Anticitrullinated protein antibodies (ACPA) are relatively specific for rheumatoid arthritis (RA), and predate disease. The oral pathogen Porphyromonas gingivalis may play a role in breaking immune tolerance to citrullinated antigens. We studied a cohort of patients with RA and their relatives looking for associations between anti-P. gingivalis antibodies and ACPA.
Patients with RA (n = 82) and their relatives (n = 205) from a North American Native (NAN) population were studied, along with 47 NAN and 60 non-NAN controls. IgM and IgA rheumatoid factor (RF) were tested by nephelometry and ELISA. Second-generation anticyclic citrullinated peptide (anti-CCP2) isotypes and IgG anti-P. gingivalis lipopolysaccharides were tested by ELISA. HLA-DRB1 typing was performed by sequencing. Oral hygiene and smoking habits were assessed by questionnaires.
Autoantibody frequency in patients with RA and relatives: ACPA 91% vs 19%, respectively; IgM RF 82% vs 17%; IgA RF 48% vs 22%. Anti-P. gingivalis levels were higher in patients with RA compared to relatives and controls (p = 0.005) and higher in ACPA-positive patients with RA than in ACPA-negative patients with RA (p = 0.04) and relatives (p
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.
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.
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).
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.
The Canadian Early Arthritis Cohort (CATCH): patients with new-onset synovitis meeting the 2010 ACR/EULAR classification criteria but not the 1987 ACR classification criteria present with less severe disease activity.
Our objective was to describe characteristics of Canadian patients with early arthritis and examine differences between those fulfilling 1987 and 2010 rheumatoid arthritis (RA) classification criteria.
The Canadian Early Arthritis Cohort (CATCH) is a national, multicenter, observational, prospective cohort of patients with early inflammatory arthritis, receiving usual care, recruited since 2007. Inclusion criteria include age > 16 years; symptom duration 6-52 weeks; swelling of = 2 joints or = 1 metacarpophalangeal/proximal interphalangeal joint; and 1 of rheumatoid factor = 20 IU, positive anticitrullinated protein antibodies (ACPA), morning stiffness = 45 min, response to nonsteroidal antiinflammatory drug, or positive metatarsophalangeal joint squeeze test. Data from patients enrolled to March 15, 2011, were analyzed.
In total, 1450 patients met the eligibility criteria (1187 were followed). At baseline, mean age was 53 ± 15 years, symptom duration was 6.1 ± 3.2 months, Disease Activity Score (DAS28) was 4.9 ± 1.6, Health Assessment Questionnaire-Disability Index was 1.0 ± 0.7. Forty-one percent (n = 450) of patients had moderate (3.2 5.1) disease activity; 28% of those with baseline radiographs (n = 250/908) had radiographic evidence of erosions. ACPA status was available for 70% (n = 831) of patients; 55% (n = 453) tested positive. Sixty percent (n = 718) of patients were treated with methotrexate (MTX) initially. Of 612 patients without erosions, 63% and 83% fulfilled 1987 and 2010 RA classification criteria, respectively. Seventy-three percent (n = 166) of those who did not fulfill 1987 criteria were newly identified by the 2010 criteria. These patients had less severe disease and more were MTX-naive compared to those satisfying the 1987 criteria. Forty-seven percent of all patients achieved remission at 1 year.
Patients with early RA present with moderate high disease activity;
To determine the proportion of patients with early inflammatory arthritis in a Canadian cohort who are at high risk for a major osteoporotic fracture using the Fracture Risk Assessment Tool (FRAX(®)), and to determine if a care gap exists in high-risk patients.
FRAX was applied to 238 patients enrolled in the Canadian Early Arthritis Cohort (CATCH) study based on norms from the United States and the United Kingdom, without the use of bone mineral density measurements.
FRAX identified 5%-13% of patients at high risk for fracture, using a conservative analysis. Based on US norms, there was a significant correlation between increasing fracture risk groups and oral glucocorticoid use (p = 0.012) and baseline erosions (p = 0.040). Calcium or vitamin D use did not vary among the different fracture risk groups (p = NS), nor did bisphosphonate use (p = NS). The Disease Activity Score with 28 joint count in the high-risk group was significantly higher compared to the low-risk group (p = 0.048).
Patients at increased risk had higher disease activity, more frequent glucocorticoid use, and more baseline erosions compared to patients at low risk. A care gap exists, in that a very low proportion of patients at high risk are being treated with calcium, vitamin D, and/or bisphosphonates. A higher fracture risk was calculated in our cohort using the US FRAX calculation tool compared to the UK calculation tool. These data highlight the need to identify and modify fracture risk in patients with early inflammatory arthritis.
Pleuritis is a common manifestation and independent predictor of mortality in systemic lupus erythematosus (SLE). We examined the prevalence of pleuritis and factors associated with pleuritis in a multicenter Canadian SLE cohort.
We studied consecutive adults satisfying the American College of Rheumatology (ACR) classification criteria for SLE who had a completed Systemic Lupus International Collaborating Clinics/ACR Damage Index (SDI) score, at least 1 evaluable extractable nuclear antigen assay, and either a SLE Disease Activity Index (SLEDAI) or a SLE Activity Measure score. Pleuritis was defined as having pleuritis by satisfying the ACR criteria or the SLEDAI. Factors related to pleuritis were examined using univariate and multivariate logistic regression.
In our cohort of 876 patients, 91% were women, 65% Caucasian, mean age (+/- SD) was 46.8 +/- 13.5 years, and disease duration at study entry was 12.1 +/- 9.9 years; the prevalence of pleuritis was 34% (n = 296). Notably, greater disease duration (p = 0.002), higher SDI score (p
From the Rheumatology Centre, St. Joseph's Health Care, London, Ontario, Canada; the Hospital for Special Surgery, New York, New York, USA; the Arthritis Centre, University of Manitoba, Winnipeg, Manitoba; the University of Toronto, Toronto; Southlake Regional Health Centre, Newmarket, Ontario; the Faculty of Medicine and Health Sciences, Division of Rheumatology, Université de Sherbrooke, Sherbrooke, Quebec; the Rheumatic Disease Unit, Institut de Rhumatologie, Montreal, Quebec; McMaster University, Hamilton, Ontario; and Western University, London, Ontario, Canada.
To determine site variation by comparing outcomes across sites in an early rheumatoid arthritis cohort.
Sites from the Canadian Early Arthritis Cohort database with at least 40 patients were studied. Comparisons were made among sites in change in 28-joint Disease Activity Score (DAS28), proportion of patients in DAS28 remission, and treatment strategies.
The study included 1138 baseline patients at 8 sites, with baseline (SD) age 52 years (16.9); 72% women; 23% erosions; 54% ever smokers; 51% rheumatoid factor-positive; 37% anticitrullinated protein antibody-positive; disease duration 187 (203) days; DAS28 4.5 (1.4). Site had an effect on outcomes when adjusting for confounders. At 6 and 12 months, sites B and H, the 2 largest sites, had the best changes in DAS28 (-1.82 and -2.09, respectively, at 6 mos, and -2.27 for both at 12 mos; p
To describe early rheumatologic management for newly diagnosed rheumatoid arthritis (RA) in Canada.
A retrospective cohort of 339 randomly selected patients with RA diagnosed from 2001-2003 from 18 rheumatology practices was audited between 2005-2007.
The most frequent initial disease-modifying antirheumatic drugs (DMARD) included hydroxychloroquine (55.5%) and methotrexate (40.1%). Initial therapy with multiple DMARD (15.6%) or single DMARD and corticosteroid combinations (30.7%) was infrequent. Formal assessment measures were noted infrequently, including the Health Assessment Questionnaire (34.6%) and Disease Activity Score for 28 joints (8.9%).
Initial pharmacotherapy is consistent with guidelines from the period. The infrequent reporting of multiple DMARD combinations and formal assessment measures has implications for current clinical management and warrants contemporary reassessment.
Secondary fibromyalgia (FM) is common among patients with inflammatory arthritis, but little is known about its incidence and the factors leading to its development. The authors examined the incidence of secondary FM in an early inflammatory arthritis cohort, and assessed the association between pain, inflammation, psychosocial variables and the clinical diagnosis of FM.
Data from 1487 patients in the Canadian Early Arthritis Cohort, a prospective, observational Canadian cohort of early inflammatory arthritis patients were analysed. Diagnoses of FM were determined by rheumatologists. Incidence rates were calculated, and Cox regression models were used to determine HRs for FM risk.
The cumulative incidence rate was 6.77 (95% CI 5.19 to 8.64) per 100 person-years during the first 12 months after inflammatory arthritis diagnosis, and decreased to 3.58 (95% CI 1.86 to 6.17) per 100 person-years 12-24 months after arthritis diagnosis. Pain severity (HR 2.01, 95% CI 1.17 to 3.46) and poor mental health (HR 1.99, 95% CI 1.09 to 3.62) predicted FM risk. Citrullinated peptide positivity (HR 0.48, 95% CI 0.26 to 0.88) was associated with decreased FM risk. Serum inflammatory markers and swollen joint count were not significantly associated with FM risk.
The incidence of FM was from 3.58 to 6.77 cases per 100 person-years, and was highest during the first 12 months after diagnosis of inflammatory arthritis. Although inflammation was not associated with the clinical diagnosis of FM, pain severity and poor mental health were associated with the clinical diagnosis of FM. Seropositivity was inversely associated with the clinical diagnosis of FM.
From the Departments of Internal Medicine (R.A.M., C.N.B., C.A.P., C.A.H., A.G.) and Community Health Sciences (R.A.M., C.A.P., R.F., A.G.), and IBD Clinical and Research Centre (C.N.B.), University of Manitoba, Winnipeg; and Manitoba Centre for Health Policy (H.C., R.F., A.G.), Winnipeg, Canada. firstname.lastname@example.org.
To compare the incidence of, and mortality after, intensive care unit (ICU) admission as well as the characteristics of critical illness in the multiple sclerosis (MS) population vs the general population.
We used population-based administrative data from the Canadian province of Manitoba for the period 1984 to 2010 and clinical data from 93% of admissions to provincial high-intensity adult ICUs. We identified 5,035 prevalent cases of MS and a cohort from the general population matched 5:1 on age, sex, and region of residence. We compared these populations using incidence rates and multivariable regression models adjusting for age, sex, comorbidity, and socioeconomic status.
From January 2000 to October 2009, the age- and sex-standardized annual incidence of ICU admission among prevalent cohorts was 0.51% to 1.07% in the MS population and 0.34% to 0.51% in matched controls. The adjusted risk of ICU admission was higher for the MS population (hazard ratio 1.45; 95% confidence interval [CI] 1.19-1.75) than for matched controls. The MS population was more likely to be admitted for infection than the matched controls (odds ratio 1.82; 95% CI 1.10-1.32). Compared with the matched controls admitted to ICUs, 1-year mortality was higher in the MS population (relative risk 2.06; 95% CI 1.32-3.07) and was particularly elevated in patients with MS who were younger than 40 years (relative risk 3.77; 95% CI 1.45-8.11). Causes of death were MS (9.3%), infections (37.0%), and other causes (52.9%).
Compared with the general population, the risk of ICU admission is higher in MS, and 1-year mortality after admission is higher. Greater attention to preventing infection and managing comorbidity is needed in the MS population.
The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13ß stratifies with ACPA-positive RA, while His13ßSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13ßSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism.
HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg59-71, vimentin-64Cit59-71 and fibrinogen ß-74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRa and ß-chains were analysed using multiplex, nested PCR and sequencing.
ACPA(+) RA in INA was independently associated with HLA-DRB1*14:02. Consequent to the His13ßSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59-71 were observed in patients with HLA-DRB1*14:02(+) RA and at-risk ACPA(-) first-degree relatives. HLA-DRB1*14:02-vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-specific CD4+ memory T cells were phenotypically distinct populations.
HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.