Tumor Necrosis Factor-α Blocker Induced Tuberculosis

J Rheumatol 2010;37:7; doi:10.3899/jrheum.100058



Patients who are treated with anti-tumor necrosis factor-α (anti-TNF-α) blockers are at risk of reactivation of latent tuberculosis (TB) infection (LTBI). The study by Dr. Malaviya, et al describes an approach to the diagnosis of LTBI prior to anti-TNF-α therapy1. 
Screening tests they advise are tuberculin skin test (TST), interferon-γ release assay, or Quantiferon TB
Gold (QTB Gold), chest radiograph (CXR), and computed tomogram (CT) of the thorax. We describe 2 patients who developed active TB while taking infliximab, despite the recommended screening tests being negative.
Case 1: In March 2009, A 30-year-old male, with long standing ankylosing spondylitis (AS), complained of worsening of axial symptoms in spite of adequate nonsteroidal antiinflammatory drugs (NSAID). As the AS
was active, infliximab therapy was offered. Baseline laboratory findings were: hemoglobin: 9.5 g/dl, leukocyte count: 10,012 cells/mm3, erythrocyte sedimentation rate (ESR) 45 mm/h, platelets: 416,000/mm3, serum
glutamic pyruvic transaminase 22 IU/l, and serum creatinine 0.8 mg/dl. The LTBI screen tests including CXR, TST, and QTB Gold test were negative. CT thorax was not done. He was given 2 doses of infliximab (3
mg/kg per dose) 5 months apart. Three weeks after the second dose he developed a low grade fever and cough. There were scattered crackles on auscultation and the CXR showed consolidation in the right upper and middle zones. Although three sputum acid-fast bacilli (AFB) smears and AFB culture were negative, anti-TB therapy (ATT) was started on clinical grounds. The patient showed clinical and radiological resolution in 6
weeks’ time.
Case 2: In March 2008, a 13-year-old boy was diagnosed to have Juvenile AS with peripheral arthritis. He improved with NSAID over 4 weeks. Six months later the AS relapsed and was refractory to NSAID and
methotrexate. Laboratory reports were: hemoglobin: 10.7 g/dl, leukocyte count: 10,700 cells/cm3, platelets: 430,000 cells/cm3, ESR: 100 mm/h, and CXR: normal; TST and QTB Gold were both negative. Infliximab (3 mg/kg) was given June 5. In September 2009, he developed low grade fever, loss of appetite, and dry cough of 2 week duration. CXR showed right sided pleural effusion, aspiration of which revealed a lymphocytic predominant exudate with elevated adenosine deaminase level (156 iu), consistent with TB pleural effusion. ATT was initiated and he is now improving.


It is important to recognize and treat LTBI prior to institution of anti-TNF-α therapy. In both our patients, an attempt was made to exclude LTBI using the screen recommended by Malaviya, et al. As both patients
initially showed no clinical evidence of TB, with a negative CXR, TST, and TB gold tests, a CT of the chest was not done. Despite having a negative screen, both our patients developed active TB after initiation of infliximab therapy.
False negative TST as a result of immune suppression can result in a false negative screen for LTBI. 
Park, et al showed that, of 86 patients who received anti-TNF-α therapy with a negative TST at the baseline2, TST (repeated annually) converted to positive after a median interval of 33.3 months in 32.6% of patients. Interferon-γ release assay (IGRA) testing was found to have a 68.6% concordance with TST. Hence, combined testing with TST and IGRA can to an extent overcome the false negative TST.


We recently reported that by T cell specific ELISPOT (T spot) assay, the prevalence of LTBI in healthy, urban Indians is around 80%. Unlike the TST, this is a specific assay for Mycobacterium tuberculosis, not confounded by previous bacillus Calmette Guerin BCG vaccination, or infection with environmental mycobacteria. The T-spot TB assay also has a lower likelihood of being rendered false negative by prednisolone therapy versus TST. This test could help identify LTBI in patients who are TST and IGRA negative.
In endemic regions like India, a new TB infection may be misclassified as a TB flare. Further, ELISPOT test, the TST and TB gold test, fail to differentiate between latent and active TB. This distinction is crucial, in order
to choose between initiation of anti-TB prophylaxis or that of full-fledged ATT4. Since a normal chest radiograph does not rule out LTBI or active TB, correlation of IGRA and TST with clinical likelihood of LTBI is important . This is especially true in India, where a CT chest cannot always be done due to cost constraints.
In conclusion, not even a battery of tests can completely exclude LTBI. Hence, even with a negative screen, the possibility of TB flare, or development of new TB infection, must always be kept in mind while initiating
anti-TNF therapy. In such patients, combination of TST and IGRA, with regular repetition of these tests, will increase the likelihood of diagnosis of LTBI. It is also recommended that LTBI prophylaxis be continued in those patients receiving anti-TNF-α therapy who have been treated for TB disease prior to initiation of the same.


PRIYANKA KHARBANDA, MD; RUCHA DAGAONKAR,
CANCHI BALAKRISHNAN, MD; ZARIR F. UDWADIA, MD, FRCP;
Rheumatology and Pulmonology Units, PD Hinduja Hospital, Mumbai,
India.


REFERENCES
1. Malaviya AN, Kapoor S, Garg S, Rawat R, Shankar S, Nagpal S, et
al. Preventing TB flare in patients with inflammatory Rheumatic
diseases receiving Tumor Necrosis Factor alpha (TNF alpha)
inhibitors in India — an audit report. J Rheumatol
2009;36:1414-20.
2. Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Positive
conversion of tuberculin skin test and performance of interferon
release assay to detect hidden tuberculosis infection during
anti-tumor necrosis factor agent trial. J Rheumatol
2009;36:2416-20.
3. Lalvani A, Nagvenkar P, Udwadia Z, Pathan AA, Wilkinson KA,
Shastri JS, et al. Enumeration of T cells specific for RD1- encoded
antigens suggests a high prevalence of latent mycobacterium
tuberculosis infection in healthy urban Indians. J Infect Dis
2001;183:469–77.
4. Winthrop KL, Chiller T. Preventing and treating
biologic-associated opportunistic infections. Nat Rev Rheumatol
2009;5:405-10.
5. Martin J, Walsh C, Gibbs A, McDonnell T, Fearon U, Keane J, et
al. Comparison of interferon {gamma} release assays and
conventional screening tests before tumour necrosis factor {alpha}
blockade in patients with inflammatory arthritis. Ann Rheum Dis
2010;69:181-5.

Immune Boosting Drug Worsens Tuberculosis in Mice

According to scientists from the National Institutes of Health, an experimental drug that boosts production of the immune system protein interferon worsens tuberculosis in mice.

The drug acts indirectly by drawing certain immune cells, in which Mycobacterium tuberculosis (M.tb) bacteria thrive, to the lungs. Most people infected with M.tb do not develop active tuberculosis.

Instead, the infection can remains dormant for decade, but 10 percent of people with latent infection do go on to develop active disease. Some causes for reactivation include aging or other conditions that lower immunity.


“Although our research was conducted in mice, our combined findings suggest that reactivation of tuberculosis should be considered as a potential side effect if compounds that boost type I interferon production, like the one used in this study, are tested in people who may be infected with M.tb,” says Alan Sher, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), NIH, who led the team of scientists.

Dr. Sher and his colleagues studied the effects of an experimental drug called poly-ICLC on immune responses to tuberculosis infection. Poly-ICLC stimulates the body to produce an immune system protein called type I interferon (type I IFN) that has the ability to interfere with viral infections.

In mouse studies, poly-ICLC protected the animals from viruses that can cause lethal infections, including pandemic influenza. It has also been shown to improve the effects of several experimental vaccines when tested in animals. Poly-ICLC also is being tested in multiple human clinical trials as a possible cancer treatment when combined with cancer vaccines.

Earlier research into the effects of type I IFN on bacterial infections produced mixed results. Some studies showed that giving IFN to mice with non-tuberculous mycobacterial infections lowered the amount of bacteria in their bodies, but in another studies, naturally occurring IFN appeared to promote rather than limit the growth of bacteria in mice infected with M.tb.

To sort things out, NIAID investigator Lis R.V. Antonelli, Ph.D., dropped poly-ICLC into the noses of mice that had been infected with M.tb. The mice were infected either one day earlier to mimic an acute tuberculosis infection, or four months earlier to make a chronic tuberculosis infection. The infected mice were then compared with untreated mice with tuberculosis. All the mice treated with poly-ICLC developed severe lung tissue damage.

Also, levels of M.tb in their lungs were 100 times greater than in M.tb-infected mice that did not receive poly-ICLC.

Next, Dr. Antonelli performed a few more experiments to see what kind of immune system cell was involved in speeding up the disease in poly-ICLC-treated mice. In the treated group of mice, the scientists found a fourfold increase in immune cells called macrophages. 

 In most infectious diseases, macrophages are drawn to the site of infection and help defend the host against disease, but when type I IFN production was elevated by poly-ICLC treatment, the surge in macrophages to the M.tb-infected lung actually harmed the host.

Researchers are currently testing the relevance of these findings to humans by determining whether under certain conditions type I IFN promotes the growth of M.tb in human macrophages. Such research could also provide important clues to how and under what conditions dormant tuberculosis is reactivated

 From:- http://techcombo.com/2010/06/30/immune-boosting-drug-worsens-tuberculosis-in-mice-123/