Comparison of the Tuberculin Skin Test (TST) and QuantiFERON ®-TB Gold Test (QFT-G) In Patients With Rheumatoid Arthritis Being Considered for Anti-TNF-Alpha Therapy

Sponsor

Walter Reed Army Medical Center (U.S. Fed)

Overall Status

Unknown status

CT.gov ID

NCT00925249

Collaborator

National Naval Medical Center (U.S. Fed)

Enrollment

Location

Duration (Months)

3.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This research will help doctors interested in the usefulness of a new test to discover hidden tuberculosis infections in patients diagnosed with rheumatoid arthritis (RA). This new test is called Quantiferon-Gold (QFT-G). After immune system medicines that block TNF-alpha (a protein manufactured by white blood cells to stimulate and activate the immune system in response to infection or cancer) started to be used, the rate of tuberculosis infections in patients treated with these medicines has increased. Doctors think that the investigators may be missing some tuberculosis infections that were hidden before the medicine is started. This new QFT-G test might better diagnose these hidden tuberculosis infections than the current tuberculosis skin test, also known as a PPD/TST. The investigators would like to compare these two tests to find out which is better at detecting these hidden infections. At the same time the investigators will measure the strength of the patient's immune system with a blood test. If you are being considered for a TNF-alpha inhibitor medicine, or are getting the patient's routine PPD/TST, the investigators are asking for the patient's participation.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis Tuberculosis

Detailed Description

In recent years the use of biologic agents for the treatment of rheumatic conditions has called into question the utility of the classic tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI). Current clinical rheumatology practice requires potential candidates of biologic therapy to have a negative TST before beginning biologic therapy. But since the TST is time consuming, operator dependent, and fraught with error, it may fail to alert physicians of LTBI in patients with autoimmune diseases and or pharmaceutical immunosuppression. Reactions to intradermal antigen placement requires many cellular interactions, but chiefly they must possess , a sufficient number of memory T cells, the ability to proliferate a clone of T cells specific to the antigen that is introduced, and the ability to traffic these effector cells to the local site. If any of these components are missing the individual may be unable to mount a type IV hypersensitivity (DTH-IV) reaction which is the basis for the TST. While many have recently compared the performance of the new IFN-gamma release assays (IGRAs) like the QuantiFERON-γ TB GOLD® (QFT-G) to the TST for the diagnosis of LTBI, no one has investigated the immunologic factors that may affect these results. Some have postulated that the QFT-G may be less affected by immune-suppression than the TST in patients with rheumatoid arthritis (RA). But recently this was called into question when significant numbers of indeterminate QFT-G results were seen in RA patients. Therefore, we plan to address two current clinical questions. First, what is the best screening strategy for LTBI in RA patients being started on biologic agents - TST, QFT-G or both? Second, is there utility in conducting immune competence testing in RA patients to predict those whom may be unable to generate a positive TST and/or QFT-G. This observational and exploratory pilot study will compare normal matched controls to RA patients being considered for anti-TNF alpha therapy. We will perform a comprehensive evaluation of the immune system by measuring memory T cell numbers with flow cytometry, the ability of memory T cells to proliferate to the tuberculin antigen or purified protein derivative (PPD), and phytohemagglutinin (PHA) antigen via the lymphocyte proliferation assay QunatiFERON-CMI.™ We will also investigate memory T cell trafficking ability via intradermal PPD and PHA antigen placement. Results of QFT-G tests will be compared to the TST with an emphasis on those results which are discordant. We will further attempt to identify immunocompetence testing which may help identify those patients who are unable to mount a DTH-IV response. In order to detect a statistical difference in this specific test population we will use analysis of variance for continuous or ordinal variables and the chi-square test (or Fisher exact test) for categorical data statistics. We hope to contribute to the body of literature regarding the best screening strategy for LTBI in patients with RA, and explore the concept of screening for immune competence in this specific population, which has not been elucidated in the literature.

Study Design

Study Type:

Observational

Anticipated Enrollment :

90 participants

Time Perspective:

Prospective

Official Title:

Comparison of the Tuberculin Skin Test (TST) and QuantiFERON ®-TB Gold Test (QFT-G) In Patients With Rheumatoid Arthritis Being Considered for Anti-TNF-Alpha Therapy

Study Start Date :

May 1, 2009

Anticipated Primary Completion Date :

May 1, 2011

Anticipated Study Completion Date :

Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
1 The study group will consist of RA patients of the Walter Reed Army Medical Center (WRAMC) rheumatology clinic being considered for treatment with anti-TNF alpha therapy. We will enter patients into the study over a projected course of 12-24 months or until we reach the statistical requirement of 60 subjects.
2 The control group will consist of healthy subjects without known immune-dysregulation or history of treatment with biologic agents who present to the WRAMC Allergy- Immunology clinic for routine screening TST as a part of current WRAMC policy.

Outcome Measures

Primary Outcome Measures

Primary endpoints are the results of the QFT-G test (defined as positive, negative or indeterminate) and the results of the TST (defined as positive or negative). [Patients will be enrolled over a 2 year time frame]

Secondary Outcome Measures

Secondary endpoints include the percentage and numbers of CD45RO (memory T cells), the response PHA intradermal antigen placement, numbers of hypoergic TSTs, and the results of cell mediated immunity (CMI) assays. [Patients will be enrolled over a 2 year time period]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Study group:

Any patient 18 years or older who has been diagnosed with RA (American College of Rheumatology (ACR) criteria) and is being considered for de novo anti-TNF alpha therapy will be invited to participate in this study.

Control group:

Control subjects will be any patient 18 years or older presenting to the Allergy/Immunology clinic for routine TST.

Exclusion Criteria:

Study group:

We will exclude any individual with a previous history of known immuno-compromising disease state or unstable medical condition other than RA resulting in overall poor health and/or protein calorie deprivation to include:
any other autoimmune disease
oral steroid use in the past 3 days (4 half-lives of prednisone is 14 hours)
inhaled steroid use at a dose of > 2000 mg beclomethasone equivalent/day
any cancer [solid organ or blood]
radiation therapy in prior three months
any bleeding disorders
chemotherapeutic agents
transfusion or blood products in past 1 year
history of HIV
chronic hepatitis
malignancy
transplant history
chronic infection
chronic renal failure
current allergy treatment (shots, antihistamines)
uncontrolled diabetes, or the inability to provide informed consent
we will also exclude individuals with immediate hypersensitivity to the TST/PPD or PHA antigens
a previous severe local ulceration with TST/PPD
suspected active TB, previous TB treatment

Control group:

We will exclude any individual with known history of anti-TNF alpha therapy.
We will also exclude any patient with a history of any immune-modulatory (DMARD) therapy (steroids, anti-TNF agents, methotrexate, azathioprine, sulfasalazine, etc.) within the previous 12 months.
Additionally we will exclude all those individuals with previous history of TB or TB therapy, diabetes mellitus, HIV, malignancy, or hepatitis that may influence the dermal reaction to PHA antigen or ex vivo CMI activity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307

Sponsors and Collaborators

Walter Reed Army Medical Center
National Naval Medical Center

Investigators

Principal Investigator: Adam T Armstrong, DO, Rheumatology Fellow - Walter Reed Army Medical Center
Study Chair: Robert O Holmes, DO, National Naval Medical Center