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Antibodies to porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives.

https://arctichealth.org/en/permalink/ahliterature143848
Source
J Rheumatol. 2010 Jun;37(6):1105-12
Publication Type
Article
Date
Jun-2010
Author
Carol A Hitchon
Fatiha Chandad
Elizabeth D Ferucci
Annemiek Willemze
Andreea Ioan-Facsinay
Diane van der Woude
Janet Markland
David Robinson
Brenda Elias
Marianna Newkirk
Rene M Toes
Tom W J Huizinga
Hani S El-Gabalawy
Author Affiliation
University of Manitoba, Winnipeg, Manitoba, Canada.
Source
J Rheumatol. 2010 Jun;37(6):1105-12
Date
Jun-2010
Language
English
Publication Type
Article
Keywords
Adult
Antibodies, Anti-Idiotypic - blood - immunology
Arthritis, Rheumatoid - blood - immunology - microbiology
Canada - epidemiology
Cohort Studies
Dental Caries - blood - immunology - microbiology
Female
Humans
Immunoglobulin A - blood - immunology
Immunoglobulin M - blood - immunology
Indians, North American
Lipopolysaccharides - immunology
Male
Middle Aged
Peptides, Cyclic - blood - immunology
Porphyromonas gingivalis - immunology - isolation & purification - pathogenicity
Rheumatoid Factor - blood - immunology
Abstract
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
Notes
Comment In: J Rheumatol. 2010 Jun;37(6):1083-520516033
PubMed ID
20436074 View in PubMed
Less detail

Anticitrullinated protein antibodies and rheumatoid factor fluctuate in early inflammatory arthritis and do not predict clinical outcomes.

https://arctichealth.org/en/permalink/ahliterature116618
Source
J Rheumatol. 2013 Aug;40(8):1259-67
Publication Type
Article
Date
Aug-2013
Author
Lillian Barra
Vivian Bykerk
Janet E Pope
Boulos P Haraoui
Carol A Hitchon
J Carter Thorne
Edward C Keystone
Gilles Boire
Author Affiliation
Department of Medicine, Division of Rheumatology, St. Joseph's Health Care London, University of Western Ontario, London, Ontario, Canada. lbarra2@uwo.ca
Source
J Rheumatol. 2013 Aug;40(8):1259-67
Date
Aug-2013
Language
English
Publication Type
Article
Keywords
Adult
Aged
Antibodies, Anti-Idiotypic - blood
Antirheumatic Agents - therapeutic use
Arthritis, Rheumatoid - blood - drug therapy
Biological Markers - blood
Canada
Cohort Studies
Disability Evaluation
Female
Follow-Up Studies
Humans
Male
Middle Aged
Peptides, Cyclic - immunology
Predictive value of tests
Questionnaires
Regression Analysis
Rheumatoid Factor - blood
Sensitivity and specificity
Severity of Illness Index
Treatment Outcome
Abstract
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.
PubMed ID
23378461 View in PubMed
Less detail

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.

https://arctichealth.org/en/permalink/ahliterature121576
Source
J Rheumatol. 2012 Nov;39(11):2071-80
Publication Type
Article
Date
Nov-2012
Author
Vivian P Bykerk
Shahin Jamal
Gilles Boire
Carol A Hitchon
Boulos Haraoui
Janet E Pope
J Carter Thorne
Ye Sun
Edward C Keystone
Author Affiliation
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. vbykerk@gmail.com
Source
J Rheumatol. 2012 Nov;39(11):2071-80
Date
Nov-2012
Language
English
Publication Type
Article
Keywords
Adult
Aged
Antirheumatic Agents - therapeutic use
Canada
Cohort Studies
Europe
Female
Finger Joint - radiography
Humans
Male
Methotrexate - therapeutic use
Middle Aged
Patient Selection
Prospective Studies
Rheumatoid Factor - blood
Severity of Illness Index
Societies, Medical
Synovitis - classification - diagnosis - drug therapy
United States
Abstract
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;
Notes
Comment In: J Rheumatol. 2012 Nov;39(11):2062-323118277
PubMed ID
22896026 View in PubMed
Less detail

Care gap in patients with early inflammatory arthritis with a high fracture risk identified using FRAX(®).

https://arctichealth.org/en/permalink/ahliterature141497
Source
J Rheumatol. 2010 Nov;37(11):2221-5
Publication Type
Article
Date
Nov-2010
Author
Carly K Cheng
Heather McDonald-Blumer
Gilles Boire
Janet E Pope
Boulos Haraoui
Carol A Hitchon
Carter Thorne
Ye Sun
Vivian P Bykerk
Author Affiliation
Division of Rheumatology, Mount Sinai Hospital, 60 Murray Street, 2nd floor, Toronto, Ontario M5T 3L9, Canada.
Source
J Rheumatol. 2010 Nov;37(11):2221-5
Date
Nov-2010
Language
English
Publication Type
Article
Keywords
Adult
Aged
Analysis of Variance
Arthritis - complications
Body Weight
Bone Density
Canada
Chi-Square Distribution
Female
Humans
Male
Middle Aged
Osteoporosis - complications
Osteoporotic Fractures - etiology
Questionnaires
Risk assessment
Risk factors
Severity of Illness Index
Abstract
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.
PubMed ID
20716658 View in PubMed
Less detail

Clinical and serologic factors associated with lupus pleuritis.

https://arctichealth.org/en/permalink/ahliterature145759
Source
J Rheumatol. 2010 Apr;37(4):747-53
Publication Type
Article
Date
Apr-2010
Author
Shikha Mittoo
Allan C Gelber
Carol A Hitchon
Earl D Silverman
Janet E Pope
Paul R Fortin
Christian Pineau
C Douglas Smith
Hector Arbillaga
Dafna D Gladman
Murray B Urowitz
Michel Zummer
Ann E Clarke
Sasha Bernatsky
Marie Hudson
Lori B Tucker
Ross E Petty
Christine A Peschken
Author Affiliation
Department of Medicine, University of Manitoba, Manitoba, Canada. shikha.hopkins@gmail.com
Source
J Rheumatol. 2010 Apr;37(4):747-53
Date
Apr-2010
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Age of Onset
Autoantibodies - immunology
Canada - epidemiology
Cohort Studies
Female
Humans
Lupus Erythematosus, Systemic - complications - epidemiology - immunology
Male
Middle Aged
Multivariate Analysis
Pleurisy - complications - epidemiology - immunology
Prevalence
Regression Analysis
Severity of Illness Index
Abstract
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
PubMed ID
20110526 View in PubMed
Less detail

Determining best practices in early rheumatoid arthritis by comparing differences in treatment at sites in the Canadian Early Arthritis Cohort.

https://arctichealth.org/en/permalink/ahliterature107248
Source
J Rheumatol. 2013 Nov;40(11):1823-30
Publication Type
Article
Date
Nov-2013
Author
Jamie A Harris
Vivian P Bykerk
Carol A Hitchon
E C Keystone
J Carter Thorne
Gilles Boire
Boulos Haraoui
Glen Hazlewood
Ashley J Bonner
Janet E Pope
Author Affiliation
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.
Source
J Rheumatol. 2013 Nov;40(11):1823-30
Date
Nov-2013
Language
English
Publication Type
Article
Keywords
Adult
Antirheumatic Agents - therapeutic use
Arthritis, Rheumatoid - drug therapy
Canada
Disease Progression
Drug Therapy, Combination
Female
Humans
Male
Methotrexate - therapeutic use
Middle Aged
Practice Guidelines as Topic
Remission Induction - methods
Severity of Illness Index
Standard of Care
Treatment Outcome
Abstract
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
PubMed ID
24037554 View in PubMed
Less detail

Early management of newly diagnosed rheumatoid arthritis by Canadian rheumatologists: a national, multicenter, retrospective cohort.

https://arctichealth.org/en/permalink/ahliterature131696
Source
J Rheumatol. 2011 Nov;38(11):2342-5
Publication Type
Article
Date
Nov-2011
Author
Ruben Tavares
Janet E Pope
Jean-Luc Tremblay
Carter Thorne
Vivian P Bykerk
Juris Lazovskis
Kenneth L N Blocka
Mary J Bell
Diane Lacaille
Carol A Hitchon
Avril A Fitzgerald
Wesley K Fidler
Arthur A M Bookman
James M Henderson
Dianne P Mosher
Dalton E Sholter
Majed Khraishi
Boulos Haraoui
Hong Chen
Xiuying Li
Andreas Laupacis
Gilles Boire
George Tomlinson
Claire Bombardier
Author Affiliation
McMaster University, Hamilton, Canada. ruben.tavares@sympatico.ca
Source
J Rheumatol. 2011 Nov;38(11):2342-5
Date
Nov-2011
Language
English
Publication Type
Article
Keywords
Adult
Antirheumatic Agents - therapeutic use
Canada - epidemiology
Cohort Studies
Disability Evaluation
Disease Management
Drug Therapy, Combination
Female
Humans
Male
Middle Aged
Outcome Assessment (Health Care)
Physician's Practice Patterns
Retrospective Studies
Rheumatic Fever - diagnosis - drug therapy - epidemiology
Severity of Illness Index
Treatment Outcome
Abstract
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.
Notes
Comment In: J Rheumatol. 2011 Nov;38(11):2287-922045932
PubMed ID
21885485 View in PubMed
Less detail

Incidence and predictors of secondary fibromyalgia in an early arthritis cohort.

https://arctichealth.org/en/permalink/ahliterature122649
Source
Ann Rheum Dis. 2013 Jun;72(6):949-54
Publication Type
Article
Date
Jun-2013
Author
Yvonne C Lee
Bing Lu
Gilles Boire
Boulos Paul Haraoui
Carol A Hitchon
Janet E Pope
J Carter Thorne
Edward Clark Keystone
Daniel H Solomon
Vivian P Bykerk
Author Affiliation
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ylee9@partners.org
Source
Ann Rheum Dis. 2013 Jun;72(6):949-54
Date
Jun-2013
Language
English
Publication Type
Article
Keywords
Adult
Aged
Antibodies - immunology
Arthritis - epidemiology
Arthritis, Rheumatoid - epidemiology
Canada - epidemiology
Cohort Studies
Female
Fibromyalgia - epidemiology
Humans
Incidence
Male
Mental Disorders - epidemiology
Middle Aged
Pain Measurement
Peptides, Cyclic - immunology
Proportional Hazards Models
Prospective Studies
Risk factors
Severity of Illness Index
Abstract
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.
Notes
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PubMed ID
22791744 View in PubMed
Less detail

Intensive care unit admission in multiple sclerosis: increased incidence and increased mortality.

https://arctichealth.org/en/permalink/ahliterature104337
Source
Neurology. 2014 Jun 10;82(23):2112-9
Publication Type
Article
Date
Jun-10-2014
Author
Ruth Ann Marrie
Charles N Bernstein
Christine A Peschken
Carol A Hitchon
Hui Chen
Randy Fransoo
Allan Garland
Author Affiliation
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. rmarrie@hsc.mb.ca.
Source
Neurology. 2014 Jun 10;82(23):2112-9
Date
Jun-10-2014
Language
English
Publication Type
Article
Keywords
Adult
Age Factors
Aged
Comorbidity
Female
Humans
Incidence
Infection - epidemiology - mortality
Intensive Care Units - statistics & numerical data
Male
Manitoba - epidemiology
Middle Aged
Multiple Sclerosis - epidemiology - mortality
Patient Admission - statistics & numerical data
Prevalence
Risk
Time Factors
Abstract
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.
PubMed ID
24808019 View in PubMed
Less detail

Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.

https://arctichealth.org/en/permalink/ahliterature285042
Source
Ann Rheum Dis. 2017 Nov;76(11):1915-1923
Publication Type
Article
Date
Nov-2017
Author
Stephen W Scally
Soi-Cheng Law
Yi Tian Ting
Jurgen van Heemst
Jeremy Sokolove
Aaron J Deutsch
E. Bridie Clemens
Antonis K Moustakas
George K Papadopoulos
Diane van der Woude
Irene Smolik
Carol A Hitchon
David B Robinson
Elizabeth D Ferucci
Charles N Bernstein
Xiaobo Meng
Vidyanand Anaparti
Tom Huizinga
Katherine Kedzierska
Hugh H Reid
Soumya Raychaudhuri
René E Toes
Jamie Rossjohn
Hani El-Gabalawy
Ranjeny Thomas
Source
Ann Rheum Dis. 2017 Nov;76(11):1915-1923
Date
Nov-2017
Language
English
Publication Type
Article
Abstract
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.
PubMed ID
28801345 View in PubMed
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