Vitamin D Deficiency Causes Immune Dysfunction and Enables or Perpetuates the Development of Rheumatoid Arthritis

Rationale : Low vitamin D levels hinders the ability of the macrophage to produce activated
1-25Dihydroxyvitamin at sites of inflammation. 1-25Dihydroxyvitamin D has important
immunoregulatory functions including down-regulation of antigen-presenting cells such as
dendritic cells. Under the influence of 1-25Dihydroxyvitamin D, these dendritic cells become
tolerogenic ─ as opposed to immunogenic ─ and abrogate an immune response at early stages.
Immunogenic dendritic cells play a key role in the development of autoimmune diseases such
as Rheumatoid Arthritis (RA) by "presenting" self-antigens to the immune system. Vitamin D
levels are frequently low in patients with RA. Restoring vitamin D availability to normal
levels in patients with RA may induce improvement of disease manifestations through
expansion of the tolerogenic dendritic cell subset.

Key Objectives:

- Conduct a double-blind randomized clinical trial, to test the hypothesis that vitamin D
administered to patients with active RA has beneficial effects on this disease.

- Determine if vitamin D administered to patients with RA. induces expansion of the
tolerogenic dendritic cell subset by analyzing patterns of cell surface marker
expression on dendritic cells at different time points during the clinical trial
(translational studies).

Study Population: We will recruit early RA patients (not more that 12 month duration of
disease)with active joint inflammation cared for at this institution.Participants must be
subjects with active RA at the time of inclusion, who are 18 years of age or older and have
no history of other autoimmune disorders or other disorders such as cancer or osteoporosis
which are also linked to vitamin D deficiency. The eligible patients with active RA should
be on treatment for RA with Methotrexate at the time of inclusion. Patients taking
anti-cytokine treatments (considered not standard) would be excluded. Other exclusions
include hypercalcemia, and a history of renal failure or renal stones.

20-25 participants will be allocated to the Vitamin D Group, Arm A. 20-25 participants will
be allocated to Placebo Group Arm B Allocation will be conducted in a randomized,
double-blind fashion.

Summary of Procedures : After signing a written consent, all potential candidates will
undergo a screening interview with the PI and screening blood tests (a blood sample of 20 ml
is required).

RA subjects who qualify to receive the study treatment will be randomized to receive oral
vitamin D 2,000 units or placebo daily for 6 months. Patients will be examined on a monthly
basis and will be drawn a 20 ml blood sample every 2 months for monitoring purposes for a
period of 12 month. The participants within the clinical trial who also participate in the
translational studies on dendritic cells, will be drawn an additional blood sample of 40 ml
on the first month and at the end of the study to isolate their blood dendritic cells. We
will study the expression of different activation markers on dendritic cells from consenting
participants using various immunologic techniques. This will allow us to identify and
quantify the tolerogenic dendritic cells..

Inclusion Criteria:

This study will involve two groups of patients fulfilling the following eligibility
requirements:

- they should have early (not more than 12 month duration) active RA as determined by
the diagnostic criteria and active status definitions as described below, and

- they should have at the time of inclusion a 25(OH)vitamin D level below 30 ng/ml.

- All RA patients in this study will satisfy the American Rheumatism Association 1987
revised criteria for the diagnosis of RA. Active disease will be defined by the
presence of at least 3 swollen joints, ≥6 tender or painful joints and at least 2 of
the following features: duration of morning stiffness 60 minutes, erythrocyte
sedimentation rate (ESR) ≥28 mm/hour and serum CRP level of at least 2.0 mg/dl (26).

- Only research subjects of either gender who are 18 years of age or older will be
invited to participate.

- One group, Group A, will include active RA patients receiving treatment with
methotrexate. A concomitant prescription of non-steroidal anti-inflammatory drugs
(NSAIDs), and/or Prednisone ≤ 10 mg/day will be allowed. Treatment with anti-TNF
agents, Abatacept or other immunosuppressives constitute exclusion criteria.

- To minimize the impact of pre-existing treatments on the final outcome of this trial,
patients taking NSAIDs and/or prednisone will be required to receive unchanged doses
of these medications for at least 1 month. No modifications of these treatments will
be allowed during the study. In addition to their methotrexate treatment, patients
within Group A will receive placebo every day for 12 consecutive months.

- The second group, Group B, will include those patients as described for Group A who
instead of placebo will receive oral vitamin D, 1,000 units every day for 12
consecutive months added to their standard RA treatment.

Exclusion Criteria:

- Because cancer and other autoimmune diseases may be more frequent in individuals with
a moderate deficiency of vitamin D, subjects with a history of these conditions will
be excluded. Because of the remote possibility of vitamin D-induced hypercalcemia, we
are aiming at recruiting patients with RA who are otherwise healthy. We will exclude
patients who in the past had or currently have cancer (except if considered cured),
kidney stones, chronic renal failure, congestive heart failure, arrythmia requiring
treatment with antiarrythmics, pulmonary conditions requiring ambulatory oxygen,
abnormal levels of calcium or elevated PTH.

- Patients who use Digoxin (drug interaction), or had experienced angina or myocardial
infarction in the last 3 years also will be excluded, but patients whose coronary
artery disease has been asymptomatic for at least 3 years and who do not have
congestive heart failure will be allowed to participate.

- Patients who develop hypercalcemia, kidney stones, elevation of 25(OH)vitamin D> 90
ng/ml also will be excluded.