A Clinician s Perspective: Improving Rheumatology Patient Care Using the T-SPOT.TB Test Solomon Forouzesh, MD, FACD, FACR Medical Director Arthritis Care & Treatment Center Clinical Associate Professor of Internal Medicine / Rheumatology University of California Los Angeles Cedars Sinai Medical Center Los Angeles, California Biologic-targeted suppression of key inflammatory pathways for the treatment of patients with rheumatoid arthritis (RA) has been beneficial to managing this condition. Management, however, must be balanced with the patient s risk of infection from other diseases, such as tuberculosis (TB). 1 Reactivating TB continues to be a serious concern for RA patients. RA patients are at an increased risk of developing TB while on tumor necrosis factor (TNF) antagonist therapy 1 because TNF plays a key role in keeping Mycobacterium tuberculosis (MTB) in granulomas and sufficiently suppressing the MTB to maintain the latent tuberculosis infection (LTBI) state. Thus, identifying patients with LTBI and prophylactically treating them before starting anti-tnfα treatment is critical to reducing the patient s risk for TB while being immunosuppressed. 2
A Clinician s Perspective: Improving Rheumatology Patient Care HOW DOES THE TEST WORK? A standard number of peripheral blood mononuclear cells (PBMCs) in combination with ESAT-6 and CFP10 are added to the wells of microtiter plates that are coated with high-affinity antibodies to interferon-gamma (IFN-γ). Activated effector T cells secrete IFN-γ in response to the specific antigens. The IFN-γ is captured by the IFN-γ antibodies coated within the well. After removal of the T cells and antigens, a conjugated second antibody followed by a substrate are added to produce spots where IFN-γ was secreted by the T cells. Thus, the number of spots provides a measure of the abundance of MTB sensitive effector T cells.6 HOW ARE T-SPOT.TB TESTS PROCESSED? Collecting and processing specimens is a simple, straightforward process. Blood is collected in one standard green-top blood collection tube, kept at room temperature, and then packaged in validated shipping containers, which are shipped to Oxford Diagnostic Laboratories via FedEx for processing. The shipping containers, provided by Oxford Diagnostic Laboratories, are designed to keep the specimens at room temperature during transit. Shipping with FedEx allows specimens to be collected throughout the day, Monday through Friday, with the option for arranging weekend pickup if needed. Results are then reported within 36 hours after receipt of the specimens via encrypted email or secure online portal. Oxford Diagnostic Laboratories is a national reference lab dedicated only to TB testing and operates 7 days a week. It currently serves 1000 customers nationwide, including customers from public health clinics, hospitals, and universities, as well as physicians in private practice.
Using the T-SPOT.TB Test For more than 100 years, the tuberculin skin test (TST) has been used to detect LTBI; however, emerging data indicate that false-negative results are higher for patients who are on immunosuppressive therapies 3 or who have defective cutaneous cell-mediated immunity. 4 In addition, false positives may result from previous administration of the bacille Calmette-Guérin (BCG) vaccine and common nontuberculosis mycobacteria such as M. avium. New tests known as interferon-gamma release assays (IGRAs) have been developed that address the issues associated with the TST. Thus, the Centers for Disease Control and Prevention (CDC) issued new guidelines in 2010, indicating that use of an IGRA for testing for LTBI is preferred for those individuals who had received a BCG vaccine and that an IGRA can be used in place of a TST. 5 WHAT IS AN IGRA? Interferon-gamma release assays (IGRAs) are in vitro blood tests for TB infection. These tests detect cell-mediated responses to Mycobacterium tuberculosis (MTB) antigens. Unlike the subjectivity of reading the TST, IGRAs provide an objective measurement of the patient s T cell response. While two commercially available IGRAs are currently FDA approved, only the T-SPOT.TB test addresses the different immune statuses of patients. The T-SPOT.TB test isolates peripheral blood mononuclear cells (PBMCs) from the patient s blood sample and uses a standard number of PBMCs in the assay to directly measure the secretion of IFN-γ, the immune response to infection with MTB. The T-SPOT.TB test uses two antigens that are specific to MTB: ESAT-6 and CFP10. Importantly, these antigens do not cross react with BCG or most common environmental mycobacteria; therefore, BCG vaccination status of the patient and exposure to nontuberculosis mycobacteria do not affect the T-SPOT.TB test results. IGRAs eliminate the multiple visits required by the TST as they require only one patient visit for the blood draw. According to the CDC, As laboratory-based assays, IGRAs are not subject to the biases and errors associated with TST placement and reading. 5 In addition, unlike the TST, IGRAs cannot boost subsequent IGRA tests. In 2010, the CDC issued updated guidelines for IGRAs that recommend the T-SPOT.TB test in all situations that require TB testing. The guidelines state that the T-SPOT.TB test is preferred over the TST for those individuals who had received a BCG vaccine. 5
HOW WILL USING THE T-SPOT.TB TEST AFFECT A RHEUMATOLOGY PRACTICE? In addition to being an associate professor in the UCLA Department of Medicine Rheumatology division, Dr. Solomon Forouzesh is a board-certified rheumatologist in private practice in Culver City, California. He began his solo practice in 1979 and his practice has become one of the leading rheumatology practices in Culver City. His practice is ethnically diverse with patients from more than 50 countries. He typically sees 25-30 adult patients per day; most of which have rheumatoid arthritis and other rheumatoid diseases. In 2011, he started using the T-SPOT.TB test to screen his patients for TB before initiating biologic therapy and also to screen patients who are currently on therapy. He used to screen with the PPD every year or two while his patients were on therapy or when he switched them to a new therapy. Currently, the T-SPOT.TB test is his preferred method for screening patients for TB. Here, he describes his experience: TB is a serious matter. I grew up in Iran, a country of TB and oil. For any patient The T-SPOT.TB test allows me to put my patients on treatment sooner. In some cases it is as much as several weeks sooner. entering the hospital, their differential diagnosis included TB: in the neurological ward it was tuberculosis meningitis; in the GI ward it was TB of the peritoneum. It is an ancient condition, and it is probably not going away. And now, I am aware of active cases of TB in my city. We can t eradicate this bacterium the mycobacteria is here to stay so, we have to treat the disease it causes. For these reasons, I am passionate about screening my patients for TB. When we were using PPD, we had several issues. First, I had about 12 patients who had adverse reactions to screening with PPD; they had overreactions that caused the tissue at the placement site to become necrotic. It took a very long time for those patients to heal. Second, we had scheduling issues with placing and reading the test. People are busy; it was hard to get my patients back into the office to read the test at the appropriate time. Third, induration results are very subjective. In addition to our testing, we relied on some primary care physicians to place and read the PPD results. Since the results are so subjective, it caused some concern when I was prescribing biologics. I don t like relying on subjective tests, but it was out of our control.
When I learned about the T-SPOT.TB test, I realized that it offered solutions to these issues. Since it is a blood test, we don t have any issues with patients having adverse reactions. I have much more confidence in the T-SPOT.TB test results. For example, I had one patient for whom I initially screened with PPD and determined that the induration was negative. I switched TB testing methods while I was treating this patient and subsequently tested the patient using the IGRA. The T-SPOT.TB test result was positive, but I received more than just a positive categorical value; I received a numeric value that helped guide my management decisions about this patient. Using the T-SPOT.TB test has definitely cut down on our administration time. We no longer have the patient scheduling issues with reading test results. I can retrieve the T-SPOT.TB test results easily, and the results are ready about the same time as the other labs that I run. This allows me to put my patients on treatment sooner than when I was screening with TST. In some cases it is as much as several weeks sooner. We also can schedule patients throughout the week. Before, I could only schedule screenings on Mondays, Tuesdays and Wednesdays because I didn t have staff available to read the PPD results on the weekends. In addition, using the T-SPOT.TB test has made it possible to screen patients regularly for TB. I always test patients before they are started on therapy and when I switch treatment to other agents. And then I try to screen patients annually beyond that. It depends on how frequently patients come into the office, and if they have extended foreign travel. It also depends which therapy the patient is on for RA. Patients who are taking a newer biologic drug for RA that inhibits granulation formation are at increased risk for contracting TB. Granuloma is the body s main self-protecting response to foreign agents, including bacteria and mycobacteria. During the first years of these biologic drugs, there was a rapid rise in the number of TB cases, so that s become a primary target and approach for prevention. The biologic drugs have changed the natural course of RA and will stay here. Therefore, we have to provide the safest approach for patient care. In my mind, that s doing regular screening for TB. The service I have gotten from Oxford Diagnostic Laboratories has been 100% reliable and helpful, and the reports they provide are detailed, precise, comprehensive and reliable. I can t find a better approach than providing specialized laboratory services for performing a TB blood test their service is impeccable. I am very happy that this test is available for my patients and the community I serve. Using the T-SPOT.TB test has made my life as a medical practitioner easier and has improved my ability to provide my patients with the best medical care to manage their disease.
Dr. Solomon Forouzesh is the Founder and Medical Director of the Arthritis Care and Treatment Center in Los Angeles, a faculty member of the UCLA Department of Medicine, and an Associate Professor of Medicine and Rheumatology at UCLA/Cedars-Sinai Medical Center. He is also Medical Director of the Rehabilitation Department at Brotman Medical Center in Los Angeles. In 2005, Dr. Forouzesh was voted the Best All-Around Physician at Brotman Medical Center by his peers in Los Angeles. Dr. Forouzesh s area of specialty is the treatment of rheumatoid arthritis. He was rated among the Top Doctors in the field of rheumatology from 2000-2003 by the Center for the Study of Services Consumer CHECKBOOK in Los Angeles, and was also recognized as the Medical Director of the Year nationwide in the Rehab Care Group. Dr. Forouzesh is also a distinguished Fellow of the American College of Physicians and Fellow of the American College of Rheumatology. www.tspot.com REFERENCES 1. Keyser FD. Choice of biologic therapy for patients with rheumatoid arthritis: the infection perspective. Curr Rheumatol Rev. 2011;7(1):77-87. 2. Keane J, Bresnihan B. Tuberculosis reactivation during immunosuppressive therapy in rheumatic diseases: diagnostic and therapeutic strategies. Curr Opin Rheumatol. 2008;20(4):443-449. 3. Keystone EC, Papp KA, Wobeser W. Challenges in diagnosing latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. J Rheumatol. 2011;38(7):1234-1243. 4. Coaccioli S, Di Cato L, Marioli D, et al. Impaired cutaneous cell-mediated immunity in newly diagnosed rheumatoid arthritis. Panminerva Med. 2000;42(4):263-266. 5. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25. 6. T-SPOT.TB [package insert]. Marlborough, MA: Oxford Immunotec; 2010. T-SPOT, Oxford Diagnostic Laboratories and the Oxford Diagnostic Laboratories logo are trademarks of Oxford Immunotec Ltd. FedEx is a registered trademark of Federal Express Corporation. 2012 Oxford Immunotec, Inc. FCS-ODL-US-V1