Vitamin D status in ANCA-associated vasculitis.

Objective: Vitamin D might participate in the pathogenesis of several immune-mediated diseases, but few related data are available for ANCA-associated vasculitis (AAV). In this study, we analysed the association between vitamin D status and disease in patients with AAV. Methods: Serum levels of 25(OH)D2/ 3 were measured in 125 randomly selected patients with AAV [granulomatosis with polyangiitis (n = 50), eosinophilic granulomatosis with polyangiitis (n = 50) or microscopic polyangiitis (n = 25)] enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies at the time of enrolment and a subsequent relapse visit. Sufficient, insufficient and deficient vitamin D status were defined as 25(OH)D3 levels >30, 20-30 and ˂20 ng/ml, respectively. Results: Seventy of 125 patients (56%) were female, with a mean age of 51.5 (16) years at diagnosis; 84 (67%) were ANCA positive. Mean 25(OH)D was 37.6 (16) ng/ml, with vitamin D deficiency in 13 (10.4%) and insufficiency in 26 (20.8%). In univariate analysis, lower vitamin D status was associated with male sex (P = 0.027) and disease activity (P = 0.047). In univariate and multivariate analyses, deficient vitamin D status was associated with disease activity (P = 0.015). Mean 25(OH)D status in the 21 patients with a subsequent relapse did not differ between baseline and relapse visit [37.8 (16) vs 38.0 (10) ng/ml, respectively; P = 0.92]. Conclusion: Most patients with AAV have sufficient 25(OH)D levels, although those with lower vitamin D status were more likely to be male and to have active disease. Whether optimization of vitamin D status alters disease manifestations or activity in AAV remains to be determined. Trial Registration: Vasculitis Clinical Research Consortium (VCRC) Longitudinal Study (LS), NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380.

Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial.

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.

Self-Reported Data and Physician-Reported Data in Patients With Eosinophilic Granulomatosis With Polyangiitis: Comparative Analysis.

BACKGROUND: Patient-based registries can help advance research on rare diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), a complex multiorgan form of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. OBJECTIVE: The aim of this study is to compare patient-reported and physician-reported data on manifestations, treatments, and outcomes for patients with EGPA. METHODS: We completed a comparative analysis of patients ≥18 years with EGPA in Canada and the United States from the following 2 cohorts: (1) The Vasculitis Patient-Powered Research Network (VPPRN), a self-enrolled secure portal with patient-entered data updated quarterly (2014-2019) and (2) the Vasculitis Clinical Research Consortium (VCRC) observational studies, a physician-entered database (2003-2019) of patients who fulfilled the 1990 American College of Rheumatology classification criteria for EGPA. The studied parameters included demographic characteristics, clinical manifestations, ANCA status, treatments, and relapses. RESULTS: Data from 195 patients with a validated diagnosis of EGPA in the VPPRN and 354 patients enrolled in the VCRC were analyzed. Compared to the VCRC cohort, the patients in the VPPRN cohort were more likely to be female (135/195, 69.2% compared to 209/354, 59%; P=.02) and younger at diagnosis (47.3 compared to 50.0 years; P=.03); both cohorts reported similar frequencies of asthma (177/184, 96.2% in the VPPRN cohort compared to 329/354, 92.9% in the VCRC cohort; P=.13) and cardiac manifestations (44/153, 28.8% compared to 75/354, 21.2%; P=.06), but the VPPRN cohort reported less frequent lung manifestations other than asthma and more frequent disease manifestations in all other organ systems. The ANCA positivity was 48.9% (64/131) in the VPPRN patients compared to 38.9% (123/316; P=.05) in the VCRC cohort. Relapsing disease after study enrollment was reported in 32.3% (63/195) of patients in the VPPRN compared to 35.7% (99/277) of patients in the VCRC. Most therapies (GC, cyclophosphamide, mepolizumab) were used at similar frequencies in both groups, except for rituximab with VPPRN patients reporting more use than the VCRC cohort (47/195, 24.1% compared to 29/277, 10.5%; P<.001). CONCLUSIONS: Overall, patients and physicians report manifestations of EGPA at similar frequencies. However, observed differences between patient and physician reports imply the potential occurrence of selection biases. These results support the use of patient-reported data in EGPA but also the need for careful consideration of disease-specific definitions for the study of EGPA and how patient- and physician-reported data are collected. TRIAL REGISTRATION: ClinicalTrials.gov NCT00315380, https://clinicaltrials.gov/ct2/show/NCT00315380; ClinicalTrials.gov NCT01241305, https://clinicaltrials.gov/ct2/show/NCT01241305.

Vasculitis: What Have We Learned in the Last 50 Years?

Realizing in the fall of 2021 that I had started medical school exactly 50 years ago, on September 7, 1971, I thought that it would be interesting for the 2022 Dunlop-Dottridge Lecture to briefly review what we knew about vasculitis prior to 1971 and then reflect on what we have learned since.

Hypothyroidism in vasculitis.

OBJECTIVE: To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. METHODS: Patients with GCA, Takayasu's arteritis (TAK), PAN and the three forms of ANCA-associated vasculitis [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)] enrolled in a prospective, multicentre, longitudinal study were included. RESULTS: The study included data on 2085 patients [63% female, 90% White] with a mean age of 54.6 years (s.d. 17.2). Diagnoses were GCA (20%), TAK (11%), PAN (5%), GPA (42%), microscopic polyangiitis (8%) and EGPA (14%). Hypothyroidism was present in 217 patients (10%) (83% female), with a mean age 59.8 years (s.d. 14.5). Age- and sex-adjusted risk of hypothyroidism was GCA, odds ratio (OR) 0.61 (95% CI 0.41, 0.90); TAK, OR 0.57 (95% CI 0.31, 1.03); PAN, OR 0.59 (95% CI 0.25, 1.38); GPA, OR 1.51 (95% CI 1.12, 2.05); microscopic polyangiitis, OR 1.81 (95% CI 1.18, 2.80) and EGPA, OR 0.82 (95% CI 0.52, 1.30). Among patients with AAV, age- and sex-adjusted risk of hypothyroidism was higher with positive MPO-ANCA [OR 1.89 (95% CI 1.39, 2.76)]. The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism, except transient ischaemic attacks, which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%; P = 0.001). CONCLUSIONS: Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.

ANCA status and renal parameters at month 12 post-diagnosis can help predict subsequent relapses in patients with granulomatosis with polyangiitis.

OBJECTIVE: To determine the predictive value of disease characteristics at 12-month follow-up after the diagnosis of GPA for subsequent relapses in a cohort of patients followed at a tertiary vasculitis clinic. METHODS: Demographic, clinical, and biological data at diagnosis and during follow-up from patients with GPA followed for at least 24 months at the Mount Sinai Hospital Vasculitis Clinic in Toronto, Canada were extracted from the Canadian Vasculitis Research Network (CanVasc) database and analyzed. The association between ANCA status and type (PR3- or MPO-ANCA), presence of microscopic hematuria, or serum creatinine level at follow-up month 12 ± 3 (M12) and relapses after M12 were assessed using Cox proportional hazard models. RESULTS: A total of 113 GPA patients were included in this study (50 ANCA positive, 63 ANCA negative at M12). Patient demographics and disease characteristics were similar at diagnosis, including the treatments used for induction and at M12. The global 5-year relapse rate was 55.8%, without any difference in the relapse rates after M12 between those ANCA-positive or negative at M12. However, in multivariate analyses, MPO-ANCA positivity at M12 was predictive of increased relapses after M12 (hazard ratio [HR] 3.54, P=0.01), as was the presence of microhematuria at M12 (HR 1.91, P=0.04). In contrast, higher serum creatinine levels at M12 were associated with a decreased risk of subsequent relapse (HR 0.99, P=0.04). CONCLUSION: In this cohort of patients with GPA, MPO-ANCA positivity and persistent microscopic hematuria at M12 were associated with increased risk of subsequent relapse, and could thus have value to predict disease outcome during follow-up.

Clinical Manifestations and Long-Term Outcomes of Eosinophilic Granulomatosis With Polyangiitis in North America.

OBJECTIVE: To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. METHODS: Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied. RESULTS: The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow-up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow-up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow-up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow-up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores. CONCLUSION: This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long-term remission to limit the accrual of disease-related damage.

An Initiative to Improve Timely Glucocorticoid Tapering in Vasculitis.

BACKGROUND/OBJECTIVE: High-dose glucocorticoids (GCs) are required in the initial treatment of systemic vasculitis. However, slow or delayed tapering can lead to unnecessary GC exposure and toxicity. In this quality improvement initiative, we aimed to increase appropriate GC tapering among newly referred patients awaiting specialty consultation at a tertiary vasculitis clinic. METHODS: For each patient referred for anti-neutrophil cytoplasm antibody-associated vasculitis (AAV) or large vessel vasculitis (LVV), recommendation-based GC tapering suggestions were faxed to referring physicians. To maximize uptake, the intervention format was modified according to feedback from referring physicians' offices. The proportion of new patients presenting to their first appointment who (1) had started to taper GCs, (2) were taking their target GC dose according to recommendations, (3) experienced a vasculitis flare during tapering were compared before (July 2017-January 2019) and after (February-October 2019) the intervention. RESULTS: Among 169 consecutive patients referred for AAV or LVV, the proportion who had started to taper GCs by their first visit increased from 84 of 117 (72%) preintervention to 49 of 52 (94%) postintervention (p < 0.01). Mean daily prednisone dose at first visit decreased from 29.9 (SD, 18) mg to 21.7 (SD, 14) mg (p < 0.01). However, the proportion who were ultimately taking "target" GC doses at their first visit did not significantly increase (72% vs. 77%). Disease flares during tapering were similar before and after the intervention (9% vs. 12%). CONCLUSIONS: Patients with AAV and LVV had increased GC tapering and lower GC doses at first visit following a preappointment intervention. Further strategies are needed to improve timely GC tapering in vasculitis.

CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update.

OBJECTIVE: In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. METHODS: A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation. RESULTS: Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations. CONCLUSION: The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2.

OBJECTIVE: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA). METHODS: Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples. RESULTS: Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2. CONCLUSION: A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus-negative idiopathic PAN.

Assessment of glucocorticoid tapering in large vessel and anti-neutrophil cytoplasmic antibody-associated vasculitides.

OBJECTIVES: Glucocorticoids (GC) remain integral to large vessel vasculitis (LVV) and ANCA-associated vasculitis (AAV) treatment. We aimed to assess real-world GC tapering trajectories among patients referred for LVV or AAV and identify factors associated with 'delayed' tapering. METHODS: Patients first assessed at a vasculitis clinic July 2017-August 2019 for LVV or AAV and taking GC were included. Delayed tapering was defined as prednisone >10 mg above target based on tapering recommendations (2010 British Society of Rheumatology Guidelines for Giant Cell Arteritis, 2015 CanVasc AAV Recommendations). We compared characteristics of patients with delayed and appropriate tapering and assessed barriers to timely tapering though chart reviews and referring physician surveys. RESULTS: 160 patients (65 LVV, 95 AAV) were taking GC at their first visit. Among the 42 (26%) patients with delayed tapering, mean daily prednisone dose was 39.2 mg (SD 14) compared to a target of 15.2 mg (SD 15). Pulse GC were administered to 19/42 (45%) patients with delayed tapering compared to 26/118 (22%) with appropriate tapering (p<0.05). Mean Birmingham Vasculitis Activity Score at treatment onset and GC duration were not significantly different between the two groups. Vision loss and/or stroke was more frequent in LVV referrals who experienced delayed (9/21, 43%) vs. appropriate (6/44, 14%) tapering (p<0.05). Managing risk of vasculitis flare was the most common challenge to tapering GC among surveyed referring physicians. CONCLUSIONS: In one quarter of patients referred for LVV or AAV taking GC, tapering was slower than recommended. Promoting timely tapering may reduce GC toxicity.

Efficacy of leflunomide in the treatment of vasculitis.

OBJECTIVES: Only a few small case series, case reports, and one small clinical trial suggested some benefit of leflunomide (LEF) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and other vasculitides. We analysed the clinical efficacy and tolerability of LEF in a large cohort of patients with various vasculitides. METHODS: This was a retrospective analysis of patients who received LEF for treatment of their vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Study and in 3 additional centres from the Canadian vasculitis research network (CanVasc). RESULTS: Data for 93 patients were analysed: 45 had granulomatosis with polyangiitis (GPA), 8 microscopic polyangiitis (MPA), 12 eosinophilic granulomatosis with polyangiitis (EGPA), 14 giant-cell arteritis (GCA), 9 Takayasu's arteritis (TAK), and 5 polyarteritis nodosa (PAN). The main reason for initiation of LEF was active disease (89%). LEF was efficacious for remission induction or maintenance at 6 months for 62 (67%) patients (64% with GCA, 89% with TAK, 80% with PAN, 69% with GPA, 75% with MPA, 33% with EGPA); 20% discontinued LEF before achieving remission because of persistent disease activity. Overall, 22 adverse events (gastrointestinal symptoms being the most common) led to drug discontinuation in 18 (19%) patients, of which 12 stopped LEF before month 6, before showing any benefit in 8/12 of these patients. CONCLUSIONS: Leflunomide can be an effective therapeutic option for various vasculitides, especially for non-severe refractory or relapsing ANCA-associated vasculitis or large-vessel vasculitis. No new safety signals for LEF were identified in this population.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Patterns of clinical presentation in Takayasu's arteritis.

OBJECTIVE: Takayasu's arteritis (TAK) is a clinically heterogenous disease. Patterns of clinical presentation in TAK at diagnosis have not been well described, and a "triphasic pattern" of constitutional symptoms evolving into vascular inflammation and fibrosis has been reported but never systematically evaluated. METHODS: Patients with TAK were prospectively recruited from the National Institutes of Health (NIH) and the Vasculitis Clinical Research Consortium (VCRC). Based on clinical presentation at diagnosis, patients were divided into five categories: (1) constitutional symptoms alone, (2) carotidynia, (3) other vascular-associated symptoms, (4) major ischemic event, or (5) asymptomatic. Associated clinical characteristics were evaluated in each category. Preceding symptoms were also assessed to determine the presence of a triphasic disease pattern. RESULTS: A total of 275 patients with TAK were included (VCRC=208; NIH=67). Similar heterogeneity of clinical presentation was identified in each cohort: constitutional symptoms (8%), carotidynia (13-15%), other vascular symptoms (43-47%), major ischemic event (28-30%), and asymptomatic (2-6%). An increased relative proportion of males was seen in patients who presented with constitutional symptoms or were asymptomatic at diagnosis (p<0.01). Patients who presented with constitutional symptoms and major ischemic events were youngest at diagnosis. Patients in the asymptomatic group were oldest at diagnosis and often were not treated (p<0.01). Relapse was most frequent in patients who presented with carotidynia (p<0.01). A minority of patients (19%) who presented with a major ischemic event reported a triphasic pattern of disease. CONCLUSION: There are diverse clinical presentations at diagnosis in TAK. Patients do not necessarily progress sequentially through phases of disease.

Efficacy of conventional immunosuppressants in relapsing or refractory eosinophilic granulomatosis with polyangiitis: evidence from a Canadian single-centre cohort.

OBJECTIVES: To describe the efficacy of conventional immunosuppressants in disease control of relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) compared to recently published mepolizumab and rituximab studies. METHODS: A retrospective analysis from the Toronto Vasculitis Clinic was conducted. Patients with relapsing or refractory EGPA with similar entry criteria as the main mepolizumab (MIRRA) or rituximab (case-series) studies, who were started on conventional immunosuppressants, were assessed for remission at 24- and 52-weeks. Remission was defined as a Birmingham Vasculitis Activity Score of 0 and a prednisone dose of ≤4mg/day, ≤7.5mg/day, corresponding to the mepolizumab trial, or any prednisone dose per day, as in the rituximab study. RESULTS: Among 110 cohort patients, 24 with relapsing or refractory EGPA met eligibility criteria. Conventional immunosuppressants used were methotrexate (n=15), azathioprine (n=8) or leflunomide (n=1). Remission rates at 24-weeks were 8.3% with prednisone ≤4mg/day (vs. 28.0% in the mepolizumab trial); 41.6% with prednisone ≤7.5mg/day (vs. 45% in the mepolizumab trial) and 62.5% with any prednisone dose (vs. 34% in the rituximab study). Remission at 52-weeks was 50.0% with any prednisone dose (vs. 49% in the rituximab study), whereas sustained remission at week 52 (as of week 24) was 4.2% with prednisone ≤4mg/day (vs. 19% in the mepolizumab trial), and 33.3% with prednisone ≤7.5mg/day (vs. 24% in the mepolizumab trial). CONCLUSIONS: Though our study was small and retrospective, rates of remission observed with conventional immunosuppressants were substantial. This should be kept in mind when interpreting results of placebo-controlled or retrospective studies on biologics in EGPA.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Predictors of fatal and non-fatal cardiovascular events in ANCA-associated vasculitis: Data from the Toronto CanVasc cohort.

OBJECTIVES: Patients with ANCA-associated vasculitis are at increased risk of cardiovascular events. The aim of the present study was to assess predictors of cardiovascular events in patients with granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. METHODS: This retrospective cohort study included patients from the Canadian Vasculitis Research Network cohort in Toronto. Characteristics at diagnosis were collected. During follow-up, non-fatal cardiovascular events were determined from the Vasculitis Damage Index; mortality and causes of death were recorded. Cox regression models were developed to determine predictors of cardiovascular events, defined as stroke or myocardial infarction. RESULTS: A total of 336 patients were included (231 [69%] granulomatosis with polyangiitis; 105 [31%] eosinophilic granulomatosis with polyangiitis). The mean age at diagnosis was 44 (±18) years and 44% were male. The incidence rate for the combined outcome of all fatal and non-fatal events was 7.2 events per 1000 patient-years. In a multivariate model, family history of cardiovascular events and a higher Birmingham Vasculitis Activity Score at diagnosis were predictive of cardiovascular events (hazard ratio and 95% confidence interval 3.46 [1.06-11.28] and 1.09 [1.02-1.16] respectively). In a subgroup analysis there was no association between cardiovascular or disease-specific characteristics and cardiovascular events in eosinophilic granulomatosis with polyangiitis. CONCLUSIONS: In this cohort of patients with granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, both traditional and disease-related risk factors were predictive of cardiovascular events. Further prospective studies should elucidate the impact of these and other modifiable risk factors on cardiovascular risk in ANCA-associated vasculitis.

Urinary soluble CD163 and monocyte chemoattractant protein-1 in the identification of subtle renal flare in anti-neutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). METHODS: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. RESULTS: Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8-1.2] in remission and 1.4 mg/dL (IQR 1.0-1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79-337), 44 (17-104) and 38 (7-76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6-23.5), 4.1 (2.5-8.4) and 4.1 (1.9-6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2. CONCLUSION: A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.

Evaluation of Potential Serum Biomarkers of Disease Activity in Diverse Forms of Vasculitis.

OBJECTIVE: We evaluated potential circulating biomarkers of disease activity in giant cell arteritis (GCA), Takayasu arteritis (TA), polyarteritis nodosa (PAN), and eosinophilic granulomatosis with polyangiitis (EGPA). METHODS: A panel of 22 serum proteins was tested in patients enrolled in the Vasculitis Clinical Research Consortium Longitudinal Studies of GCA, TA, PAN, or EGPA. Mixed models were used for most analyses. A J48 classification tree method was used to find the most relevant markers to differentiate between active and inactive GCA. RESULTS: Tests were done on 418 samples from 152 patients (60 GCA, 29 TA, 26 PAN, 37 EGPA), during both active vasculitis and remission. In GCA, these showed significant (p < 0.05) differences between disease states: B cell-attracting chemokine 1 (BCA)-1/CXC motif ligand 13 (CXCL13), erythrocyte sedimentation rate (ESR), interferon-γ-induced protein 10/CXC motif chemokine 10, soluble interleukin 2 receptor α (sIL-2Rα), and tissue inhibitor of metalloproteinase-1 (TIMP-1). In EGPA, these showed significant increases during active disease: granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF, interleukin (IL)-6, IL-15, and sIL-2Rα. BCA-1/CXCL13 also showed such increases, but only after adjustment for treatment. In PAN, ESR and matrix metalloprotease (MMP)-3 showed significant differences between disease states. Differences in biomarker levels between diseases were significant for 11 markers and were more striking (all p < 0.01) than differences related to disease activity. A combination of lower values of TIMP-1, IL-6, interferon-γ, and MMP-3 correctly classified 87% of samples with inactive GCA. CONCLUSION: We identified novel biomarkers of disease activity in GCA and EGPA. Differences of biomarker levels between diseases, independent of disease activity, were more apparent than differences related to disease activity. Further studies are needed to determine whether these serum proteins have potential for clinical use in distinguishing active disease from remission or in predicting longer-term outcomes.

Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America.

OBJECTIVES: To develop and replicate, using data-driven methods, a novel classification system in Takayasu's arteritis based on distribution of arterial lesions. METHODS: Patients were included from four international cohorts at major academic centres: India (Christian Medical College Vellore); North America (National Institutes of Health, Vasculitis Clinical Research Consortium and Cleveland Clinic Foundation). All patients underwent whole-body angiography of the aorta and branch vessels, with categorization of arterial damage (stenosis, occlusion or aneurysm) in 13 territories. K-means cluster analysis was performed to identify subgroups of patients based on pattern of angiographic involvement. Cluster groups were identified in the Indian cohort and independently replicated in the North American cohorts. RESULTS: A total of 806 patients with Takayasu's arteritis from India (n = 581) and North America (n = 225) were included. Three distinct clusters defined by arterial damage were identified in the Indian cohort and replicated in each of the North American cohorts. Patients in cluster one had significantly more disease in the abdominal aorta, renal and mesenteric arteries (P < 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P < 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P < 0.01). Demographics, clinical symptoms and clinical outcomes differed by cluster. CONCLUSION: This large study in Takayasu's arteritis identified and replicated three novel subsets of patients based on patterns of arterial damage. Angiographic-based disease classification requires validation by demonstrating potential aetiological or prognostic implications.