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Objectives: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry., Methods: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019., Results: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%)., Conclusions: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

Background: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update., Methods: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations., Results: Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV., Conclusions: In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance., Competing Interests: Competing interests: AB received honoraria for consulting from GSK. AJM received speaker fees and/or consultancies from Amgen, Lilly, Vifor, Roche and GSK. AJM received speaker fees and/or consultancies from Amgen, Celgene, Chugai, Novartis, Roche and Vifor. AK received speaker fees and/or consultancies from Catalyst Biosciences, Walden Bioscience, Delta4, Otsuka, UriSalt and Vifor. BH received speaker fees and/or consultancies from AbbVie, Amgen, AstraZeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. BT received consulting fees from AstraZeneca, GlaxoSmithKline, Vifor and Pharma. DB received consultancies from Roche. DJ received speaker fees and/or consultancies from Amgen, AstraZeneca, BMS, Boehringer, Chemocentryx, Chugai, GSK, Novartis, Roche, Takeda and Vifor. DV received speaker fees and/or consultancies and/or grants from AbbVie, Genesis-Pharma, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and UCB. The work is supported by the Greek Rheumatology Society and Professional Association of Rheumatologists (ERE-EPERE) and the Special Account for Research Grants (SARG), National and Kapodistrian University of Athens, Greece. JHS received research grants from the John Grube Foundation and the Deutsche Gesellschaft für Rheumatologie (German Society for Rheumatology). MAL received unrestricted research funding and consultancy fees from Vifor with Chemocentryx. MCC received consulting fees from GSK, Vifor, AbbVie and Janssen, and a research grant from Kiniksa Pharmaceuticals. MS has received consultancy fees from Hansa Biopharma, Vifor, AstraZeneca, Toleranzia and Chemocentryx. PM reports receiving funds for the following activities in the past 2 years: consulting: AbbVie, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chemocentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, NS Pharma, Pfizer, Regeneron, Sparrow, Takeda and Talaris; research support: AbbVie, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chemocentryx, Eicos, Electra, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi and Takeda; stock options: Kyverna. OK reports receiving speaking fees and/or consultancies from Amgen, AbbVie, Lilly, UCB-Pharma, Novartis, Celltrion; and research support from AbbVie, Viela-Bio, Roche and Novartis. RAL received speaker fees and/or consultancies and/or grants from AbbVie, BMS/Celgene, Chemocentryx, Chugai, GSK, InflaRx, Pfizer Global, Roche and Vifor. The LUMC received on behalf of YKOT an unrestricted research grant from CSL Vifor, GlaxoSmithKline, Aurinia Pharmaceuticals. The LUMC received consulting fees from Aurinia Pharmaceuticals, Novartis, GSK, KezarBio, Vifor Pharma and Otsuka Pharmaceuticals on consultancies delivered by YKOT. The work of YKOT is supported by the Dutch Kidney Foundation (17OKG04) and by the Arthritis Research and Collaboration Hub (ARCH) foundation. ARCH is funded by Dutch Arthritis Foundation (ReumaNederland). AV, BS-A, CBM, FP-K, GT, JH, JM, NH, PV and SM reported no conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To summarise and update evidence to inform the 2022 update of the EULAR recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitis (AAV)., Methods: A systematic literature review (SLR) was performed to identify current evidence regarding treatment of AAV. PubMed, EMBASE and the Cochrane library were searched from 1 February 2015 to 25 February 2022. The evidence presented here is focused on the treatment of granulomatosis with polyangiitis and microscopic polyangiitis., Results: 3517 articles were screened and 175 assessed by full-text review. Ninety articles were included in the final evidence synthesis. Cyclophosphamide and rituximab (RTX) show similar efficacy for remission induction (level of evidence (LoE) 1a) but RTX is more effective in relapsing disease (LoE 1b). Glucocorticoid (GC) protocols with faster tapering result in similar remission rates but lower rates of serious infections (LoE 1b). Avacopan can be used to rapidly taper and replace GC (LoE 1b). Data on plasma exchange are inconsistent depending on the analysed trial populations but meta-analyses based on randomised controlled trials demonstrate a reduction of the risk of end-stage kidney disease at 1 year but not during long-term follow-up (LoE 1a). Use of RTX for maintenance of remission is associated with lower relapse rates compared with azathioprine (AZA, LoE 1b). Prolonged maintenance treatment results in lower relapse rates for both, AZA (LoE 1b) and RTX (LoE 1b)., Conclusion: This SLR provides current evidence to inform the 2022 update of the EULAR recommendations for the management of AAV., Competing Interests: Competing interests: JHS received research grants from the John Grube Foundation and the Deutsche Gesellschaft für Rheumatologie (German Society for Rheumatology). BH received speaker fees and/or consultancies from AbbVie, Amgen, AstraZeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. DJ received speaker fees and/or consultancies from Amgen, AstraZeneca, BMS, Boehringer, Chemocentryx, GSK, InflaRx, Janssen, Novartis, Roche, UCB and Vifor. RAL received speaker and/or consulting fees and/or grants from AbbVie, BMS/Celgene, Chemocentryx, Chugai, GSK, InflaRx, Pfizer Global, Roche and Vifor., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To summarise and update evidence to inform the 2022 update of the European Alliance of Associations of Rheumatology (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: Three systematic literature reviews (SLR) were performed. PubMed, EMBASE and the Cochrane library were searched from 1 February 2015 to 25 February 2022. The evidence presented herein covers the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) as well as diagnostic testing and general management of all AAV syndromes., Results: For the treatment of EGPA, diagnostic procedures and general management 3517, 4137 and 4215 articles were screened and 26, 110 and 63 articles were included in the final evidence syntheses, respectively. For EGPA patients with newly diagnosed disease without unfavourable prognostic factors, azathioprine (AZA) combined with glucocorticoids (GC) is not superior to GC monotherapy to induce remission (LoE 2b). In patients with active EGPA and unfavourable prognostic factors, cyclophosphamide or rituximab can be used for remission induction (LoE 2b). Treatment with Mepolizumab added to standard treatment results in higher rates of sustained remission in patients with relapsing or refractory EGPA without active organ-threatening or life-threatening manifestations (LoE 1b) and reduces GC use. Kidney biopsies have prognostic value in AAV patients with renal involvement (LoE 2a). In the context of suspected AAV, immunoassays for proteinase 3 and myeloperoxidase-ANCA have higher diagnostic accuracy compared with indirect immunofluorescent testing (LoE 1a)., Conclusion: This SLR provides current evidence to inform the 2022 update of the EULAR recommendations for the management of AAV., Competing Interests: Competing interests: JHS received research grants from the John Grube Foundation and the Deutsche Gesellschaft für Rheumatologie (German Society for Rheumatology). BH received speaker fees and/or consultancies from Abbvie, Amgen, Astra-Zeneca, BMS, Boehringer, Chugai, GSK, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, Roche and Vifor. DJ received speaker fees and/or consultancies from Amgen, Astra-Zeneca, BMS, Boehringer, Chemocentryx, GSK, InflaRx, Janssen, Novartis, Roche, UCB and Vifor. RL received speaker and/or consulting fees and/or grants from Abbvie, BMS/Celgene, Chemocentryx, Chugai, GSK, InflaRx, Pfizer Global, Roche, and Vifor. BSA, GT and SM reported no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis factor-α (TNF-α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients. Serum levels of anti-SARS-CoV-2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti-TNF-α patients (n = 10) and controls (n = 24 healthy individuals; n = 12 patients under other disease-modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS-CoV-2-specific B- and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti-SARS-CoV-2 IgG levels, IgG avidity and anti-pre-VOC NA titres were significantly reduced in anti-TNF-α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti-TNF-α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS-CoV-2-specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti-BA.2 NA titres compared to both other groups. We show a reduced SARS-CoV-2 neutralizing capacity in patients under TNF-α blockade. In this cohort, the plasma cell response appears to be less specific and shows stronger bystander activation. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: The persistence of the SARS-CoV2 pandemic, partly due to the appearance of highly infectious variants, has made booster vaccinations necessary for vulnerable groups. Questions remain as to which cohorts require SARS-CoV2 boosters. However, there is a critical lack of data on the dynamics of vaccine responses in patients with chronic inflammatory diseases (CID) undergoing immunosuppressive/disease modifying anti-rheumatic (DMARD) treatment. Here, we present the first data regarding the decline of the vaccine-induced humoral immune responses in patients with CID., Methods: 23 patients with CID were monitored clinically and for anti-spike IgG and IgA levels, neutralization efficacy and antigen-specific CD4+ T cell responses over the first 6 months after SARS-CoV2 vaccination. 24 healthy individuals were included as controls., Results: While anti-spike IgG-levels declined in CID patients and healthy controls, patients receiving anti-TNF treatment showed significantly greater declines at 6 months post second vaccination in IgG and especially neutralizing antibodies. IgA levels were generally lower in CID patients, particularly during anti-TNF therapy. No differences in SARS-CoV2 spike-specific CD4+ T-cell frequencies were detected., Conclusion: Although the long-term efficacy of SARS-CoV2 vaccination in CID patients undergoing disease-modifying therapy is still not known, the pronounced declines in humoral responses towards SARS-CoV2 6 months after mRNA vaccination in the context of TNF blockade should be considered when formulating booster regimens. These patients should be considered for early booster vaccinations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID., Objective: Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls., Methods: 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations., Results: Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare., Conclusion: We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort., Competing Interests: Competing interests: Both BFH and SS received funding from Pfizer and other companies., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic inflammatory diseases (CID) are emerging disorders which do not only affect specific organs with respective clinical symptoms but can also affect various aspects of life, such as emotional distress, anxiety, fatigue and quality of life. These facets of chronic disease are often not recognized in the therapy of CID patients. Furthermore, the symptoms and patient-reported outcomes often do not correlate well with the actual inflammatory burden. The discrepancy between patient-reported symptoms and objectively assessed disease activity can indeed be instructive for the treating physician to draw an integrative picture of an individual's disease course. This poses a challenge for the design of novel, more comprehensive disease assessments. In this mini-review, we report on the currently available patient-reported outcomes, the unmet needs in the field of chronic inflammatory diseases and the challenges of addressing these., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tran, Schirmer, Ratjen, Lieb, Helliwell, Burisch, Schulz, Schrinner, Jaeckel, Müller-Ladner, Schreiber and Hoyer.)

IgG4-related disease (IgG4-RD) is an entity first described less than 20 years ago, characterized by tumorous swelling of affected organs. Differentiation from malignant disease, systemic infections and other systemic autoimmune diseases can be challenging. Typical histopathologic findings facilitate a diagnosis in a compatible clinical context. Because nearly every organ system can be affected, management of IgG4-RD is a challenging task requiring multidisciplinary work-up and treatment. Medical treatment usually consists of glucocorticoids, which may be combined with other immunosuppressives. Surgical or interventional treatment may be necessary if complications arise. Since high-quality evidence is lacking for most aspects of the management of IgG4-RD, international collaborative studies are urgently needed., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Among the eosinophilic diseases treated by rheumatologists other than eosinophilic granulomatosis with polyangiitis, there are further organ-related and systemic diseases with hypereosinophilia. Only the exact differential diagnostic demarcation of the diseases enables a pathogenetic oriented treatment. This article focuses on the hypereosinophilic syndromes. The potential differential diagnoses of Ig(immunoglobulin)G4-related disease, eosinophilic fasciitis and drug-induced vasculitis as well as eosinophilia-myalgia syndrome and toxic oil syndrome as historic drug-induced inflammatory rheumatic diseases are described and the clinical manifestations and treatment are summarized.

Polyarteritis nodosa (PAN) is a necrotizing arteritis of medium-sized vessels, which is often fatal if untreated. It frequently affects the skin (nodules and ulcers), the peripheral nervous system (mononeuritis multiplex) and the visceral vessels (stenoses and microaneurysms). The complex diagnostic work-up requires discriminating PAN from infectious, malignant, drug-induced and other inflammatory conditions. It can be subclassified into further variants (idiopathic, associated with hepatitis B, associated with hereditary inflammatory diseases or isolated cutaneous disease). While idiopathic and hereditary inflammatory variants require immunosuppressive treatment, the hepatitis B-associated variant is treated with virustatic agents and plasmapheresis. The isolated cutaneous variant has a good prognosis and rarely requires highly potent immunosuppressives.

Objectives: To date, no specific serum marker for giant cell arteritis and polymyalgia rheumatica has been established in routine practice. Therefore, the aim of this study was to examine whether immunoglobulin G4 serum concentrations could be a potential biomarker for the differentiation of both diseases., Methods: Serum immunoglobulin G4 (IgG4) concentrations were measured in patients with giant cell arteritis (n=41) and polymyalgia rheumatica (n=27) by an in-house enzyme-linked immunosorbent assay. In the subgroup of untreated patients with disease activity (polymyalgia rheumatica n=27, giant cell arteritis n=19) additional parameters of T-helper 2 cell inflammatory responses were analysed., Results: IgG4-values above the prior determined cut-off value of 1400 μg/ml in giant cell arteritis were rare and also significantly less frequent in giant cell arteritis than in polymyalgia rheumatica patients (7.3% vs. 44.4%; p<0.001). The relative risk that patients with clinical features of PMR, presenting without elevated IgG4 levels, have simultaneously GCA was 5.8 compared to those patients with elevated IgG4 levels. In untreated patients absolute counts of eosinophilic leukocytes were lower in giant cell arteritis than in polymyalgia rheumatica (p=0.002) and the cytokines interleukin-4 (p=0.013) and interleukin-10 (p=0.033) were less frequently detectable in giant cell arteritis than in polymyalgia rheumatica., Conclusions: In giant cell arteritis serum levels of IgG4 usually are within the normal range. In polymyalgia rheumatica however, increased IgG4 serum levels are frequently found. Normal IgG4 serum levels in polymyalgia rheumatica may have predictive value in identifying patients with additional, clinically non-apparent giant cell arteritis.

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., (© 2016, American College of Rheumatology.)

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.

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 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., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium size arteries that may affect various organs. The clinical appearance is very variable. The most common manifestations are of the skin, the peripheral nervous system presenting as mononeuritis multiplex and the mesenteric and renal blood vessels due to the development of stenoses and small aneurysms. Of the cases one third are estimated to be associated with hepatitis B virus (HBV). The therapy depends on the pathogenesis of the disease: primary PAN is treated with immunosuppressants, whereas patients with HBV-related PAN should receive antiviral therapy and plasmapheresis. Differentiating PAN from other forms of vasculitis can be difficult and requires complex differential diagnostics.

Chronic periaortitis is an inflammatory and fibrosing disease presenting as periaortal fibrosis and formation of aortic aneurysms which are mostly localized in the retroperitoneum and occasionally in the mediastinum. Inflammatory vasculitic involvement of large vessels is also possible. In addition to symptoms of systemic inflammation, mechanical complications also occur whereby obstruction of the ureter is the most frequent. The diagnosis is made by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and if the findings are atypical the diagnosis should be confirmed by biopsy. After exclusion of a secondary genesis, in which case therapy of the underlying illness would be necessary, idiopathic chronic periaortitis can be treated with steroids. In cases of refractory and relapsing courses the administration of further immunosuppressive medication can be necessary. Duration of therapy, dosage and indications for immunosuppressive medication are currently unclear and have to be defined in further randomized controlled trials with larger cohorts. If complications occur, interventional or operative treatment can be necessary; in cases of hydronephrosis the placement of double-J-stents is usually sufficient.