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Ryan W Gan,
Kevin D Deane,
Gary O Zerbe,
M Kristen Demoruelle,
Michael H Weisman,
Jane H Buckner,
Peter K Gregersen,
Ted R Mikuls, James R O'Dell,
Richard M Keating,
V Michael Holers,
Jill M Norris
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ABSTRACT: INTRODUCTION: Studies suggest that respiratory exposures including smoking, proximity to traffic and air pollution might be associated with development of rheumatoid arthritis (RA). RA-related autoantibodies are predictive of the development of RA. OBJECTIVE: We evaluated the relationship between RA-related autoantibodies and exposure to particulate matter (PM), a measure of air pollution of interest to health, in individuals without RA. METHODS: The Studies of the Etiology of Rheumatoid Arthritis (SERA) is a multicentre study following first-degree relatives (FDRs) of a proband with RA. FDRs are without the 1987 ACR (American College of Rheumatology) classifiable RA at enrolment and are followed for the development of RA-related autoimmunity. RA-related autoantibody outcomes as well as tender and swollen joint outcomes were assessed. Exposure to PM was assigned using ambient air pollution monitoring data and interpolated with inverse distance weighting spatial analyses using Geographic Information Systems. PM exposures were linked to FDR's residential zip codes. RESULTS: RA-related autoantibodies as well as tender or swollen joints are not associated with ambient PM concentrations. DISCUSSION: While other respiratory exposures may be associated with increased risk of RA, our data suggest that ambient PM is not associated with autoantibodies and joint signs among individuals without RA, but at increased risk of developing RA.
Annals of the rheumatic diseases 04/2013; · 8.11 Impact Factor
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Jan M Hughes-Austin,
Kevin D Deane,
Lezlie A Derber,
Jason R Kolfenbach,
Gary O Zerbe,
Jeremy Sokolove,
Lauren J Lahey,
Michael H Weisman,
Jane H Buckner,
Ted R Mikuls, James R O'Dell,
Richard M Keating,
Peter K Gregersen,
William H Robinson,
V Michael Holers,
Jill M Norris
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ABSTRACT: OBJECTIVE: We investigated whether rheumatoid arthritis (RA)-related autoantibodies were associated with systemic inflammation in a prospective cohort of first-degree relatives (FDRs) of RA probands, a population without RA but at increased risk for its future development. METHODS: We studied 44 autoantibody positive FDRs, of whom 29 were rheumatoid factor (RF) positive, 25 were positive for the high risk autoantibody profile (HRP), that is, positive for anti-cyclic citrullinated peptide and/or for at least two RF IgM, IgG or IgA isotypes, and nine FDRs who were positive for both; and 62 FDRs who were never autoantibody positive. Twenty-five cytokines/chemokines were measured using a bead-based assay in serum. As a comprehensive measure of inflammation, we calculated a Cytokine Score by summing all cytokine/chemokine levels, weighted by their regression coefficients for RA-autoantibody association. We compared C-reactive protein, individual cytokines/chemokines and Cytokine Score to the outcomes: positivity for RF and for the HRP using logistic regression. RESULTS: Adjusting for age, sex, ethnicity and ever smoking, the Cytokine Score and levels of IL-6 and IL-9 were associated with both RF and HRP. IL-2, granulocyte macrophage-colony stimulating factor (GM-CSF), and interferon (IFN)-γ were associated with HRP only. Associations between the Cytokine Score and RF and HRP positivity were replicated in an independent military personnel cohort. CONCLUSIONS: In first-degree relatives of patients with RA, RA-related autoimmunity is associated with inflammation, as evidenced by associations with multiple cytokines and chemokines.
Annals of the rheumatic diseases 08/2012; · 8.11 Impact Factor
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Arthritis care & research. 06/2012; 64(10):1623-4.
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Ted R Mikuls,
Geoffrey M Thiele,
Kevin D Deane,
Jeffrey B Payne, James R O'Dell,
Fang Yu,
Harlan Sayles,
Michael H Weisman,
Peter K Gregersen,
Jane H Buckner,
Richard M Keating,
Lezlie A Derber,
William H Robinson,
V Michael Holers,
Jill M Norris
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ABSTRACT: PURPOSE: To examine the relationship of Porphyromonas gingivalis (Pg) with the presence of autoantibodies in individuals at risk for rheumatoid arthritis (RA). METHODS: Participants included: 1) a cohort enriched with HLA-DR4 and 2) those at risk for RA by virtue of having a first-degree relative with RA. None satisfied 1987 ACR RA classification criteria. Autoantibodies measured included anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF; nephelometry, IgA, IgM, IgG). Individuals were considered autoantibody positive (n = 113) with ≥ 1 positive autoantibody with individuals further categorized as 'high-risk' (n = 38; positive ACPA or ≥ 2 RF assays). Autoantibody negative individuals served as comparators (n = 171). Antibody to Pg, P. intermedia (Pi), and F. nucleatum (Fn) were measured. Associations of bacterial antibodies with group status were examined using logistic regression. RESULTS: Anti-Pg concentrations were higher in high-risk (p = 0.011) and autoantibody positive group (p = 0.010) than in the autoantibody negative group. There were no group differences in anti-Pi or anti-Fn concentrations. After multivariable adjustment, anti-Pg concentrations (but not anti-Pi or anti-Fn) were significantly associated with autoantibody positive and high-risk status (p < 0.05). CONCLUSION: Immunity to Pg, but not Pi or Fn, is significantly associated with the presence of RA-related autoantibodies in individuals at risk for RA. These results support the hypothesis that infection with Pg may play a central role in the early loss of tolerance to self-antigens in RA pathogenesis.
Arthritis & Rheumatism 06/2012; · 7.87 Impact Factor
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ABSTRACT: Although the systematic measurement of disease activity facilitates clinical decision making in rheumatoid arthritis (RA), no recommendations currently exist on which measures should be applied in clinical practice in the US. The American College of Rheumatology (ACR) convened a Working Group (WG) to comprehensively evaluate the validity, feasibility, and acceptability of available RA disease activity measures and derive recommendations for their use in clinical practice.
The Rheumatoid Arthritis Clinical Disease Activity Measures Working Group conducted a systematic review of the literature to identify RA disease activity measures. Using exclusion criteria, input from an Expert Advisory Panel (EAP), and psychometric analysis, a list of potential measures was created. A survey was administered to rheumatologists soliciting input. The WG used these survey results in conjunction with the psychometric analyses to derive final recommendations.
Systematic review of the literature resulted in identification of 63 RA disease activity measures. Application of exclusion criteria and ratings by the EAP narrowed the list to 14 measures for further evaluation. Practicing rheumatologists rated 9 of these 14 measures as most useful and feasible. From these 9 measures, the WG selected 6 with the best psychometric properties for inclusion in the final set of ACR-recommended RA disease activity measures.
We recommend the Clinical Disease Activity Index, Disease Activity Score with 28-joint counts (erythrocyte sedimentation rate or C-reactive protein), Patient Activity Scale (PAS), PAS-II, Routine Assessment of Patient Index Data with 3 measures, and Simplified Disease Activity Index because they are accurate reflections of disease activity; are sensitive to change; discriminate well between low, moderate, and high disease activity states; have remission criteria; and are feasible to perform in clinical settings.
Arthritis care & research. 05/2012; 64(5):640-7.
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Arthritis & Rheumatism 04/2011; · 7.87 Impact Factor
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Arthritis & Rheumatism 03/2011; 63(3):587-9. · 7.87 Impact Factor
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ABSTRACT: The understanding of the pathogenesis and optimal therapeutics for rheumatoid arthritis (RA) has advanced remarkably over the last decade. This review highlights these key advances, particularly the outcomes of genome-wide scans which have provided an increasingly robust appraisal of the complex genetics that underpin RA. Such observations are placed in pathogenetic context, particularly concerning the breach of tolerance that presages synovitis and the mechanisms that subserve chronicity. The key therapeutic strategies and treatment agents, both conventional and biological, now available to effectively manage the disease are described. Throughout the review, emphasis is placed on unanswered questions and challenges in this exciting field.
Annals of the rheumatic diseases 11/2010; 69(11):1898-906. · 8.11 Impact Factor
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Ted R Mikuls,
Karen A Gould,
Kimberly K Bynoté,
Fang Yu,
Tricia D Levan,
Geoffrey M Thiele,
Kaleb D Michaud, James R O'Dell,
Andreas M Reimold,
Roderick Hooker,
Liron Caplan,
Dannette S Johnson,
Gail Kerr,
J Steuart Richards,
Grant W Cannon,
Lindsey A Criswell,
Janelle A Noble,
S Louis Bridges,
Laura Hughes,
Peter K Gregersen
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ABSTRACT: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE).
Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction.
A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050).
This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.
Arthritis research & therapy 11/2010; 12(6):R213. · 4.27 Impact Factor
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Clinical Orthopaedics and Related Research 09/2010; · 2.53 Impact Factor
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James R O'Dell
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ABSTRACT: The prognosis for patients with rheumatoid arthritis has improved dramatically, thanks in large part to many new therapies and therapeutic approaches. Paradoxically, this has created problems for rheumatologists since clinically useful information from appropriate clinical trials has not kept pace with all the new therapeutic options. Essentially, rheumatologists now have many more therapeutic options than they know what to do with. This article discusses why we are in this situation and suggests opportunities to move forward.
Best practice & research. Clinical rheumatology 08/2010; 24(4):457-61. · 2.90 Impact Factor
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Benjamin J Miriovsky,
Kaleb Michaud,
Geoffrey M Thiele, James R O'Dell,
Grant W Cannon,
Gail Kerr,
J Steuart Richards,
Dannette Johnson,
Liron Caplan,
Andreas Reimold,
Roderick Hooker,
Ted R Mikuls
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ABSTRACT: To examine associations of anti-cyclic citrullinated peptide (aCCP) antibody and rheumatoid factor (RF) concentrations with future disease activity in men with rheumatoid arthritis (RA).
Outcome measures were examined in male US veterans with RA and included (1) proportion of observations in remission (disease activity score (DAS28) < or =2.6); (2) remission for > or =3 consecutive months; and (3) area under the curve (AUC) for DAS28. The associations of autoantibody concentration (per 100 unit increments) with outcomes were examined using multivariate regression.
826 men with RA were included in the analysis; the mean (SD) age was 65 (10.5) years and follow-up was for 2.6 (1.3) years. Most were aCCP (75%) and RF (80%) positive. After multivariate adjustment, aCCP (OR 0.93; 95% CI 0.89 to 0.96) and RF concentrations (OR 0.92; 95% CI 0.90 to 0.94) were associated with a lower odds of remission, a lower proportion of observation in remission (p=0.017 and p=0.002, respectively) and greater AUC DAS28 (p=0.092 and p=0.007, respectively). Among patients with discordant autoantibody status, higher concentrations of both aCCP and RF trended towards an inverse association with remission (OR 0.93; 95% CI 0.83 to 1.05 and OR 0.80; 95% CI 0.59 to 1.10, respectively).
Higher aCCP concentrations (particularly in RF-positive patients) are associated with increased disease activity in US veterans with RA, indicating that aCCP concentration is predictive of future disease outcomes in men.
Annals of the rheumatic diseases 07/2010; 69(7):1292-7. · 8.11 Impact Factor
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Arthritis care & research. 01/2010; 62(1):1-3.
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder primarily targeting the synovium. Unchecked disease activity is associated with significant morbidity and an increased mortality. Recent advances in the understanding of the pathogenesis of RA and the capability of biologically engineered treatments for RA have expanded the armamentarium of antirheumatic agents.
A systematic literature review was conducted through PubMed.
At present, a common strategy for the treatment of RA uses methotrexate either as monotherapy or in combination with a variety of conventional and/or biologic disease-modifying antirheumatic drugs (DMARDs), with the goal of inducing remission of active disease. The choice of which agent(s) to use is based upon patient-specific criteria (activity of disease, comorbidities, patient preferences, costs etc.). Emerging therapies that target specific cytokines and growth factors in the inflammatory cascade of RA offer a potent new means of modifying disease activity, but many questions regarding their use remain unanswered.
Expert Opinion on Pharmacotherapy 08/2009; 10(13):2095-106. · 3.20 Impact Factor
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ABSTRACT: Hydroxychloroquine (HCQ) is an antimalarial agent that is commonly used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The present report documents a case of hypoglycaemia due to HCQ in a patient with SLE and diabetes mellitus type 2, in which the HCQ completely replaced the need for daily subcutaneous insulin.
Case Reports 01/2009; 2009.
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ABSTRACT: Antibody titers to P. gingivalis are increased in patients with rheumatoid arthritis and are associated with disease-specific autoimmunity.
Periodontitis (PD) has been implicated as a risk factor for rheumatoid arthritis (RA). We sought to characterize antibody titers to P. gingivalis (a pathogen in PD) in subjects with RA, PD, and in healthy controls and to examine their relationship with disease autoantibodies.
P. gingivalis antibody was measured in subjects with RA (n=78), PD (n=39), and in controls (n=40). Group frequencies of bacterial titer elevations were compared using the Chi-square test and antibody titers were compared using non-parametric tests. Correlations of P. gingivalis titer with C-reactive protein (CRP), antibody to cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were examined in those with RA while CRP and autoantibody concentrations were compared based on seropositivity to P. gingivalis.
Antibody titers to P. gingivalis were highest in PD, lowest in controls, and intermediate in RA (p=0.0003). Elevations in P. gingivalis (titer> or =800) were more common in RA and PD (67% and 77%, respectively) than in controls (40%) (p=0.002). In RA, there were significant correlations with P. gingivalis titer with CRP, anti-CCP-IgM, and -IgG-2. CRP (p=0.006), anti-CCP-IgM (p=0.01) and -IgG2 (p=0.04) concentrations were higher in RA cases with P. gingivalis titers > or =800 compared to cases with titers <800.
Antibodies to P. gingivalis are more common in RA subjects than controls, although lower than that in PD. Associations of P. gingivalis titers with RA-related autoantibody and CRP concentrations suggests that infection with this organism plays a role in disease risk and progression in RA.
International Immunopharmacology 10/2008; 9(1):38-42. · 2.38 Impact Factor
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ABSTRACT: Minocycline is recognized as an effective, well-tolerated therapy in rheumatoid arthritis (RA), although its use has been associated with the development of cutaneous hyperpigmentation.
To assess the clinical determinants and frequency of minocycline-induced hyperpigmentation in patients with RA.
A retrospective medical record review of all patients with RA seen in 2 academic rheumatology practices was performed to identify subjects who had received at least 1 month of continuous minocycline therapy. Patient demographics, disease characteristics, medication use, and medication side effects were abstracted from the medical record. Using Cox proportional hazards regression and restricting the analysis to the initial minocycline course, we examined the association of patient factors and concomitant medications with the development of hyperpigmentation.
Of 121 patients with at least 1 minocycline course of 30 days or more, 44 (36%) developed documented hyperpigmentation, including 33 during the initial course over a median duration of 9.1 month (range 2.2-77.8 months). Hyperpigmentation was most commonly seen on the upper and lower extremities and the head/neck region. Minocycline-induced hyperpigmentation led to the discontinuation of treatment in 3 patients, with 12 additional patients receiving a dose reduction. Increasing age was the only clinical determinant significantly associated with hyperpigmentation (HR = 1.04; 95% CI 1.00-1.07, P = 0.04). There were no significant associations of sex, weight, concomitant prednisone, or aspirin use with the development of hyperpigmentation.
Minocycline-induced hyperpigmentation is a common complication seen with minocycline use in the treatment of RA, and seems to increase with age.
Journal of clinical rheumatology: practical reports on rheumatic & musculoskeletal diseases 03/2008; 14(1):17-20. · 1.19 Impact Factor
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James R O'Dell
Arthritis & Rheumatism 01/2008; 56(12):3884-6. · 7.87 Impact Factor
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James R O'Dell
Annals of internal medicine 04/2007; 146(6):459-60. · 16.73 Impact Factor
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James R O'Dell
Arthritis & Rheumatism 04/2007; 57(2):189-90. · 7.87 Impact Factor
