Vitamin D and rheumatoid arthritis: an ongoing mystery - Autoimmunity ...

CE: Alpana; BOR/290406; Total nos of Pages: 11;

BOR 290406

REVIEW URRENT C OPINION

Vitamin D and rheumatoid arthritis: an ongoing mystery Nicola L. Bragazzi a,, Abdulla Watad b,c,d,, Shana G. Neumann d, Michael Simon d, Stav B. Brown d, Arsalan Abu Much b,d, Adam Harari d, Shmuel Tiosano b,d, Howard Amital b,c,d, and Yehuda Shoenfeld c,d

Purpose of review In recent years, there has been a growing interest in the value of vitamin D and its effects on autoimmunity. The aim of this review is to summarize the current knowledge on the association between vitamin D and rheumatoid arthritis (RA) in terms of prevalence, disease activity, clinical expression, serology and gene polymorphisms of vitamin D receptors. Recent findings Studies have shown contrasting findings concerning the association between vitamin D levels and RA. Vitamin D seems to have immunomodulatory properties. Therefore, low vitamin D levels could contribute to increased immune activation. However, the potential role of vitamin D supplementation in preventing RA manifestation and its beneficial role as a component of RA treatment remain controversial. The relationship between RA susceptibility and vitamin D polymorphisms is also unclear. Summary Despite advancements synthesized by some recent meta-analyses, the relationship between vitamin D and RA requires further evaluation. Further research is needed to confirm the relationship between RA susceptibility and vitamin D polymorphisms and to determine whether vitamin D plays a role in preventing the manifestation of RA. Finally, additional studies are required to determine the impact and optimal amount of vitamin D supplementation in the treatment of RA patients. Keywords autoimmunity, gene polymorphism, immunomodulation, rheumatoid arthritis, vitamin D

INTRODUCTION Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation involving the joints, synovial membrane, and occasionally, extra-articular organs. RA prevalence ranges from 0.4 to 1.3% worldwide [1,2], increasing with age and being more common among women [3,4]. RA causes a high disability rate and may lead to premature death [5]. Inflammatory arthritis which has a substantial socioeconomic burden is mostly caused by RA [6]. Still, the cause of RA has yet to be elucidated. Recently, vitamin D has been shown to possibly serve as a therapeutic agent in RA patients [7]. Infection and autoimmune responses play a main role in RA development and progression, as well as genetic and environmental factors [8]. Antibodies to citrullinated peptide antigens [9,10] activate Th-1 cells and stimulate secretion of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-a [11,12], which serve as mediators of the continuous

activation process of B cells [11–13]. As such, therapies like anti-TNF-a agents can decrease bone and cartilage damage by cell-specific targeting of cytokine activity [14]. Vitamin D can decrease IL-17, IL-6, IL-1 and TNF-a production inhibiting Th1 cells, as well as the release of IL-2 and interferon g by CD4þ cells, a

School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy, bDepartment of Medicine B, c Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer and dSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Correspondence to Professor Yehuda Shoenfeld, MD, FRCP, MaACR, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (Affiliated to Tel-Aviv University), Tel-Hashomer 5265601, Israel. Tel: +972 3 535 2855; fax: +972 52 666 9020; e-mail: [email protected]

Nicola L. Bragazzi and Abdulla Watad share equal contribution.

Curr Opin Rheumatol 2017, 29:000–000 DOI:10.1097/BOR.0000000000000397

1040-8711 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.

www.co-rheumatology.com

Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

CE: Alpana; BOR/290406; Total nos of Pages: 11;

BOR 290406

Infections and environmental aspects of autoimmunity

KEY POINTS From a biological standpoint, it has been hypothesized that vitamin D could have immunomodulatory properties and that, as such, low vitamin D levels could contribute to increased immune activation, thus playing a role in RA pathogenesis. Studies have shown contrasting findings concerning the association between vitamin D levels and RA, both in terms of the potential impact of vitamin D supplementation on RA and the relationship between RA susceptibility and vitamin D polymorphisms. Further research is needed to confirm the relationship between RA susceptibility and vitamin D polymorphisms and to determine whether vitamin D plays a role in preventing the manifestation of RA.

implicated in the etiopathogenesis of RA [15,16]. Vitamin D may also inhibit the proliferation of B cells and induce apoptosis, leading to reduced autoantibody production due to decreased plasma cell production and immunoglobulin class switching [17]. Moreover, vitamin D decreases autoreactivity by modulating the proinflammatory and antiinflammatory cytokines secreted by antigen-presenting cells (APCs) [18,19]. Polymorphisms of the vitamin D receptor (VDR) and 1-a-hydroxylase [20] genes can also confer susceptibility.

THE CORRELATION BETWEEN VITAMIN D AND RHEUMATOID ARTHRITIS Several interventional studies have evaluated the relationship between vitamin D insufficiency and RA (Table 1) [7,11,21–49]. Yang et al. [7] investigated the effect of vitamin D supplementation on RA, enrolling two groups of patients: one with sufficient vitamin D amount and one with vitamin D deficiency. The latter group was further divided into a subgroup receiving vitamin D treatment (a-calcidol, 0.25 mg twice/day) and one under no pharmacological treatment. All groups were followed up for 2 years, and their visual analogue scale (VAS), as well as inflammatory biomarkers [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)] and the number of painful and swollen joints were recorded every 2–3 months. No difference was found between the vitamin D insufficient subgroups. However, RA flare rate in the vitamin D sufficient group was lower compared with the vitamin D-deficient subgroup receiving no treatment. Chandrashekara et al. [43] evaluated the use of vitamin D supplementation in 150 RA patients 2

www.co-rheumatology.com

under disease-modifying antirheumatic drugs for at least 3 months. Disease activity score with the 28 Joints-CRP (DAS28-CRP) and vitamin D levels were measured. A total of 49% of patients showed a DAS28-CRP more than 2.6 and vitamin D levels less than 20 ng/ml, and therefore, received vitamin D supplement of 60 000 IU/week for 6 weeks, followed by 60 000 IU/month for a total duration of 12 weeks. A significant improvement in the mean DAS-28-CRP was found (3.68 at baseline versus 3.08 after vitamin D treatment). Vitamin D significantly increased from a mean of 10.05 to 57 ng/ml. A meta-analysis by Song et al. [49], pooling together three cohort studies (215 757 participants and 874 incident RA cases) and eight studies (2885 RA patients and 1084 controls), showed a 24.2% lower risk of developing RA with higher vitamin D intake. Considering vitamin D uptake, the relative risk (RR) of suffering from RA was 0.76 [95% confidence interval (CI) 0.58–0.94], whereas considering vitamin D supplement intake, RR was 0.76 (95% CI 0.63–0.93). Varenna et al. [42] assessed the relationship between vitamin D supplementation and age and bone density. More than one-half of the population was not taking supplements. However, among those taking supplementation, more than one-third were taking insufficient dosages (440 IU/day). Among those taking the recommended daily dose of at least 800 IU, approximately 30% were still unable to reach adequate vitamin D levels, probably because of a decreased sun exposure and/or to a higher health assessment questionnaire (HAQ) score. Atwa et al. [22], recruiting 95 individuals (55 cases and 40 controls), found that 25(OH)D levels were significantly decreased in RA patients (15.45 6.42 versus 24.55 11.21 ng/ml). The prevalence of vitamin D deficiency was evaluated in 1191 RA patients versus 1019 controls [32]. A total of 55% of the RA patients were not taking supplementation and, within this group, only 52% were vitamin D deficient, similarly to healthy controls. However, many RA patients who received supplementation still remained vitamin D deficient. In addition, vitamin D inversely correlated with disease activity and the Steinbrocker functional state. When adjusting vitamin D levels for BMI and sun exposure time, the negative association between disease activity and vitamin D levels remained significant. A prospective cohort study [45] assessed the association between vitamin D and RA activity. Twenty-nine thousand three hundred and sixtyeight women without a history of RA, aged 55–69, were observed. Their diet included supplemental vitamin D usage. During the 11-year follow up, Volume 29 Number 00 Month 2017

Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Study design

1040-8711 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.

Retrospective

Retrospective

Cohort study

Retrospective case–control

Retrospective

Higgins et al. [27]

Kerr et al. [28]

Kostoglou-Athanassiou et al. [29]

Kostoglou-Athanassiou et al. [29]

Moghim et al. [30]

Population-based study

Retrospective

Haque et al. [26]

Raczkiewicz et al. [33]


Cutolo et al. [25]

Retrospective


Baykal et al. [24]


Retrospective

Azzeh et al. [23]

Rossini et al. [32]

Cross-sectional study

Atwa et al. [22]

Oelzner et al. [31]

Retrospective

Abourazzak et al. [21]

Observational studies which found a correlation

Reference

2015

2010

1998

2012

2012

2008

2011

2013

2010

2006

2012

2015

2013

2015

Year

97

1191

96

158 87 active 71 silent RA

44

44

850

176

62

64 Estonian 54 Italian

55

102

55

170

No. of RA patients

76.3% of patients

52%

The VD levels in patients with active RA were lower than in those with silent RA (49.38 38.2 versus 64.64 43.61 nmol/l; P ¼ 0.022)

15.26 1.07 ng/ml

The VD insufficiency and deficiency were 84 and 43%, respectively VD level 15.26 1.07 ng/ml

Mean VD level was 39.42 nmol/l

61% were VD deficient

90.9% of patients had VD