Factors associated with incident cardiovascular disease in patients with rheumatoid arthritis: A scoping review.

INTRODUCTION: Rheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis and is associated with various comorbidities including cardiovascular disease (CVD). This scoping review summarizes the current evidence on longitudinal cohort studies assessing potential factors associated with the incidence of cardiovascular events among patients with RA. METHODS: Scopus, PubMed, Ovid MEDLINE and Cochrane databases were used to identify longitudinal cohort studies investigating the incidence of CVD among RA patients. Using predetermined inclusion and exclusion criteria, two reviewers screened and extracted the relevant studies independently to map the existing literature on this topic. The extracted data included study characteristics, demographics, comorbidities, behavioural and RA-related factors. RESULTS: Thirty-three research papers were included with a mean follow-up duration of 7.8 years. The sample size of the studies ranged from 182 to 4,311,022 subjects, the mean age from 46.1 to 72.3 years, and on average, 34.6% of the participants were male. The following factors were reported to be associated with a higher incidence of CVD in RA patients: older age, male sex, co-morbid hypertension, diabetes, and/or dyslipidemia, the presence of rheumatoid factor (RF) and/or acute phase reactants. Among RA treatments, glucocorticoids were shown to increase CVD incidence while DMARDs, especially methotrexate, were associated with a lower incidence of CVD. CONCLUSION: This review offers a comprehensive summary of the current literature reporting on risk factors for CVD incidence among RA patients. Future research should focus on the less studied factors, including socioeconomic status, physical inactivity, alcohol consumption, sleep habits and dietary patterns as well as some RA-related factors such as anti-citrullinated protein antibodies and functional impairment.

Phase-Specific Healthcare Costs Associated With Giant Cell Arteritis in Ontario, Canada.

OBJECTIVE: To estimate the additional healthcare system costs associated with giant cell arteritis (GCA) in the 1-year prediagnosis and postdiagnosis periods and over long-term follow-up compared to individuals with similar demographics and comorbidities without GCA. METHODS: We performed a population-based study using health administrative data. Newly diagnosed cases of GCA (between 2002 and 2017 and aged ≥ 66 years) were identified using a validated algorithm and matched 1:6 to comparators using propensity scores. Follow-up data were accrued until death, outmigration, or March 31, 2020. The costs associated with care were determined across 3 phases: the year before the diagnosis of GCA, the year after, and ongoing costs thereafter in 2021 Canadian dollars (CAD). RESULTS: The cohort consisted of 6730 cases of GCA and 40,380 matched non-GCA comparators. The average age was 77 (IQR 72-82) years and 68.2% were female. A diagnosis of GCA was associated with an increased cost of CAD $6619.4 (95% CI 5964.9-7274.0) per patient during the 1-year prediagnostic period, $12,150.3 (95% CI 11,233.1-13,067.6) per patient in the 1-year postdiagnostic phase, and $20,886.2 (95% CI 17,195.2-24,577.2) per patient during ongoing care for year 3 onward. Increased costs were driven by inpatient hospitalizations, physician services, hospital outpatient clinic services, and emergency department visits. CONCLUSION: A diagnosis of GCA was associated with increased healthcare costs during all 3 phases of care. Given the substantial economic burden, strategies to reduce the healthcare utilization and costs associated with GCA are warranted.

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.

Teaching NeuroImage: Unilateral Primary Angiitis of the CNS.

A 48-year-old woman was referred with an 18-year history of focal-onset seizures. She also reported years-long slowly progressive right-sided weakness that was corroborated on examination. Repeated brain MRIs over 15 years showed multifocal left hemispheric T2 fluid-attenuated inversion recovery-hyperintense lesions with patchy enhancement and microhemorrhages, no diffusion restriction, and a left cerebellar infarct (Figure 1, A-F). Only 2 nonspecific white matter lesions were seen contralaterally, indicating largely unihemispheric disease. Differential diagnosis included unilateral primary angiitis of the CNS (PACNS), Rasmussen encephalitis, and myelin oligodendrocyte glycoprotein antibody-associated disease.1 Serum and CSF testing for autoimmune, infectious, and malignant etiologies and whole-body fluorodeoxyglucose-PET, whole-exome genetic sequencing, and MR vessel-wall imaging were nondiagnostic. Brain biopsy revealed vasculitis (Figure 2, A-F), and the patient was diagnosed with unilateral PACNS. Treatment with mycophenolate mofetil has been initiated. Unilateral PACNS is a rare unihemispheric disease characterized by an indolent course and seizures, recognition of which is critical to accurate diagnosis.1,2.

The effect of HLA-DRB1*04:01 on a mouse model of atherosclerosis.

Objectives: HLA-DRB1 is associated with an increased risk of cardiovascular disease in patients with rheumatoid arthritis (RA). This study aimed to determine the effect of HLA-DRB1 on atherosclerotic cardiovascular disease (ASCVD) using a novel mouse model. Methods: Mice transgenic for HLA-DRB1*04:01 (DR4tg) were crossed with low density lipoprotein receptor knock-out (Ldlr-/-) mice that develop atherosclerosis when fed a high fat, high cholesterol (HFHC) diet. Male and female DR4tgLdlr-/- (n = 48), Ldlr-/- (n = 24), DR4tg (n = 24), and C57Bl/6 (B6) background (n = 24) mice were fed HFHC or regular diet (RD) for 12 weeks. Blood samples were analyzed for serum lipoproteins using a colorimetric assay. C-reactive protein (CRP) and oxidized LDL (OxLDL) were measured using ELISA. Atherosclerosis in the aortas was assessed using the lipid stain, Sudan IV. The presence of citrulline in atherosclerotic plaque was determined by immunohistochemistry. Results: Sera low-density lipoprotein cholesterol (LDL-C) levels were higher in HFHC-fed Ldlr-/- versus DR4tgLdlr-/--; p = 0.0056, but the aortic plaque burden and degree of citrullination in the plaque were similar for these two strains. The ratio of pro-atherogenic OxLDL to LDL levels was higher in DR4tgLdlr-/- than Ldlr-/-mice; p = 0.0017. All mice had an increase in CRP when fed a HFHC diet, most pronounced for DR4tgLdlr-/-; p = 0.0009. There were no significant sex differences for DR4tgLdlr-/- mice; however, male Ldlr-/- mice had worse atherosclerosis. B6 and DR4tg mice did not have significant elevations in serum cholesterol levels and did not develop atherosclerosis. Conclusions: Expression of HLA-DRB1 resulted in an elevation of OxLDL and a reduction in the male bias for atherosclerosis, mimicking what is observed in RA.

Outcomes in ANCA-associated vasculitis patients with end-stage kidney disease on renal replacement therapy-A meta-analysis.

BACKGROUND: End-stage kidney disease (ESKD) is associated with poor prognosis in patients with anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study summarizes the existing evidence regarding outcomes in AAV patients with ESKD on renal replacement therapy. METHODS: Searches of the MEDLINE and Embase databases were performed from inception until December 2021. Any study reporting outcomes after ESKD in patients with AAV on haemodialysis or peritoneal dialysis was included. The mortality rate per 100 person-years (100 py) calculated with a random-effects meta-analysis model was the primary outcome. Rates of infections and relapses were secondary outcomes. RESULTS: 2470 citations were found; 22 studies of 952 adult patients with over 3600 person-years of follow-up were included. The pooled mortality rate was 10.90 per 100 py (95% CI: 7.11 - 14.68, I2 = 90.8%). The pooled 1-year survival was 80.9% (95% CI: 75.6 - 86.1%, I2 = 86.1%) while the pooled 5-year survival was 61.0% (95% CI: 46.0 - 76.0%, I2 = 0.0%). The pooled severe infection rate was 66.57 per 100 py (95% CI: 13.64 - 119.50, I2 = 99.6%). The pooled relapse rate was 6.22 per 100 py (95% CI: 4.64 - 7.80, I2 = 46.6%). Only 1 paediatric study met the inclusion criteria and reported a mortality rate of 11.7 ± 1.9 deaths per 100 py (95% CI: 0.23 - 23.20) amongst 9 patients. CONCLUSIONS: Patients with AAV and ESKD have a lower risk of relapse, but higher infection and mortality rates. More prospective research exploring the role of immunosuppression after ESKD is needed.

Restoring Balance: Immune Tolerance in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic musculoskeletal disease where immune dysregulation and subsequent autoimmunity induce significant synovial joint inflammation and damage, causing pain and disability. RA disease onset is promoted through multifaceted interactions between genetic and environmental risk factors. However, the mechanisms of disease onset are not completely understood and disease-specific treatments are yet to be developed. Current RA treatments include nonspecific disease-modifying antirheumatic drugs (DMARDs) that suppress destructive immune responses and prevent damage. However, DMARDs are not curative, and relapses are common, necessitating lifelong therapy in most patients. Additionally, DMARD-induced systemic immunosuppression increases the risk of serious infections and malignancies. Herein, we review the current understanding of RA disease pathogenesis, with a focus on T and B cell immune tolerance breakdown, and discuss the development of antigen-specific RA therapeutics that aim to restore a state of immune tolerance, with the potential for disease prevention and reduction of treatment-associated adverse effects.

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.

Presence of Autoantibodies in Males and Females With Rheumatoid Arthritis: A Systematic Review and Metaanalysis.

OBJECTIVE: Rheumatoid arthritis (RA) is more common in females, and although the cause of RA is unknown, it is characterized by the production of autoantibodies. The aims of this study were to determine whether RA-associated autoantibodies are more often found in females than males and to identify factors that influence the relationship between sex and seropositivity. METHODS: Databases were searched and studies of RA (N ≥ 100) were included if they reported proportion of seropositive patients with RA by sex. Metaanalyses and metaregression were conducted using the random-effects model. Covariates regressed were smoking, age, BMI, Health Assessment Questionnaire-Disability Index (HAQ-DI), and the Disease Activity Score in 28 joints (DAS28). RESULTS: Eighty-four studies with a total of 141,381 subjects with rheumatoid factor (RF) seropositivity and 95,749 subjects with anticitrullinated protein antibody (ACPA) seropositivity met inclusion criteria. The mean age of participants ranged from 37 to 68 years and the proportion of female subjects ranged from 9% to 92%. Results indicated that females were less likely than males to be seropositive: odds ratio (OR) 0.84 [95% CI 0.77-0.91] for RF and OR 0.88 [95% CI 0.81-0.95] for ACPA. BMI, smoking, mean age, DAS28, and HAQ-DI did not affect the relationship between sex and seropositivity. CONCLUSION: Although studies report that females have higher RA disease activity than males and that seropositivity predicts worse outcomes, females were less likely to be seropositive than males.

Variations in Takayasu arteritis characteristics in a cohort of patients with different racial backgrounds.

OBJECTIVES: We aimed to describe differences in disease characteristics and outcomes in Takayasu arteritis (TA) patients with different racial backgrounds. METHODS: This was a retrospective cohort study consisting of TA patients seen at specialty vasculitis clinics from five academic hospitals across Canada. Disease features, treatments and outcomes were compared between White and non-White patients. RESULTS: The cohort included 113 patients, of which 51 were White. Over 50% of the non-White patients were Asian. Compared to non-White patients, White patients had higher CRP and ESR at diagnosis (33.6 mg/l versus 9.4 mg/l, p = 0.033; and 51 mm/h versus 24 mm/h, p = 0.047; respectively), and were less likely to have baseline cardiovascular comorbidities including dyslipidemia (11.8% versus 29%, p = 0.037). There were no significant differences between racial groups for other disease characteristics or outcomes. CONCLUSION: Patient race did not appear to play a significant role in determining disease characteristics and outcomes when comparing TA patients from various racial backgrounds living in the same country.

Increased Mortality for Individuals With Giant Cell Arteritis: A Population-Based Study.

OBJECTIVE: Reports of mortality risks among individuals with giant cell arteritis (GCA) have been mixed. Our aim was to evaluate all-cause mortality among individuals with GCA relative to the general population over time. METHODS: We performed a population-based study in Ontario, Canada using health administrative data. We studied a cohort of 22,677 GCA patients ages ≥50 years that was identified using a validated case definition (with 81% positive predictive value, 100% specificity). General population comparators were residents ages ≥50 years without GCA. Deaths were ascertained from vital statistics. Annual crude, age- and sex-standardized, and age- and sex-specific all-cause mortality rates were determined for individuals with and without GCA between 2000 and 2018. Standardized mortality ratios (SMRs) were estimated. RESULTS: Age- and sex-standardized mortality rates were significantly higher for GCA patients than comparators, and trending to increase over time with 50.0 deaths per 1,000 GCA patients in 2000 (95% confidence interval [95% CI] 34.0-71.1) and 57.6 deaths per 1,000 GCA patients in 2018 (95% CI 50.8-65.2), whereas mortality rates in the general population significantly declined over time. The annual SMRs for GCA patients generally increased over time, with the lowest SMR occurring in 2002 (1.22 [95% CI 1.03-1.40]) and the highest in 2018 (1.92 [95% CI 1.81-2.03]). GCA mortality rates were more elevated for male patients than female patients. CONCLUSION: Over a 19-year period, mortality rates were increased among GCA patients relative to the general population, and more premature deaths were occurring in younger age groups. The relative excess mortality for GCA patients did not improve over time.

Risk factors for hypertension in rheumatoid arthritis patients-A systematic review.

INTRODUCTION: Rheumatoid arthritis is frequently associated with hypertension, which has been shown to increase the risk of cardiovascular disease in these patients. The aim of this systematic review was to explore demographic, behavioural or clinical factors including medication use, associated with incident hypertension in rheumatoid arthritis. METHODS: MEDLINE and Scopus were searched for eligible studies that longitudinally investigated incident hypertension or changes in blood pressure (BP) in rheumatoid arthritis patients. Publications were screened by two reviewers according to predetermined inclusion and exclusion criteria. The quality of included studies was assessed via the Newcastle Ottawa Scale and Cochrane Risk of Bias Tool. RESULTS: Fourteen studies were deemed eligible and included in this review. The proportion of female subjects ranged from 12 to 87% and the mean age ranged from 47 to 61 years. Regular exercise was associated with a decrease in systolic BP, p = 0.021. Methotrexate was associated with decreased risk of hypertension in two studies. LEF was associated with increased BP in two studies. COX-2 inhibitors were associated with systolic BP and diastolic BP variability (p = 0.009, 0.039, respectively) in one study. Prednisone was found to increase BP and risk of hypertension in three studies. The risk of hypertension in patients taking biologic disease modifying anti-rheumatic drugs (DMARDs) is unclear as some studies report increased BP while others report no difference for biologic compared to conventional DMARDs. CONCLUSION: Despite limited longitudinal studies exploring this topic, methotrexate and exercise were shown to protect against risk of hypertension in RA patients, while prednisone and COX-2 inhibitors may increase risk of hypertension.

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.

Efficacy of leflunomide in the treatment of vasculitis.

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

Primary CNS vasculitis: A systematic review on clinical characteristics associated with abnormal biopsy and angiography.

BACKGROUND: Primary Central Nervous System Vasculitis (PCNSV) remains a diagnostic challenge due to its variable and non-specific clinical manifestations. In part, the clinical heterogeneity of PCNSV may be a consequence of the modalities used for diagnosis; accordingly, there may be different subtypes of PCNSV based on whether the diagnosis was attained by biopsy or cerebral angiography. OBJECTIVE: To examine the frequency of symptoms, laboratory, and radiological features associated with PCNSV, and to identify distinct clinical features between biopsy and angiography defined PCNSV. METHODS: We conducted a systematic review of articles published in the English language from 1991 to 2019 that met all diagnostic criteria of PCNSV. RESULTS: We identified 55 studies, reporting on 907 PCNSV cases. Median age was 45 (IQR 50-36), and 53% were women. Biopsy compared to angiography defined PCNSV had a higher percentage of cognitive impairment, and seizures on initial presentation, and were more likely to have a subacute or progressive onset, abnormal CSF profile, small vessel involvement on angiography, and tumor-like lesions and gadolinium enhancement on MRI. Angiography defined PCNSV were more likely to have an acute onset, focal weakness and visual impairment on initial presentation, medium vessel involvement on angiography, and infarcts on MRI. Brain biopsy was diagnostic of PCNSV in 71% of cases, and demonstrated an alternative diagnosis in 37% of cases, the most common being infection (19%) and lymphoproliferative disease (18%). CONCLUSIONS: This study provides further evidence that there are distinct clinical features between biopsy and angiography defined PCNSV, which may aid in selecting patients for appropriate invasive tests.

Efferocytic Defects in Early Atherosclerosis Are Driven by GATA2 Overexpression in Macrophages.

The loss of efferocytosis-the phagocytic clearance of apoptotic cells-is an initiating event in atherosclerotic plaque formation. While the loss of macrophage efferocytosis is a prerequisite for advanced plaque formation, the transcriptional and cellular events in the pre-lesion site that drive these defects are poorly defined. Transcriptomic analysis of macrophages recovered from early-stage human atherosclerotic lesions identified a 50-fold increase in the expression of GATA2, a transcription factor whose expression is normally restricted to the hematopoietic compartment. GATA2 overexpression in vitro recapitulated many of the functional defects reported in patient macrophages, including deficits at multiple stages in the efferocytic process. These findings included defects in the uptake of apoptotic cells, efferosome maturation, and in phagolysosome function. These efferocytic defects were a product of GATA2-driven alterations in the expression of key regulatory proteins, including Src-family kinases, Rab7 and components of both the vacuolar ATPase and NADPH oxidase complexes. In summary, these data identify a mechanism by which efferocytic capacity is lost in the early stages of plaque formation, thus setting the stage for the accumulation of uncleared apoptotic cells that comprise the bulk of atherosclerotic plaques.

The effect of sex on immune responses to a homocitrullinated peptide in the DR4-transgenic mouse model of Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) is more common and severe in women compared to men. Both women and men with RA express autoantibodies to post-translationally modified antigens, including citrullinated and homocitrullinated proteins or peptides. These autoantibodies are strongly linked with the HLA-DR4 gene. The objective of this study was to determine sex differences in immune responses to homocitrullinated antigens. We used a humanized animal model of RA, DR4-transgenic mice and immunized them with a homocitrullinated peptide called HomoCitJED. Immune responses in these mice were measured for splenocyte proliferation by tritiated thymidine incorporation, serum autoantibody production by ELISA and cytokine levels by multiplex. We found that T cell and antibody responses to homocitrullinated antigens were similar in male and female mice. However, we found sex differences in serum cytokine profiles with female mice having higher ratio of IL-1α to IL-5, suggesting imbalances in immune regulation. This is the first study to report that immune responses to homocitrullinated antigens can be differentiated by sex.