Carol A. Hitchon

Oxidation in rheumatoid arthritis

Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. Reactive oxygen species (ROS) produced in the course of cellular oxidative phosphorylation, and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. They also serve as important intracellular signaling molecules that amplify the synovial inflammatory–proliferative response. Repetitive cycles of hypoxia and reoxygenation associated with changes in synovial perfusion are postulated to activate hypoxia-inducible factor-1α and nuclear factor-κB, two key transcription factors that are regulated by changes in cellular oxygenation and cytokine stimulation, and that in turn orchestrate the expression of a spectrum of genes critical to the persistence of synovitis. An understanding of the complex interactions involved in these pathways might allow the development of novel therapeutic strategies for rheumatoid arthritis.

Macrophage-derived cytokine and nuclear factor κB p65 expression in synovial membrane and skin of patients with psoriatic arthritis

OBJECTIVE Monocyte-derived cytokines are important mediators in synovitis and represent novel therapeutic targets. This study was undertaken to analyze their expression in synovial membrane (SM) of patients with psoriatic arthritis (PsA) compared with that in skin of patients with PsA and SM of patients with rheumatoid arthritis (RA). METHODS Multiple synovial biopsy samples (24 from patients with PsA, 20 from patients with RA, 5 from patients with osteoarthritis [OA]) and skin biopsy samples (lesional and perilesional skin from 25 PsA patients) were obtained. Standard leukocyte antigens, cytokines (tumor necrosis factor alpha [TNFalpha], interleukin-1apha [IL-1alpha], IL-1beta, IL-15, and IL-10) and the transcription factor nuclear factor KB (NF-kappaB; active p65 subunit) were localized and quantified immunohistochemically by light microscopy and digital image analysis. RESULTS Sublining cellular infiltration, lymphoid aggregation, and vascularity were similar in PsA and RA SM. Lining layer thickness was greater in RA SM, associated with more CD68+ macrophages. In PsA SM, TNFalpha, IL-1alpha, IL-1beta, IL-15, and IL-10 were primarily localized to lining layer and perivascular macrophages, as were cells expressing the active subunit of NF-kappaB (p65). TNFalpha, IL-1p, and IL-15 expression in PsA lining layer was less than that in RA lining layer, likely reflecting lower macrophage numbers. In sublining areas, levels of TNFalpha and IL-15 were lower in PsA patients than in RA patients, whereas IL-lalpha and IL-1beta expression was equivalent. IL-10 was identified at similar levels in RA and PsA SM lining layer and sublining. Expression of NF-kappaB (p65) was equal in lining layer from both patient groups, but lower in PsA than RA sublining. Histologic findings did not correlate with clinical parameters of disease. Cytokine expression in skin did not correlate directly with that in SM. Cytokine expression was greater in PsA and RA SM than in OA SM. CONCLUSION This study shows, for the first time, that monocyte-derived cytokines are found in PsA SM and demonstrates the relative paucity of the antiinflammatory cytokine IL-10 in PsA skin and SM. Significant divergence from RA SM expression was observed, despite similar clinical and demographic features in the 2 patient groups.

Antibodies to Porphyromonas gingivalis Are Associated with Anticitrullinated Protein Antibodies in Patients with Rheumatoid Arthritis and Their Relatives

Objective. 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. Methods. 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. Results. 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 < 0.001), but comparable in RF-positive and RF-negative patients and relatives. Poor oral hygiene and smoking were prevalent, but with no clear association with autoantibodies. Relatives with 2 shared-epitope alleles were more likely to be ACPA-positive (OR 2.5, p = 0.02). Conclusion. In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalis antibodies were associated with ACPA. These findings suggest that immune responses to P. gingivalis may be involved in breaking immune tolerance to citrullinated antigens.

Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients

OBJECTIVE Rheumatoid arthritis (RA) is prevalent in North American Native populations, with a high frequency of multicase families and seropositivity in first-degree relatives. This study was undertaken to determine whether the serum cytokine profile of first-degree relatives of North American Native patients with RA differed from that of individuals with no family history of autoimmunity and whether there was an association with RA autoantibodies. METHODS North American Native patients with RA (n = 105), their first-degree relatives (n = 273), healthy North American Native controls (n = 200), and Caucasian controls (n = 150) were studied. Serum levels of 42 cytokines were tested using a multiplex laser bead assay. Rheumatoid factor (RF), anti-cyclic citrullinated peptide 2 (anti-CCP-2), monocyte chemotactic protein 1 (MCP-l), and high-sensitivity C-reactive protein (hsCRP) were tested by enzyme-linked immunosorbent assay, and HLA-DRB1 alleles by specific primers. Discriminant analysis and logistic regression classified individuals based on their cytokine profile. RESULTS The prevalence of RF (cutoff level predetermined to include 5% of Caucasian controls) and anti-CCP (cutoff level of ≥40 units) was, respectively, 88% and 81% in the RA patients, 34% and 9% in first-degree relatives, and 9% and 4% in North American Native controls; the prevalence of anti-CCP was 0% in Caucasian controls. Levels of most cytokines were highest in RA patients; 17 of 40 cytokines (43%) were significantly higher in first-degree relatives than in controls, including multiple proinflammatory cytokines. Discriminant analysis showed a notable distinction between the groups, with 85% classification accuracy. First-degree relatives had markedly higher MCP-1 and hsCRP levels than North American Native controls, but there was no consistent association with RA autoantibodies. CONCLUSION Our findings indicate that levels of multiple cytokines and hsCRP are higher in first-degree relatives of North American Native patients with RA compared to individuals from a nonautoimmune background. These data suggest that elevated baseline cytokine levels may be part of the risk profile for developing RA.

Association of Smoking With Cutaneous Manifestations in Systemic Lupus Erythematosus

To examine the association between smoking and cutaneous involvement in systemic lupus erythematosus (SLE).

Incidence and predictors of secondary fibromyalgia in an early arthritis cohort

Objectives 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. Methods 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. Results 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. Conclusions 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.

Vitamin D receptor polymorphism rs2228570 (Fok1) is associated with rheumatoid arthritis in North American natives.

Objective. Vitamin D (VitD) has immunomodulatory activity relevant to rheumatoid arthritis (RA) and acts by binding nuclear receptors that regulate gene transcription. VitD receptor polymorphisms have been variably associated with RA. Because North American Native (NAN) populations have a high prevalence of RA with a strong genetic contribution, we studied potential associations of the rs2228570 (Fok1) VitD receptor polymorphism in a Canadian NAN population. Methods. The single-nucleotide polymorphism (SNP) Fok1 was tested by sequencing NAN patients with RA (n = 448) and unrelated NAN controls (n = 704). Associations were tested using genotypic, dominant, and recessive models. Results. The minor allele frequency (F/C) in the NAN control population was 0.44 and lower than reported in white subjects of the same geographical area. The Fok1 VitD receptor SNP was significantly associated with RA. Comparing patients with RA to unaffected NAN controls, the Fok1 SNP was associated with RA using both genotypic [FF vs Ff vs ff: RA 20%, 54%, 26% vs control 22%, 44%, 34% (chi-square 13.35, p = 0.003)] and dominant models [FF/Ff vs ff: RA 74% vs 26% control 66% vs 34% (OR 1.5, 95% CI 1.16–1.96, p = 0.003)]. This association was strongest in shared-epitope-positive RA. Conclusion. VitD receptor polymorphisms may contribute to the high prevalence of RA in NAN populations.

Remission in Early Rheumatoid Arthritis — A Comparison of New ACR/EULAR Remission Criteria to Established Criteria

Objective. To describe the frequency of remission in an early rheumatoid arthritis (ERA) cohort. Methods. The frequency of remission was evaluated, based on 8 definitions including the Boolean-based American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. Results. Of 369 patients, remission at 12 months ranged from 18% according to the ACR/EULAR clinical trial criteria to 40% according to the 28-joint Disease Activity Score (DAS28) < 2.6. Higher tender joint count, swollen joint count, and physician global scores were seen for DAS28-based definitions, and patient global assessment (PtGA) scores were almost 5-fold higher for DAS28 remission. Conclusion. Remission is achievable in ERA but its frequency differs according to the remission definition applied. Adoption of the new ACR/EULAR definition will limit the number classified as in remission, especially if the PtGA criteria are rated high for reasons other than inflammatory arthritis.

Rheumatoid arthritis in a north american native population: longitudinal followup and comparison with a white population.

Objective. To describe differences in phenotype and outcomes in North American Native (NAN) patients with rheumatoid arthritis (RA) followed prospectively and compared to white patients with RA. Methods. Patients from a single academic center were followed over 20 years using a custom database. Data included diagnoses, year of disease onset, ethnicity, modified Health Assessment Questionnaire (mHAQ) score, patient and physician global scores, tender and swollen joint counts, treatment, serology, and erythrocyte sedimentation rate (ESR). Records of all white (n = 1315) and NAN (n = 481) patients with RA were abstracted. Cumulative treatment data and clinical measures were compared. Results. Disease duration was longer in white patients compared to NAN patients (16 ± 11 vs 14 ± 10 years, respectively; p = 0.03). Onset age was 34 years for NAN patients and 43 years for white patients (p < 0.001). NAN patients were more frequently positive for rheumatoid factor (89% vs 74%; p < 0.001) and antinuclear antibody (57% vs 21%; p < 0.001). Although mean tender joint counts and swollen joint counts were similar, NAN patients had higher Lansbury scores (weighted joint count; 66.5 vs 49.7; p < 0.001), mHAQ scores (1.1 vs 0.9; p = 0.001), and ESR (31 vs 25 mm/h; p < 0.012). NAN patients had more frequent knee (53% vs 34%; p < 0.001) and elbow (62% vs 48%; p = 0.007) involvement. Compared to white patients, NAN patients took a higher lifetime number of disease-modifying antirheumatic drugs (3.2 ± 1.9 vs 2.2 ± 1.7; p < 0.001), had more combination therapy (38% vs 29%; p = 0.002), and had more frequent prednisone use (55% vs 39%; p < 0.001). Conclusion. Compared to white patients, NAN patients with RA develop disease earlier, are more frequently seropositive, have greater large joint involvement, and greater disease burden, although treatment is more aggressive. These differences are present early and persist throughout the disease course.

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

Objective. 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. Methods. 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. Results. 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 < DAS28 ≤ 5.1) and 46% (n = 505) had high (DAS28 > 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. Conclusion. Patients with early RA present with moderate high disease activity; < 50% achieve remission at 1 year, despite MTX treatment in the majority. The 2010 RA classification criteria identify more patients with RA who would previously have been designated as having undifferentiated disease. However, these patients have lower disease activity at the time of identification.