Stroke frequency, associated factors, and clinical features in primary systemic vasculitis: a multicentric observational study.

OBJECTIVES: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV. METHODS: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed. RESULTS: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00-4.06): 102 (2.13% 95% CI 1.73-2.56) with stroke and 81 (1.68% 95% CI 1.33-2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet's disease (9.5%, 95% CI 5.79-14.37), polyarteritis nodosa (6.2%, 95% CI 3.25-10.61), and Takayasu's arteritis (6.0%, 95% CI 4.30-8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09-3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20-3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05-9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01-2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period. CONCLUSION: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet's. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence.

Clinical Characteristics and Outcomes of Polyarteritis Nodosa: An International Study.

OBJECTIVE: We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL-PAN). METHODS: Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease-related damage, and survival were analyzed. RESULTS: Three hundred fifty-eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty-five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow-up, relapse occurred in 48.5% of patients. One, 5- and 10-year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis >140 µmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement. CONCLUSION: The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine >140 µmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN.

Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials.

OBJECTIVE: To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). METHODS: The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. RESULTS: 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). CONCLUSIONS: According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

Aneurysmal Disease in Patients With Takayasu Arteritis.

OBJECTIVE: Takayasu arteritis (TA) leads to stenotic disease. Aneurysmal lesions are rarer. This study assessed the main characteristics of aneurysmal disease in a Canadian cohort of patients with TA. METHODS: This monocentric retrospective study included patients with TA followed at the Mount Sinai Hospital Vasculitis Clinic in Toronto. Diagnosis of TA was based on clinical findings and/or satisfied the 1990 American College of Rheumatology classification criteria. RESULTS: Seventy-four patients were included. At any time, aneurysmal disease was found in 23 (31%) patients. Median disease duration was 9.0 (IQR 7.0-19.0) years. Prior hypertension (P = 0.02), fever (P = 0.04), and seizure disorders (P = 0.03) were more common. Limb claudication was less frequent (P = 0.01). Persistent and/or new aneurysms were demonstrated in 22/23 patients at follow-up. Thoracic aorta aneurysm (13/22) was most common, followed by abdominal aorta (8/22), subclavian (7/22), and carotid (6/22) artery disease. Aortic valve regurgitation was more frequent (9/23 vs 3/48; P = 0.001). Twenty-one patients had been treated with glucocorticoids (median 6.1 years [IQR 3.7-8.1]). Methotrexate, azathioprine, and leflunomide were repeatedly used. Infliximab (7/23) was used more often (P = 0.04), whereas tocilizumab was received by only 4 patients with aneurysmal disease (P = 0.01). Patients with aneurysms suffered more frequent relapses (2.0 [IQR 0.0-4.0] vs 1.0 [IQR 0.0-2.0], P = 0.04). CONCLUSION: Aneurysmal disease was found in a significant proportion of patients with TA. Given that aneurysms may carry a risk of rupture, and are associated with a higher rate of relapse, this finding should be reported systematically in TA studies.

Urine and Plasma Complement Ba Levels During Disease Flares in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Although the alternative complement pathway has been implicated in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), the specific nature of its involvement is unclear. This study measured levels of urine and plasma complement fragment Ba at multiple time points in a group of patients with AAV. Methods: The complement fragment Ba was measured by enzyme-linked immunosorbent assay in serial urine and plasma samples from 21 patients with AAV who developed a renal flare, 19 who developed a nonrenal flare, and 20 in long-term remission. Urine Ba levels were corrected for urine creatinine concentration. Changes in Ba levels were modeled using mixed linear-effect models. A logistic regression model was fit to predict a renal flare using Ba levels at the time of flare versus the nonrenal flare and long-term remission groups. Results: Data from 60 patients with AAV were used for this analysis; 53% were male, 93% were White, and 74% had antiproteinase3-ANCA. Urine Ba levels increased at renal flare (P < 0.001) but remained stable during a nonrenal flare or long-term remission. Plasma Ba levels were stable over time in all groups. Urine Ba levels predicted a renal flare with an area under the curve of 0.76 (P < 0.001), with a cutoff of 12.53 ng/mg urine creatinine yielding a sensitivity of 76.2% and a specificity of 68.4%. Conclusion: Urine Ba levels, but not plasma Ba levels, are increased at the time of a renal flare in AAV, suggesting intrarenal complement activation and highlighting the potential use of this biomarker for surveillance of active renal vasculitis.

Comparison of patients with biopsy positive and negative primary angiitis of the central nervous system.

OBJECTIVE: There is limited evidence on when to obtain a central nervous system (CNS) biopsy in suspected primary angiitis of the central nervous system (PACNS). Our objective was to identify which clinical and radiological characteristics were associated with a positive biopsy in PACNS. METHODS: From the multicenter retrospective Cohort of Patients with Primary Vasculitis of the CNS (COVAC), we included adults with PACNS based on a positive CNS biopsy or otherwise unexplained intracranial stenoses with additional findings supportive of vasculitis. Baseline findings were compared between patients with a positive and negative biopsy using logistic regression models. RESULTS: 200 patients with PACNS were included, among which a biopsy was obtained in 100 (50%) and was positive in 61 (31%). Patients with a positive biopsy were more frequently female (OR 2.90, 95% CI 1.25-7.10, p = 0.01) and more often presented with seizures (OR 8.31, 95% CI 2.77-33.04, p < 0.001) or cognitive impairment (OR 2.58, 95% CI 1.11-6.10, p = 0.03). On imaging, biopsy positive patients more often had non-ischemic parenchymal or leptomeningeal gadolinium enhancement (OR 52.80, 95% CI 15.72-233.06, p < 0.001) or ≥ 1 cerebral microbleed (OR 8.08, 95% CI 3.03-25.13, p < 0.001), and less often had ≥ 1 acute brain infarct (OR 0.02, 95% CI 0.004-0.08, p < 0.001). In the multivariable model, non-ischemic parenchymal or leptomeningeal gadolinium enhancement (aOR 8.27, 95% CI 1.78-38.46), p < 0.01) and absence of ≥ 1 acute brain infarct (aOR 0.13, 95% CI 0.03-0.65, p = 0.01) were significantly associated with a positive biopsy. CONCLUSIONS: Baseline clinical and radiological characteristics differed between biopsy positive and negative PACNS. These results may help physicians individualize the decision to obtain a CNS biopsy in suspected PACNS.

Serum calprotectin and renal function decline in ANCA-associated vasculitides: a post hoc analysis of MAINRITSAN trial.

OBJECTIVE: Serum calprotectin appears to be an interesting biomarker associated with renal vascular disease activity in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to assess whether serum calprotectin levels can predict decline in renal function in AAV patients receiving maintenance therapy. METHODS: Serum calprotectin levels were assessed at inclusion and month 6 in AAV patients, in complete remission after induction therapy, randomly assigned to rituximab or azathioprine. Renal function decline was defined as a 25% decrease in estimated glomerular filtration rate (eGFR) and a change in the eGFR category, or a decrease of 15 mL/min/1.73 m2. Relapse was defined as a Birmingham Vasculitis Activity Score >0 attributable to active vasculitis. RESULTS: Seventy-six AAV were included. Serum calprotectin increased from baseline to month 6 in patients with renal function decline (7940 (-226.0, 28 691) ng/ml vs -4800 (-18 777, 3708) ng/ml; p<0.001). An increase of calprotectin level was associated with a higher risk of subsequent renal function decline even after adjustment (OR 6.50 (95% CI 1.7 to 24.9) p=0.006). A significantly higher risk of relapse was observed in proteinase 3- AAV patients with an increase of serum calprotectin levels (OR 5.6 (95% CI 1.0 to 31.2), p=0.03). CONCLUSION: An increase in serum calprotectin by month 6 compared with inclusion during remission-maintenance therapy in AAV was associated with a higher risk of renal function decline in the following 12 months. TRIAL REGISTRATION NUMBER: NCT00748644.

Mitochondrial-mediated inflammation and platelet activation in giant cell arteritis.

Markers of extracellular mitochondria are present in giant cell arteritis (GCA) patients. However, their role in promoting inflammation and platelet activation is no known. To investigate this, isolated mitochondria were opsonized with plasma from GCA patients or healthy individuals and incubated with peripheral blood mononuclear cells (PBMCs) or platelets and assessed for inflammatory cytokine production and platelet activation. Plasma from GCA patients promoted increased mitochondrial-mediated cytokine production by PBMCs as compared to healthy controls (p < 0.05). Mitochondria opsonized with plasma factors from patients with GCA induced higher platelet activation as compared to mitochondria opsonized with plasma factors from healthy individuals (p = 0.0015). Platelet levels of P-selectin were associated with disease activity in GCA (r = 0.34, p = 0.01). GCA patients have impaired ability to regulate the clearance of extracellular mitochondria, possibly contributing to excessive inflammation and platelet activation. Targeting key drivers of mitochondrial extrusion and/or their clearance could lead to new therapeutic interventions in GCA.

Interstitial lung disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis: an update on pathogenesis and treatment.

PURPOSE OF REVIEW: Interstitial lung disease (ILD) is now recognized as a common complication of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), especially myeloperoxidase (MPO)-ANCA-positive AAV and microscopic polyangiitis (MPA). This review focuses on current concepts pertaining to the pathogenesis, clinical assessment, and management of AAV-ILD. RECENT FINDINGS: ILD is typically identified before or at the onset of systemic AAV, and usual interstitial pneumonia (UIP) is the most common CT pattern. MPO-ANCA production, neutrophil extracellular traps formation, reactive oxidative species production, complement activation, environmental exposures, and genetic background might play a role in the pathogenesis of AAV-ILD. Recent research has identified promising biomarkers as potential diagnostic and prognostic tools in AAV-ILD. The optimal treatment for AAV-ILD is not well defined but might rely on a combination of immunosuppression and antifibrotics, especially in patients with progressive lung fibrosis. Despite the effectiveness of current therapies for AAV, the outcome of patients with AAV-ILD remains poor. SUMMARY: ANCA screening should be considered in patients with newly diagnosed ILD. Management of AAV-ILD should be overviewed by a collaborative team comprising vasculitis experts and respirologists. VIDEO ABSTRACT: http://links.lww.com/COPM/A33.

The Association Between Age at Diagnosis and Disease Characteristics and Damage in Patients With ANCA-Associated Vasculitis.

OBJECTIVE: This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013-2021). Disease cohorts were divided by age at diagnosis (years): children (<18), young adults (18-40), middle-aged adults (41-65), and older adults (>65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease-specific and non-disease-specific damage scores built from VDI and AVID items. RESULTS: Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3-ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P < 0.001) except the disease-specific damage score, which did not differ (P = 0.44). For EGPA, VDI scores increased with age at diagnosis (P < 0.009), whereas all other scores were not significantly different. CONCLUSION: Age at diagnosis is associated with clinical characteristics in AAV. Although VDI and AVID scores increase with age at diagnosis, this is driven by non-disease-specific damage items.

Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicenter retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicenter study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with 4 controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in 6 (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%), and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in 7 (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in 4 (11%). ATD were reintroduced in 7 cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs. 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs. 25%, P = 0.007), but less frequent kidney (38 vs. 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95%CI 0.01-0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Advances in the pharmacotherapeutic management of eosinophilic granulomatosis with polyangiitis.

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but potentially lethal systemic vasculitis. Only a few prospective therapeutic trials had been conducted in EGPA, and its treatment was mostly adapted from other vasculitides. Monoclonal antibodies inhibiting various pathways (e.g. interleukin-5 [IL5] or B cells) have been investigated. AREAS COVERED: Published studies on treatments for EGPA using glucocorticoids, conventional immunosuppressants (such as cyclophosphamide or azathioprine), antiIL5 pathway agents (mepolizumab, approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for EGPA; benralizumab and reslizumab), other and future possible treatments [PubMed search, 01/1990-02/2023] are reviewed. EXPERT OPINION: With advances made in the pharmacotherapeutic management of EGPA, the prognosis has gradually shifted from a potentially fatal to a more chronic course, for which more targeted and safer treatments can be used. However, glucocorticoids remain central. Rituximab is now a possible alternative to cyclophosphamide for induction, although data are still limited. AntiIL5 pathway therapies have been shown to be safe and effective in relapsing patients with EGPA, who often experience asthma and/or ears, nose, and throat (ENT) manifestations, but long-term data are needed. Treatment strategies need to be optimized based on individual patient characteristics, likely with sequential, combination-based approaches, while topical airway treatments should not be forgotten.

A Canadian vasculitis patient-driven survey to highlight which prednisone-related side effects matter the most.

OBJECTIVES: Although management of vasculitis has evolved over the last decades, glucocorticoids (GC) have remained the cornerstone of treatment. The side effects (SE) of GC are well known by the clinicians; their importance for patients with vasculitis has not been investigated as extensively as in other rheumatological conditions. METHODS: An online questionnaire surveyed between April 29th. to July 31st, 2022 with Vasculitis Foundation Canada about the patient experience and SE of prednisone. The survey included 5 questions about prednisone dose and duration, 21 about specific SE (with a rating of 1-10, and one question each on worst prednisone, and worst vasculitis, SE), and four other questions about knowledge and perception of possible alternatives to prednisone (namely, avacopan). RESULTS: A total of 97 patients (53 GPA/MPA, 44 other vasculitides) completed the survey. Their mean duration of GC use was 62.7±83.7 months, and 49.5% of patients were still on GC (daily dose, 8.4±6.2mg). All the patients reported ≥1 GC-related SE, and 67.0% reported ≥11/19 pre-specified SE of interest. Among ranked SEs, acne was the lowest score, whereas moon face/torso hump had the highest score, just above weight gain, insomnia and decreased quality of life. Around half of the GPA/MPA patients and one-third of the others had heard about avacopan, and 68% of patients (similarly in both groups) stated they would prefer being the first to take a very new medication, such as avacopan, instead of prednisone. CONCLUSIONS: Ranking given to some GC-related SEs may differ between patients and physicians. GC toxicity/SE indexes should reflect this difference.

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.

Score to assess the probability of relapse in granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: To develop a score assessing the probability of relapse in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Long-term follow-up data from GPA and MPA patients included in five consecutive randomised controlled trials were pooled. Patient characteristics at diagnosis were entered into a competing-risks model, with relapse as the event of interest and death the competing event. Univariate and multivariate analyses were computed to identify variables associated with relapse and build a score, which was then validated in an independent cohort of GPA or MPA patients. RESULTS: Data collected from 427 patients (203 GPA, 224 MPA) at diagnosis were included. Mean±SD follow-up was 80.6±51.3 months; 207 (48.5%) patients experienced ≥1 relapse. Relapse risk was associated with proteinase 3 (PR3) positivity (HR=1.81 (95% CI 1.28 to 2.57); p<0.001), age ≤75 years (HR=1.89 (95% CI 1.15 to 3.13); p=0.012) and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² (HR=1.67 (95% CI 1.18 to 2.33); p=0.004) at diagnosis. A score, the French Vasculitis Study Group Relapse Score (FRS), from 0 to 3 points was modelised: 1 point each for PR3-antineutrophil cytoplasmic antibody positivity, eGFR ≥30 mL/min/1.73 m² and age ≤75 years. In the validation cohort of 209 patients, the 5-year relapse risk was 8% for a FRS of 0, 30% for 1, 48% for 2 and 76% for 3. CONCLUSION: The FRS can be used at diagnosis to assess the relapse risk in patients with GPA or MPA. Its value for tailoring the duration of maintenance therapy should be evaluated in future prospective trials.

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.

Neutrophil extracellular trap formation in anti-neutrophil cytoplasmic antibody-associated and large-vessel vasculitis.

Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides.

Traditional and disease-related cardiovascular risk factors in ANCA-associated vasculitis: A prospective, two-centre cohort study.

OBJECTIVES: ANCA-associated vasculitis (AAV) has been associated with increased risk of cardiovascular (CV) events. The aim was to assess traditional and disease-related CV risk determinants in a two-centre prospective cohort of AAV patients. METHODS: Patients were recruited from centres in the Netherlands and Canada. A comprehensive CV risk assessment was performed at inclusion. Subjects were followed up yearly for 3-5 years until the first CV event, death or end of follow-up. Cox proportional hazards analyses were performed to relate baseline characteristics to the first CV event. RESULTS: A total of 144 patients were included (mean age 62 years, female sex 44%, median Framingham risk score 14.3%). Insulin resistance was present in 73% of patients tested at inclusion, independent of concurrent prednisone therapy. After a median follow-up of 2.90 years, 16 patients (11%) experienced a CV event (14 non-fatal and 2 fatal). The incidence of CV events was 5.45 per 100 patient-years. Age, Framingham risk score, HbA1c level, Diabetes Mellitus (DM), and previous CV event were significantly associated with CV events. Other factors, such as sex, impaired renal function, dyslipidemia, hypertension, smoking history and microalbuminuria, or disease-specific variables, like ANCA serotype or disease activity, were not significantly related to CV events in univariable or age-adjusted cox regression analysis. CONCLUSIONS: Determinants of an increased CV risk were identified. Disease-related factors and treatments can further modify individual risk factors, such as for steroids causing chronic insulin resistance and DM. Treatment of risk factors is essential to optimize long-term outcomes in AAV patients.

CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.