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

NCT ID: NCT00279461

Last Updated: 2015-08-04

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE2
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-31
• Study Completion Date: 2011-05-31

Brief Summary

Recent studies have demonstrated that subjects with low blood levels of vitamin D are at a higher risk of developing autoimmune diseases such as Rheumatoid Arthritis (RA). We are pursuing these studies to test the hypothesis that restoration of vitamin D levels ameliorates the manifestations of RA. We will test this hypothesis by inviting patients with RA to participate in a trial that examines the effects of oral vitamin D administration on the clinical expression of this disease. For this purpose, the participants of this trial will be asked to take an oral dose of 2,000 units of vitamin D daily for 6 months. We will examine the participant's joints, assess disease activity measures, and determine his/her blood levels of vitamin D before starting this treatment and periodically thereafter.

Detailed Description

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..

Conditions

Arthritis, Rheumatoid; Vitamin D Deficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

A,

Arm A: Vitamin D 2,000 units daily all in one capsule for 6 months

Group Type: EXPERIMENTAL

Placebo in arm A and Vitamin D in arm B

Intervention Type: DRUG

Vitamin D3 at 2,000 units daily, all in one capsule, for 6 months and Placebo provided in matching capsule, one capsule daily, for 6 months

B

Arm B: matching placebo one capsule daily for 6 months

Group Type: PLACEBO_COMPARATOR

vitamin D 3 for arm A ,and matching placebo for arm B

Intervention Type: DRUG

Arm A 2,000 units of Vitamin D3 in one capsule daily for 6 months. Arm B matching placebo capsule, one daily for 6 months

Interventions

Placebo in arm A and Vitamin D in arm B

Vitamin D3 at 2,000 units daily, all in one capsule, for 6 months and Placebo provided in matching capsule, one capsule daily, for 6 months

Intervention Type: DRUG

vitamin D 3 for arm A ,and matching placebo for arm B

Arm A 2,000 units of Vitamin D3 in one capsule daily for 6 months. Arm B matching placebo capsule, one daily for 6 months

Intervention Type: DRUG

Other Intervention Names

Vitamin D3 is also called cholecalciferol; Cholecalciferol

Eligibility Criteria

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.

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.

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Indiana University

OTHER

Sponsor Role: lead

Responsible Party

Indiana University

Principal Investigators

Ernesto N Levy, MD

Role: PRINCIPAL_INVESTIGATOR

India na University

Locations

Indiana University

Indianapolis, Indiana, United States

Countries

United States

References

Andjelkovic Z, Vojinovic J, Pejnovic N, Popovic M, Dujic A, Mitrovic D, Pavlica L, Stefanovic D. Disease modifying and immunomodulatory effects of high dose 1 alpha (OH) D3 in rheumatoid arthritis patients. Clin Exp Rheumatol. 1999 Jul-Aug;17(4):453-6.

Reference Type: BACKGROUND

PMID: 10464556 (View on PubMed)

Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxycholecalciferol inhibits the progression of arthritis in murine models of human arthritis. J Nutr. 1998 Jan;128(1):68-72. doi: 10.1093/jn/128.1.68.

Reference Type: BACKGROUND

PMID: 9430604 (View on PubMed)

Adorini L, Penna G, Giarratana N, Roncari A, Amuchastegui S, Daniel KC, Uskokovic M. Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):437-41. doi: 10.1016/j.jsbmb.2004.03.013.

Reference Type: BACKGROUND

PMID: 15225816 (View on PubMed)

Other Identifiers

No secondary ID at this time

Identifier Type: -

Identifier Source: secondary_id

21562

Identifier Type: -

Identifier Source: org_study_id