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.

[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.

[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.

[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.

Genetically distinct subsets within ANCA-associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)). CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

Toll-like receptor TLR2 and TLR9 ligation triggers neutrophil activation in granulomatosis with polyangiitis.

OBJECTIVE: The aim of the study was to characterize the expression of TLR2, TLR4 and TLR9 in PMNs of patients with granulomatosis with polyangiitis (GPA) and to elucidate the role of these receptors in GPA with respect to neutrophil activation. METHODS: The expression of TLR2, TLR4 and TLR9 was determined on ex vivo PMNs in whole blood samples of GPA patients (n = 35) and healthy controls (HCs) (n = 24). Isolated PMNs were stimulated in vitro with TLR agonists and assessed for degranulation, membrane proteinase 3 (mPR3) expression, soluble l-selectin shedding and cytokine production (IL-8) in five GPA patients and five HCs. The priming effects of TLR2 and TLR9 ligation were assessed by measurement of serine protease activity after stimulation with PR3-ANCA. RESULTS: There were no significant differences in the ex vivo expression of TLRs on PMNs in HCs and GPA patients. Stimulation of TLR4 and TLR9 induced MPO release, stimulation with TLR2, TLR4 and TLR9 ligands elicited IL-8 production and stimulation of TLR2 and TLR9 led to an upregulation in mPR3 expression on PMNs with no significant differences between GPA and HC after 1 or 24 h stimulation. Priming of PMNs with TLR2 and TLR9 ligands induced degranulation after subsequent stimulation with PR3-ANCA, which was comparable to priming with TNF-α. CONCLUSION: Expression of TLR2, TLR4 and TLR9 in PMNs and the TLR-induced activation of PMNs was comparable in GPA and HC. mPR3 upregulation by TLR2 and TLR9 stimulation and the priming effect of TLR ligands on PMNs may have a potential implication for triggering disease activity during infection in GPA.

Orbital masses in granulomatosis with polyangiitis are associated with a refractory course and a high burden of local damage.

OBJECTIVES: To identify and characterize patients with orbital masses in a monocentric cohort of 1142 GPA patients followed up from 1990 until the end of 2010 with regard to disease stage, local orbital inflammation, course of disease and outcome and to assess the efficacy of immunosuppressive treatment. METHODS: All GPA patients fulfilling ACR criteria or Chapel Hill Consensus Conference definitions or who had localized GPA and who developed orbital masses were evaluated regarding the course and outcome of the orbital masses (assessed by MRI, ophthalmologist and ENT specialist), all other clinical manifestations, disease stages, ANCA status, immunosuppression and its side effects and surgical procedures. RESULTS: Of 1142 GPA patients 58 developed orbital masses during a median follow-up of 101.5 months (range 23-255 months). Forty patients fulfilled the inclusion criteria and had complete clinical assessments [44% females, median age 43 (20-74) years, 85% ANCA positive]. Seventy-five per cent (29/40) had systemic disease when orbital masses occurred; both orbits were affected in 30%. Seventy-two per cent had evidence of infiltration from paranasal sinuses. Under highly potent immunosuppression (mostly CYC and glucocorticoids), 41% were refractory, 24% had unchanged activity, 24% showed a response and 8.1% had complete remission. Forty-four per cent had relapses of orbital masses. Seventy-two per cent developed visual impairment, 19% suffered blindness. Blindness was associated with a longer time to remission and a relapsing and refractory course. CONCLUSION: Orbital masses are a rare manifestation of GPA and are characterized by a refractory course and by a high rate of local damage. Patients with a refractory or relapsing course are at higher risk of developing blindness.

Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.

Rituximab for refractory granulomatosis with polyangiitis (Wegener's granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations.

OBJECTIVE: First, to investigate the overall efficacy and safety of rituximab (RTX) in refractory granulomatosis with polyangiitis (GPA) in a tertiary referral centre. Second, to compare the efficacy of RTX in granulomatous and vasculitic manifestations in GPA. PATIENTS AND METHODS: This study comprised a retrospective, standardised data collection from all patients who received RTX for refractory Wegener's granulomatosis from 2002 to 2010. Patients were assessed by a standardised interdisciplinary diagnostic procedure (including ear, nose and throat and ophthalmology assessment, MRI, immunodiagnostics, B-cell levels and Birmingham Vasculitis Activity Score) and were treated by standardised therapeutic regimens according to available evidence. RESULTS: 59 patients received 75 cycles of RTX. 9.3% achieved complete remission. A response was documented in 61.3% (improvement in 52%, unchanged disease activity in 9.3%), 26.7% had refractory disease. Birmingham Vasculitis Activity Score, disease extent index, erythrocyte sedimentation rate, C-reactive protein and prednisolone demand decreased significantly. All patients achieved B-cell depletion. Granulomatous manifestations such as orbital granuloma and pachymeningitis were more frequently refractory to RTX than vasculitis or other granulomatous manifestations. Thus, for example, complete remission/improvement was found in 89.2% of patients with renal disease and in only 44.4% of those with orbital masses (p=0.003). The relapse rate was 44.4% after a median period of 13.5 months. Adverse events occurred in 29%, pneumonia in 15% and death in 3%. CONCLUSION: The overall response rate of refractory GPA to RTX was high (61.3% complete remission or improvement). Response rates of vasculitic manifestations were excellent; failure of response/progress was mostly due to granulomatous manifestations, especially orbital masses. Relapse rates were high (40%) despite maintenance treatment.

Comparative analysis of different commercial ELISA systems for the detection of anti-neutrophil cytoplasm antibodies in ANCA-associated vasculitides.

OBJECTIVES: To assess the diagnostic performance of 11 commercial PR3- and MPO-ANCA ELISA systems (direct, capture and high sensitive [hs] ELISA). METHODS: Sera from 90 patients with AAV (GPA, MPA and CSS) and 20 disease controls (SLE; RA) and healthy individuals were tested for the presence of ANCA by IFT and by different ELISAs for the presence of PR3-and MPO-ANCA, respectively. Furthermore, the binding capacity of the IUIS-CDC reference sera for PR3-/MPO-ANCA in different commercial assays was analysed. RESULTS: Commercial ELISA kits for PR3-ANCA differed moderately in their sensitivity (from 45% to 62.5%). The highest sensitivity for PR3-ANCA was obtained with hs ELISA (kit A) and capture ELISA (kit N). Testing for MPO-ANCA the highest sensitivity (85%) was obtained with direct ELISA (kit D and I). Specificity was high in all kits. Only three PR3-ANCA commercial kits and three MPO-ANCA kits produced binding at the expected value for the IUIS-CDC reference sera (100 U/ml). In all of the kits, serial dilutions of the reference sera did not yield linearity. CONCLUSIONS: Second (capture) and third (high sensitivity) generation PR3-ANCA ELISA kits are superior to conventional ELISAs. Direct and capture MPO-ANCA ELISAs showed a good overall performance in all kits. Most of the kits have not been standardised to allow their results to be compared.

Improved outcome in 445 patients with Wegener's granulomatosis in a German vasculitis center over four decades.

OBJECTIVE: To determine the long-term outcome in patients with Wegener's granulomatosis (WG) over 4 decades in an academic hospital unit specializing in rheumatology. METHODS: We included 290 patients, divided them into 2 cohorts, and compared them with the historical cohort of 155 patients. Comparisons were retrospective regarding disease manifestations, therapy, mortality, and incidence of malignancies. The historical cohort (cohort 1) included 155 patients diagnosed between 1966 and 1993, cohort 2 included 123 patients diagnosed between 1994 and 1998, and cohort 3 included 167 patients diagnosed between 1999 and 2002. RESULTS: Over time, the interval between first symptoms and diagnosis was reduced by half (from 8 months to 4 months). Organ manifestations were similar in the 3 cohorts, and more than 80% of patients still required cyclophosphamide (CYC); however, the median cumulative dose was reduced significantly (from 67 gm in cohort 1 to 36 gm in cohort 2 and to 24 gm in cohort 3). The standardized mortality ratios (SMRs) declined (from 2.1 in cohort 1 to 1.41 in cohort 2 and to 1.03 in cohort 3), with fewer deaths related to WG and/or therapy (86.4% in cohort 1, 76.9% in cohort 2, 50% in cohort 3), decreasing relapse rates (63.9% in cohort 1, 51.2% in cohort 2, 35.3% in cohort 3), and no increased rate of malignancies. Compared with young females, young males had a considerably higher SMR (8.87 [95% confidence interval 4.05-16.8]) and more frequent renal manifestations (54.4% versus 33.8%). CONCLUSION: Mortality of WG patients declined over the last 4 decades, probably due to improved diagnostic and therapeutic procedures and increased awareness of WG, which led to earlier diagnosis and therapy, reduction in relapse rates, and lower cumulative CYC dose with fewer deaths related to therapy.