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The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV by several prospective randomized clinical trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS, as well as to identify potential prognostic factors.Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models.478 (56%) patients had Granulomatosis with polyangiitis (GPA) and 370 (44%) Microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. Median follow-up time was 8 years (IQR: 2.9-13.6). During the observation period, there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared to a matched cohort, (regarding country, age-group, and sex) from the background population there was 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. Estimated median survival time (from diagnosis) was 17.8 years (95%CI: 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate, and low platelet count were identified as predictors of death in a multivariate Cox model.Patients with AAV still have an increased risk of mortality compared to the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival, and infections remain the leading cause of mortality among patients with AAV.

IgA nephropathy is the most common form of inflammatory kidney disease causing uraemia world-wide and initially often a silent disease with microscopic haematuria as the only clinical finding. If left untreated, progress to terminal uraemia and dialysis is not uncommon as at least 30 % develop end stage renal failure. Awareness of the existence of the disease among GPs, internists and urologists may be helpful, not disregarding microscopic haematuria, particularly in combination with albuminuria or finding of renal casts in the urine, especially in younger individuals. No diagnostic marker in blood or urine for the disease has yet been established so kidney biopsy is still needed to confirm diagnosis. The degree of renal dysfunction, hypertension, albuminuria, and histology findings at time of diagnosis have significant impact on renal outcome. Potential biomarkers for progressive disease have been described but no one has so far been implicated in clinical practice. Until now, the only evidence-based medication consists of blockers of the renin-angiotensin-system and corticosteroids. However, new and potentially more specific drugs are under clinical investigation. Early intervention is mandatory to prevent disease progression. Thus, we want to alarm other specialists to an increased alertness for this disease, referring patients at an early stage of possible IgA nephropathy to the nephrologist for diagnosis and interventions.

Objective.Patients with ANCA-associated vasculitides (AAV) exhibit higher rates of malignancy than the general population. We assessed whether the cancer risk is increased in a well-characterized population-based cohort of AAV in southern Sweden, followed for a median time of 8 years.Methods.With case record review, the outcomes and malignancy development in a cohort of 195 patients with AAV [granulomatosis with polyangiitis (GPA), microscopic polyangiitis, and eosinophilic GPA] diagnosed between 1997 and 2010 were assessed. The patients were followed until death or December 31, 2015. The age- and sex-standardized incidence ratios (SIR) were estimated using the Swedish population data as a reference.Results.During the observation period of about 1500 person-years, we found 60 cancers in 52 of the 195 patients. SIR (95% CI) was 2.8 (2.1–3.6) for cancers at all sites, 1.8 (1.3–2.5) for all cancers excluding squamous cell carcinoma (SCC), 12.9 (8.4–18.8) for SCC, 4.3 (1.4–10.0) for bladder cancer, and 7.0 (1.4–20.5) for pancreatic cancer. Cumulative doses of cyclophosphamide (CYC) < 10 g were not associated with higher incidence of cancers other than SCC (SIR 1.63, 95% CI 0.8–2.9).Conclusion.In contrast to previous publications assessing malignancy risk in patients with AAV, we show in this population-based cohort of patients a persistent increased risk for overall malignancy, bladder cancer, and pancreatic cancer as well as a markedly increased risk for SCC. There was no increase in incidence of cancers other than SCC for those treated with < 10 g CYC.

BACKGROUND Living anonymous donation (LAD) of kidneys was introduced in Sweden in 2004. This study reports on outcomes of Swedish LAD experiences from 2004 to 2016, focusing on donors' motives, the care they received, psychosocial aspects, and medical status at follow-up. MATERIAL AND METHODS Donor data were collected through a physician interview, medical check-up, review of medical charts, the Hospital Anxiety Depression Scale (HADS), and a routine national questionnaire. Of the 26 LADs during the study period, 1 donor died and 1 declined to participate, leaving a study population of 24. RESULTS Half of the donors were male, which is a higher proportion than for directed living donors. The major motive detected was altruism. Of the 24 LADs, 96% were very satisfied and would donate again if possible, 46% noted increased self-esteem, and a third were happier after the donation. Sixty-two percent received anonymous information about the recipient and 40% would have liked to meet the recipient. HADS scores were normal. Two donors had antidepressant treatment, 1 of whom had received treatment before donation. Half mentioned that the pre-donation assessment took too long. At follow-up, mean eGFR was 62±12 mL/min/1.73 m², of which 16 were in CKD II and 8 were in CKD III. Four donors had developed hypertension, 1 of whom also developed type 2 diabetes. CONCLUSIONS Swedish LADs are very satisfied and medical outcomes are acceptable. We propose that the transplant community and the National Board of Health and Welfare take a more active approach to informing the general public about LAD.

Background and Aims ANCA-associated vasculitis (AAV) is the most common cause of rapidly progressive glomerulonephritis globally and the most common finding in renal biopsies for those above 75 years of age. Patients with AAV have had an improved outcome after the introduction of immunosuppressive therapy. However, there is still an increased risk of end stage renal failure, complications to therapy, comorbidities and death. The European Vasculitis Society (EUVAS) has run several prospective randomized clinical trials (RCT) since late -90’ies as an attempt to improve the outcome for patients with a broad spectrum of AAV. The aim of the current study was to analyze results from a 10-year follow-up of patients who have participated in EUVAS’s randomized clinical trials to report on patient outcomes using current standard of care immunosuppressive treatment. Method Data on patient outcomes were collected from questionnaires to the principal investigators of the original RCTS (74 centers from 17 countries in Europe): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC. All patients were well characterized at inclusion in the trials respectively, as was the type and duration of induction therapy. Long-term follow-up data regarding cumulative duration and type of immunosuppressive therapy, end stage renal failure (ESRF), renal transplantation, patient survival and comorbidities as cardiovascular events, infections were recorded. Efforts have been made to control and validate the collected data. Results The current dataset comprises 858 patients, of whom 708 were eligible to include in this study. We received questionnaires regarding patient outcomes from 70% of the cohort. The median age was 60 years at time of the diagnosis of AAV; 487 patients had GPA (57%) and 371 MPA (43%). The median follow-up time was 8.0 years (IQR: 2.9-13.6). During the observation period, there were 305 deaths: 78 patients died within the first year of follow up, 69 during the following 5 years, and another 158 patients after 5 years. The main causes of death were infections (25%), cardiovascular disease (14%) and malignancies (13%), followed by pulmonary diseases, vasculitis, others, kidney disease and gastrointestinal disease. Vasculitis were a major contributor to the causes of death in 18% of the patients. Median survival time for the whole cohort was 17.8 years (95%CI: 15.6 – 20.1). Survival rate at 5 and 10 years was 81.6% and 66.5% respectively. Advanced age, low estimated glomerular filtration rate and male sex were negative prognostic factors for patient survival in the Cox model. When we categorized the deaths according to their initial CKD stage, the highest number of deaths was found in the group of patients with low eGFR i.e. an initial CKD stage V (40%). The initial CKD stage, as shown in the Kaplan-Meier curve, was found to have an important impact on the patient survival (LR: 144.4 p In our cohort, 159 patients (18.5%) reached ESRF, of whom 110 patients died (69%); the main cause of death in this group was infection. Conclusion In a series of over 800 patients with AAV, ten-year mortality was predominantly associated with impaired renal function at onset, older age and male gender, rather than subtype of disease. The main strength of this study is that we have a well-defined cohort of patients with AAV, all with well-defined induction treatments and a long period of follow-up with the possibility to analyze possible prognostic factors regarding outcomes. Further analyses are ongoing regarding comparative statistics, cumulative incidence of malignancies, renal transplantation and comorbidities. The data supports efforts to diagnose these patients at an earlier stage, when they have a higher eGFR and to tailor therapy for the individual patient. Although newer treatment modalities are available, there is still a considerable morbidity and mortality in the long-term.

Objective To investigate the occurrence of venous thromboembolic events (VTE) in a large cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) across the European Union, Turkey, Russia, UK and North America. Methods Patients with a definite diagnosis of AAV who were followed for at least 3 months and had sufficient documentation were included. Data on VTE, including either deep vein thrombosis or pulmonary embolism, were collected retrospectively from tertiary vasculitis centres. Univariate and multivariate regression models were used to estimate odds ratios (ORs) and 95% CIs. Results Over a median follow-up of 63 (interquartile range: 29, 101) months, VTE occurred in 278 (9.7%) of 2869 AAV patients with a similar frequency across different countries (from 6.3% to 13.7%), and AAV subtype [granulomatosis with polyangiitis: 9.8% (95% CI: 8.3, 11.6%); microscopic polyangiitis: 9.6% (95% CI: 7.9, 11.4%); and eosinophilic granulomatosis with polyangiitis: 9.8% (95% CI: 7.0, 13.3%)]. Most VTE (65.6%) were reported in the first-year post-diagnosis. Multiple factor logistic regression analysis adjusted for sex and age showed that skin (OR 1.71, 95% CI: 1.01, 2.92), pulmonary (OR 1.78, 95% CI: 1.04, 3.14) and kidney [eGFR 15–60 ml/min/1.73 m2, OR 2.86 (95% CI: 1.27, 6.47); eGFR Conclusion Two-thirds of VTE occurred during the initial phase of active disease. We confirmed previous findings from smaller studies that a decrease in kidney function, skin involvement and pulmonary disease are independently associated with VTE.

Objective.Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown.Methods.Consecutive patients from Sweden, the United Kingdom, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide (CYC), rituximab (RTX), and corticosteroids the first 3 months was registered. Outcomes up to 2 years from diagnosis included Vasculitis Damage Index (VDI), hospitalization, and cause of death.Results.Treatment data were available for 167 of 202 patients. At 2 years, 4% had no items of damage. There was a positive association between VDI score at 2 years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using CYC or RTX. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. Myeloperoxidase–antineutrophil cytoplasmic antibody positivity and lower creatinine levels decreased the odds of readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose.Conclusion.Immunosuppressive treatment with CYC or RTX in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first 3 months was associated with treatment-related damage and fatal infections.

Background The European League Against Rheumatism (EULAR) Recommendation for primary and small vessel vasculitis were published in 2009. Objectives To update the 2009 recommendations with the focus being ANCA-Associated Vasculitis (AAV) using systematic literature review, as well as expert opinion where appropriate. Methods A combined taskforce from European League Against Rheumatism (EULAR), the European Renal Association (ERA-EDTA) and European Vasculitis Society (EUVAS) conducted a modified Delphi exercise to identify key areas of guideline for update. The identified themes were then used to generate keywords for literature searches. For the purpose of update a date period of 1st January 2007 to 1st February 2015 was chosen, to interrogate the main medical literature databases (MEDLINE, EMBASE, CENTRAL). From an initial 1,347 hits, 82 clinically relevant studies were identified. The evidence presented was discussed and summarized by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Results The 15 recommendations cover general aspects, such as attainment of remission and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting immunosuppressive therapy using a strategy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance. For remission induction of life or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy. Azathioprine, rituximab and methotrexate are the preferred choices for remission maintenance. The recommendations address plasma exchange which is recommended, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. To enable the recommendations to have maximum validity the voting process was also repeated amongst the members of EUVAS. Conclusions The recommendations have been updated and changes include; choice of drug therapy (both for induction, relapse and remission maintenance), monitoring for complications, the usefulness of repeated biopsy in those thought to having relapsing disease, monitoring for hypoimmunoglobulinaemia and recommendations on patient education. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations. Disclosure of Interest None declared

Objective: We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up.Methods: Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months.Results: During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative).Conclusion: Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually.

Podeu consultar la correcció d'errades a: http://dx.doi.org/10.1136/annrheumdis-2016-209133corr1, In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

ObjectivesThe RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown.MethodsForty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m2/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3–6 months followed by azathioprine (n=11, control group).ResultsThe primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return.ConclusionsAt 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse.Trial registration numberISRCTN28528813.

Background/Aims: Renal function deteriorates with age, but a few studies have addressed this longitudinally in elderly women. Our objective was, using 5 estimated glomerular filtration rates (eGFR)-equations, to evaluate changes in renal function and association with adverse outcomes for a decade in 75-year-old women. Methods: Plasma creatinine was measured at ages 75 (n = 1,011), 78 (n = 827), 80 (n = 689) and 85 (n = 363). Glomerular filtration rates were estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI); Modification of Diet in Renal Disease (MDRD); revised Lund-Malmö (LM-rev); Berlin Initiative Study 1 (BIS1) and Cockcroft-Gault/body surface area (CG/BSA) equations. Mortality and comorbidity were investigated in women with chronic kidney disease (CKD) stage 3A and 3B-5. Results: Approximately, 95% of women had eGFR indicating CKD stage 2-3 and progression towards stage 3 was continuous. The women lost 22% of their eGFR during follow-up and loss accelerated between 80 and 85. Mean loss per decade was 16.6 ml/min/1.73 m2. Women in CKD stage 3B-5 had an adjusted hazard ratio for death of 3.5 (95% CI 2.1-5.8) compared to stage 1-2 during follow-up and increased risk of diabetes, heart failure and hypertension. The CG/BSA, BIS1 and LM-rev equations continuously predicted lower eGFR than the MDRD and CKD-EPI equations. Conclusion: eGFR in women aged 75-85 ranges from 30 to 89 ml/min/1.73 m2 (stage 2-3). Decline was 16.6 ml/min/1.73 m2 per decade; accelerated with age and appeared nonlinear. Women with CKD 3B-5 demonstrate an over 3-fold risk of death. eGFR 2 was associated with mortality, confirming the new KDIGO classification 3A and 3B, as clinically applicable in the elderly.

© 2017 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)., The 2016 European Vasculitis Society (EUVAS) meeting, held in Leiden, the Netherlands, was centered around phenotypic subtyping in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). There were parallel meetings of the EUVAS petals, which here report on disease assessment; database; and long-term follow-up, registries, genetics, histology, biomarker studies, and clinical trials. Studies currently conducted will improve our ability to discriminate between different forms of vasculitis. In a project that involves the 10-year follow-up of AAV patients, we are working on retrieving data on patient and renal survival, relapse rate, the cumulative incidence of malignancies, and comorbidities. Across Europe, several vasculitis registries were developed covering over 10,000 registered patients. In the near future, these registries will facilitate clinical research in AAV on a scale hitherto unknown. Current studies on the genetic background of AAV will explore the potential prognostic significance of genetic markers and further refine genetic associations with distinct disease subsets. The histopathological classification of ANCA-associated glomerulonephritis is currently evaluated in light of data coming out of a large international validation study. In our continuous search for biomarkers to predict clinical outcome, promising new markers are important subjects of current research. Over the last 2 decades, a host of clinical trials have provided evidence for refinement of therapeutic regimens. We give an overview of clinical trials currently under development, and consider refractory vasculitis in detail. The goal of EUVAS is to stimulate ongoing research in clinical, serological, and histological management and techniques for patients with systemic vasculitis, with an outlook on the applicability for clinical trials.

Objective Endothelial dysfunction, increased cardiovascular events (CVE), and accelerated atherosclerosis have been described in patients with small vessel vasculitis and collagen vascular disease. Identifying predictors of cardiovascular risk will help to optimize short- and long-term care of patients with vasculitis. The present study investigates the predictive role of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) and its stereoisomer symmetric dimethylarginine (SDMA) for cardiovascular risk, all-cause mortality, and renal function in patients with anti-neutrophil-cytoplasmic antibodies-associated small vessel vasculitis (AASV) subjected to standardized treatment regimens in four European Vasculitis Study Group trials representing all stages of renal disease. Methods Sera from 89 patients with AASV were available for measuring SDMA, ADMA, and arginine using liquid chromatography/mass spectrometry at the time of active disease and remission. Clinical data on disease activity, remission, relapse rate, and 5-year follow-up data for CVE and renal outcome were collected. Results Symmetric dimethylarginine and ADMA levels were not predictive of CVE at 5 years of follow-up. The overall CVE rate was low in the present cohort of AASV (8%). However, SDMA, and not ADMA, levels were significantly associated with poorer survival (death/ESRD) independent of entry glomerular filtration rate. Conclusion This novel outcome in a well-defined group of patients with AASV might indicate a different mechanism of endothelial response in AASV as compared with atherosclerosis. This should be further explored in a larger cohort of AASV patients with a higher CVE rate and/or a longer follow-up. Moreover, these findings should be correlated to other markers of vascular damage.

Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). It is unclear whether persistent ANCA when starting maintenance therapy increases the risk of relapse. We examined the association between ANCA status and relapse in two randomised controlled trials. ANCA-positive patients in two trials, CYCLOPS and IMPROVE, were switched from cyclophosphamide to maintenance therapy after achieving clinical remission. We classified patients as being either ANCA-positive or ANCA-negative at the time they started maintenance therapy. We compared the risk of relapse in ANCA-positive and ANCA-negative patients. Of 252 patients included, 102 (40%) experienced at least one relapse during the follow-up period. At the time of the switch from induction to maintenance therapy, 111 were ANCA-positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA-negative, of whom 47 (33%) relapsed. In multivariable time-to-event analysis, a reduced risk of relapse was associated with having become ANCA-negative at the time of switching to maintenance therapy (hazard ratio 0.63, 95% confidence interval 0.42–0.95; p = 0.026). In addition, initial proteinase 3 (PR3)-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction, and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse. Becoming ANCA-negative before the switch to maintenance is associated with a reduced risk of relapse. CYCLOPS: ClinicalTrials.gov, NCT00430105 . Registered retrospectively on 31 January 2007. IMPROVE: ClinicalTrials.gov, NCT00307645 . Registered retrospectively on 27 March 2006.

Objective.To compare the rate of severe infections after the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with the rate in the background population, and to identify predictors of severe infections among patients with AAV.Methods.The study cohort was 186 patients with AAV diagnosed from 1998 to 2010, consisting of all known cases in a defined population in southern Sweden. For each patient, 4 age-and sex-matched reference subjects were randomly chosen from the background population. Using the Skåne Healthcare Register, all International Classification of Diseases codes of infections assigned from 1998 to 2011 were identified. Severe infections were defined as infectious episodes requiring hospitalization. Rate ratios were calculated by dividing the rate in AAV by the rate among the reference subjects.Results.The rate ratio for all severe infections was 4.53 (95% CI 3.39–6.00). The highest rate ratios were found for upper respiratory tract: 8.88 (3.54–25.9), Clostridium difficile: 5.35 (1.54–23.8), nonspecific septicemia 4.55 (1.60–13.8), and skin 5.35 (1.69–19.8). Of the severe infections, 38.4% occurred within 6 months of diagnosis, 30.2% from 7–24 months, and 31.4% after 24 months. High serum creatinine and older age at diagnosis were associated with severe infection (p < 0.001). Of those with severe infection, 46.5% died during followup compared to 26% of patients without severe infection (p = 0.004).Conclusion.Patients with AAV have markedly higher rates of severe infection compared with the background population, especially patients with older age and impaired renal function. The risk of severe infection is particularly high in the first 6 months following the diagnosis of vasculitis.

The European League Against Rheumatism recommendations for the management of antineutrophil cytoplasmic antibody-associated vasculitis have been recently published. Unique to recommendation development, they were also voted on by members of a learned society. This paper explores the wider validity of the recommendations among people who self-identify as clinicians caring for patients with vasculitis. In addition to the task force, a learned society (European Vasculitis Society-EUVAS) was invited, through online survey, to rate independently the strength of evidence of each recommendation to obtain an indication of the agreement among the final target audience and ultimate end-users of the recommendations. The survey took place in June 2015. Of the 158 EUVAS members surveyed, there were 88 responses (55.7%). There was a large degree of agreement in the voting patterns between EUVAS survey participants and task force members. Notable exceptions were lower grades for the recommendation of the use of rituximab for remission induction in patients with eosinophilic granulomatosis with polyangiitis and for methotrexate and mycophenolate mofetil as remission maintenance agents in patients with granulomatosis with polyangiitis/microscopic polyangiitis by EUVAS members. These results are encouraging and suggest that the voting patterns of the task force are representative of the wider vasculitis community. We recommend future recommendations adopt this approach for data/expert-based treatment guidelines, especially for multisystem diseases.

Background and objectives Treatment with azathioprine within 3 months of remission induction with cyclophosphamide is a common treatment strategy for patients with ANCA-associated vasculitis. This study comprised patients undergoing long-term follow-up who were randomly allocated to azathioprine after 3–6 months or after 12 months of cyclophosphamide treatment. Design, setting, participants, & measurements Patients from 39 European centers between 1995 and 1997 with a new diagnosis of ANCA-associated vasculitis that involved the kidneys or another vital organ were eligible. At the time of diagnosis, participants were randomly allocated to convert to azathioprine after 3–6 months (the azathioprine group) or after 12 months of cyclophosphamide (the cyclophosphamide group). Patients who did not achieve a remission within 6 months were excluded. This study assessed relapses, ESRD, and death during long-term follow-up. Results Patients were allocated to the azathioprine group ( n =71) and the cyclophosphamide group ( n =73). Of these patients, 63 (43.8%) developed a relapse, 35 (24.3%) developed a renal relapse, 13 (9.0%) developed ESRD, and 21 (14.6%) died. Although there were worse outcomes in the azathioprine group, none were statistically significant. The subdistribution hazard ratio [sHR] for relapse was 1.63 (95% confidence interval [95% CI], 0.99 to 2.71), the composite of relapse or death hazard ratio [HR] was 1.59 (95% CI, 1.00 to 2.54), the ESRD sHR was 1.71 (95% CI, 0.56 to 5.19), and the death HR was 0.75 (95% CI, 0.32 to 1.79). Conclusions It remains uncertain whether converting to azathioprine after 3–6 months of induction cyclophosphamide therapy is as effective as converting after 12 months. Outcomes are still poor for this group of patients and further research is required to determine the optimal timing of maintenance therapy.

Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

In previous phases of this project, proteinase 3 (PR3) and myeloperoxidase (MPO), the main antigenic target molecules of antineutrophil cytopiasmic antibodies, were isolated and applied in standardized ELISAs. In this study, standardized ELISAs with three PR3 preparations (from Copenhagen (CO), Raisdorf (RS) and Leiden (LF)) and one MPO preparation (from Copenhagen), were evaluated in a large retro-and prospective clitiical study. New patients (n=174) with primary systemic vasculitis (Wegener's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive glomerulonephritis, classical PAN and Churg-Strauss Syndrome) were included. Retrospectively, another 190 patients were evaluated. Furthermore control sera were obtained from patients with other forms of vasculitis, glomerulonephritis or granulomatous diseases (disease controls, n = 184) and healthy donors (healthy controls, n = 728). All patients were categorized by a system based on clinical and histoiogical data. Patients were followed up for at least 1 year after diagnosis in order to evaluate a possible correlation between ANCA levels and disease activity. The sensitivity of the anti-PR3 assays for histologically proven WG was between 59% and 69% in new patients, with a sensitivity of 22% for the anti-MPO assay. Similar figures were found for patients with clinically suspected WG. This was comparable with the results of the IIF test. In MPA and IRPGN a larger percentage of patients had antiMPO antibodies than in WG. Only a few patients with PAN and CSS were investigated, and most of these were negative in the ELISAs. The specificity ofthe assays for disease controls was 89-91% for the anti-PR3 assays and 95% for the anti-MPO assay. In the healthy controls the specificity was 98-99%. The specificity of the IIF test was 97% for a cANCA pattern and 81 % for a pANCA pattern in disease controls. The combination of cANCA with anti-PR3 and pANCA with anti-MPO both had a specificity of 99%. Further details will be presented during the meeting, in addition to the results of a follow-up study with correlation ofdisease activity and ANCA level. From this study we can conclude that ELISAs using purified PR3 or MPO are not more sensitive than the IIF test. However, the anti-MPO assay is more specific for systemic vascuitis as compared to disease controls with related diseases. Furthermore, the combination of the IIF test with antigen-specific ELISAs is very specific for the diagnosis Wegetier's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive gtomerulonephritis.

BACKGROUND: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity. OBJECTIVE: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission. DESIGN: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment. SETTING: 42 centers in 12 European countries. PATIENTS: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease. INTERVENTION: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone. MEASUREMENT: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes). RESULTS: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]). LIMITATIONS: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited. CONCLUSION: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia. PRIMARY FUNDING SOURCE: The European Union.

Objective. To assess potential associations for the development of venous thromboembolic events in patients with ANCA-associated vasculitides (AAV). Methods. Four hundred and seventeen patients enrolled to participate in randomized controlled trials conducted by the European Vasculitis Society were identified. Univariate and multivariate analyses were performed to validate previously proposed and identify novel risks associated with venous thromboembolism (VTE) in AAV. Results. VTE occurred in 41 of 417 (9.8%) patients. Uncorrected univariate analysis identified BVAS (odds ratio, OR= 1.05, 95% CI: 1.01, 1.10; P = 0.013), subsequent development of malignancy (OR = 2.6, 95% CI: 1.19, 5.71; P = 0.017), mucous membrane or eye involvement (OR = 2.13, 95% CI: 1.10, 4.11; P = 0.024) and baseline creatinine (OR = 1.08, 95% CI: 0.99, 1.18; P = 0.037) as being associated with the development of VTE. Multivariate analysis highlighted CRP (per 10 mg/l increase, OR= 1.05, 95% CI: 1.01, 1.09; P = 0.025), cutaneous involvement (OR = 4.83, 95% CI: 1.63, 14.38; P = 0.005) and gastrointestinal involvement (OR = 6.27, 95% CI: 1.34, 29.37; P = 0.02) among the BVAS items as well as baseline creatinine (per 100 mmol/l increase, OR= 1.17, 95% CI: 1.02, 1.35; P = 0.029) as being associated with VTEs. Conclusion. Our results highlight a role of CRP, baseline creatinine, and cutaneous and gastrointestinal involvement in the risk stratification as being associated with thromboembolic events. Moreover, there might be an association between VTEs and subsequent development of malignancy and disease activity in general. (Less)

Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild-moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray's regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8-14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray's model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.

Objective The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission-inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibodyassociated vasculitis. Duration of relapse-free survival was longer among CYC-treated patients than among MTX-treated patients during short-term followup. The aim of the present study was to describe the long-term outcome in patients enrolled in the randomized clinical trial. Methods Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC-treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse-free survival, mortality, and occurrence of other clinical events. Results The median duration of followup was 6 years (range 0.110.8 years). One patient developed end-stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse-free survival tended to be lower in the MTX group (P = 0.056). Conclusion In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long-term followup. However, first-line treatment with MTX was associated with less effective disease control than CYC-based induction therapy. (Less)

BackgroundGranulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) are subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) defined historically by clinical and histological features. GPA and MPA are heterogeneous entities with overlapping phenotypes. To identify novel subgroupings, cluster analysis was used to explore the phenotypic spectrum of AAV.MethodsThis study used a dataset of patients newly diagnosed as having GPA and MPA enrolled in five clinical trials. One cluster model included nine clinical baseline variables as input variables, and a second cluster model additionally included ANCA specificities. The clustering process involved multiple correspondence analyses followed by hierarchical ascendant cluster analysis. The clinical relevance of the generated clusters was analysed by their summary characteristics and outcomes.ResultsThe analyses involved data for 673 subjects: 396 (59%) with GPA and 277 (41%) with MPA. Both cluster models resulted in five partially redundant clusters of subjects, and the model including ANCA resulted in more pertinent separations. These clusters were named ‘renal AAV with proteinase 3 (PR3)-ANCA’ (40% of subjects), ‘renal AAV without PR3-ANCA’ (32%) and ‘non-renal AAV’ (12%), ‘cardiovascular AAV’ (9%) and ‘gastrointestinal AAV’ (7%). The five clusters had distinct death and relapse rates. On the basis of 4 variables, 651 subjects (97%) could be accurately allocated to 1 of the 5 classes.ConclusionsThis analysis suggests that AAV encompasses five classes associated with different outcomes. As compared with the traditional GPA–MPA separation, this classification system may better reflect the phenotypic spectrum of AAV.

To determine the association between characteristics at diagnosis and the time to first relapse in a large cohort of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).We studied long-term followup data from 4 clinical trials that included newly diagnosed patients with a broad spectrum of AAV severity and manifestations. Patient and disease characteristics at baseline were used in competing risk regression models with relapse as the event of interest and death as the competing event.We assessed 535 patients with 1,804 patient-years at risk of relapse. At diagnosis, the median age was 60.7 years (interquartile range [IQR] 48.8-69.1 years), 284 patients (53%) had granulomatosis with polyangiitis (Wegener's), and the median creatinine level was 203 μmoles/liter (IQR 97-498). A total of 201 patients (38%) experienced a relapse and 133 patients (25%) died, 96 of whom had not had prior relapse. Anti-proteinase 3 antibodies (subhazard ratio [sHR] 1.62 [95% confidence interval 1.39-1.89]) and cardiovascular involvement (sHR 1.59 [95% confidence interval 1.07-2.37]) were independently associated with a higher risk of relapse. Compared with patients with a creatinine level ≤100 μmoles/liter, patients with higher creatinine levels had a lower risk of relapse (sHR 0.81 [95% confidence interval 0.77-0.85] for a creatinine level of 101-200 μmoles/liter; sHR 0.39 [95% confidence interval 0.22-0.69] for a creatinine level200 μmoles/liter).Relapse of disease is common for patients with AAV. A creatinine level200 μmoles/liter at the time of diagnosis is strongly associated with a reduced risk of relapse and may help guide monitoring and treatment of patients with AAV.

Objectives To compare the Vasculitis Damage Index (VDI) with the Combined Damage Assessment Index (CDA) as measures of damage from vasculitis.Methods A total of 283 patients with vasculitis from 11 European centres were evaluated in a cross-sectional study using the VDI and CDA.Results Wegener's granulomatosis (58.4%) and microscopic polyangiitis (11.0%) were the most common diagnoses. Agreement between VDI and CDA scores (Spearman's correlation) was 0.90 (95% CI 0.87 to 0.92). There was good correlation between individual comparably evaluated organ systems (Spearman's correlation 0.70-0.94). Interobserver reliability (assessed by intraclass correlation coefficient (ICC)) was 0.94 (95% CI 0.89 to 0.98) for VDI and 0.78 (95% CI 0.63 to 0.93) for CDA. Intraobserver reliability was 0.92 (95% CI 0.83 to 1.00) for VDI and 0.87 (95% CI 0.75 to 1.00) for CDA. A total of 13 items were not used in the VDI compared to 23 in the CDA. Observers agreed that the CDA covered the full spectrum of damage attributable to vasculitis but was more time consuming and thus possibly less feasible for clinical and research purposes.Conclusions The VDI and CDA capture reliable data on damage among patients with vasculitis. The CDA captures more detail but is more complex and less practical than the VDI. Further evolution of damage assessment in vasculitis is likely to include key elements from both instruments.

Background: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. Methods: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. Results: The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(sup 2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). Conclusions: A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.) N Engl J Med 2010;363:211-20.

Objective. To estimate the incidence of and survival rates for WG, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and PAN within a defined population in southern Sweden. Methods. Cases were retrieved using hospital records and a serology database. All new cases of WG, MPA, CSS and PAN between 1997 and 2006 were included, provided they met pre-defined criteria, and were followed until 30 June 2008. The study area comprised two health care districts with a total population of 641 000. The standardized mortality ratio (SMR) was estimated using Swedish population data as a reference. Results. A total of 140 (WG, 63; MPA 65; CSS 6; and PAN 6) cases (52% women) with a median age of 67.6 (range 20-96) years fulfilled the inclusion criteria. The annual incidence per million of the population (95% CI) was estimated to be 9.8 (7.4-12.2) for WG, 10.1 (7.7-12.6) for MPA and 0.9 (0-1.7) for both CSS and PAN. The highest incidence was found in patients aged >/=75 years (79.1/million). The 1- and 5-year survival rates were 87.8 and 71.6% for all patients, but lower for MPA (80 and 55%) compared with WG (95 and 83%; P = 0.001), although the difference was not significant in the multivariate analysis. The SMR was 2.77 (95% CI 2.02, 3.71) for all patients. Conclusions. The incidence of WG and MPA was equal in our district, but there was a difference in survival rates related to age and renal function. A progressive increase in age-specific incidence rates was observed. (Less)

The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH2-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and α1-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B1 receptors, but did not bind to B2 receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B2 receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B1 and B2 receptors as demonstrated using wild-type and B1 overexpressing rats as well as wild-type and B2 receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.

Objectives:To develop European League Against Rheumatism (EULAR) recommendations for the management of large vessel vasculitis.Methods:An expert group (10 rheumatologists, 3 nephrologists, 2 immunolgists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search through a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of large vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.Results:Seven recommendations were made relating to the assessment, investigation and treatment of patients with large vessel vasculitis. The strength of recommendations was restricted by the low level of evidence and EULAR standardised operating procedures.Conclusions:On the basis of evidence and expert consensus, management recommendations for large vessel vasculitis have been formulated and are commended for use in everyday clinical practice.

ObjectivesTo describe short-term (up to 12 months) and long-term (up to 7 years) damage in patients with newly diagnosed antineutrophil-cytoplasm antibody-associated vasculitis (AAV).MethodsData were combined from six European Vasculitis Study group trials (n=735). Long-term follow-up (LTFU) data available for patients from four trials (n=535). Damage accrued was quantified by the Vasculitis Damage Index (VDI). Sixteen damage items were defined a priori as being potentially treatment-related.ResultsVDI data were available for 629 of 735 patients (85.6%) at baseline, at which time 217/629 (34.5%) had ≥1 item of damage and 32 (5.1%) ≥5 items, reflecting disease manifestations prior to diagnosis and trial enrolment. LTFU data were available for 467/535 (87.3%) at a mean of 7.3 years postdiagnosis. 302/535 patients (56.4%) had VDI data at LTFU, with 104/302 (34.4%) having ≥5 items and only 24 (7.9%) no items of damage. At 6 months and LTFU, the most frequent items were proteinuria, impaired glomerular filtration rate, hypertension, nasal crusting, hearing loss and peripheral neuropathy. The frequency of damage, including potentially treatment-related damage, rose over time (pConclusionsIn AAV, renal, otolaryngological and treatment-related (cardiovascular, disease, diabetes, osteoporosis and malignancy) damage increases over time, with around one-third of patients having ≥5 items of damage at a mean of 7 years postdiagnosis.

BACKGROUND AND OBJECTIVES: ANCA-associated vasculitis is commonly found in elderly patients, but there are few data concerning outcome and treatment in the highest age groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Consecutive patients (N=151) presenting between 1997 and 2009 were retrospectively included from local registries in six centers in Sweden, the United Kingdom, and the Czech Republic if diagnosed with microscopic polyangiitis or granulomatosis with polyangiitis at age ≥75 years during the study period. Patients were followed until 2 years from diagnosis or death. Data on survival and renal function were analyzed with respect to age, sex, ANCA specificity, renal function, C-reactive protein, comorbidities, and Birmingham Vasculitis Activity Score at diagnosis as well as treatment during the first month. RESULTS: Median follow-up was 730 days (interquartile range, 244-730). Overall 1-year survival was 71.5% and 2-year survival was 64.6%. Older age, higher creatinine, and lower Birmingham Vasculitis Activity Score were associated with higher mortality in multivariable analysis. Patients who were not treated with standard immunosuppressive therapy had significantly worse survival. Renal survival was 74.8% at 1 year. No new cases of ESRD occurred during the second year. High creatinine at diagnosis was the only significant predictor of renal survival in multivariable analysis. CONCLUSIONS: ANCA-associated vasculitis is a disease with substantial mortality and morbidity among elderly patients. This study showed a better prognosis for those who received immunosuppressive treatment and those who were diagnosed before having developed advanced renal insufficiency.

Patients with generalized ANCA-associated small vessel vasculitis (AAV) have a very poor outcome if the ANCA-associated vasculitis is not diagnosed, evaluated and treated properly. The introduction of treatment with immunosuppressive therapy has improved patient survival dramatically but with considerable side effects. Besides, almost 50% of surviving patients experience a relapse of vasculitis. Since 1995, the European Vasculitis Society (EUVAS) has designed and conducted several clinical trials on patients with AAV independently of pharmaceutical companies. The studies included patients with newly diagnosed AAV and were stratified according to renal function and generalized versus more localized forms. As the immediate patient survival has improved, the longer term outcome has become more important. There are several reports on outcome of patients with ANCA-associated vasculitis, but the patient groups were heterogeneous regarding diagnosis as well as treatment and follow-up. Therefore, EUVAS decided to further evaluate the effect and possible adverse events of the original randomized trials. This review presents an overview on long-term follow-up of patients with ANCA-associated vasculitis, with focus on relapse rate, patient and renal survival and development of cardiovascular disease and malignancy.

Participants were 40 persons from a group of 44 end-stage renal disease patients in southern Sweden who in 1985 received home hemodialysis under the auspices of a hospital renal unit, together with their spouses (n = 35). At a 10-year follow-up, 15 of the patients had died and 25 had survived. Univariate log rank tests of the influence of physical and demographic factors, the patient's dialysis-linked complaints and the burdens of the illness indicated the most important predictors of 10-year survival to be the patient's age, severity of the illness, the patient's dialysis-linked complaints (notably that of itching), and the burdens of the patient's disease on the spouse (particularly burdens of a sexual character). Copyright (C) 2004 John Wiley Sons, Ltd.

Objectives Patients with antineutrophil cytoplasmatic antibodies-associated vasculitides (AAV) exhibit higher mortality than the general population. In the current study, we assessed whether cluster affiliation based on clinical presentation might predict mortality. Methods With case record review, the outcomes for a population-based cohort of patients diagnosed with AAV in southern Sweden (catchment area of 0.7 million inhabitants) between 1997 and 2010 were assessed. Based on organ involvement at presentation, the cohort was stratified into the following clusters: gastrointestinal, cardiovascular, non-renal, renal with proteinase 3 (PR3) and renal without PR3. Cluster affiliation, demographics, clinical and laboratory values at entry were tested as prognostic factors for survival in multivariable models. Results 195 patients (98 female) with a median age of 69 years (IQR 55–77) at diagnosis were included in the cohort. The median time of follow-up was 4 years for the 98 patients (50%) who died during follow-up and 11 years for those alive at end of follow-up. The 1-year, 2-year, 5-year and 10-year survival was 87%, 82%, 70% and 55%, respectively. Prognostic factors for survival were sex, age, renal function and cluster affiliation. The mortality of patients with AAV was significantly increased compared with the general population except in the non-renal cluster. The cardiovascular and gastrointestinal clusters showed the highest mortality. Conclusion Even though the mortality in patients with AAV is increased compared with the general population this does not apply to patients without gastrointestinal, cardiovascular or renal involvement at diagnosis. We suggest that the initial clinical presentation is an important predictor for survival.

OBJECTIVE: Granulomatosis with polyangiitis and microscopic polyangiitis are ANCA-associated vasculitides (AAVs). The Vasculitis Damage Index (VDI) quantifies damage. This study aims to determine the factors associated with long-term damage in the AAVs. METHODS: Data from 535 patients from four European Vasculitis Study Group trials were studied. A long-term follow-up (LTFU) questionnaire at 7 years post-diagnosis was completed. The associations between baseline (age, creatinine and BVAS score) and cumulative (number of relapses and duration of glucocorticoid use) factors and damage accrued (total VDI scores and individual treatment-related damage items) during follow-up were explored. Multiple regressions identified independent associations between baseline measures, cumulative factors and VDI scores at LTFU. RESULTS: Two hundred and ninety-six patients had glucocorticoid use and VDI data available at LTFU, with the mean length of glucocorticoid use being 40.4 months (s.d. 16.7). High levels of damage were independently associated with older age at baseline (P = 0.051), lower glomerular filtration rate (P = 0.041), higher BVAS scores (P = 0.046), increased cumulative glucocorticoid use (P = 0.016) and increasing number of relapses. Patients with longer duration of glucocorticoid treatment were more likely to have a total VDI score ≥5 [odds ratio 1.26 per 12 months of glucocorticoid use (95% CI 1.03, 1.53), P = 0.022]. The main limitation is that approximately half of the patients enrolled had no LTFU data available; these patients were older with more severe initial disease. CONCLUSION: Long-term damage in the AAVs may be associated with severity of initial disease, age, number of relapses and duration of glucocorticoid use.

OBJECTIVE In childhood onset GH deficiency (GHD) a reduction in left ventricular mass (LV-mass) and impairment of systolic function as well an impairment in glomerular filtration rate (GFR) has been shown. The aim of the present study was to assess if a low GH dose resulted in an improvement in morphological and functional parameters of these organs. DESIGN AND PATIENTS Eleven patients with childhood onset GHD were investigated before and after 10 months of GH treatment at a dose of 1.5 IU/day (range 1-2), corresponding to 0.02 IU/kg/day or 7 mug/kg/day. The GH dose resulted in a serum IGF-I level in the normal range in all but one patient. MEASUREMENTS Doppler echocardiography of the heart and ultrasound examination of the kidneys was performed. Glomerular filtration rate (GFR) was estimated with iohexol clearance and urinary proteinuria was measured with 24-h urinary samples collected for analyses of albumin, alpha-1-microglobulin, IgG and albumin/creatinine clearance ratio. Body composition was measured by bioelectric impedance analysis. RESULTS L V-mass index increased significantly after GH treatment (P = 0.04), and there was a clear trend for a positive correlation between the increase in serum IGF-I and the increase in LV-mass index, although it did not reach significance (r = 0.57, P = 0.07). GH treatment did not increase cardiac fractional shortening. Kidney length increased significantly (P = 0.02) with an average increase of 1 cm (range -0.5-1.5 cm). No significant changes in median GFR or serum creatinine were recorded. Three patients with subnormal GFR before GH treatment normalized after 10 months of treatment. Urine analysis showed no abnormalities before or after GH treatment. A significant decrease in percentage fat mass was recorded (P = 0.03). CONCLUSION A low individualized GH dose to adults with childhood onset GHD resulted in an increase in LV-mass index and kidney length. Re-establishing GH treatment with a low dose in this patient group can lead to a further somatic maturation of these organs, probably not accomplished previously. (Less)

SUMMARYIn ANCA-associated small vessel vasculitis few genetic factors have proven to be of importance for disease susceptibility, an exception being deficiency of α1-anti-trypsin, the main inhibitor of proteinase 3 (PR3). Alerted by our finding that myeloperoxidase has affinity for C3, and the finding of an increased frequency of the C3F allele in systemic vasculitis in a British cohort, we examined polymorphism of C3 and C4 in patients with ANCA+ small vessel vasculitis. After identification of all patients at our department with a positive ANCA test during the period 1991–95 and a diagnosis of small vessel vasculitis, blood samples were collected after informed consent. The 67 included patients were grouped according to ANCA serology and disease phenotype using the Chapel Hill nomenclature. The gene frequency of C3F was found to be increased (0.32) compared with controls (0.20; P

The prevalence of thyroid antibodies, indicating an autoimmune thyroiditis, has been shown to be significantly increased in patients with autoimmune diseases. A 3-year prospective follow-up study of 42 patients with biopsy-confirmed glomerulonephritis is presented. Although the majority of patients had been treated with immunosuppressants, the prevalence of thyroid peroxidase antibodies was unchanged in both females and males, 47 and 15% respectively, at follow-up. Likewise, the prevalence of thyroglobulin antibodies was unaffected as was that of antinuclear antibodies (ANA) when analysing males and females together. However, for males there was a trend to higher prevalence for ANA at follow-up. On the other hand, the prevalence of antineutrophil cytoplasmic antibodies declined. Furthermore, thyroid antibodies were not restricted to membranous nephropathy, and notably found in 4 out of the 8 patients with vasculitis.