Plasma proteome profiling in giant cell arteritis.

OBJECTIVES: This study aimed to identify plasma proteomic signatures that differentiate active and inactive giant cell arteritis (GCA) from non-disease controls. By comprehensively profiling the plasma proteome of both patients with GCA and controls, we aimed to identify plasma proteins that (1) distinguish patients from controls and (2) associate with disease activity in GCA. METHODS: Plasma samples were obtained from 30 patients with GCA in a multi-institutional, prospective longitudinal study: one captured during active disease and another while in clinical remission. Samples from 30 age-matched/sex-matched/race-matched non-disease controls were also collected. A high-throughput, aptamer-based proteomics assay, which examines over 7000 protein features, was used to generate plasma proteome profiles from study participants. RESULTS: After adjusting for potential confounders, we identified 537 proteins differentially abundant between active GCA and controls, and 781 between inactive GCA and controls. These proteins suggest distinct immune responses, metabolic pathways and potentially novel physiological processes involved in each disease state. Additionally, we found 16 proteins associated with disease activity in patients with active GCA. Random forest models trained on the plasma proteome profiles accurately differentiated active and inactive GCA groups from controls (95.0% and 98.3% in 10-fold cross-validation, respectively). However, plasma proteins alone provided limited ability to distinguish between active and inactive disease states within the same patients. CONCLUSIONS: This comprehensive analysis of the plasma proteome in GCA suggests that blood protein signatures integrated with machine learning hold promise for discovering multiplex biomarkers for GCA.

Glucocorticoid Minimization in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: An International Survey of Clinicians.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important.

Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.

Optic nerve sheath measurement to monitor disease activity in giant cell arteritis: a pilot study.

INTRODUCTION/OBJECTIVES: Optic nerve sheath (ONS) enhancement using magnetic resonance imaging of the orbits was observed in patients with giant cell arteritis (GCA). We previously showed that ONS diameter (ONSD) by bedside ultrasound is increased in patient with active GCA. This study aims to assess whether ONSD decreases with clinical remission in patients with GCA. METHODS: A prospective cohort study was conducted from June 2022 to January 2023. Patients who had an optic nerve ultrasound at GCA diagnosis as part of a previous crosssectional study were eligible. Optic nerve ultrasound was performed by the same investigator at diagnosis and month 3. ONSD (includes the optic nerve and its sheath) and optic nerve diameter (OND) were measured. Descriptive statistics for baseline characteristics and paired sample t-test were performed to assess the mean difference in OND and ONSD between diagnosis and month 3. RESULTS: Nine patients with GCA were included. The median age at disease onset was 79 years (interquartile range (IQR) of 79-82 years), and 7 patients were males. All patients were in clinical remission at month 3 on prednisone (median dose of 15 mg/day, IQR of 10-25 mg). The mean ONSD was lower at month 3 (3.76 mm) compared to baseline (5.98 mm), with a paired mean difference of 2.22 mm (95% CI 1.41-3.03 mm, p < 0.001). As anticipated, OND measurements did not vary between diagnosis and month 3. CONCLUSION: ONSD on ultrasound improves after 3 months of therapy in patients with GCA. A longer prospective study is required to determine if ONSD is useful to assess disease activity in GCA. Key Points • ONS ultrasound can identify patients with active GCA. • The ONSD on ultrasound is dynamic and improved after 3 months of GCA therapy. • ONS ultrasound may be useful to monitor disease activity in GCA.

Social determinants of health as barriers to care for vasculitis: perspectives of patients and healthcare providers.

OBJECTIVE: This study examined patient and healthcare provider (HCP) perspectives on the impact of unmet social needs on healthcare barriers for patients with vasculitis. METHODS: Two surveys were developed to gather perspectives from patients with vasculitis, and HCPs specializing in vasculitis care. The patient survey also included a 20-question social needs assessment. The data were analyzed using descriptive statistics. RESULTS: One hundred patients and 31 HCPs completed the surveys between September 2022 and June 2023. Fifty-six percent of patients reported unmet social needs, with poor social and mental health (30%) being the most common. Sixty-three percent of patients with vasculitis perceived unmet social need(s) as barriers to healthcare access. Financial insecurity (30%), poor mental health (29%), and poor health knowledge (25%) were the most common barriers identified. Overall, HCPs perceived SDOH have a greater impact on healthcare access than the patients surveyed. Most patients (82%) and HCPs (90%) believed rheumatologists should help in the management of SDOH, specifically health knowledge and mental health. Few HCPs (10%) felt well-positioned to address patients' mental health. Suggested interventions that address social needs and improve healthcare access included referrals to community-based resources, providing educational materials, and virtual visits. CONCLUSION: Through patient and HCP perspectives, the impact of SDOH on healthcare access for patients with vasculitis was explored. Understanding the positive experiences and challenges faced by patients is crucial for developing targeted interventions to enhance healthcare access. These findings underscore the importance of ongoing efforts to improve the healthcare experience for patients with vasculitis. Key Points • The impact of unmet social needs on healthcare access for patients with vasculitis, illustrates the complex relationship between SDOH and healthcare outcomes. • Unmet social needs among patients with vasculitis, included poor social and mental health, financial and food insecurity, and a lack of health literacy, which may exacerbate challenges leading to poor health outcomes. • The differences in perspectives between patients and healthcare providers regarding the impact of certain SDOH on healthcare access, necessitates the importance of co-production in the development of interventions to improve healthcare delivery. • The importance of patient-centered care and tailored solutions was highlighted by the need for various interventions to address social needs and improve healthcare access, such as referrals to community-based resources, educational materials, and interprofessional collaboration.

Optic Nerve Sheath Measurement on Ultrasound: A Novel Diagnostic Test for Giant Cell Arteritis.

OBJECTIVE: Optic nerve sheath enhancement on magnetic resonance imaging has been reported in patients with giant cell arteritis (GCA), with or without visual manifestations. Whether similar findings can be documented on ultrasound is unknown. Optic nerve ultrasound is a point-of-care, easy to learn, rapid, and noninvasive technique. This study aims to investigate whether optic nerve sheath diameter (ONSD) measured on ultrasound is useful in the diagnosis of active, new-onset GCA. METHODS: A single-center, diagnostic accuracy study was performed from June to November 2022 on consecutive eligible patients referred for suspected GCA. Optic nerve ultrasound was performed on both eyes. The ONSD (includes the optic nerve and its sheath) and optic nerve diameter (OND) were measured 3 mm behind the ocular globe. The presence or absence of GCA was confirmed clinically 6 months later. Multivariable linear regression, adjusting for age and sex, was used to determine the association between optic nerve ultrasound measures and final GCA diagnosis. RESULTS: Thirty participants were enrolled, including nine participants with a final diagnosis of GCA. Mean ± SD ONSD was 5.98 ± 1.17 mm in patients with GCA and 4.02 ± 0.99 mm in patients without GCA. Mean ONSD was greater by 1.26 mm in patients with GCA (95% confidence interval 0.30-2.21 mm, P = 0.01) compared with those without GCA, adjusting for age and sex. Mean ± SD OND was 2.97 ± 0.46 mm in patients with GCA and 2.47 ± 0.58 mm in patients without GCA. There was no evidence of an association between GCA diagnosis and OND. CONCLUSION: Patients with GCA had a significantly greater ONSD on ultrasound than patients without GCA. Optic nerve ultrasound may represent a novel, rapid, bedside diagnostic test for GCA. A large prospective study is required to confirm these findings and evaluate whether ONSD can be used as a disease activity biomarker in GCA.

Antiplatelet therapy to prevent ischemic events in giant cell arteritis: protocol for a systematic review and meta-analysis.

BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis in adults. Presenting features include new-onset headaches, constitutional symptoms, jaw claudication, polymyalgia rheumatica, and visual symptoms. Arterial inflammation with subsequent stenosis and occlusion may cause tissue ischemia, leading to blindness, strokes, and myocardial infarction. Oral antiplatelet therapy has been hypothesized to reduce GCA-related ischemic events. However, previous studies have demonstrated conflicting results regarding the efficacy of antiplatelet agents in GCA. The objective of this systematic review is to assess the safety and efficacy of antiplatelet therapy for the prevention of these events in adults with giant cell arteritis. METHODS: In this systematic review, we will include randomized controlled trials (RTCs), quasi-randomized trials, non-randomized intervention studies, cohort studies, and case-control studies on patients with new-onset or relapsing GCA. The intervention of interest will be pre-existing use or initiation of an oral antiplatelet medication (aspirin, clopidogrel, prasugrel, or ticagrelor) at GCA onset or relapse. The comparator of interest will be the absence of antiplatelet therapy. Endpoints will be evaluated after 6 and 12 months of follow-up. The primary outcome will be GCA-related ischemic events, including permanent blindness, stroke, myocardial infarction, and ischemic event-related deaths. Adverse events such as major bleeding and death caused by a bleeding event will be assessed. DISCUSSION: GCA-related ischemic events are catastrophic, sudden, often irreversible, and lead to significant morbidity. Antiplatelet agents are affordable, accessible, and could be effective for the prevention of these events. Nevertheless, the potential benefits of platelet aggregation inhibition must be weighed against their associated risk of bleeding. Assessing the efficacy and safety of antiplatelet therapy in GCA is therefore clinically important. SYSTEMATIC REVIEW REGISTRATION: Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42023441574.

Signal Regulatory Protein α Expression in Systemic Vasculitis.

OBJECTIVE: Signal regulatory protein α (SIRPα) is found primarily on myeloid cells, including macrophages and neutrophils; binds to CD47; and regulates phagocytosis, antigen presentation, cellular fusion, cell proliferation, and migration. Therefore, SIRPα may be involved in the pathogenesis of autoimmune diseases, including systemic vasculitis. This study aimed to assess SIRPα expression in tissue samples from patients with vasculitis. METHODS: Immunohistochemical staining for SIRPα was performed on temporal artery (TA), kidney, and lung biopsy samples from patients with giant cell arteritis (GCA), patients with microscopic polyangiitis (MPA), patients with granulomatosis with polyangiitis (GPA), and patients without vasculitis. A score of SIRPα+ expression was calculated, derived from the percentages of monocytes, macrophages, and dendritic cells and neutrophils with different staining intensities in affected tissues. RESULTS: A total of 46 samples from patients with different vasculitides (GCA, MPA, and GPA) were included in the study. Tissue samples included TA samples from 15 patients with GCA; kidney samples from 11 and 9 patients with GPA and MPA, respectively; and lung samples from 11 patients with GPA. Most tissue samples from patients with active vasculitis (15 of 15 TA samples, 17 of 20 kidney samples, and 9 of 11 lung samples) showed SIRPα staining. SIRPα staining intensity was less in kidney samples compared to TA and lung samples. CONCLUSION: This study demonstrates high-level expression of SIRPα in macrophages and monocytes in affected tissue in systemic vasculitis. These findings provide a foundation for further studies exploring the role of the SIRPα-CD47 pathway in the pathogenesis of systemic vasculitis and the potential for the blockade of SIRPα and/or the depletion of SIRPα+ cells as treatment of systemic vasculitis.

Assessment of Damage in Takayasu's Arteritis.

OBJECTIVES: To evaluate damage and clinical characteristics associated with damage in Takayasu's arteritis (TAK). METHODS: Patients with TAK enrolled in a multicentre, prospective, observational study underwent standardized damage assessment every 6 months using the Vasculitis Damage Index (VDI) and the Large-Vessel Vasculitis Index of Damage (LVVID). RESULTS: The study included 236 patients with TAK: 92% female, 81% Caucasian; median (25th, 75th percentile) disease duration = 2.6 (0.12, 6.9) years. Eighty-four percent had follow-up: median (25th, 75th) duration 4.1 (1.9, 7.5) years.Items of damage were present in 89% on VDI, 87% on LVVID, in the peripheral vascular (76% VDI, 74% LVVID), cardiac (40% VDI, 45% LVVID) systems. During follow-up, 42% patients had new damage;, including major vessel stenosis/arterial occlusion (8%), limb claudication (6%), hypertension (7%), aortic aneurysm (4%), and bypass surgery (4%). Disease-specific damage accounted for >90% new items. Older age, relapse, and longer duration of follow-up were associated with new damage items; a higher proportion of patients without new damage were on methotrexate (p< 0.05). Among 48 patients diagnosed with TAK within 180 days of enrolment, new damage occurred in 31% on VDI and 52% on LVVID. History of relapse was associated with new damage in the entire cohort while in patients with a recent diagnosis, older age at diagnosis was associated with new damage. CONCLUSION: Damage is present in > 80% of patients with TAK even with recent diagnosis and >40% of patients accrue new, mainly disease-specific damage. Therapies for TAK that better control disease activity and prevent damage should be prioritized.

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.

Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre 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 multicentre 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 four 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 six (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 seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven 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.

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.

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.

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.

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.

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.