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Vitamin D, Autoimmune Disease and Rheumatoid Arthritis.

ABSTRACT: Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)₂D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH)₂D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells. In addition, antigen-presenting cells have been shown to express the enzyme 1?-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH)₂D3, so that immune microenvironments are able to both activate and respond to vitamin D. As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA). The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA. As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA. The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.

SUBMITTER: Harrison SR

PROVIDER: S-EPMC6960236 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Vitamin D, Autoimmune Disease and Rheumatoid Arthritis.

Harrison Stephanie R SR Li Danyang D Jeffery Louisa E LE Raza Karim K Hewison Martin M

Calcified tissue international 20190708 1

Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)<sub>2</sub>D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH)<sub>2</sub>D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory ...[more]

PMID: 31286174

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Project description:BackgroundPrevious studies have linked rheumatoid arthritis (RA) risk and disease activity with vitamin D-deficiency (low serum 25-hydroxyvitamin D (25OHD)), but a causal role for vitamin D in RA is still unclear, with conflicting results from many previous studies, partly due to heterogeneity in study design and patient populations. In this study we aimed to (1) analyse serum 25OHD in early inflammatory arthritis, (2) compare 25OHD with disease activity and fatigue in early RA and (3) determine whether low 25OHD is associated with progression to RA.MethodsAn analysis of 790 patients recruited to the Birmingham Early Inflammatory Arthritis Cohort and followed longitudinally to determine clinical outcomes. The following were recorded at baseline: demographic data, duration of symptoms, duration of early morning stiffness (EMS), tender and swollen joint counts, Visual Analogue Scale (VAS) pain/fatigue/EMS, PHQ-9, HAQ and FACIT-Fatigue scores, DAS28-ESR, DAS28-CRP, CRP, ESR, anti-CCP antibody status, rheumatoid factor status, and serum 25OHD (ng/ml). Diagnosis was recorded at 0 and 12 months onwards as either RA, Undifferentiated Inflammatory Arthritis (UIA; synovitis not meeting other classification/diagnostic criteria), Clinically Suspect Arthralgia (CSA; arthralgia of an inflammatory type without synovitis), or Other.ResultsBaseline demographic data were similar between all groups, with median symptom duration of 16.8-34.0 days. Baseline 25OHD was not significantly different between groups [median, interquartile range (IQR): RA 46.7, 30.0-73.3; UIA 51.4, 30.0-72.3; CSA 47.7, 30.3-73.0; Other 39.9, 28.6-62.2]. In RA (n = 335), there were no significant differences between 25OHD and measures of disease activity or fatigue. No association between 25OHD and progression from UIA or CSA to RA was observed.ConclusionsThere was no clear association between serum 25OHD and baseline diagnosis, RA disease activity, or progression from UIA or CSA to RA. Future studies of other vitamin D metabolites may better define the complex role of vitamin D in RA.

Project description:IntroductionIn rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.MethodsThe level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.ResultsPlasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.ConclusionsThe plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.

Project description:ImportanceAutoimmune thyroid disease ([AITD] including hypothyroidism and hyperthyroidism) is the most common organ-specific autoimmune disorder and is more prevalent among patients with rheumatoid arthritis (RA). Real-world studies on when and how this increased risk of AITD develops, in association with the time before or after the onset of RA, are lacking.ObjectiveTo estimate the risk of thyroxine-treated AITD among patients with RA at different time points before and after the diagnosis of RA.Design, setting, and participantsA nationwide register-based case-control and cohort study was conducted between January 1, 2006, and June 30, 2013, with a maximum follow-up time of 7 years before and 8 years after diagnosis of RA. The study used the Swedish Rheumatology Quality Register and linkage to other nationwide registers to identify 8090 adults with new-onset RA and a random population-based sample of 80 782 referents matched by age, sex, and residential area. Statistical analysis was performed from July 1, 2015, to June 30, 2017.ExposuresPresence of AITD in the participants in the case-control design and RA in the participants in the cohort design.Main outcomes and measuresPrevalence and relative risk of incident AITD before (odds ratios) and after (hazard ratios) diagnosis of RA compared with the population as reference.ResultsThere were 8090 patients with RA (5529 women and 2561 men; mean [SD] age, 58.3 [15.2] years) and 80?782 population-based participants as reference who were identified. By the time of diagnosis of RA, the prevalence of AITD was 10.3% among the patients with RA (n?=?832) vs 7.1% among the controls (5725 of 80?350) (odds ratio, 1.5; 95% CI, 1.4-1.7). This increased risk of AITD developed during the 5 years (range, 2-5 years) before diagnosis of RA (odds ratio, 1.5; 95% CI, 1.2-1.8) and peaked by the time of diagnosis of RA (range, 0-3 months before diagnosis of RA) (odds ratio, 5.3; 95% CI, 3.7-7.6). From diagnosis of RA and onward, the risk of developing AITD decreased (range, 2-5 years after diagnosis of RA) (hazard ratio, 0.7; 95% CI, 0.5-1.0).Conclusions and relevanceCompared with the general population, Swedish patients with RA appear to have a higher prevalence of thyroxine-treated AITD at diagnosis of RA and an increased incidence of AITD during the 5-year period before diagnosis of RA. After diagnosis of RA, the risk of developing AITD is suggested to decrease below the expected rate. Besides temporal changes in diagnostic intensity, this pattern of risk raises the question whether AITD may influence the pathogenesis of RA (or vice versa) and, conversely, the question whether antirheumatic therapies may prevent AITD.

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Vitamin D, Autoimmune Disease and Rheumatoid Arthritis.

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Vitamin D, Autoimmune Disease and Rheumatoid Arthritis.

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