EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

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.

[Update on treatment of ANCA-associated vasculitis]. / Therapie-Update der ANCA-assoziierten Vaskulitiden.

This article summarizes the current guidelines and recommendations published by the European Alliance of Associations for Rheumatology (EULAR), the Kidney Disease Improving Global Outcomes (KDIGO) and the American College of Rheumatology (ACR). In addition to glucocorticoids (GC), treatment with biologics is nowadays an established option to treat Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV). Rituximab (RTX) is used for remission induction and maintenance in organ-threatening and non-organ-threatening granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). For eosinophilic GPA (EGPA) anti-interleukin 5 (IL5) strategies are an important component of treatment for remission induction and maintenance of refractory or relapsing non-organ-threatening diseases in conjunction with GC. The dosing of GC for remission induction in GPA and MPA is now lower than was previously used and additionally, avacopan is approved as a new GC-sparing medication for GPA and MPA over 52 weeks. Conventional strategies, such as cyclophosphamide (CYC) are important for remission induction in severe or refractory organ-threatening disease for all AAVs. The use of methotrexate (MTX) and azathioprine (AZA) is becoming less prominent. The most important unanswered questions in the treatment of AAVs are with respect to the duration of remission maintenance treatment and the individualized treatment guidance based on biomarkers.

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study.

OBJECTIVES: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B-cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab. METHODS: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centres. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months. RESULTS: The study included 227 patients. IgG levels at 6 months were lower than baseline (P < 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (P = 0.004). Age [ß (95% CI): -0.23 (-0.38, -0.08) per 10 years, P = 0.003], oral glucocorticoid dose at induction [ß (95% CI): -0.37 (-0.51, -0.24) per sqrt-transformed mg prednisone, P < 0.001] and concomitant use of intravenous glucocorticoid pulses [ß (95% CI): -0.88 (-1.73, -0.02), P = 0.044] were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age [OR (95% CI): 1.46 (1.15, 1.86) per 10 years, P = 0.002] and oral glucocorticoid dose at induction [OR (95% CI): 1.52 (1.23, 1.89) per 10 mg prednisone, P < 0.001]. CONCLUSIONS: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses.

[Eosinophilia: hypereosinophilic syndrome vs. eosinophilic granulomatosis with polyangiitis]. / Eosinophilie: hypereosinophiles Syndrom versus eosinophile Granulomatose mit Polyangiitis.

Hypereosinophilic syndrome (HES) is defined as a peripheral eosinophil count of > 1500/µl (assessed twice at an interval of ≥ 2 weeks) and an eosinophil-induced organ damage. Idiopathic HES is differentiated from primary (clonal or neoplastic) HES and secondary (reactive) HES, depending on the etiology. Eosinophilic granulomatosis with polyangiitis (EGPA) is categorized as a secondary form of HES and is characterized by hypereosinophilia and vasculitis of small to medium-sized vessels and can be associated with an antineutrophil cytoplasmic antibody (ANCA). The treatment of HES is dependent on the etiology. Clonal HES is treated according to the respective genetic aberration, e.g. with tyrosine kinase inhibitors or chemotherapy and allogenic stem cell transplantation. Secondary forms should be treated according to the underlying cause (e.g. parasitic infection). The treatment of EGPA is carried out with immunosuppressants depending on the disease stage and disease activity. Conventional drugs, such as glucocorticoids (GC), cyclophosphamide (CYC) and methotrexate (MTX) or biologics, such as the monoclonal anti-IL5 antibody mepolizumab are commonly used. Mepolizumab is also a good option for the treatment of idiopathic HES.

[Eosinophilic granulomatosis with polyangiitis : Update on classification and management]. / Eosinophile Granulomatose mit Polyangiitis : Update zu Klassifikation und Management.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare chronic inflammatory systemic disease that occurs in patients with bronchial asthma and is associated with significant blood and tissue eosinophilia. Another characteristic is vasculitis of small and/or medium-sized vessels, which may be absent in prodromal stages of the disease and is therefore no longer an obligatory part of the disease definition. Antineutrophil cytoplasmic antibodies (ANCA) can be detected in approximately one third of patients. The ANCA-positive and ANCA-negative EGPA are genetically distinct diseases with common clinical manifestations, which, however, occur with different frequencies. Cardiac involvement is associated with a poor prognosis. Permanent organ damage often occurs as a result of the underlying disease or treatment, especially with glucocorticoids (GC). The standard treatment of EGPA consists of GC in combination with cyclophosphamide for severe organ involvement or medium potency immunosuppressants for more prognostically favorable manifestations. Biologics are increasingly being used in the treatment of EGPA. The interleukin (IL) 5 antagonist mepolizumab reduces the risk of relapses and decreases the demand for GC in patients with relapsing EGPA without severe organ involvement. In analogy to the approach to other ANCA-associated vasculitides, the use of rituximab in ANCA-positive EGPA patients with severe vasculitis recurrence is a possible option, even though formal evidence for such an approach is currently low and formal approval is lacking.

[Update on treatment of ANCA-associated vasculitis: Granulomatosis with polyangiitis and Microscopic Polyangiitis]. / Therapie-Update der ANCA-assoziierten Vaskulitiden: Granulomatose mit Polyangiitis und Mikroskopische Polyangiitis.

In the past 2 years several important studies on the treatment of granulomatosis with polyangiitis (PGA) and microscopic polyangiitis (MPA) have been published, which led to a change in the therapeutic procedure of these diseases. Rituximab is now established as the standard treatment for remission induction and maintenance in cases of organ-threatening disease. Adjunctive glucocorticoid treatment can be tapered according to a new reduced dose scheme and avacopan, a C5a receptor inhibitor, offers even more potential in the future for additional economization of glucocorticoids. Uncertainties remain regarding the duration of treatment for maintaining remission. New studies suggest that treatment for maintaining remission for longer than 24 months is meaningful.

[Cortisone-free rheumatology-Vasculitides]. / Kortisonfreie Rheumatologie ­ Vaskulitiden.

Glucocorticoids (GC) still represent an essential pillar of treatment in the phase of remission induction of vasculitides, which are often organ or life-threatening; however, they entail a significant potential for side effects. In the phase of remission maintenance prednisolone should be reduced to 7.5 mg/day or less. Whether a discontinuation can alway be achieved for any form of vasculitis without increasing relapse rates, is unclear. By the use of biologics, e.g. tocilizumab in giant cell arteritis (GCA), a fast tapering and discontinuation of GC seems to be more easily achievable compared to using a GC monotherapy regimen. Avacopan could in the future be an efficient agent to spare GC in the phase of remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), e.g. granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Mepolizumab is a promising option to reduce the use of GC in eosinophilic granulomatosis with polyangiitis (EGPA).

[German Society of Rheumatology Recommendations for the management of glucocorticoid-induced Osteoporosis. German version]. / Empfehlungen der Deutschen Gesellschaft für Rheumatologie zum Management der Glukokortikoid-induzierten Osteoporose.

BACKGROUND: Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use. OBJECTIVE: To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment. METHODS: A systematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in a structured group consensus process. RESULTS: Recommendations include supplementation with calcium and vitamin D under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, a switch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after a treatment duration of 3-5 years or after termination of long-term GC treatment. CONCLUSION: This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.

German Society of Rheumatology recommendations for management of glucocorticoid-induced osteoporosis.

BACKGROUND: Glucocorticoids are of substantial therapeutic importance in the treatment of inflammatory diseases, but are also associated with bone mineral density loss, osteoporosis, and fractures, especially with long-term use. OBJECTIVE: To develop recommendations for the management of glucocorticoid-induced osteoporosis (GIOP) in adult patients on long-term glucocorticoid (GC) treatment. METHODS: A systematic literature search (SLR) was conducted to synthesize the evidence for GIOP prevention and treatment options. Recommendations were developed based on SLR/level of evidence and by previously defined questions and in a structured group consensus process. RESULTS: Recommendations include supplementation with calcium and vitamin D under long-term GC therapy in adults. If specific osteologic treatment is indicated, we recommend bisphosphonates or denosumab as first-line treatment. If fracture risk is high, we recommend teriparatide as primary specific osteologic treatment. Denosumab should be used in cases of severe renal insufficiency, and specific osteologic treatment should not be given in pregnancy. For patients who have not reached the treatment goal, a switch to another class of specific osteologic drugs should be performed. We recommend re-evaluation after a treatment duration of 3-5 years or after termination of long-term GC treatment. CONCLUSION: This work aims to provide evidence-based and consensus-based recommendations for the best possible management of GIOP in Germany and to support treatment decisions.

A Genome-wide Association Study Identifies Risk Alleles in Plasminogen and P4HA2 Associated with Giant Cell Arteritis.

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.

[Recommendations of the German Society for Rheumatology for management of patients with inflammatory rheumatic diseases in the context of the SARS-CoV-2/COVID-19 pandemic - Update July 2020]. / Handlungsempfehlungen der Deutschen Gesellschaft für Rheumatologie e. V. für die Betreuung von Patienten mit entzündlich rheumatischen Erkrankungen im Rahmen der SARS-CoV-2/COVID-19-Pandemie ­ Update Juli 2020.

A few days after the SARS-CoV-2 infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled first recommendations for the care of patients with inflammatory rheumatic diseases (IRD). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registers, cross-sectional studies, case reports and case series are available, the present update is intended to update the previous recommendations and to add new findings. The current recommendations are based on a literature search of publications available up to 15 June 2020 and address preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. An important goal of the current recommendations is also to prevent harm to patients with IRD through unjustified restriction of care. The DGRh will continue to update its recommendations in the case of new aspects and will publish them as well as further information on the COVID-19 pandemic on its homepage ( www.dgrh.de ) in an ongoing process.

[Three years of the appointment service office: high rate of false referrals and no show patients-A retrospective anaysis of the Rheumatism Center Schleswig-Holstein Mitte]. / Drei Jahre Terminservicestelle: hohe Rate an Fehlzuweisungen und No-show-Patienten ­ Eine retrospektive Auswertung des Rheumazentrum Schleswig-Holstein Mitte.

This article presents a retrospective analysis of patients who attended a rheumatology specialist practice (with two specialist rheumatologists) between 2016 and 2018 via an appointment arranged by the appointment service office (Terminservicestelle, TSS). Patients were analyzed in a pseudonymized manner and categorized according to the following criteria: 1. patient did not keep the appointment, 2. patient had no inflammatory rheumatic disease, 3. patient suffered from an inflammatory rheumatic disease but had no urgent indications to be seen and 4. patient suffered from an inflammatory rheumatic disease with urgent indications to be seen. Since the start of the TSS at the beginning of 2016 until the end of 2018 a total of 103 patients were allocated to this specialist practice via the TSS. An appointment was offered to 102 patients who underwent further analysis: 4.9% of the patients (n = 5) suffered from an acute inflammatory rheumatic disease and had urgent indications to be seen, 18.63% of patients (n = 19) suffered from an inflammatory rheumatic disease with no urgent indications to attend, 28.43% of patients (n = 29) did not keep the appointment and 48.04% of patients (n = 49) did not have an inflammatory rheumatic disease but other diseases, such as osteoarthritis, fibromyalgia and other forms of chronic pain syndromes. The positive predictive value (PPV) for patients with inflammatory rheumatic disease and urgent indications was 0.05 when all patients were included in the analysis and 0.07 when only patients who showed up were included. This retrospective analysis demonstrates that the TSS does not fulfill its purpose, namely to promptly arrange appointments at a specalist rheumatologist practice for patients with an acute inflammatory rheumatic disease.

Immune stimulatory effects of neutrophil extracellular traps in granulomatosis with polyangiitis.

OBJECTIVES: The aim of this study was to analyse the role of netting neutrophils in the pathogenesis of granulomatosis with polyangiitis (GPA), especially their interplay with peripheral blood mononuclear cells (PBMCs). METHODS: The amount of cell-free DNA (cfDNA) was determined in sera from GPA patients (pairs active/inactive state of disease, n=18) and from healthy controls (HCs, n=10). Furthermore, we performed in vitro incubation experiments using PBMCs and NETs from patients and HCs for accessing the effect of NETs on PBMC behaviour. We determined proliferation of T- and B-cells (CSFE assay), B-cell maturation (CD38 staining and flow cytometry), production of IgG (ELISpot, ELISA), and secretion of the cytokines IFN-γ, IL-4, IL-10, IL-17A (ELISA). RESULTS: We detected a significant increase in serum cfDNA levels of GPA patients compared to HCs. The concentration of cfDNA was associated with disease activity. NETs of patients and HCs induced proliferation of CD4+ T- cells and CD19+ B-cells and maturation of B-cells. Furthermore, we detected an increase in IL-17A secretion after stimulating PBMCs with NETs. A significant difference between PBMCs from GPA patients and HCs was not detectable. CONCLUSIONS: NETs activate PBMCs of HCs and GPA patients. Our findings give supportive evidence that NETosis plays a role in the pathogenesis of GPA.

Serum immunoglobulin G4 in giant cell arteritis and polymyalgia rheumatica.

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.

Clinical presentation and long-term outcome of 144 patients with microscopic polyangiitis in a monocentric German cohort.

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.