Severe deficiency of 25-hydroxy vitamin D3 (25-OH-D3) is associated with high disease activity of Rheumatoid arthritis.

Clin Rheumatol.2013 May;32(5):629-633

 Haga H-J, Schmedes AM, Naderi Y, Moreno AM, Peen E

Aalborg University Esbjerg, Denmark

 

ABSTRACT:

Objective:  Measure the serum level of 25-hydroxyvitamin D3 (25-OH-D3) in 302 patients with Rheumatoid arthritis (RA), studying the association to disease activity.

Methods: 302 RA-patients underwent clinical examination and serological analysis. 25-hydroxy vitamin D3 (25-OH-D3) was determined by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS).

Results:  Vitamin D3 deficiency defined as serum levels of 25-hydroxyvitamin D3 (25-OH-D3) below  50 nmol/l, were detected in 101 RA patients (33.4%). There was no significant correlation between the serum level of 25-hydroxyvitamin D3 and DAS28 (3W) score.

In a subpopulation of RA patients with very low serum level of 25-OH-D3 (< 15 nmol/l) (n=15), there were significant differences compared to patients with normal 25-OH-D3 (n=200):  higher percentage of patients with positive rheumatoid factor (100.0 versus 77.5%; p=0.05), higher CRP (28.7 versus 14.8 mg/l; p=0.001), higher number of patients treated with at least 3 DMARDS (40.0 versus 14.5%;p=0.02) higher number of patients with high disease activity DAS 28 score > 5.1 (20.0 versus 4.5%; p=0.01), lower age (54.5 versus 64.0 years;p=0.003) and shorter disease duration (5.1 versus 10.3 years; p=0.06).

Conclusions: Deficiency of 25-hydroxyvitamin D3 (25-OH-D3) was detected in 33,4% of the RA patients. A subpopulation of patients with severe deficiency of vitamin D3 serum level < 15 nmol/l,  was characterized by all being positive for rheumatoid factor, high percentage of patients with very high disease activity, and high percentage of patients treated with at least 3 DMARDs.

 

SUPPLEMENT:

It has been demonstrated  that vitamin D in its physiologically active form (1,25(OH)2D3) has immunoregulatory activities (1), in addition to being a hormone controlling the intestinal  absorption of calcium and phosphorous (2). The  vitamin D receptor (VDR) has been detected in the immune system such as mononuclear cells, dendritic cells, antigen-presenting  cells and activated T-B lymphocytes, and in addition activated dendritic cells produce vitamin D (3,4).

Vitamin D insuffiency 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 rheumatologic autoimmune disorders such as Systemic Lupus Erythematosus and Rheumatoid arthritis (RA).

In the Women’s Iowa Health Study with data from 29.368 women, it was demonstrated that vitamin D intake was inversely associated with the risk of rheumatoid arthritis (RA) (5).  Several studies have confirmed that vitamin D 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% (6).

One might assume  that  if  vitamin D is  important for the development of  RA, the serum level  of vitamin D  would  correlate to disease activity. It is still unclear, however, whether vitamin D insufficiency results in higher disease activity of RA .

The purpose of the present study was therefore to investigate the association between the serum level of vitamin D and disease activity in a large population of 302 patients with RA in a cross sectional study design.

Most of the patients in the present study were treated with Methotrexate (n=213, 70.5%), Sulphasalazine (n=98, 32.5%) and prednisolone (n=90, 29.8%), while 65 patients (21.5 %) were treated with anti-TNF- alpha.

The mean level of 25-hydroxyvitamin D3 (25-OH-D3) in the 302 RA patients was 62.5 nmol/l  (range 4-135). The serum level was 63.8 and 59.7 nmol/l for women and men respectively(NS).  Serum level less than 50 nanomeles/l, the cut-off for normal values, were found in 101 patients (33.4%).

There was neither significant correlation between the serum level of 25-hydroxyvitamin D3 and DAS28 (3W) score , nor to the number of swollen joints.

By comparing demographic, clinical and serological data of the 102 patients with low 25-OH-D3 (< 50 nmol/l) with the 200 patients with normal  25-OH-D3 (> 50 nmol/l) in Table I, the only significant differences were that the age was lower (59.7 versus 64.0 years; p=0.004) and the ESR was higher (24.0 versus 18.6 mm/hour; p=0.02)  in the low versus the normal s-Vitamin D population respectively.  The vitamin D level in men > 60 years (n=63) was not significantly different from rest of the patient population, 65.3 versus 62.0 nmol/l.

We compared  a subpopulation of patients with very low serum level of 25-OH-D3 (< 15 nmol/l) (n=15) versus patients with normal 25-OH-D3 (n=200). There were significant differences in several parameters, such as higher percentage of patients with positive rheumatoid factor (100.0 versus 77.5%), higher CRP (28.7 versus 14.8 mg/l), higher number of patients treated with at least 3 DMARDS (40.0 versus 14.5%), higher number of patients with high disease activity DAS 28 score > 5.1 (20.0 versus 4.5%), lower age (54.5 versus 64.0 years) and lower disease duration since time of diagnosis (5.1 versus 10.3 years).  Among the 307 patients, 262 were examined in the period between October and April, and 45 were examined in the period May and September. There were no significant difference in the Vitamin D level in these periods being 63.1 nmol/l in winter versus 59.6 nmol/l in the summer period. In the winter 13 patients had low Vitamin D lever< 15 nmol/l versus 2 patients in the summer period.

As a conclusion, deficiency of 25-hydroxyvitamin D3 (25-OH-D3) was detected in 33,4% of the RA patients studied. We could not demonstrate any correlation  of serum level of Vitamin D and measures of disease activity, but we found a subpopulation of patients with very low serum level of 25-hydroxyvitamin D3 (25-OH-D3)< 15 nmol/l  characterized by all being positive for rheumatoid factor, high percentage of patients with very high disease activity, and high percentage of patients treated with at least 3 DMARDs.  The population of RA patients with severe Vitamin D deficiency (<20 ng/ml) has recently been demonstrated to be associated with the metabolic syndrome suggesting a potential role in cardiovascular disease risk (7), illustrating the importance of identifying this subpopulation of RA patients.

Our results has recenty been confirmed in study including 1191 patients with RA and 1019 controls recruited from 22 Italian rheumatology centers, concluding that lower serum 25(OH)D levels were associated with active disease defined by a DAS28 score > 3.1 , lack of remission and poor response to therapy, even after adjusting for sun light exposure and body mass index BMI (8)

As these studies indicate that vitamin D insufficiency is associated with high disease activity of RA ,it would be logical to supplement these patients with vitamin D. This view has been supported in murine models where experimental arthritis can be prevented by supplementation of 1,25 dihodroxy vitamin D3 (9). In a recent study, supplemenation of 500 IU 1,25 dihydroxy vitamin D3 daily 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 than compared to patients treated with triple DMARD and calcium (10).

The effects of supplementation of vitamin D in RA have been adressed only in small open-label studies and interventional trials. Vitamin D 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 Keer GS et.al (11) that with the increasing adverse health outcomes associated with hypovitaminosis D, screening and supplementation should be performed routinely in the RA population.

For review of Vitamin D in Rheumatoid Arthritis, see Ref. 12.

 

References:

  1. Arnson Y, Amital H, Shoenfeld Y: Vitamin D and autoimmunity: new ethiological and therapeutic considerations. Ann Rheum Dis  2007; 66: 1137-42.
  2.  Holick MF: Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;  6:1678S-1688S.
  3. Deluca HF, Cantorna MT: Vitamin D: its role and uses in immunology. FASEB  J 2001; 15: 2579-2589.
  4. Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M:  Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha 25-dihydroxyvitamin D3 by human dendritic cells. Blood 2003; 102: 2214-3316.
  5. Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KW, Iowa Women’s Health Study : Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 2004; 50:72-77.
  6. Furuya T, Hosoi T, Tanaka E, et al. Prevalence of and factors associated with vitamin D deficiency in 4793 Japanese patients with rheumatoid arthritis. Clin Rheumatol 2013; Jul 32(7): 1081-87
  7. Baker JF, Mehta NN, Baker DG, Toedter G, Von Feldt JM Leonard MB. Vitamin D, metabolic dyslipidemia, and metabolic syndrome in rheumatoid arthritis. Am J Med 2012; oct125(10): 1036.e9- 1036.e15.
  8. Rosini M, Maddali Bondi S, Montagna G, et al. Vitamin D deficiency in rheumatod arthritis: prevalence, determinants and associations with disease activity and disability. Arthritis Res Ther 12(6): R216 (2010)
  9. Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxycholeclciferol inhibits the progression of arthritis in murine models of human arthritis. J Nutr 128:68-72( 1998).
  10. Gopinath K, Danda D:. Supplementation of 1,25 dihydroxy vitamin D3 in patients with treatment naive early rheumatoid arthritis: a randomised controlled trial. Int J of Rheumatic Diseases 14:332-339 (2011)
  11. Kerr GS, Sabahi I, Rchards JS, et al. Prevalence of Vitamin D deficiency in Rheumatoid Arthritis and Associations with Disease Severity and Activity. J Rheumatol 38(1):53-9 (2011).
  12. Haga HJ: Vitamin D in Rheumatoid Arthritis. Expert Rev Clin Immunol 2013 Jul; 9(7):591-3.
Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann