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.

An update on the microbiome in vasculitis.

PURPOSE OF REVIEW: To summarize recent evidence regarding the presence and potential role of the microbiome in systemic vasculitides. RECENT FINDINGS: Microbiomic descriptions are now available in patients with small, medium and large vessel vasculitis. The majority of studies have evaluated gastrointestinal inhabitants, with a smaller number of studies describing the nasal, pulmonary or vascular microbiomes. Most published studies are observational and cross-sectional. Dysbiosis is seen frequently in vasculitis patients with reduced microbial diversity observed in nasal, fecal and vascular samples compared with disease and/or healthy controls. Predominant bacteria vary, but overall, patients with vasculitis tend to have more pathogenic and less commensal bacteria in active disease. In the few longitudinal studies available, improvement or resolution of dysbiosis has been observed following vasculitis treatment and improved disease activity. SUMMARY: Dysbiosis and reduced microbial diversity has been identified in patients with small, medium and large vessel vasculitis. Although limited data suggests microbiomes may 'normalize' following immunosuppression, cause or effect cannot be determined. It is hypothesized that microbial disruption in a genetically susceptible individual may trigger excessive host immune activation and vasculitis; however, larger studies with longitudinal and translational design are needed to further our current understanding.

Evidence for a vascular microbiome and its role in vessel health and disease.

PURPOSE OF REVIEW: We have summarized available evidence for and against the presence of a vascular microbiome. Studies that have attempted to detect bacteria and viruses in blood vessels in both health and disease are critiqued in an attempt to explain contrary results that may be due to variations in methodology. RECENT FINDINGS: Many studies have demonstrated the presence of both bacteria and viruses within diseased blood vessels. Evidence is most compelling in atherosclerosis; however, recent reports have raised questions about the potential role of microbes in nonatherosclerotic aortic aneurysms and vasculitis. Preliminary evidence also suggests that apparently normal vessels may harbor microbes. With the exception of certain viral infections (e.g. hepatitis C virus, HIV, Epstein-Barr virus, and cytomegalovirus) and infectious endocarditis, systemic vasculitides have not been convincingly associated with infectious agents. However, emerging data suggest that different communities of microbes may be present in noninflammatory and inflammatory large-vessel diseases. Whether variations in vascular microbial communities are the cause or a secondary result (epiphenomena) of vessel injury remains to be determined. SUMMARY: Blood vessels may not be sterile. Future studies of microbes in vessel health and disease may provide important insights into disease pathogenesis and suggest new therapies for diseases now considered to be idiopathic and refractory.

Recent advances in the medical management of Takayasu arteritis: an update on use of biologic therapies.

PURPOSE OF REVIEW: To critically review recent advances in medical management of Takayasu arteritis, with a special focus on the rationale and evidence to support the use of biologic agents in this disease. RECENT FINDINGS: Multiple case series and observational studies support the use of anti-tumor necrosis factor (TNF) medications, in particular infliximab, in patients who relapse upon tapering steroids and/or adding nonbiologic immunosuppressive agents. However, these medications must be continued to maintain effect, and often patients require increased doses over time. Tocilizumab and rituximab have been shown to lead to improved disease activity in small numbers of Takayasu's patients, including those refractory to anti-TNF treatment. SUMMARY: Anti-TNF agents are recommended for the treatment of Takayasu's patients who are unable to taper prednisone despite treatment with a nonbiologic immunosuppressive medication. Whether these biologic agents should be considered earlier in the treatment algorithm of these complicated patients remains an area of interest. Tocilizumab and rituximab may also be of benefit in refractory patients. Prospective randomized controlled trials are needed to confirm these findings.

The Utility of Laboratory Investigations for the Assessment and Management of Rheumatic Immune Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have greatly improved survival of several cancers with historically very poor prognosis. ICIs act by stimulating the patient's own immune system to fight cancer. Simultaneously, this immune activation can lead to immune-related adverse events (irAEs), including rheumatic manifestations (Rh-irAEs). Rh-irAEs mimic primary rheumatic diseases including arthritis, polymyalgia rheumatica, myositis, vasculitis, sarcoidosis, and sicca. This article summarizes the latest evidence regarding the utility of laboratory investigations in Rh-irAEs.

Cardiovascular Disease in Large Vessel Vasculitis: Risks, Controversies, and Management Strategies.

Takayasu's arteritis (TAK) and giant cell arteritis (GCA) are the 2 most common primary large vessel vasculitides (LVV). They share common vascular targets, clinical presentations, and histopathology, but target a strikingly different patient demographic. While GCA predominantly affects elderly people of northern European ancestry, TAK preferentially targets young women of Asian heritage. Cardiovascular diseases (CVD), including ischemic heart disease, cerebrovascular disease, aortic disease, and thromboses, are significantly increased in LVV. In this review, we will compare and contrast the issue of CVD in patients with TAK and GCA, with respect to prevalence, risk factors, and mechanisms of events to gain an understanding of the relative contributions of active vasculitis, vascular damage, and accelerated atherosclerosis. Controversies and possible mitigation strategies will be discussed.

COVID-19 Vaccination Perceptions in Patients With Rheumatic Disease: A Cross-Sectional Online Survey.

OBJECTIVE: To identify the factors that affect coronavirus disease 2019 (COVID-19) vaccine decision making among individuals diagnosed with a rheumatologic condition, given that previous international studies have demonstrated that a significant proportion of patients with rheumatic disease (RD) are vaccine hesitant. METHODS: This cross-sectional study involved an online survey with adult patients with RD from the Kaye Edmonton Clinic Rheumatology Clinic between June and August 2021. Quantitative results were descriptively analyzed, whereas qualitative thematic analysis was conducted for open-ended responses. RESULTS: The survey had a response rate of 70.9% (N = 231). Regarding COVID-19 vaccines, patients with RD were most concerned about the possible effect of vaccination on their rheumatic condition (45.2%) and about vaccine effectiveness (45.1%). Most patients had discussed COVID-19 vaccination (75.9%) and its risks and benefits (66.1%) with their medical team, and 83.6% of respondents were confident in the information provided. Patients' perceptions of the government's role in handling the COVID-19 pandemic varied: 33% reported that they found government-instituted public health measures effective. Surprisingly, 9.7% of patients with RD still reported concerns that they could develop COVID-19 from an approved COVID-19 vaccine. CONCLUSION: This study describes factors implicated in COVID-19 vaccine decision making among patients with RD. Three important themes included possible adverse effects of the vaccine on RD control, reduced vaccine efficacy because of RD/treatment, and risk of contracting SARS-CoV-2 from the COVID-19 vaccine. Knowledge from this study can assist healthcare providers in looking after patients with RD to initiate discussions with patients to share evidence-based vaccine information and assist with informed decision making.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia: PR3-versus MPO-ANCA-associated vasculitis, an exploratory cross-sectional study.

Background: Persistent fatigue is a common complaint in ANCA-vasculitis (AAV) patients and has a profound impact on patient's quality of life. The symptoms associated with this fatigue mirror those found in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. Etiologic and pathophysiologic differences exist between PR3- and MPO-ANCA disease, yet differences in their fatigue manifestations have not been well researched. We compared fatigue and its associations in healthy controls, AAV patients and fibromyalgia controls. Methods: The Canadian consensus criteria were used for ME/CFS diagnosis, and American College of Rheumatology criteria for fibromyalgia diagnosis. Factors such as cognitive failure, depression, anxiety, and sleep disturbances were assessed by patient reported questionnaires. Clinical factors such as BVAS, vasculitis damage index, CRP and BMI were also collected. Findings: Our AAV cohort comprised 52 patients, with a mean age of 44.7 (20-79), 57% (30/52) of the patients were female. We found 51.9% (27/52) of patients fulfilled the diagnostic criteria for ME/CFS, with 37% (10/27) of those having comorbid fibromyalgia. Rates of fatigue were higher in MPO-ANCA patients, than in PR3-ANCA patients, and their symptoms were more similar to the fibromyalgia controls. Fatigue in PR3-ANCA patients was related to inflammatory markers. These differences may be due to the varied pathophysiology of the PR3- and MPO-ANCA serotypes. Interpretation: A large proportion of AAV patients suffer from debilitating fatigue consequential enough to meet the diagnostic criteria for ME/CFS. Fatigue associations were not the same between PR3- and MPO-ANCA patients, suggesting that the underlying mechanisms may be different. Future studies should consider ANCA serotype, as further research may inform different clinical treatment strategies for AAV patients suffering from ME/CFS. Funding: This manuscript was funded by the Dutch Kidney Foundation (17PhD01).

Understanding COVID-19 vaccine hesitancy in vasculitis patients.

Objective: To identify the factors that impact COVID-19 vaccine decision-making in vaccine-hesitant vasculitis patients, and compare their perceptions with other rheumatology patients, given existence of data suggesting rheumatology patients may have disease-specific factors that influence their COVID-19 vaccine decision-making. Methods: This cross-sectional study surveyed adult rheumatology patients from the Kaye Edmonton Clinic Rheumatology Clinic, in Canada, between June and August 2021, using an anonymous online questionnaire. Survey responses were analyzed for statistical differences using chi-square analysis. Results: The COVID-19 Vaccine Perceptions Survey had a response rate of 70.9%. Of the total 231 respondents, 103 patients were diagnosed with vasculitis. At the time of the survey, 10.6% of vasculitis patients refused to receive a COVID-19 vaccine compared to 6.3% for other rheumatology patients. Compared to other rheumatology patients, vaccine-hesitant vasculitis patients were significantly more concerned about almost every aspect of available COVID-19 vaccines [e.g., safety (p < 0.001), components (p < 0.001)], and feared that they could contract SARS-CoV-2 from a vaccine (p < 0.001). These vaccine-hesitant patients were also significantly less pleased with the government's pandemic response, less confident in healthcare team-provided information (p < 0.001), and more likely to report that healthcare providers had no role in their COVID-19 vaccine decision-making (p < 0.001). Conclusion: Vaccine-hesitant vasculitis patients may have multiple considerations influencing COVID-19 vaccine hesitancy, including vaccine and disease-specific concerns, along with unfavorable perceptions of the healthcare system (government and healthcare providers). Healthcare providers can address some of these concerns by initiating patient-centered discussions around immunizations to help support educated decision-making.

Intracranial Involvement in Takayasu's Arteritis.

Takayasu's arteritis (TAK) is a large-vessel vasculitis that targets the aorta and its major branches. Although extracranial vascular involvement is uniformly present in this disease, the frequency of intracranial involvement in TAK has not been well studied. We retrospectively reviewed the clinical and imaging records of patients diagnosed with TAK at a single Canadian university medical centre to determine the prevalence of intracranial vascular involvement. Intracranial vascular and non-vascular findings were described, and a review of the literature was performed. Of 20 patients with TAK, 12 had vascular neuroimaging completed. Intracranial vascular lesions were identified in 4 patients (33.3% of those with imaging available, 20% of all patients). The frequency of intracranial vessel involvement in TAK may be more common than appreciated. Imaging of both the intra- and extra-cranial vessels should be considered in these young patients.

Cardiovascular events and the role of accelerated atherosclerosis in systemic vasculitis.

The spectrum of inflammatory blood vessel diseases includes both atherosclerosis and the primary systemic vasculitides. Although the inciting triggers differ, significant overlap exists in the mechanisms that contribute to sustained inflammation and vascular damage in both entities. With improvement in therapeutics to control acute vasculitis leading to longer survival, cardiovascular morbidity and mortality has emerged as the leading cause of death for vasculitis patients. Cardiovascular events likely occur as a consequence of vasculitis, vascular damage from prior inflammation causing a sustained procoagulant state, and accelerated atherosclerosis. In this review, we discuss the latest evidence regarding risk of cardiovascular events in patients with major forms of primary systemic vasculitis, and review the mechanisms by which accelerated atherosclerosis may occur.

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.

Optimal length and usefulness of temporal artery biopsies in the diagnosis of giant cell arteritis: a 10-year retrospective review of medical records.

BACKGROUND: In giant cell arteritis, temporal artery biopsies often show vasculitis with giant cell formation, but optimal biopsy length for diagnosis is debated. We reviewed temporal artery biopsies from a 10-year period in the province of Alberta, Canada, to identify an ideal biopsy length in the diagnostic process for giant cell arteritis. METHODS: We retrospectively reviewed electronic medical records of patients who had undergone a temporal artery biopsy procedure in Alberta between Jan 1, 2008, and Jan 1, 2018, as reported in the Data Integration and Management Repository of Alberta Health Services. We extracted data on baseline demographic characteristics (sex and age), inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), temporal artery biopsy characteristics (side of biopsy and postfixation length), and final pathological diagnoses. All positive biopsies were reviewed by a single pathologist to ensure uniformity of pathological interpretation, with subsequent discordant results removed from analysis. Predictors of positive pathological diagnosis of giant cell arteritis were modeled by logistic regression, and the Akaike information criterion was used to compare logistic regression models with varying biopsy length cutoffs (0·5, 1·0, 1·5, 2·0, and 2·5 cm) to determine a change point for diagnostic sensitivity in postfixation length. FINDINGS: We extracted data on 1203 temporal artery biopsies; after removal of 13 discordant biopsies, 1190 biopsies from 1163 patients were reviewed. The mean age of patients was 72·0 years (SD 10·3) and 799 (68·7%) patients were women. 222 (18·7%) temporal artery biopsies were positive for giant cell arteritis. In univariable analysis, increases in age (71·3 years [SD 10·6] in negative biopsies vs 75·3 years [8·3] in positive biopsies; odds ratio [OR] 1·04 [95% CI 1·02-1·06]; p<0·0001)), ESR (36 mm/h [IQR 18-62] in negative biopsies vs 57 [31-79] in positive biopsies; 1·01 [1·01-1·02]; p<0·0001), CRP (12·1 mg/L [IQR 3·3-35·1] in negative biopsies vs 41·8 [14·6-82·4] in positive biopsies; 1·01 [1·01-1·01]; p<0·0001), and biopsy length (1·2 cm [IQR 0·9-1·7] in negative biopsies vs 1·6 [1·1-2·0] in positive biopsies; 1·28 [1·09-1·51]; p=0·0025) were associated with a positive pathological diagnosis. In multivariable analysis adjusted for age, ESR, and CRP, age (adjusted OR 1·04 [95% CI 1·02-1·05]; p=0·0001), CRP (1·01 [1·00-1·01]; p=0·0006), and biopsy length (1·22 [1·00-1·49]; p=0·047) remained statistically significant predictors. The Akaike information criterion determined a change point of 1·5 cm for diagnostic sensitivity. INTERPRETATION: Accounting for postfixation shrinkage, our findings suggest a 1·5-2·0 cm prefixation length as the optimal biopsy length to diagnose patients with giant cell arteritis, with greater lengths unlikely to provide significant additional diagnostic yield to justify risks associated with surgery. FUNDING: None.

Outcomes Among 196 Patients With Noninfectious Proximal Aortitis.

OBJECTIVE: Noninfectious aortitis may occur in the context of a recognized systemic disease or as a topographically limited lesion without systemic features, which is called clinically isolated aortitis (CIA). This study was undertaken to better define and stress the limitations of this diagnostic category in a large population of patients in a single center dedicated to aortic diseases and to suggest recommendations for care. METHODS: Records of patients undergoing thoracic aortic surgery (1996-2012) at the Cleveland Clinic were reviewed to identify 196 patients with histopathologically proven aortitis. Clinical diagnoses (giant cell arteritis [GCA], Takayasu arteritis [TAK], CIA, or Other) were determined at the time of surgery. Clinical features, laboratory findings, and imaging results were recorded throughout the follow-up period. At least 6 months of follow-up data were available for 73 CIA patients. RESULTS: The mean age of the patients at time of surgery was 65.6 years (range 15-88 years); 67% of patients were female, and 90.3% were white. At the time of surgery, 129 patients (65.8%) met criteria for CIA, 42 (21.4%) for GCA, 14 (7.1%) for TAK, and 11 (5.6%) met criteria for other systemic inflammatory diseases. During a mean follow-up period of 56.2 months, 19% of CIA patients developed new symptoms, 45% developed new radiographic vascular lesions, 40% underwent additional vascular surgery, and 12% died (n = 9). Eleven of 73 patients (15%) initially classified as having CIA developed features of a systemic disease, most often GCA. CONCLUSION: The majority of patients (66%) with histopathologically proven aortitis have CIA at the time of surgery. CIA patients infrequently report new symptoms over time, but new vascular lesions requiring surgery commonly occur. Serial follow-up including large vessel imaging is strongly advised for all aortitis patients.

The Microbiome of Temporal Arteries.

OBJECTIVE: A role for microorganisms in giant cell arteritis (GCA) has long been suspected. We describe the microbiomes of temporal arteries from patients with GCA and controls. METHODS: Temporal artery biopsies from patients suspected to have GCA were collected under aseptic conditions and snap-frozen. Fluorescence in situ hybridization (FISH) and long-read 16S rRNA-gene sequencing was used to examine microbiomes of temporal arteries. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinate analysis (PCoA) with comparative Unifrac distances and predicted functional profiling using PICRUSt. RESULTS: Forty-seven patients, including 9 with biopsy-positive GCA, 15 with biopsy-negative GCA and 23 controls without GCA, were enrolled. FISH for bacterial DNA revealed signal in the arterial media. Beta, but not alpha, diversity differed between GCA and control temporal arteries (P = 0.042). Importantly, there were no significant differences between biopsy-positive and biopsy-negative GCA (P > 0.99). The largest differential abundances seen between GCA and non-GCA temporal arteries included Proteobacteria (P), Bifidobacterium (g), Parasutterella (g), and Granulicatella (g) [Log 2-fold change ≥ 4]. CONCLUSION: Temporal arteries are not sterile, but rather are inhabited by a community of bacteria. We have demonstrated that there are microbiomic differences between GCA and non-GCA temporal arteries, but not between biopsy-positive and biopsy-negative GCA.

Microbiomes of Inflammatory Thoracic Aortic Aneurysms Due to Giant Cell Arteritis and Clinically Isolated Aortitis Differ From Those of Non-Inflammatory Aneurysms.

OBJECTIVE: We sought to characterize microbiomes of thoracic aortas from patients with non-infectious aortitis due to giant cell arteritis (GCA) and clinically isolated aortitis (CIA) and to compare them to non-inflammatory aorta aneurysm controls. We also compared microbiomes from concurrently processed and separately reported temporal arteries (TA) and aortas. METHODS: From 220 prospectively enrolled patients undergoing surgery for thoracic aorta aneurysm, 49 were selected. Inflammatory and non-inflammatory cases were selected based on ability to match for age (+/-10 years), gender, and race. Biopsies were collected under aseptic conditions and snap-frozen. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinates analysis. RESULTS: Forty-nine patients with thoracic aortic aneurysms (12 CIA, 14 GCA, 23 non-inflammatory aneurysms) were enrolled. Alpha (P=0.018) and beta (P=0.024) diversity differed between specimens from aortitis cases and controls. There were no significant differences between CIA and GCA (P>0.7). The largest differential abundances between non-infectious aortitis and non-inflammatory control samples included Enterobacteriaceae, Phascolarctobacterium, Acinetobactor, Klebsiella, and Prevotella. Functional metagenomic predictions with PICRUSt revealed enrichment of oxidative phosphorylation and porphyrin metabolism pathways and downregulation of transcription factor pathways in aortitis compared to controls. Microbiomes of aortic samples differed significantly from temporal artery samples from a companion study, in both control and GCA groups (P=0.0002). CONCLUSION: Thoracic aorta aneurysms, far from being sterile, contain unique microbiomes that differ from those found in temporal arteries. The aorta microbiomes are most similar between aneurysms that were associated with inflammation, GCA, and CIA, but differed from those associated with non-inflammatory etiologies. These findings are promising in that they indicate that microbes may play a role in the pathogenesis of aortitis-associated aneurysms or non-inflammatory aneurysms by promoting or protecting against inflammation. However, we cannot rule out that these changes are related to alterations in tissue substrate that favor secondary changes in microbial communities.

Update on the management of giant cell arteritis.

Giant cell arteritis (GCA) is a large vessel vasculitis that may be associated with significant complications such as blindness, stroke, or aortic aneurysm and dissection in a subset of patients. Given the serious side effects associated with prolonged courses of glucocorticoids and frequent relapses experienced when doses are tapered, increased efforts are being dedicated to the discovery of safer and more effective therapies to control this disease. The purpose of this review is to critically evaluate the role of glucocorticoid-sparing agents in the medical management of GCA with a special focus on the most recent evidence regarding the role of biologic agents, including tocilizumab (TCZ), abatacept and ustekinumab, and other novel therapies.

Varicella Zoster Virus and Large Vessel Vasculitis, the Absence of an Association.

OBJECTIVE: It is controversial whether microorganisms play a role in the pathogenesis of large and medium vessel vasculitides (eg, giant cell arteritis [GCA], Takayasu arteritis [TAK] and focal idiopathic aortitis [FIA]). Recent studies have reported the presence of Varicella Zoster Virus (VZV) within formalin-fixed, paraffin-embedded temporal arteries and aortas of about three-quarters or more of patients with these conditions, and in a minority of controls. In a prospective study, we sought to confirm these findings using DNA extracted from vessels that were harvested under surgically aseptic conditions and snap frozen. METHODS AND RESULTS: DNA samples extracted from 11 surgically sterile temporal arteries and 31 surgically sterile thoracic aortas were used in an attempt to identify the vessel-associated VZV genome. Two different validated PCR methods were used. Thirty-one thoracic aorta aneurysm specimens included biopsies from 8 patients with GCA, 2 from patients with TAK, 6 from patients with FIA, and 15 from patients without vasculitis, who had non-inflammatory aneurysms. Eleven temporal artery biopsies were collected from 5 patients with GCA and 6 controls. The presence of VZV was not identified in either the specimens from patients with large vessel vasculitis or from the controls. CONCLUSIONS: Using surgically sterile snap-frozen specimens, we were unable to confirm recent reports of the presence of VZV in either aortas or temporal arteries from patients with large vessel vasculitis or controls.