Vitamin D in rheumatoid arthritis

Keywords::

• disease activity
• rheumatoid arthritis
• vitamin D

Adequate vitamin D (25(OH)D₃) levels are important for optimal functioning of many organs and tissues in the body, being well illustrated by the consequences of 25(OH)D₃ insufficiency. Epidemiological studies indicate that 25(OH)D₃ insufficiency is widespread, exemplified in the Danish population where 25(OH)D₃ insuffiency ≤50 nmoles/l has been demonstrated in 40% of women 45–58 years of age, and 25(OH)D₃ deficiency ≤25 nmoles/l in 7% of perimenopausal women [1].

25(OH)D₃ insufficiency has been associated with many common diseases in the general population, such as osteoporosis, Type I diabetes, thyroiditis, Crohn’s disease, dementia, several types of cancers and cardiovascular diseases, in addition to rheumatic autoimmune disorders such as systemic lupus erythematosus and rheumaoid arthritis (RA). Several studies have confirmed that 25(OH)D₃ insufficiency is common among patients with RA [2,3]. In a recent study, the prevalence of vitamin deficiency (<20 ng/ml) in 4793 Japanese patients with RA was 71.8%, and severe deficiency (<10 ng/ml) was demonstrated in 11.5% of patients [4]. We have recently demonstrated among 302 RA patients in Denmark that the prevalence of 25(OH)D₃ insuffiency (≤50 nmoles/l) was 33.4%, while severe deficiency (≤15 nmoles/l) was found in 5% of the patients [5]. Others have demonstrated, however, that although the prevalence of 25(OH)D₃ insufficiency in RA patients is high, it may not differ from healthy controls [6].

Although the pathogenic importance of hypovitamosis D in RA is still unclear, there appears to be a clearer picture about the risk of developing RA with insufficient intake of 25(OH)D₃ in the diet.

In the Iowa Women’s Health Study, data from a prospective cohort study of 29,368 women 55–69 years of age without a history of RA at study baseline were analyzed [7]. Through 11 years of follow up, 152 cases of RA were validated, and dietary analysis indicated that greater intake of 25(OH)D₃ was inversely associated with risk of RA. The authors concluded that greater intake of 25(OH)D₃ may be associated with a lower risk of RA in elderly women. This hypothesis has not been supported by the Nurses Health Study II, however, which includes a large cohort of 186,389 women followed from 1980 to 2002 [8]. Increasing levels of 25(OH)D₃ intake had no relationship to the relative risk of developing RA in this cohort. A recent meta-analysis of studies with 215,757 participants and 874 incident cases of RA demonstrated, however, that individuals in the highest group for total 25(OH)D₃ supplement intake were found to have a 24.2% lower risk of developing RA than those in the lowest group [9].

One might assume that if 25(OH)D₃ is important for the development of RA, the serum level of 25(OH)D₃ would correlate to disease activity. Accordingly, it has been demonstrated that high disease activity in 96 patients with RA was associated with decreased level of 1,25 dihydroxyvitamin D₃ [10], using CRP as a measure of disease activity. Other small studies have demonstrated a significant negative correlation between the serum level of 25(OH)D₃ and the RA disease activity measured by DAS 28 score, pain and disability. A large study including 1191 patients with RA and 1019 controls recruited from 22 Italian rheumatology centers, concluded that lower serum 25(OH)D3 levels were associated with active disease by a DAS 28 score of >3.1, lack of remission and poor response to therapy, even after adjusting for sunlight exposure and BMI [11]. In a recent study from the UK, however, there was no significant correlation between 25(OH)D₃ and DAS 28 scores with or without the inclusion of VAS, while there was a significant relationship between 25(OH)D₃ and VAS itself [12]. The mean DAS 28 scores were greater in 25(OH)D₃-deficient patients, being explained by their higher VAS scores.

We have recently demonstrated in 302 RA patients no correlation between the disease activity measure DAS 28 without VAS score, and the serum level of vitamin D3 25(OH)D₃ [5]. We did find, however, a subpopulation of RA patients with very low serum level of 25(OH)D₃ (≤15 nmol/l) characterized by all being positive for rheumatoid factor, high proportion of patients with very high disease activity, and high proportion of patients treated with at least three DMARDs, compared with RA patients with normal levels of 25(OH)D₃.

Most of these studies therefore point to an association between low serum level of 25(OH)D₃ and high disease activity, but the results are not entirely clear and unequivocal. It has even been suggested that the 25(OH)D₃ level may decrease in the acute phase response, thereby explaining the low levels in patients with high disease activity [13], and 25(OH)D₃ level may therefore be low for reasons other than lack of exposure to 25(OH)D₃ and may result from the disease rather than produce the disease.

The importance of 25(OH)D₃ deficiency per se for the pathogenesis and development of RA is still unclear, but other factors may act together with 25(OH)D₃ deficiency. 25(OH)D₃ is an immune modulator and regulator of various immune-mediated processes through its effects on monocytes, macrophages and dendritic cells by activation of its receptors (VDRs) on these cells [14]. 25(OH)D₃ may induce innate tolerance by promoting tolerogenic dendritic cells and increase the macrophagic response to infections [15], and exposure to 25(OH)D₃ has also been demonstrated to reduce the antibody production by B cells [16]. The many effects of 25(OH)D₃ on the immune system in relation to RA have been reviewed recently by several authors [14,15,17].

Cardiovascular disease is the most common cause of mortality in patients with RA, accounting for up to 50% of all mortality. An association between 25(OH)D level with dyslipidemia and metabolic syndrome in 499 RA patients [18] has recently been demonstrated. Low-density lipoprotein and triglyceride levels were inversely associated with 25(OH)D3, but high-density lipoproteins were not. The authors of this study also demonstrated an increased risk of metabolic syndrome in RA patients deficient in 25(OH)D₃ with serum levels <20 ng/ml.

As most studies indicate that 25(OH)D₃ insufficiency is associated with high disease activity of RA, probably mediated through the immune system, it would be logical to supplement these patients with 25(OH)D₃. This view has been supported in murine models where experimental arthritis can be prevented by supplementation of 1,25 dihydroxyvitamin D3 [19]. In a recent study, supplementation of 500 IU 1,25 dihydroxyvitamin D3 daily given to previously DMARD-naive patients with early RA along with triple DMARD therapy resulted in significant higher pain relief (50 vs 30%) at the end of 3 months, compared with patients treated with triple DMARD and calcium [20].

The effects of supplementation of 25(OH)D₃ in RA have been addressed only in small open-label studies and interventional trials. 25(OH)D₃ therapy may modify the increased risk of falls and fracture in this group of patients, and possibly exert additional immunomodulatory effects on disease onset. Most clinicians agree with Kerr et al. [2] that with the increasing adverse health outcomes associated with hypovitaminosis D, screening and supplementation should be performed routinely in the RA population.

Financial & competing interests disclosure

H-J Haga was previously a member of the advisory board for Abbvie Denmark. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.