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Was ist neu? Remissionsinduktion bei Granulomatose mit Polyangiitis (GPA)/mikroskopischer Polyangiitis (MPA) Das Komplementsystem spielt in der Pathogenese, anders als früher vermutet, eine bedeutsame Rolle. Durch diese Erkenntnis war es möglich, einen vollständig neuen Therapieansatz zu etablieren. Die Blockade des C5a-Rezeptors mit Avacopan erwies sich in klinischen Studien als effektiv und ermöglichte erstmals eine (fast) GC-freie Remissionsinduktion. Avacopan ist eine kleines, gezielt eingreifendes Molekül und wird absehbar in die Therapie der GPA/MPA Einzug halten. Die therapeutische Bedeutung der Plasmapherese tritt weiter in den Hintergrund. Diese Therapieform bleibt aktuell wenigen Ausnahmesituationen vorbehalten und kann nicht mehr generell bei Glomerulonephritis oder pulmorenalem Syndrom empfohlen werden. Therapieprotokolle mit vermindertem GC-Einsatz zeigen ähnlich gute Erfolge wie Hochdosisprotokolle. Der GC-Einsatz kann daher weiter limitiert werden. GPA/MPA-Remissionserhaltung Vor allem die MAINRITSAN-Studien zeigen, dass Rituximab dem Azathioprin in der Remissionserhaltung überlegen ist und dass eine längere Erhaltungstherapie, insbesondere bei Risikopatienten, mit klinisch relevant geringeren Rezidivraten einhergeht. Genetik der eosinophilen Granulomatose mit Polyangiitis (EGPA) Trotz der Seltenheit der EGPA konnte ein internationales Konsortium eine genomweite Assoziationsstudie (GWAS) durchführen. Hierbei bestätigte sich auch auf der genetischen Ebene der klinische Eindruck zweier distinkter Subgruppen. Es kann ein mehr vaskulitisch geprägter Subtyp von einem durch die Eosinophilie dominierten unterschieden werden. Diese Ergebnisse werden für zukünftige Therapiekonzepte relevant sein. EGPA-Therapie Die bisher größte RCT bei EGPA wies eine verminderte Rezidivrate sowie einen GC-einsparenden Effekt eines Anti-IL-5-Antikörpers (Mepolizumab) nach. Der klinische Nutzen bestätigte sich in einer weiteren Analyse der Daten und auch in der „Real Life“-Anwendung.

Glukokortikoide (GC) stellen nach wie vor eine wesentliche Saule in der Phase der Remissionsinduktion der oft organ- oder lebensbedrohlichen Vaskulitiden dar, bergen jedoch ein erhebliches Nebenwirkungspotenzial. In der Phase der Remissionserhaltung sollte Prednisolon bis auf 7,5 mg/Tag oder weniger reduziert werden. Ob ein Absetzen bei jeder Form der Vaskulitis immer ohne Anstieg der Rezidivrate moglich ist, ist unklar. Durch den Einsatz von Biologika, z. B. von Tocilizumab bei der Riesenzellarteriitis (RZA), scheinen eine schnelle Reduktion und ein Absetzen der GC eher moglich als mit einer GC-Monotherapie. Avacopan konnte zukunftig zur Einsparung von GC bereits in der Phase der Remissionsinduktion bei AAV (ANCA[Anti-Neutrophile Zytoplasmatische Antikorper]-assoziierte Vaskulitis) (GPA [Granulomatose mit Polyangiitis]/MPA [Mikroskopische Polyangiitis]) eingesetzt werden. Mepolizumab ist eine vielversprechende Option zur GC-Einsparung bei EGPA (Eosinophile Granulomatose mit Polyangiitis).

Die Frage, ob eine laufende MTX(Methotrexat)-Therapie tatsächlich die protektive Immunantwort nach SARS-CoV-2-Impfung in relevanter Form abschwächt, lässt sich anhand der vorliegenden Daten definitiv nicht beantworten. In Kenntnis der Tatsache, dass ein kurzes z. B. 1‑ oder 2‑maliges Pausieren der wöchentlichen MTX-Gabe bei Patienten in stabiler Krankheitssituation mit einem vergleichsweise geringen Risiko der Auslösung eines Schubes der Grundkrankheit verbunden ist, kann eine solche kurze Unterbrechung der Therapie nach individueller Entscheidung zwischen Patient*in und behandelnder/m Rheumatolog*in durchaus erwogen werden. Zwingend notwendig erscheint sie aber nicht – zumal diese Pause bei den meisten Impfstoffen 2‑mal innerhalb relativ kurzer Zeit erfolgen müsste. Keinesfalls aber sollte eine längere Therapiepause gemacht werden – die Auslösung eines Schubes der Grundkrankheit wäre eine mögliche kritische Folge. Für eine ausführlichere Einschätzung der Datenlage und der Konsequenzen daraus (auch in Bezug auf weitere DMARD [„disease-modifying anti-rheumatic drugs“]) wird auf die demnächst erscheinenden aktualisierten Handlungsempfehlungen der DGRh (Deutsche Gesellschaft für Rheumatologie e. V.) für die Betreuung von Patienten mit entzündlich rheumatischen Erkrankungen im Rahmen der SARS-CoV-2/COVID-19-Pandemie verwiesen.

An international consensus on antineutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of patients with EGPA. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms; purpura; polyneuropathy; unexplained heart, gastrointestinal, or kidney disease; and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic workup for EGPA. Patients with MPO-ANCA-associated EGPA have vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations, more frequently than patients with ANCA-negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab, or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.

In der aktuellen SARS-CoV-2 Pandemie bestehen viele Fragen mit Blick auf die sichere Behandlung von Patienten mit entzundlich-rheumatischen Erkrankungen. Auf viele dieser Fragen gibt es zur Zeit noch keine evidenzbasierte Antwort und das macht die Betreuung der Patienten nicht leicht. Die Deutsche Gesellschaft fur Rheumatologie e. V. (DGRh) will mit diesen ersten Empfehlungen Hilfestellung fur spezielle Belange in der Betreuung von Rheumapatienten angesichts der aktuellen Bedrohung durch SARS-CoV-2 geben. Um den dynamischen weltweiten Erkenntnisgewinn fur unsere Patienten zu nutzen, werden die Empfehlungen regelmasig aktualisiert. Die aktualisierten Versionen der Empfehlungen werden auf der Homepage der DGRh hinterlegt.

The current outbreak of the SARS-CoV-2 infection provides countless unprecedented challenges—also with regard to the management of patients with inflammatory rheumatic disease. In an attempt to provide guidance, the German Society of Rheumatology instructed its commission for pharmacotherapy (Kommission Pharmakotherapie) to develop up-to-date recommendations for the management of patients with inflammatory rheumatic diseases during the Covid-19 pandemic. As to date there are little, if any, evidence-based data to scientifically justify guidance, the present preliminary recommendations are based on an expert consensus by 17 experienced rheumatologists in Germany, taking into account analogies to the procedures for other, longer known viral infections, theoretical considerations and already known facts about the SARS-CoV-2 infection. A deviation from these recommendations may be useful in each individual case. The recommendations will be updated frequently (www.dgrh.de). Every physician should also be aware of novel developments while the infection proceeds. 1.1. Patients with inflammatory rheumatic diseases may have an increased risk of infection (box 1). Whether this also applies to SARS-CoV-2 infections is not known. It is also not known whether Covid-19 is more severe in patients with inflammatory rheumatic …

ZusammenfassungDieser Artikel gibt eine Übersicht über die aktuellen deutschen und europäischen Therapieempfehlungen zu den ANCA-assoziierten Vaskulitiden (AAV) sowie ein Update zu seither publizierten wichtigen Therapiestudien. Nach den deutschen und europäischen Empfehlungen erfolgt die Remissionsinduktion bei GPA/MPA mit organbedrohender Erkrankung mit Glucocorticoiden und Cycloposphamid oder Rituximab, bei nicht organbedrohender Erkrankung mit Glucocorticoiden und Methotrexat (MTX) oder Mycophenolat-Mofetil (MMF). Die kürzlich publizierte MYCYC-Studie unterstützt die Empfehlungen; sie zeigte eine Nicht-Unterlegenheit gegenüber i. v. Cyclosphamid bei GPA/MPA-Patienten mit nicht-organbedrohender und organbedrohender Erkrankung auf. Die remissionserhaltende Therapie soll mit niedrig-dosierten Glucocorticoiden sowie Azathioprin, MTX und Rituximab durchgeführt werden. Rituximab wurde Ende 2018 auf der Basis der MAINRITSAN-Studie als remissionserhaltende Therapie zugelassen und ist damit nun die formal einzige zur Remissionserhaltung zugelassene Therapie. Mehrere Studien zur untersuchten zudem die kurze Anwendung von Glucocorticoiden (z. B. durch additive Therapie mit Avacopan) in der Remissionsinduktion und das komplette Ausschleichen von Glucocorticoiden in der Remissionserhaltung. Die ersten Ergebnisse hierzu sind vielversprechend; Langzeitdaten stehen allerdings aus. Für die sehr viel seltenere EGPA liegen insgesamt deutlich weniger Studiendaten vor. Die Therapie wird jedoch im Wesentlichen nach den gleichen Prinzipien wie bei den anderen AAV durchgeführt. Neuerdings steht, in Deutschland für diese Indikation aber noch nicht zugelassen, eine Biologikatherapie mit dem Anti-IL-5-Antikörper Mepolizumab zur Verfügung.

Diese Arbeit stellt eine retrospektive Analyse von Patienten dar, die sich im Zeitraum von 2016 bis 2018 uber die Terminservicestelle (TSS) in einer internistisch-rheumatologischen Gemeinschaftspraxis mit 2 Sonderbedarfssitzen vorstellten. Die Patienten wurden pseudonymisiert ausgewertet und nach folgenden Kriterien kategorisiert: 1. Termin nicht wahrgenommen, 2. keine entzundlich-rheumatische Erkrankung, 3. entzundlich-rheumatische Erkrankung ohne Indikation fur eine dringliche Vorstellung, 4. entzundlich-rheumatische Erkrankung mit Indikation fur eine dringliche Vorstellung. Im Zeitraum vom Start der Terminservicestelle Anfang 2016 bis Ende 2018 wurden 103 Patienten uber die Terminservicestelle angemeldet, 102 Patienten wurde ein Termin angeboten. Diese Patienten wurden in die Auswertung mit einbezogen. 4,9 % der Patienten (n = 5) hatten eine entzundlich-rheumatische Erkrankung mit dringlicher Indikation fur eine internistisch-rheumatologische Vorstellung, 18,63 % aller Patienten (n = 19) hatten eine entzundlich-rheumatische Grunderkrankung, jedoch keine Indikation fur eine dringliche Vorstellung, in 28,43 % der Falle (n = 29) wurde der Termin nicht mehr gewunscht bzw. nicht wahrgenommen, und in 48,04 % der Patienten (n = 49) bestand gar keine rheumatologische Grunderkrankung, sondern es bestanden Erkrankungen wie z. B. Arthrose, Fibromyalgie und andere Schmerzsyndrome. Der positive pradiktive Wert (PPV) fur Patienten mit rheumatischer Erkrankung und dringlicher Behandlungsindikation betragt 0,05 bezogen auf alle Patienten und 0,07 bezogen auf die erschienenen Patienten. Die hier vorgelegte retrospektive Auswertung zeigt fur den internistisch-rheumatologischen Bereich, dass die TSS ihren Zweck, namlich akut erkrankten Patienten zu einem zugigen Termin bei einem entsprechenden Facharzt zu verhelfen, nicht erfullt.

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.

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)

A few days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled the first group of recommendations for the care of patients with inflammatory rheumatic diseases in light of SARS-CoV-2/coronavirus disease 2019 (COVID-19). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registries, cross-sectional studies, case reports and case series are available, the DGRh has developed a timely update. This update is based on a literature search of publications available through 15 June 2020 and addresses preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. Driven by the commitment to let patients benefit from these new evidence-based recommendations as quickly as possible, the DGRh published the update in German on its homepage and in the Zeitschrift für Rheumatologie immediately after completion. Here we report the key recommendations to make them available to the international community, provide the scientific methodology used to develop the recommendations, give additional thoughts and advice for the management of patients with rheumatic diseases during the COVID-19 pandemic and discuss our recommendations in the context of other international recommendations.

ObjectiveThis multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs).MethodsSera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays.ResultsThe area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945).ConclusionsOur comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.

BACKGROUND: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission. OBJECTIVE: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses. METHODS: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/μL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg. RESULTS: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/μL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395). CONCLUSION: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab.

Eosinophilic granulomatosis with polyangiitis (EGPA: formerly Churg-Strauss syndrome) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasm antibodies (ANCA) specific for myeloperoxidase (MPO). We performed a genome-wide association study (GWAS) of EGPA, testing 7.5 million genetic variants in 684 cases and 6,838 controls. Case-control analyses were performed for EGPA as a whole, and stratified by ANCA. To increase power, we used a conditional false discovery rate method to leverage findings from GWASs of related phenotypes. In total, 11 variants were associated with EGPA, two specifically with ANCA-negative EGPA, and one (HLA-DQ) with MPO+ANCA EGPA. Many variants were associated with asthma, eosinophilic and immune-mediated diseases and, strikingly, nine were associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia underlies EGPA susceptibility. We demonstrate that EGPA comprises two genetically and clinically distinct syndromes, with ANCA-negative EGPA genetically more similar to asthma. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an MHC association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Five identified candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Background:Average life spans of patients with rheumatoid arthritis (RA) are approaching those of the general population. This results in a large proportion of RA patients being elderly at some point and underlines effective RA treatments needed for this population. Pivotal clinical trials have demonstrated the efficacy of tocilizumab (TCZ) for the treatment of RA. However, real-world studies that explore the effectiveness of TCZ especially in the elderly are lacking. ICHIBAN was a large, observational study that followed patients with RA treated with TCZ under real-world conditions in Germany for up to 2 years.Objectives:In this analysis of ICHIBAN, we examined the safety and effectiveness of long-term TCZ treatment according to patient baseline (BL) age (65 years).Methods:ICHIBAN (NCT01194401) was a prospective, non-interventional study that observed adult patients with active moderate to severe RA in German rheumatology clinics and practices. Patients were treated with TCZ according to the local label. The safety analyses set (SAF) included all patients who received at least one dose of TCZ. The effectiveness set (EFF) included all patients from the SAF who had no prior TCZ therapy. Patient-reported outcomes (PROs) were assessed using the visual analogue scale. Last observation carried forward was used to substitute for missing values.Results:At baseline (BL), 3,164 patients were included in the SAF: 29.2% 65 years old (1.2% ≥80 years). Patients >65 years old were not only the most likely to have comorbidities such as hypertension, anaemia, renal insufficiency, osteoporosis, diabetes, and coronary heart disease, but also had the highest BL disease activity according to Disease Activity Score-28 erythrocyte sedimentation rate (DAS28-ESR) and Clinical Disease Activity Index (CDAI) (Table 1).Proportions of patients with adverse events (AEs) considered related to treatment were similar in patients 65 years (22.2%). More patients >65 years (20.2%) and 50–65 years (14.4%) experienced serious AEs (SAEs) than patients 65 years old experienced infectious SAEs (4.8%) than younger patients (65 years).2,902 patients were included in the EFF. Patients 65 years (59.5%). However, patients >65 years had numerically greater improvements in DAS28-ESR (Table 1). Patients Table 1.Model summary for prediction of DAS28CRP using time and etanercept originator (relative to biosimilar)50–65 years>65 yearsDAS28-ESR, mean ± SDn*7771237617BL4.9 ± 1.45.3 ± 1.35.4 ± 1.3Last visit2.8 ± 1.73.1 ± 1.73.2 ± 1.7Change from BL-2.0 ± 1.7-2.2 ± 1.7-2.2 ± 1.8CDAI, mean ± SDn*7681217590BL25.7 ± 12.828.4 ± 13.328.8 ± 12.8Last visit13.3 ± 12.814.6 ± 13.214.5 ± 12.8Change from BL-12.5 ± 13.6-13.8 ± 14.0-14.3 ± 13.8*271 patients with missing data at BL**327 patients with missing data at BLConclusion:Although elderly patients experienced a higher rate of infections, the proportion of patients withdrawing due to AE was not higher than in the other age groups. Starting with higher baseline disease activity, patients >65 years had similar benefits to disease activity and PROs when compared with younger patients. Overall, these results indicate that long-term TCZ treatment of elderly patients is effective and has an acceptable safety profile.Disclosure of Interests:Christof Specker Speakers bureau: AbbVie, Celgene, Chugai, Janssen-Cilag, Lilly, MSD, Novartis, Pfizer, Roche, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Chugai, Lilly, Novartis, Sobi, and UCB, Grant/research support from: Boehringer, Chugai, GSK, and Roche, Martin Aringer Speakers bureau: Roche and Chugai, Consultant of: Roche and Chugai, Grant/research support from: Roche, Gerd Rüdiger Burmester Consultant of: Lilly, Pfizer, Sanofi, and Roche, Grant/research support from: Roche, Marvin Peters Employee of: Roche Pharma AG, Michael W. Hofmann Employee of: Chugai Pharma Germany GmbH, Herbert Kellner Consultant of: Roche, Grant/research support from: Roche, Frank Moosig Grant/research support from: Roche, Hans-Peter Tony Speakers bureau: Roche, Abbvie, BMS, Chugai, Janssen, Novartis, Sanofi, and Lilly, Consultant of: Roche, Abbvie, BMS, Chugai, Janssen, Novartis, Sanofi, and Lilly, Grant/research support from: Roche, Gerhard Fliedner Grant/research support from: Roche, Chugai, Abbvie, and Lilly

Rheumatologist should be familiar with the concept of IgG4-related disease (IgG4-RD). Due to the clinical spectrum IgG4-RD can fall directly within the scope of rheumatology and are often diagnosed primarily by rheumatologists. Furthermore, IgG4RD are relevant differential diagnoses for many other rheumatic conditions. Finally, there are an increasing amount of data suggesting an important role of immunological processes observed in IgG4-RD for other rheumatic diseases.

Sarcoidosis is characterized by multiorgan involvement and granulomatous inflammation. Its origin is unknown and the potential role of autoimmunity has not been sufficiently determined. We investigated the presence of autoantibodies in sarcoidosis using protein array technology. The derivation cohort consisted of patients with sarcoidosis (n = 25) and controls including autoimmune disease and blood donors (n = 246). In addition, we tested a validation cohort including pulmonary sarcoidosis patients (n = 58) and healthy controls (n = 13). Initially, sera of three patients with sarcoidosis were screened using a protein array with 28.000 proteins against controls. Thereby we identified the Negative Elongation Factor E (NELF-E) as an autoantigen. With confirmatory Enzyme-linked Immunosorbent Assay (ELISA)testing, 29/82 patients (35%) with sarcoidosis had antibodies against NELF-E of the Immunoglobulin (Ig) G type, whereas 18/253 (7%) sera of the controls were positive for NELF-E. Clinically, there was an association of the frequency of NELF-E antibody detection with lung parenchymal involvement and corresponding x-ray types. NELF-E autoantibodies are associated with sarcoidosis and should be further investigated.

Die Polyarteriitis nodosa (PAN) ist eine nekrotisierende Arteriitis mittelgroser Gefase, die unbehandelt oftmals letal verlauft. Sie manifestiert sich haufig an der Haut (Noduli oder Ulzera), am peripheren Nervensystem (Mononeuritis multiplex) und durch Stenosen und Mikroaneurysmen der viszeralen Gefase. Die Diagnose erfordert eine komplexe diagnostische Aufarbeitung zur Abgrenzung von infektiosen, malignen, medikamenteninduzierten und anderen inflammatorischen Erkrankungen. Die PAN kann in weitere Varianten unterteilt werden (idiopathisch, Hepatitis-B-assoziiert, mit hereditaren inflammatorischen Syndromen assoziiert und eine isoliert kutane Verlaufsform). Wahrend idiopathische und hereditar inflammatorische Formen einer immunsuppressiven Therapie bedurfen, wird die Hepatitis-B-assoziierte Variante mit Virostatika und Plasmapherese behandelt. Die Prognose der isoliert kutanen Form ist gut und bedarf selten hochpotenter Immunsuppression.

Introduction: Besides an obvious clinical involvement of the ear, nose and throat (ENT)-region in Eosinophilic Granulomatosis with Polyangiitis (EGPA), systematic data is sparse. Only a few case series and case reports are available that particularly describe rhinological, otological or other manifestations of EGPA in the ENT-region. Therefore, the objective of this study is to systematically describe data on ENT-region involvement in a large series of EGPA patients. Method: EGPA patients examined in the Department of Otorhinolaryngology of the Christian-Albrechts-University of Kiel between 1990 and 2010 were included in the study. Criteria for ENT-manifestation were assigned to five subgroups (history, ENT examination, audiological and rhinological diagnostic findings and cranial MRI) and documented cumulatively. EGPA patients were examined in a standardized way based on the validated Ear Nose and Throat Activity Score (ENTAS) or its precursor, including audiological and rhinological diagnostic findings. MRI scans were analysed to further evaluate ENT involvement. Results: A total of 95 EGPA patients were included in the study. In approximately 80% of them, ENT-involvement was documented and the assumption of a frequent rhinological manifestation in patients with EGPA was confirmed. Moreover, the data reveals remarkable evidence for an otological manifestation. A missing correlation between the rhinological and the otological manifestation indicates an independent autoimmune-inflammatory process for this manifestation. Conclusion: The data of the largest monocentric study presented here confirms the hypothesis of a frequent ENT involvement in EGPA patients, in whom rhinological and otological manifestations are most common. Therefore, treatment should include long term follow-up and should be managed interdisciplinary.

Objective To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. Methods We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. Results Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. Conclusion MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.

Einleitung: Eine deutschsprachige Leitlinie zur Diagnostik und Therapie der ANCA-assoziierten Vaskulitiden sollte erstellt werden. Methoden: Eine Expertenkommission aus 13 Mitgliedern wurde von der DGRh mit der Erstellung der Leitlinie beauftragt. Für eine systematische Literaturrecherche wurden[zum vollständigen Text gelangen Sie über die oben angegebene URL], 45. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 31. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), 27. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Detection of antineutrophil cytoplasmic antibodies (ANCAs) is a well-established diagnostic test used to evaluate suspected necrotizing vasculitis of small blood vessels. Conditions associated with these antibodies, collectively referred to as ANCA-associated vasculitides, include granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). The diagnostic utility of ANCA testing depends on the type of assay performed and on the clinical setting. Most laboratories worldwide use standard indirect immunofluorescence tests (IFT) to screen for ANCA and then confirm positive IFT results with antigen-specific tests for proteinase 3 (PR3) and myeloperoxidase (MPO). Developments such as automated image analysis of immunofluorescence patterns, so-called third-generation PR3-ANCA and MPO-ANCA ELISA, and multiplex technology have improved the detection of ANCAs. However, challenges in routine clinical practice remain, including methodological aspects of IFT performance, the diverse antigen-specific assays available, the diagnostic value of testing in clinical settings and the prognostic value of serial ANCA monitoring in the prediction of disease relapse. This Review summarizes the available data on ANCA testing, discusses the usefulness of the various ANCA assays and advises on the clinical indications for the use of ANCA testing.

Zusammenfassung Seit der Entdeckung der ANCA vor 30 Jahren haben sich die Testmethoden weiter verfeinert. Aktuellen Standards ist die Testung in der Indirekten Immunfluoreszenz (IFT) gefolgt von Antigen-spezifischen-Tests. Diese konnten in ihrer Sensitivität und Spezifität weiter deutlich gesteigert werden, insbesondere durch den Einsatz von “capture” und “anchor” ELISA-Techniken, wobei die Qualität der verfügbaren kommerziellen Testsysteme gemessen an internationalen Standards z.T. unzureichend ist. Ihr alleiniger Einsatz unter Verzicht auf die IFT wird weiter nicht empfohlen. Proteinase3- und Myeloperoxidase-ANCA haben die größte gesicherte diagnostische Bedeutung für die ANCA-assoziierten Vaskulitiden. Der Steigerung der Sensitivität und Spezifität steht ein zunehmend ungezielter klinischer Einsatz gegenüber, der, bei sehr niedriger Prävalenz der infrage stehenden Erkrankungen, zu einer dennoch hohen Rate an “falsch” positiven Befunden führt. Neue Testmethoden, die eventuell den Einsatz von zwei Methoden ablösen könnten, befinden sich in der Entwicklung, bedürfen aber der Evaluation in geeigneten internationalen multizentrischen Studien.

Aim: Correlation of outcomes of cyclophosphamide (CP) therapy in antineutrophil cytoplasmic antibody-associated vasculitis with genotype polymorphisms in prodrug activating cytochrome P450 enzyme genes CYP2C9 and CYP2C19. Patients & methods: One hundred and ninety six patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with CP, either as intravenous pulse or as daily oral medication, were included. Genotypes of CYP2C9 and CYP2C19 were correlated with clinical outcomes (leukopenia, infection, urotoxicity and treatment response). Results: Sixty five (33.2%) patients had variant CYP2C9 and 55 (28.1%) had variant CYP2C19 genotype. In patients bearing variant CYP2C9, leukopenia was documented significantly more frequent than in carriers of wild-type CYP2C9 (55.4 vs 37.4%; odds ratio: 2.08; 95% CI: 1.14–3.80; p = 0.017). The impact of the CYP2C9 genotype was stronger in patients treated with oral CP (69.6 vs 45.6%; odds ratio: 2.73; 95% CI: 1.27–5.89; p = 0.009), but was not present in patients treated with intravenous pulsed CP. We observed less refractory disease courses in patients with variant CYP2C9, not reaching statistical significance. Conclusion: Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment.

Objective To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA). Methods We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center. Results Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA. Conclusion Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk.

To evaluate the ability of MRI to detect subglottic stenosis and to differentiate between active and inactive subglottic inflammation in patients with granulomatosis with polyangiitis (GPA). MRI studies of the larynx of 18 GPA patients with suspected SGS were included. The MRI protocol included T1- and T2-weighted and STIR-sequences, dynamic contrast enhancement (DCE) and diffusion weighted imaging (DWI). Two independent observers reviewed the MR images. SGS were identified and quantified, inflammatory activity was assessed using edema imaging, DCE and DWI. Final MRI diagnoses were compared to the clinical, laryngoscopic and histopathologic results. MRI confirmed SGS in all GPA patients with significant narrowing of the airway lumen and thickening of subglottic wall. Assessing the subglottic inflammatory activity, MRI showed a sensitivity of 87.5 % and a specificity of 60.0 %. Interrater agreement was κ = 0.769. Of the different MR technical approaches tested, edema imaging was most sensitive and specific. DWI led to significant differences in the apparent diffusion coefficient between active and inactive subglottic inflammation. No significant differences were found with DCE imaging. MR imaging has shown the ability to detect and grade SGS in patients with GPA. It non-invasively assesses the status of inflammatory activity utilizing edema sensitive sequences and DWI.

Since the introduction of combined immunosuppressive therapy with oral cyclophosphamide (CYC) and glucocorticosteroids in the 1970s, the outcome of antineutrophil cytoplasmic antibody-associated vasculitides, for example, in granulomatosis with polyangiitis (Wegener`s), improved dramatically. However, the long-term follow-up of patients treated with CYC plus glucocorticosteroids has revealed high treatment-related morbidity and mortality and a high relapse rate (up to 50%), often re-requiring CYC and glucocorticosteroids. Today, according to the European League Against Rheumatism recommendations for the management of small- and medium-vessel vasculitis, the treatment paradigm for severe courses of granulomatosis with polyangiitis consists of CYC for the induction of remission, followed by a less-toxic maintenance therapy for the prevention of relapses. Azathioprine, methotrexate, leflunomide and mycophenolate mofetil proved efficacy for maintaining remission in randomized controlled trials. However, despi...

ObjectiveTo evaluate a vasculitis centre based management strategy for eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA).MethodsA retrospective cohort study at a vasculitis referral centre was performed. All EGPA patients admitted from 1990 to 2009 were included. A structured interdisciplinary work-up for proof of diagnosis, Disease Extent Index and Birmingham Vasculitis Activity Score was performed. Immunosuppressive therapy was initiated and regularly adapted. Treatment targets were induction and maintenance of remission according to definitions given by the European League Against Rheumatism and the European Vasculitis Study Group. Outcomes were mortality, rate of remission, relapses, adverse events and prednisolone-dose.ResultsOut of 269 patients with suspected EGPA 150 fulfilled the inclusion criteria. Of those, 104 had more than one follow-up visit resulting in a mean follow up of 53±4.9 months. By using additional data sources the follow-up concerning survival was extended to 92±5 month. Severe organ manifestations occurred at heart (46%), kidney (18%) and lungs (10%). Cyclophosphamide was used in 107 patients (71%). The prednisolone-doses of all patients were within the targeted range (i.e. ≤7.5mg) in 69% of the total follow-up time; the median dose at end of follow-up was 5mg/d. The 10-year survival rate was 89% resulting in mortality comparable to the general population (SMR 1.29). Only patients with cardiac failure associated with EGPA had an increased mortality (SMR 3.06).ConclusionsRegular re-evaluation and target-orientated adaption of therapy may lead to normalization of life expectancy and attenuation of disease progression. Continued centre based interdisciplinary treatment should be standard of care.

Objectives Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are relatively common inflammatory disorders. Establishing the diagnosis however may be difficult, since so far no specific biomarkers of the disorders are available. Methods As a screening procedure, the authors used protein arrays for the detection of new autoantigens in GCA and PMR. The results of the protein array were confirmed by different ELISAs detecting IgG antibodies against the human ferritin heavy chain, N-terminal 27 amino acids of the human ferritin heavy chain or the homologous peptide of Staphylococcus epidermidis . Sera of patients with only GCA (n=64), only PMR (n=47) and both PMR and GCA (n=31) were used. Results In the ELISA using the human ferritin peptide, the sensitivity of IgG antibodies against ferritin was 92% in 36 GCA and/or PMR patients before initiation of treatment, 22/32 (69%) in patients with disease flares and 64/117 (55%) in the total cohort including treated and inactive patients. In controls, the false positive rate was 11/38 (29%) in systemic lupus erythematosus, 1/36 (3%) in rheumatoid arthritis, 0/31 (0%) in late onset rheumatoid arthritis, 3/46 (6.5%) in B-non-Hodgkin9s lymphoma and 1/100 (1%) in blood donors. In the ELISA using the ferritin peptide of S epidermidis , 89% of 27 patients with untreated GCA and PMR were positive. Conclusion Antibodies against the ferritin peptide were present in up to 92% of untreated, active GCA and PMR patients. They can be useful as a diagnostic marker of PMR and GCA.

PURPOSE OF REVIEW Churg-Strauss syndrome (CSS) has a clear clinical phenotype but its pathogenesis is not fully elucidated. Recent studies have focused on its immunogenetic aspects and cytokine and chemokine-mediated pathogenetic mechanisms, providing the rationale for the use of newer targeted therapies. This study will review recent findings on the pathogenesis of CSS and its therapeutic approaches. RECENT FINDINGS CSS is usually considered a Th2-mediated disease, but Th1 and Th17 responses might also play a role; the reported association between CSS and HLA-DRB4 further underlines the pathogenetic relevance of CD4 T cells which, thanks to their ability to secrete cytokines such as IL4, IL5, and IL13, promote allergic and eosinophilic reactions. Resident cells such as endothelial and epithelial cells might also amplify the immune response by producing eosinophil-attracting chemokines such as eotaxin-3 and CCL17. Conventional immunosuppressive therapies offer high chances of achieving sustained remission, but steroid exposure remains high. Targeting IL5 with mepolizumab seems promising in sparing steroids, but relapses often follow its withdrawal. B-cell depletion using rituximab has proved effective in refractory CSS cases. SUMMARY Current knowledge on CSS pathogenesis is evolving; the identification of key molecular mechanisms will pave the way for newer, more specific treatments.

Objectives. To determine the potential of eotaxin-3 as a diagnostic marker for active disease and genetic susceptibility factor for Churg-Strauss syndrome (CSS). Methods. A total of 37 patients with active, relapsed or inactive CSS, 123 healthy controls and 138 disease controls were studied. Clinical data were collected and serum levels of eotaxin-3 were determined. Ex vivo stability of eotaxin-3 in serum samples was tested. Furthermore, the association of single nucleotide polymorphisms (SNPs) in the eotaxin-3 gene with CSS was determined in 161 CSS patients and 124 healthy controls. Results. Serum eotaxin-3 was highly elevated in active CSS patients. Neither eosinophilic diseases nor other small-vessel vasculitides were associated with high serum eotaxin-3 levels. Receiver operating characteristic curve analysis determined a sensitivity and specificity of 87.5 and 98.6% at a cut-off level of 80 pg/ml. None of the tested SNPs within the eotaxin-3 gene influenced the susceptibility to develop CSS. Conclusions. Serum eotaxin-3 is a sensitive and specific marker for the diagnosis of active CSS suitable for routine clinical practice. Previously described SNPs in the eotaxin-3 gene do not predict the risk of developing CSS.

Systemische Vaskulitiden stellen eine Gruppe heterogener chronisch-rezidivierender Krankheitsbilder dar. Erste Daten zeigen, dass die gesundheitsbezogene Lebensqualitat aus Patientensicht in allen Dimensionen (physisches, psychisches und soziales Befinden) reduziert ist. Die Arbeiten weisen darauf hin, dass generische Instrumente zur Messung der HRQoL („Health-Related Quality of Life“) nicht alle Dimensionen bei Patienten mit Vaskulitiden erfassen. Daruber hinaus liegen Hinweise darauf vor, dass Erschopfung/Mudigkeit („Fatigue“) und ein vermindertes Energieniveau eine grose Rolle spielen. Diese Arbeit gibt einen Uberblick uber den aktuellen Stand der Literatur.

This article focuses on the clinical application and technical aspects of imaging methods which are used alternatively or additionally to angiography or magnetic resonance imaging in patients with Takayasu's arteritis or giant cell arteritis. Providing a high spatial resolution, duplex ultrasound is particularly suitable for the evaluation of peripheral arteries. With the exception of cranial arteries, positron emission tomography as a whole body examination is the best imaging modality for the assessment of inflammatory activity. Computed tomography is used for angiographic examinations and enables evaluation of wall thickening in large arteries. It is the method of choice in the case of emergencies due to aortic aneurysm or dissection. In addition to angiographic and ultrasound techniques, ophthalmological methods comprise biomicroscopy, including funduscopy and optical coherence tomography.

Churg-Strauss syndrome is a rare small-vessel vasculitis that is associated with asthma, granulomatous inflammation, peripheral/tissue eosinophilia and a positive antineutrophil cytoplasmic antibody status (in approximately 40% of patients). The disease can be organ- and life-threatening, either due to tissue eosinophil infiltration such as myocarditis or due to vasculitis manifestations, for example glomerulonephritis. Furthermore, life-threatening disease can also occur due to the side effects of immunosuppression, for example, infection. A thorough diagnostic work-up should be performed in order to identify all organs involved and to rule out other disorders with similar features, such as hypereosinophilic syndrome. Therapeutic management is conducted according to disease stage and activity. Glucocorticoids remain the mainstay of therapy; however, further immunosuppressants (e.g., cyclophosphamide for life-threatening disease) are usually required. Future promising therapy options target cytokines involved in the disease process, such as IL-5.

Imaging methods have become indispensable for the diagnosis and follow-up of giant cell arteritis and Takayasu's arterititis, in addition to physical examination and laboratory parameters. The choice of method is predominantly determined by clinical presentation and localization of the vascular territory to be examined. Furthermore, aspects of radiation protection, contrast media intolerance and other contraindications, as well as the varying costs of the different procedures need to be considered. This article reviews the clinical and morphological features of primary large vessel vasculitides which are fundamental to the identification of the disease and the assessment of inflammatory activity using imaging modalities. Angiography is the gold standard for the evaluation of stenotic lesions and can be combined with interventional treatment. Vessel wall thickening as a defining diagnostic criterion is outlined only by cross-sectional imaging. In addition to MR angiography, MRI techniques in particular enable vizualization of inflammatory processes in central as well as in peripheral arteries.

Giant cell arteritis and Takayasu's arteritis are classified as primary large-vessel vasculitides. Inflammatory cell infiltrates and cytokines induce destruction and hyperplasia of the vessel wall, leading to stenoses or aneurysms. When extracranial large arteries are involved, there is often a similar clinical and radiologic disease pattern of an inflammatory aortic arch syndrome. Rare causes of large-vessel vasculitis include Behcet's disease, association with other autoimmune diseases, and infection. Depending on the localization, imaging is usually performed by means of duplex ultrasound, magnetic resonance imaging, computed tomography, or positron emission tomography. These imaging modalities are used not only to establish the diagnosis but also to determine the disease extent and activity and to perform follow-up in the course of medical therapy. Angiography offers the option to perform interventional therapy for vascular stenoses and occlusions.

Giant cell arteritis is the most common systemic vasculitis and affects large and medium-sized vessels. Glucocorticoids are the current standard in the therapy of giant cell arteritis. To reduce the glucocorticoid dose the European League Against Rheumatism (EULAR) suggests the addition of disease-modifying antirheumatic drugs. Of these, methotrexate represents the best investigated drug; possible alternatives include azathioprine, tumor necrosis factor-alpha inhibitors and cyclophosphamide.