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.

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.

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.

Incidence and prevalence of giant cell arteritis in Ontario, Canada.

OBJECTIVE: To estimate trends in the incidence and prevalence of GCA over time in Canada. METHODS: We performed a population-based study of Ontario health administrative data using validated case definitions for GCA. Among Ontario residents ≥50 years of age we estimated the annual incidence and prevalence rates between 2000 and 2018. We performed sensitivity analyses using alternative validated case definitions to provide comparative estimates. RESULTS: Between 2000 and 2018 there was a relatively stable incidence over time with 25 new cases per 100 000 people >50 years of age. Age-standardized incidence rates were significantly higher among females than males [31 cases (95% CI: 29, 34) vs 15 cases (95% CI: 13, 18) per 100 000 in 2000]. Trends in age-standardized incidence rates were stable among females but increased among males over time. Incidence rates were highest among those ≥70 years of age. Standardized prevalence rates increased from 125 (95% CI 121, 129) to 235 (95% CI 231, 239) cases per 100 000 from 2000 to 2018. The age-standardized rates among males rose from 76 (95% CI 72, 81) cases in 2000 to 156 (95% CI 151, 161) cases per 100 000 population in 2018. Between 2000 and 2018, the age-standardized rates among females similarly increased over time, from 167 (95% CI 161, 173) to 304 (95% CI 297, 310) cases per 100 000 population. CONCLUSION: The incidence and prevalence of GCA in Ontario is similar to that reported in the USA and northern Europe and considerably higher than that reported for southern Europe and non-European populations.

Immune responses to peptides containing homocitrulline or citrulline in the DR4-transgenic mouse model of rheumatoid arthritis.

Antibodies to proteins/peptides containing citrulline are hallmarks of Rheumatoid Arthritis (RA). These antibodies are strongly associated with the expression of the Shared Epitope (SE). RA patients also generate antibodies to homocitrulline-containing proteins/peptides (also referred to as anti-carbamylated protein antibodies (Anti-CarP)). This study was undertaken to investigate the relationship between homocitrulline and citrulline immune responses using an established mouse model of RA: DR4-transgenic (DR4tg) mice that express the human SE. C57BL/6 (B6) and DR4tg (on a B6 background) mice were immunized subcutaneously with a homocitrullinated peptide (HomoCitJED). Splenic T cell proliferation was evaluated by 3H-thymidine incorporation assay. Antibodies to homocitrullinated and citrullinated antigens were screened by enzyme-linked immunosorbent assay (ELISA). Antibody cross-reactivity was examined by inhibition with HomoCitJED and its citrullinated counterpart peptide, CitJED (the number of homocitrullines in HomoCitJED is equal to the number of citrullines in CitJED). HomoCitJED-immunized DR4tg mice developed early T and B cell responses to HomoCitJED and late responses to CitJED. These mice also developed anti-CCP2 antibodies. In some mice, antibodies to HomoCitJED were also reactive to CitJED. B6 mice immunized with HomoCitJED developed late T and B cell responses to HomoCitJED, but did not generate responses to citrullinated antigens. Unlike DR4tg mice, anti-HomoCitJED antibodies from B6 mice did not react to CitJED. In conclusion, DR4tg mice immunized with HomoCitJED developed immune responses to CitJED, indicating cross-reactivity. CitJED immune responses were dependent on the SE. HomoCitJED responses occurred in the absence of the SE (B6 mice); however, they developed earlier in DR4tg SE-expressing mice.

Rate of infections in severe necrotising vasculitis patients treated with cyclophosphamide induction therapy: a meta-analysis.

OBJECTIVES: Infections are common complications of necrotising vasculitis. We aimed to determine the rate of infections in patients with severe necrotising vasculitis treated with cyclophosphamide (CYC) combined with high dose glucocorticoids (GC). METHODS: Searches of MEDLINE, Embase and Cochrane Library databases (1990 to May 2016) were performed. Inclusion criteria were randomised controlled trials of intravenous (IV) or oral (PO) CYC induction therapy for granulomatosis and polyangiitis (GPA), microscopic poyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and systemic polyarteritis nodosa (PAN). Pooled rates of infectious complications were determined by random effects meta-analyses. Meta-regression was performed to identify variables associated with severe infection. RESULTS: Search results yielded 2636 references; 14 studies with a total of 888 subjects met inclusion criteria. The mean age of participants ranged from 39 to 75 years. Mean cumulative doses of CYC were 2.7 to 50.4 g and of GC were 6 to 13 g. The pooled rate per year per gram of CYC of severe infection was 2.2% (95% CI: 0.9, 5.3%, I2 = 58.7%), any infection was 5.6% (95% CI: 1.8, 16.7%, I2 = 79.1%) and infection-related deaths was 1.7% (95% CI: 0.8, 3.9%, I2 = 0%). By meta-regression, age, creatinine and cumulative GC dose were not significantly associated with the rate of severe infections. CONCLUSIONS: The rate of severe infections and infection related mortality in patients with severe necrotising vasculitis treated with CYC + GC induction therapy is high.

Impact of vasculitis on employment and income.

OBJECTIVES: Work disability associated with rheumatic diseases accounts for a substantial financial burden. However, few studies have investigated disability among patients with vasculitis. The purpose of this study was to examine the impact of vasculitis on patient employment and income. METHODS: Patients enrolled in the Vasculitis Clinical Research Consortium (VCRC) Patient Contact Registry, living in the USA or Canada, and followed for >1 year post-diagnosis, participated in an online survey-based study. RESULTS: 421 patients with different systemic vasculitides completed the survey between June and December 2015. The majority of patients were female (70%) and Caucasian (90%); granulomatosis with polyangiitis (GPA) was the most common type of vasculitis (49%), and the mean age at the time of diagnosis was 53 years. At the time of their diagnosis of vasculitis 76% of patients were working a paid job, 6% were retired, and 2% were on disability. Over the course of their disease, and with a mean follow-up of 8±6.4 years post-diagnosis, 26% of participants became permanently work disabled or had to retire early due to vasculitis. Variables that were independently associated with permanent work disability included work physicality, less supportive work environment, and symptoms such as respiratory disease, pain, and cognitive impairment. Overall, patients reported a mean productivity loss of 6.9% and income was reduced by a median of 45%. CONCLUSIONS: Due to their vasculitis, patients frequently suffer substantial limitations in work and productivity, and personal income loss.

The effect of rheumatoid arthritis-associated autoantibodies on the incidence of cardiovascular events in a large inception cohort of early inflammatory arthritis.

Objective: . RA is associated with an increased risk of cardiovascular events (CVEs). The objective was to estimate independent effects of RA autoantibodies on the incident CVEs in patients with early RA. Methods: Patients were enrolled in the Canadian Early Inflammatory Arthritis Cohort, a prospective multicentre inception cohort. Incident CVEs, including acute coronary syndromes and cerebrovascular events, were self-reported by the patient and partially validated by medical chart review. Seropositive status was defined as either RF or ACPA positive. Multivariable Cox proportional hazards survival analysis was used to estimate the effects of seropositive status on incident CVEs, controlling for RA clinical variables and traditional cardiovascular risk factors. Results: . A total of 2626 patients were included: the mean symptom duration at diagnosis was 6.3 months ( s . d . 4.6), the mean age was 53 years ( s . d . 15), 72% were female and 86% met classification criteria for RA. Forty-six incident CVEs occurred over 6483 person-years [incidence rate 7.1/1000 person-years (95% confidence interval 5.3, 9.4)]. The CVE rate did not differ in seropositive vs seronegative subjects and seropositivity was not associated with incident CVEs in multivariable Cox regression models. Baseline covariates independently associated with incident CVEs were older age, a history of hypertension and a longer duration of RA symptoms prior to diagnosis. Conclusion: The rate of CVEs early in the course of inflammatory arthritis was low; however, delays in the diagnosis of arthritis increased the rate of CVEs. Hypertension was the strongest independent risk factor for CVEs. Results support early aggressive management of RA disease activity and co-morbidities to prevent severe complications.

Anti-homocitrullinated protein antibody isotype usage in rheumatoid arthritis and their unaffected first-degree relatives.

OBJECTIVES: The majority of rheumatoid arthritis (RA) patients express anti-citrullinated protein antibodies (ACPA). Unaffected first-degree relatives of RA patients (FDR) also express ACPA, commonly of the IgA isotype. IgG anti-homocitrullinated/carbamylated protein antibodies (AHCPA) have been detected in both RA and FDR. It is unknown whether other isotypes are expressed. We aim to investigate the AHCPA isotype profile in unaffected FDR of RA patients. METHODS: The enrolled subjects were examined by a rheumatologist. FDR and healthy controls (HC) were excluded if they had swollen joints. Serum AHCPA targeting homocitrullinated fibrinogen was determined using enzyme linked immunoabsorbant assay (ELISA). FDR were genotyped for HLA-DR4 alleles encoding the shared epitope (SE). RESULTS: 125 RA (35 probands), 61 FDR and 40 HC were included. 20% of FDR expressed IgG AHCPA, compared to 30% in RA patients and 5% in HC (p=0.0010 for RA vs. HC). Levels of IgG AHCPA in FDR were similar to RA. FDR rarely expressed IgM (8%) and did not express IgA AHCPA. 20% of RA and 13% of HC subjects expressed IgM, but very few expressed IgA AHCPA (<7% in both groups). AHCPA expression in FDR was not significantly associated with joint symptoms, smoking or SE. CONCLUSIONS: IgG AHCPA is the most commonly expressed isotype in RA and FDR. The significance of IgG AHCPA in FDR is unclear as it was not associated with joint symptoms or other risk factors for RA. Longitudinal studies are needed to determine whether AHCPA is meaningful in populations at risk for RA.

Assessment of work limitations and disability in systemic vasculitis.

OBJECTIVES: Despite advances in the management of systemic vasculitis (SV), direct consequences of the disease, leading to impairments in physical and mental function can cause disability. The objective of this study was to assess work limitations in SV. METHODS: SV patients were recruited from a tertiary care clinic. Work disabled (WD) was defined as not working, early retirement, or reduced hours at work. Participants who were working at the time of enrolment completed the Work Limitations Questionnaire (WLQ). Other work-related measures were self-reported by questionnaire. Disease outcome measures (Vasculitis Damage Index (VDI), Health Assessment Questionnaire-Disability Index (HAQ) and pain visual analogue score (VAS)) were obtained at time of WLQ. RESULTS: 103 participants were enrolled with mean age 58 (SD17), 60% females, 48% with anti-neutrophilic cytoplasmic antibody-associated vasculitis (AAV), 26% with large vessel vasculitis (LVV) and 26% with other types of SV. 22 (21%) were WD secondary to SV, 29 (28%) were working and 52 (51%) subjects were not working for reasons other than SV. SV-related WD subjects were more likely to have a lower level of education (p=0.003) than non-WD subjects. The VDI was higher in SV-related WD vs. non-WD subjects: 1.9 (SD 2.7) vs. 2.9 (SD 1.4); p=0.015. 38 subjects were working in some capacity and completed the WLQ; their productivity loss was 8.2% and this was highly correlated with HAQ and pain VAS (rho=0.585 and rho=0.458, respectively). CONCLUSIONS: SV-related work disability occurred in 21% and was associated with lower levels of education, higher disease severity and worse functional outcomes.

Anti-citrullinated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients.

OBJECTIVE: First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients sharing genetic and environmental risk factors for RA may represent a pre-RA state. Since anti-cyclic citrullinated protein/peptide antibodies (ACPAs) appear years before the onset of RA, the purpose of this study was to determine the prevalence of various ACPAs in FDRs of RA patients. METHODS: We evaluated 88 RA patients, 50 unaffected FDRs, and 20 healthy control subjects. Six different types of ACPAs were determined by enzyme-linked immunosorbent assay. Joint and periodontal disease symptoms were self-reported. Patients and FDRs were HLA typed for the shared epitope (SE) and the RA-protective alleles HLA-DRB*1301/1302. RESULTS: FDRs had a high prevalence of ACPAs (48%) as compared to controls (10%). Prevalence of the SE and smoking in FDRs was also high (62% and 49%, respectively). Of all of the ACPAs in the FDRs, 13 of 32 (41%) were of the IgA isotype. The most commonly expressed IgG ACPA targeted citrullinated vimentin, occurring in 20% of FDRs. The FDRs had an average of 1 type of ACPA, whereas the RA patients expressed a median of 5 different ACPAs. The only FDR to later develop RA expressed 4 different ACPAs. Joint and periodontal disease symptoms in the FDRs were significantly associated with smoking (OR 5.714 [95% confidence interval (95% CI) 1.151-28.3] and OR 12.25 [95% CI 2.544-58.99], respectively), but not with ACPAs. CONCLUSION: The rate of ACPA positivity in unaffected FDRs of RA patients with a high prevalence of the SE and smoking was 48%, whereas ACPAs were rare in the healthy controls. ACPAs in the FDRs of RA patients was most commonly of the IgA isotype, but IgG ACPA targeting citrullinated vimentin was also frequently found.

Social persuasion in rheumatology: a randomized trial of testimonials on television in the rheumatology clinic waiting room to increase attendance for multidisciplinary education.

Multidisciplinary self-management programs are important in inflammatory arthritis as adjunctive treatment. Patients often have excuses as to why they do not attend these programs. The purpose of this study was to determine whether an intervention of televised testimonials from rheumatologists and allied health professionals increases attendance at a multidisciplinary education day for rheumatology patients seen in a large university hospital clinic. This was an RCT of intervention: playing televised interviews in the waiting room where rheumatology patients were seen versus no TV. There was a total of 6 months (3 months with and 3 without the televised interview playing). All eligible patients who attended the rheumatology outpatient clinic were then tracked to determine whether they attended a subsequent education day over the next 10 months. The sample size was calculated to have a 15% increase in attendance at the education days. There was a 20% increase in attendees at the multidisciplinary education days for patients who saw the televised testimonials. Sixty-three patients who viewed the testimonials (2.17% of 2,908) attended the education day compared to 39 who did not receive the intervention (1.80% of 2,168); however, the increase was not statistically significant (p = 0.36). Attendance of eligible patients increased using televised testimonials; however, the increase was not significant as the rates of attendance were still very low in both groups. Many eligible patients did not attend the program. Other interventions are necessary to encourage attendance in a multidisciplinary program.

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.

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.

Risk factors for prevalent and incident hypertension in rheumatoid arthritis: data from the Canadian Early Arthritis Cohort.

Objective: Hypertension (HTN) is a common comorbidity in RA. This study aimed to explore the prevalence and incidence of HTN and baseline factors associated with incident HTN in early RA (ERA). Methods: Data were from the Canadian Early Arthritis Cohort (CATCH), an inception cohort of ERA patients having <1 year of disease duration. HTN was determined by patient- or physician-reported diagnosis, the use of anti-hypertensives and/or blood pressure. Multivariable logistic regression was performed to determine baseline factors associated with prevalent and incident HTN in this population. Results: The study sample included 2052 ERA patients [mean age 55 years (s.d. 14), 71% female). The prevalence of HTN at study enrolment was 26% (23% in females and 34% in males). In both sexes, prevalent HTN was associated with older age, diabetes and hyperlipidaemia. HTN was associated with being overweight or high alcohol consumption in females. Of the RA patients who did not have HTN at enrolment, 24% (364/1518) developed HTN during the median follow-up period of 5 years (range 1-8). Baseline factors significantly associated with incident HTN were older age, being overweight, excess alcohol consumption and having hyperlipidaemia. Incident HTN was associated with high alcohol consumption in males and with hyperlipidaemia in females. RA-associated disease factors and treatments were not significantly associated with prevalent or incident HTN. Conclusions: Early RA patients had a high incidence of hypertension with the highest risk in older patients with traditional cardiovascular risk factors.

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.

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.