Hypomethylation of CYP2E1 and DUSP22 Promoters Associated With Disease Activity and Erosive Disease Among Rheumatoid Arthritis Patients.

OBJECTIVE: Epigenetic modifications have previously been associated with rheumatoid arthritis (RA). In this study, we aimed to determine whether differential DNA methylation in peripheral blood cell subpopulations is associated with any of 4 clinical outcomes among RA patients. METHODS: Peripheral blood samples were obtained from 63 patients in the University of California, San Francisco RA cohort (all satisfied the American College of Rheumatology classification criteria; 57 were seropositive for rheumatoid factor and/or anti-cyclic citrullinated protein). Fluorescence-activated cell sorting was used to separate the cells into 4 immune cell subpopulations (CD14+ monocytes, CD19+ B cells, CD4+ naive T cells, and CD4+ memory T cells) per individual, and 229 epigenome-wide DNA methylation profiles were generated using Illumina HumanMethylation450 BeadChips. Differentially methylated positions and regions associated with the Clinical Disease Activity Index score, erosive disease, RA Articular Damage score, Sharp score, medication at time of blood draw, smoking status, and disease duration were identified using robust regression models and empirical Bayes variance estimators. RESULTS: Differential methylation of CpG sites associated with clinical outcomes was observed in all 4 cell types. Hypomethylated regions in the CYP2E1 and DUSP22 gene promoters were associated with active and erosive disease, respectively. Pathway analyses suggested that the biologic mechanisms underlying each clinical outcome are cell type-specific. Evidence of independent effects on DNA methylation from smoking, medication use, and disease duration were also identified. CONCLUSION: Methylation signatures specific to RA clinical outcomes may have utility as biomarkers or predictors of exposure, disease progression, and disease severity.

Validity and Responsiveness of a 10-Item Patient-Reported Measure of Physical Function in a Rheumatoid Arthritis Clinic Population.

OBJECTIVE: We assessed implementation of the 10-item Patient-Reported Outcomes Measurement Information System (PROMIS) physical function form (PF-10a) in routine practice in a racially and ethnically diverse population with rheumatoid arthritis (RA). Objectives were to determine feasibility of implementing PF-10a in the electronic health record (EHR) and PF-10a validity and longitudinal responsiveness. METHODS: Clinical and demographic data were abstracted from EHRs for all RA patients seen at a university-based rheumatology clinic between February 2013 and February 2015. We evaluated floor and ceiling (edge) effects and construct validity of PF-10a in a subgroup of patients with Health Assessment Questionnaire (HAQ) scores (n = 189). We used linear mixed-effects models to assess responsiveness of PF-10a to longitudinal changes in the Clinical Disease Activity Index (CDAI) for patients in the entire clinical cohort, with both scores recorded on at least 2 encounters (n = 326). RESULTS: Half of the patients were nonwhite, and 15% were non-English speakers. Over a 2-year period, PF10a was successfully implemented; 97% of patients and 89% of encounters had at least 1 measurement performed. PF-10a had fewer ceiling (defined as best) effects than the HAQ (8% versus 22%), and convergent validity was high (r = -0.85). PF-10a was sensitive to expected differences (older versus younger patients, more versus less active disease). Longitudinal changes in PF-10a were highly associated with changes in the CDAI score (P < 0.0001). CONCLUSION: PF-10a was feasible to implement in a diverse RA population. It strongly correlates with the HAQ but has fewer ceiling effects and is responsive to changes in RA disease activity, suggesting its validity for use in routine clinical practice.

PTP4A1 promotes TGFß signaling and fibrosis in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFß signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFß signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFß-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases.

Extraarticular manifestations of rheumatoid arthritis in a multiethnic cohort of predominantly Hispanic and Asian patients.

We conducted a study to determine the prevalence of extraarticular manifestations (ExRA) in a cohort of predominantly Hispanic and Asian patients with rheumatoid arthritis (RA), to identify factors associated with the development of ExRA, and to compare the prevalence of ExRA between Hispanic and Asian patients. Patients with RA followed in the outpatient rheumatology clinics of a public hospital were included if they were aged ≥18 years and met the 1987 American College of Rheumatology criteria for the diagnosis of RA. We performed a cross-sectional analysis in which patients with ExRA were identified based on predefined criteria. We compared sociodemographic and clinical characteristics in patients with and without ExRA. Multivariate logistic regression was used to examine the association between sociodemographic variables, clinical characteristics, and the presence of ExRA. The prevalence of ExRA was 21.5%, and the most common manifestations were subcutaneous nodules (17.2%) and interstitial lung disease (3.6%). Hispanic patients were significantly more likely to develop ExRA than Asian patients (odds ratio, 2.53; 95% confidence interval, 1.26-5.09). The development of ExRA was also associated with disease duration, male sex, and seropositivity for serum rheumatoid factor.