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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.

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.

Objective.Takayasu arteritis (TA) is a rare large-vessel vasculitis that puts patients at high risk of developing severe ischemic events (SIE). Outcomes for TA patients with SIE are poorly understood. We aim to describe the characteristics of TA patients experiencing SIE.Methods.All TA patients with at least 1 followup visit seen between 1988 and 2015 were included from 3 academic centers in Ontario, Canada. Diagnosis was based on American College of Rheumatology criteria, physician opinion, and vascular imaging. SIE were defined as cerebrovascular accident (CVA), acute coronary syndrome (ACS), ischemic cardiomyopathy, ischemic blindness, and/or ischemic bowel or limb requiring surgery.Results.Of the 52 patients with TA included in the study, 51 (98%) were female and 22 (42%) were of European descent. The mean age was 31 (SD 12) at the time of diagnosis and the followup time was 6 years (SD 5). Fifteen (29%) experienced an SIE: 5 CVA, 5 ACS, 1 ischemic cardiomyopathy, and 4 limb ischemia. Thirteen out of 15 SIE (87%) occurred at or before diagnosis. Patients with SIE were more likely than those without SIE to be started on corticosteroids combined with immunosuppressants (p = 0.04) and antiplatelet agents (p = 0.004). Outcomes including disease activity and damage scores were similar between patients with and without SIE.Conclusion.SIE are common in patients with TA and occur early in the disease. With aggressive treatment, patients with SIE had a favorable prognosis.

Objective.Antibodies that target citrullinated protein/peptide (ACPA) and homocitrullinated/carbamylated protein/peptide (AHCPA) are associated with rheumatoid arthritis (RA). The relationship between ACPA and AHCPA remains unclear. We examined the expression and cross-reactivity of these antibodies using citrulline- and homocitrulline-containing synthetic peptides, CitJED and HomoCitJED, respectively, which have equal numbers of citrulline or homocitrulline residues on the same peptide backbone.Methods.Serum from healthy subjects (n = 51) and patients with RA (n = 137), systemic lupus erythematosus (SLE; n = 37), and psoriatic arthritis (PsA; n = 37) were screened for IgG anti-CitJED and anti-HomoCitJED antibodies by ELISA. Cross-reactivity of these antibodies was examined by inhibition with various concentrations of CitJED and HomoCitJED.Results.Out of 137 patients with RA, antibodies to CitJED and HomoCitJED were detected in 69 (50%) and 78 (57%), respectively. Anti-CitJED and HomoCitJED antibodies were 77% concordant and their levels were strongly correlated [Spearman correlation coefficient (rs) = 0.6676]. Sera from 25/27 patients (93%) with RA were inhibited by both CitJED and HomoCitJED with equal or higher affinity for the cognate (homologous) peptide.Conclusion.Antibodies to CitJED and HomoCitJED frequently occurred in RA, but were not found in SLE or PsA, suggesting that these antibodies are specific to RA. Cross-reactivity between anti-HomoCitJED and anti-CitJED antibodies suggests that ACPA and AHCPA are derived from the same B cell population and both may contribute to the pathogenesis of RA.

Objective.Involvement of intracranial arteries in giant cell arteritis (GCA) is rare. We describe the neurologic complications of intracranial GCA (IC GCA) and available treatment options.Methods.We describe 5 IC GCA cases from 3 Canadian vasculitis centers and review the literature. We searched English-language publications reporting similar patients meeting American College of Rheumatology (ACR) criteria for GCA and having intracranial artery involvement diagnosed by autopsy, magnetic resonance angiography, computed tomography angiography, or conventional angiography.Results.All 5 cases of IC GCA met ACR criteria for GCA; 4 cases had a temporal artery biopsy that was consistent with GCA. All cases experienced cerebrovascular accident(s). Arteritis involved the following vessels: intracranial internal carotid (n = 1), vertebrobasilar arteries (n = 1), or both (n = 3). All cases received aspirin and oral prednisone (preceded by intravenous methylprednisone in 3 cases), combined with an immunosuppressant in 4 cases. All patients survived; 2 had complete neurological recovery, 3 had residual neurologic sequelae. The literature review included 42 cases from 28 publications. The clinical features of the reported cases were similar to those of our 5 cases. However, mortality was 100% in untreated cases (n = 2), 58% in those treated with corticosteroid alone (n = 31), and 40% in those treated with corticosteroid and an immunosuppressant (n = 10).Conclusion.IC GCA appears to be associated with neurologic complications and mortality. In some cases corticosteroid alone was not sufficient to prevent neurologic complications. The role of additional immunosuppressive agents needs further investigation.

To the Editor: Giant cell arteritis (GCA) is a large-vessel vasculitis with a predilection for cranial arteries. Based on retrospective studies, GCA is associated with an increased prevalence of traditional cardiovascular (CV) risk factors and CV events, including myocardial infarction and stroke1,2,3,4,5. However, studies regarding management of CV disease (CVD) in GCA are lacking. We report here on CV risk factors and CV complications, and describe physician adherence to guidelines for prevention of CV events in a Canadian population with GCA. We studied a single-center retrospective cohort of patients with GCA assessed at the St. Joseph’s Health Care rheumatology clinic in London, Ontario, by rheumatologists between 2006 and 2015. Patients were identified by diagnostic codes, met American College of Rheumatology classification criteria for GCA, and had at least 1 followup visit. CV complication (CVC) was defined as a composite outcome: any acute coronary syndrome (ACS), stroke, transient ischemic event, or severe peripheral vascular disease (PVD) requiring surgical intervention. Ethics approval was given by … Address correspondence to Dr. L.J. Barra, St. Joseph’s Health Care, 268 Grosvenor St., Room D2-160, London, Ontario N6A 4V2, Canada. E-mail: lillian.barra{at}sjhc.london.on.ca

Objective.In inflammatory arthritis, rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are believed to be associated with more severe clinical outcomes. Our objective was to determine whether ACPA and RF remain stable in early inflammatory arthritis and whether their trajectories over time or baseline levels predicted clinical outcomes.Methods.The study population consisted of patients enrolled in the Canadian Early Arthritis Cohort Study with baseline and at least 12-month followup values of RF and ACPA. Primary outcomes were Disease Activity Score (DAS) remission and the presence of erosions at 12 and 24 months. Other objectives included swollen joint count, Health Assessment Questionnaire score, and DAS.Results.At baseline, 225/342 (66%) patients were ACPA-positive and 334/520 (64%) were RF-positive. At 24 months, 15/181 (8%) ACPA-positive patients became negative. A larger number of patients changed from ACPA-negative to positive: 13/123 (11%). For RF, fluctuations were more common: 67/240 (28%) reverted from positive to negative and 21/136 (18%) converted from negative to positive. RF and ACPA fluctuations did not predict disease outcomes. Patients who remained ACPA-positive throughout followup were more likely to have erosive disease (OR 3.86, 95% CI 1.68, 8.92).Conclusion.RF and ACPA have the potential to revert and convert during the early course of disease. Fluctuations in RF and ACPA were not associated with clinical outcomes.

Objective.The Canadian Vasculitis research network (CanVasc) is composed of physicians from different medical specialties and researchers with expertise in vasculitis. One of its aims is to develop recommendations for the diagnosis and management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada.Methods.Diagnostic and therapeutic questions were developed based on the results of a national needs assessment survey. A systematic review of existing non-Canadian recommendations and guidelines for the diagnosis and management of AAV and studies of AAV published after the 2009 European League Against Rheumatism/European Vasculitis Society recommendations (publication date: January 2009) until November 2014 was performed in the Medline database, Cochrane library, and main vasculitis conference proceedings. Quality of supporting evidence for each therapeutic recommendation was graded. The full working group as well as additional reviewers, including patients, reviewed the developed therapeutic recommendations and nontherapeutic statements using a modified 2-step Delphi technique and through discussion to reach consensus.Results.Nineteen recommendations and 17 statements addressing general AAV diagnosis and management were developed, as well as appendices for practical use, for rheumatologists, nephrologists, respirologists, general internists, and all other healthcare professionals more occasionally involved in the management of patients with AAV in community and academic practice settings.Conclusion.These recommendations were developed based on a synthesis of existing international guidelines, other published supporting evidence, and expert consensus considering the Canadian healthcare context, with the intention of promoting best practices and improving healthcare delivery for patients with AAV.

Objective.Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are believed to be associated with more severe rheumatoid arthritis; however, studies in early inflammatory arthritis (EIA) have yielded conflicting results. Our study determined the prognosis of baseline ACPA-negative and RF-negative patients.Methods.Patients enrolled in the Canadian Early Arthritis Cohort had IgM RF and IgG anticyclic citrullinated peptide antibodies 2 (anti-CCP2) measured at baseline. Remission was defined as a Disease Activity Score of 28 joints (DAS28) < 2.6 using logistic regression accounting for confounders at 12-month and 24-month followup.Results.Of the 841 patients, 216 (26%) were negative for both RF and anti-CCP2. Compared to seropositive subjects, seronegative subjects were older (57 ± 15 vs 51 ± 14 yrs), more males proportionately (31% vs 23%), and had shorter length of symptoms (166 ± 87 vs 192 ± 98 days), and at baseline had higher mean swollen joint count (SJC; 8.8 ± 6.8 vs 6.5 ± 5.6), DAS28 (5.0 ± 1.6 vs 4.8 ± 1.5), and erosive disease (32% vs 24%, p < 0.05). Treatment was similar between the 2 groups. At 24-month followup, seronegative compared to seropositive subjects had greater mean change (Δ ± SD) in disease activity measures: ΔSJC counts (−6.9 ± 7.0 vs −5.1 ± 5.9), ΔDAS28 (−2.4 ± 2.0 vs −1.8 ± 1.8), and ΔC-reactive protein (−11.0 ± 17.9 vs −6.4 ± 17.5, p < 0.05). Accounting for confounders, antibody status was not significantly associated with remission. However, at 12-month followup, ACPA-positive subjects were independently more likely to have new erosive disease (OR 2.94, 95% CI 1.45–5.94).Conclusion.Although seronegative subjects with EIA have higher baseline DAS28 compared to seropositive subjects, they have a good response to treatment and are less likely to develop erosive disease during followup.

Objective.Various cytokines have been implicated in the pathogenesis of rheumatoid arthritis (RA) and it is known that elevations in multiple cytokines occur prior to disease onset. The objective of our study is to determine whether the cytokine profile in unaffected first-degree relatives (FDR) of patients with RA is distinct from healthy controls.Methods.The sera of patients with RA, their unaffected FDR, and healthy controls were measured for 27 cytokines using a luminex-based multiplexed immunoassay. Subjects were also tested for rheumatoid factor and 6 different anticitrullinated protein/peptide antibodies (ACPA). Discriminant analysis was performed to define the cytokine profile of the 3 study groups.Results.Fourteen patients with RA, 37 unaffected FDR, and 27 healthy controls were enrolled. All patients with RA and 49% of FDR were ACPA-positive. Patients with RA had elevated levels of inflammatory cytokines compared to FDR and controls. Lower interleukin 13 (IL-13) levels were independently associated with RA. IL-4 was significantly lower in FDR compared to controls. Using discriminant analysis based on the levels of all cytokines measured, RA, FDR, and healthy controls could be distinguished with 91% accuracy. ACPA-positive subjects had higher levels of IL-9, but lower levels of IL-12p70 and macrophage inflammatory protein-1β. No individual cytokine was associated with ACPA-positivity in FDR, but the entire cytokine profile accurately distinguished ACPA-positive from ACPA-negative FDR.Conclusion.The cytokine profiles of patients with RA, healthy controls, unaffected ACPA-positive FDR, and ACPA-negative FDR appear to be distinct.

Objective.To determine the effectiveness and cost-effectiveness of anti-tumor necrosis factor (anti-TNF) medications in a real-world environment for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) using the Health Assessment Questionnaire (HAQ).Methods.We created a database of patients with RA, PsA, or AS treated with anti-TNF agents (etanercept, infliximab, or adalimumab) at a large outpatient rheumatology clinic. Patient characteristics, baseline HAQ prior to treatment, subsequent yearly HAQ, and reasons for termination were collected. The cost based on percentage of patients achieving ≥ 0.2 improvement in HAQ (minimal clinically important difference, MCID) was calculated using the 2008 direct cost (Cdn) of the medication.Results.Data were available on 297 patients (206 with RA, 57 PsA, 34 AS). The mean age was 55 years, with 12 years of disease, and the mean baseline HAQ (standard error, SE) was 1.37 (0.04). The changes in HAQ (SE) at Years 1, 2, and 3 were −0.31 (0.04), −0.24 (0.06), and −0.27 (0.07) for annual cost to achieve MCID of $41,636, $42,077, and $42,147, respectively. The number needed to treat (NNT) was 1.94 (RA), 1.88 (PsA), and 2.30 (AS). There were no statistical differences between the diseases studied.Conclusion.We obtained data on the effectiveness and cost-effectiveness of anti-TNF drugs using the HAQ score, which is known to be an excellent predictor of work disability, morbidity, and mortality. HAQ scores decreased with treatment and were sustained throughout the 3–5 years of followup. The NNT of approximately 2 seems favorable and was similar between diseases.