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

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.

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.