RA eingreifen. Sie haben bereits zu einem deutlichen Anstieg der Remissionsraten gefuhrt. Seit 2017 sind in Deutschland zusatzlich Januskinase(JAK)-Inhibitoren zugelassen, die die therapeutischen Optionen noch deutlich erweitern und oral appliziert werden. Die Ansprechraten auf die Therapie sind umso besser, je eher die Erkrankung diagnostiziert und behandelt wird. Patienten, bei denen wegen einer neu aufgetretenen Polyarthritis der Verdacht auf eine RA besteht, sollten daher kurzfristig einem Rheumatologen vorgestellt werden.

Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases.

Die axiale Spondyloarthritis (axSpA) ist eine haufige Erkrankung. Sie ist in der Anfangsphase, bevor typische Veranderungen in den konventionellen Rontgenbildern nachweisbar sind, schwer zu diagnostizieren. Mittlerweile wird die Magnetresonanztomographie (MRT) der Sakroiliakalgelenke und der Wirbelsaule in der Diagnostik der axSpA haufig verwendet. Die Erlauterung der typischen Befunde und der Bedeutung der MRT in der Diagnostik der axialen Spondyloarthritis erfolgt anhand eines Literaturuberblicks Die Bildgebung der Sakroiliakalgelenke mittels MRT nimmt bei den ASAS (Assessment of Spondyloarthritis International Society)-Klassifikationskriterien fur axSpA eine zentrale Rolle ein. In der Definition einer „positiven“ MRT der Sakroiliakalgelenke ist der Nachweis eines Knochenmarkodems wichtig. Zusatzlich helfen chronische Veranderungen in den Sakroiliakalgelenken wie vermehrte Fettsignale und Erosionen in der Diagnostik. Bei nicht eindeutigen Befunden kann zusatzlich die MRT von Wirbelsaulenabschnitten erfolgen, in denen der Patient die starksten Beschwerden hat. Der Nachweis eines Knochenmarkodems in mindestens 3 Wirbelkorperkanten kann mit der axSpA assoziiert sein. Die MRT der Sakroiliakalgelenke ist mittlerweile eine der wichtigsten Methoden in der Diagnostik der axSpA geworden.