Vitamin D in Rheumatoid Arthritis This document summarizes several studies that examine the relationship between vitamin D levels and rheumatoid arthritis (RA). RA is an autoimmune disease characterized by inflammation of the joints that can lead to disability. Some studies found that RA patients had lower vitamin D levels compared to healthy individuals, and lower vitamin D levels were associated with higher disease activity and reduced remission rates. However, one study found no correlation between vitamin D levels and RA risk. Vitamin D may help regulate the immune system and inhibit inflammatory responses, so maintaining adequate vitamin D levels could potentially help moderate RA symptoms, but more research is still needed to fully understand this relationship.

1. Vitamin D in Rheumatoid Arthritis
Abstract
Objectives
Introduction and Background
Physiological Aspects of RA
Associated Role of Vitamin D
Research: The Correlation Between Vitamin D and RA
Implications and Conclusions
References
Fall 2015
Madysen Jourgensen, Elizabeth Harris, Molly Carroll
Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO.
(Lang PO, Aspinall R, 2015)10
Purpose Methods Results
Study 1: Determine whether serum vitamin D levels
influence the recurrence rate of RA.6(1812-1816)
RA remission patients divided into normal vitamin D
(n=168) and vitamin D deficient groups (n=172) at
baseline of the study. Vitamin D deficient group divided
into vitamin D treatment (n=84) and non-
treatment/control (n=88) groups. Followed for 24
months.
Normal vitamin D group had lower recurrence rate
(16.7%) of RA with a statistically significant difference
(P=0.02) between recurrence rate in control group
(29.5%). Difference between recurrence rate of vitamin
D treatment group (19.0%) and control group was not
statistically significant (P=0.11).
Study 2: Discover whether RA activity and treatment
success is correlated with serum vitamin D levels at
time of diagnosis.3(1-8)
Patients recently diagnosed with RA (n=37) had vitamin
D levels measured at baseline of study. Patients divided
into low and adequate vitamin D groups. RA activity
observed in two groups for 12 months.
Low vitamin D group had higher disease activity than
adequate vitamin D group. Significantly lower remission
rates (P<0.001) in low vitamin D group (16% remission)
versus adequate vitamin D group (68% remission).
Study 3: Determine the correlation of vitamin D levels
and RA.7(1994-2001)
Serum levels of active vitamin D measured in RA
patients (n=130) and healthy control group (n=80).
Disease activity compared to vitamin D status within RA
group.
Serum vitamin D levels significantly lower in RA patients
than control group (P<0.01). RA patients with severe
disease activity had significantly lower vitamin D levels
compared to RA patients with moderate and low
disease activity (P<0.01).
Study 4: Examine the relationship between vitamin D
status and incidence of RA using electronic health
records.8(1475-1479)
Most recent vitamin D status of individuals with RA
(n=270) and non-RA controls (n=1,341) compared in
final analysis. Vitamin D levels of groups analyzed with
three cut-off values – continuous, <30 ng/mL, and <20
ng/mL – and compared.
No correlation found between vitamin D status and RA
development. Odds ratios RA vs. controls at continuous,
<30 ng/mL, and <20 ng/mL vitamin D levels: 1.00, 0.98,
1.12.
Study 5: Understand how serum vitamin D relates to RA
and RA disease activity.9(246-250)
Vitamin D levels of RA patients (n=181) and healthy
controls (n=186) assessed with diet history
questionnaires and serum measurements. Disease
activity of RA patients evaluated as well.
Serum vitamin D levels significantly lower in RA patients
versus healthy controls (P<0.01), but disease activity
not correlated to vitamin D levels in RA patients
(P=0.129).
Rheumatoid arthritis (RA) is a serious autoimmune
disease that can cause severe disability. Research has
shown a possible correlation between low serum
vitamin D levels and the risk for developing RA and
experiencing increased disease activity. Because it is
known that vitamin D acts as an immunoregulatory
component in the body, it is hypothesized that vitamin
D may moderate an antigen-specific autoimmune
response in RA. However, not all studies have shown a
correlation between serum vitamin D and RA risk and
disease activity; therefore, further research is
encouraged to provide more knowledge about the
relation of vitamin D to the disease.
1. Discuss the disease process, symptoms, and etiology
of RA.
2. Discuss how the nutrient vitamin D could possibly
relate to the disease process of RA and affect its
symptoms.
3. Analyze what recent research has concluded about
vitamin D and RA.
4. Discuss the implications of vitamin D/RA research
and its importance in the treatment of RA.
Rheumatoid Arthritis
RA is an autoimmune disease that is classified by affecting five
or more joints in the body. The synovial membrane of the
joints is predominantly affected by inflammation, and this
leads to corrosion of bones and cartilage which may cause
deformity.1 Across the world, RA is the most widespread of
inflammatory diseases. In America, it affects 1.5 million adults
and 294,000 individuals under the age of 18.2(4403) RA can
eventually lead to an individual’s demise by causing disability
and early death.1
Vitamin D
The biologically active form of vitamin D (1,25-
dihydroxyvitamin D) contributes to calcium, bone and
immunological homeostasis. Research has shown that vitamin
D may reduce disease activity levels of RA while
hypovitaminosis D has shown a correlation with increased risk
of developing the disease.3(2)
RA affects the synovium – a soft-tissue membrane lining the joint
cavity.2(4403) Immune cells and the release of inflammatory
cytokines create inflammation in this membrane.4(1-2) Eventually,
the synovium thickens due to chronic inflammation,4(1) causing a
restriction of movement, hindrance of ligaments, and a
breakdown of the cartilage and bone in the joint.2(4403) RA
generally begins in the smaller joints of the body, commonly in
the feet and hands, and later moves to the larger joints.2(4404)
However, the effects of RA are not limited to the joints.
Inflammation known as vasculitis may be present in the blood
vessels, limiting flow blood, causing ulcers on the skin and heart
problems. Additionally, rheumatoid nodules – hard bumps
resulting from inflammation – may eventually develop beneath
the skin and on organs. Reduced bone density and osteoporosis
can occur from mobility loss and inadequate vitamin D.4(2-6) The
etiology and disease process of RA are not yet fully understood. It
is hypothesized that factors in the environment, such as an
infection, may begin the development of RA in those that already
have the genetic predisposition; however, no antigen that may
cause the disease can be identified.2(4404) Although no cure is
available for RA, early treatment – such as disease modifying
drugs, physical therapy, and diet, can moderate symptoms.2(4406-
4407)
Multiple studies have shown that hypovitaminosis D may be
linked to increased disease activity in those suffering from
RA.5(61) This could be related to evidence that vitamin D can act
as an immunoregulatory component in the body. Vitamin D
receptors are located in the primary lymphoid organs, which
consist of the bone marrow and the thymus, the chief centers
for immune system development and differentiation. In
addition, vitamin D receptors are found on several immune
cells including mononuclear cells, dendritic cells, activated T
and B cells, and antigen-presenting cells. The number of
vitamin D receptors on helper T cells (CD4+ T cells) increases
after their activation, further emphasizing the apparent
involvement of vitamin D in an immune response.5(60) Multiple
immune cells have even been found to have the ability to
produce vitamin D.10(2045) In relation to autoimmunity, studies
show that vitamin D may act primarily through the inhibition of
Th1 cell proliferation, which are cells involved in the activation
of many other immune cells in the antigen-specific response of
the immune system. In the case of RA, vitamin D may inhibit
Th1 cell differentiation and proliferation and therefore impede
a resultant antigen-specific autoimmune response.5(61-62)
Refer to figure
1. Rheumatoid Arthitis. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/arthritis/basics/rheumatoid.htm.
Updated November 6, 2014. Accessed October 11, 2015.
2. Laberge M, Cataldo LJ, Alic M. Rheumatoid arthritis. In: Longe JL, eds. Gale Encyclopedia of Medicine. 5th ed. Vol. 7. Farmington
Hills, MI: Gale Research Inc; 2015:4403-4408.
3. Franco M, Barchetta I, Iannuccelli C, et al. Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced
response to treatment and increased disease activity: a 12 month follow-up study. BMC Musculoskelet Di. March 2015; 16 (53):1-
8. doi: 10.1186/s12891-015-0505-6.
4. Wordsworth P, Holden W. Rheumatoid arthritis. Encyclopedia of Life Sciences. Chichester, England: John Wiley & Sons Ltd; 2006:1-
8.
5. Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B. Vitamin D in rheumatoid arthritis. Autoimmun Rev. 2007; 7(1): 59-64. doi:
10.1016/j.autrev.2007.07.001.
6. Yang J, Liu L, Zhang Q, Li M, Wang J. Effect of vitamin D on the recurrence rate of rheumatoid arthritis. Exp Ther Med. 2015; 10(1):
1812-1816. doi: 10.3892/etm.2015.2747.
7. Hong Q, Xu J, Xu S, Lian L, Zhang M, Ding C. Associations between serum 25-hydroxyvitamin D and disease activity, inflammatory
cytokines and bone loss in patients with rheumatoid arthritis. Rheumatology. 2014; 53(1): 1994-2001. doi:
10.1093/rheumatology/keu173.
8. Cote J, Berger A, Kirchner LH, Bili A. Low vitamin D level is not associated with increased incidence of rheumatoid arthritis.
Rheumatol Int. 2014; 34: 1475-1479. doi: 10.1007/s00296-014-3019-x.
9. Matsumoto Y, Sugioka Y, Tada M, et. al. Relationships between serum 25-hydroxycalciferol, vitamin D intake and disease activity in
patients with rheumatoid arthritis – TOMORROW study. Mod Rheumatol. 2014; 25(2): 246-250. doi:
10.3109/14397595.2014.952487.
10. Lang PO, Aspinall R. Can we translate vitamin D immunomodulating effect on innate and adaptive immunity to vaccine response?
Nutrients. 2015; 7(3): 2044-2060. doi: 10.3390/nu7032044.
Considerable amounts of research have been done in regards to
vitamin D status and its relationship to the risk and severity of RA.
Although most research has shown a positive relationship between
vitamin D status and decreased RA activity, some studies have shown
no correlation. Due to inconclusive evidence between studies, it is
highly suggested that research continue on the topic of vitamin D
status and its role in RA.
Depiction of how vitamin D works in the immune system
The active form of vitamin D is produced in the body through the action of sunlight, the
liver, and the kidney. Through intracrine, paracrine, and endocrine signaling in immune
cells, vitamin D can assist in both increasing a protective immune response and
modulating an over-active immune response. Shown here, vitamin D impairs dendritic
cell maturation via an intracrine pathway, inhibiting the proliferation of the helper T-cell
and its release of inflammatory cytokines via a paracrine pathway.10(2047-2049)