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Editorial
 
Rheumatoid Arthritis and Tuberculosis: Time To Take Notice
MICHAEL GARDAM, MSc, MD, CM, FRCPC, Division of Infectious Disease; KAREN IVERSON, BSc, MHSc, MSc, Infection Prevention and Control, University Health Network, 200 Elizabeth Street, NUW 13-117, Toronto, Ontario M5G 2C4, Canada. Address reprint requests to Dr. Gardam. E-mail: michael.gardam@uhn.on.ca Mycobacterium tuberculosis remains one of the major pathogens affecting humans, infecting roughly one-third of the population and being responsible for almost 2 million deaths annually1. The continued presence of the disease, in association with a global increase in drug resistant strains and increasing coinfection with the human immunodeficiency virus (HIV), resulted in the World Health Organization declaring tuberculosis (TB) a global emergency one decade ago, a situation that continues today. Developed countries, in sharp contrast to the rest of world, have seen a remarkable decline in TB over the past century: the Canadian TB incidence rate, which peaked at over 120 cases per 100,000 sixty years ago, has since decreased to roughly 6 cases per 100,0002. While the overall incidence has decreased, the relative proportion of active disease occurring in foreign-born versus Canadian-born non-aboriginals has increased substantially, illustrating the impact of the global epidemic on industrialized nations2. This decline in developed countries has resulted in TB becoming a medical rarity. Frequently, the diagnosis may be missed by healthcare providers who have little to no experience with the disease. Opportunities for preventing TB through the treatment of latent infection may be missed because of unfamiliarity with screening tests, at-risk populations, and preventive regimens. This lack of awareness, in association with the development of immunosuppressive therapies to treat a host of autoimmune disorders, may lead to the development of TB in patients with latent infection that may otherwise have been prevented. Indeed, cases of active TB in patients with rheumatoid arthritis (RA) have recently been reported, and this has brought about a renewed interest in the relationship between the 2 diseases3. It is generally believed that rheumatologic diseases such as systemic lupus erythematosus and possibly RA may be associated with an increased risk of TB4. What proportion of this increased risk stems from the immunologic disease itself, rather than immunosuppressive therapy, remains largely unknown. While profound immune suppression such as that required for organ transplantation is clearly associated with an increased risk of developing active TB, the risk afforded by lesser degrees of immune suppression is not well defined5. Cases of active TB occurring in patients receiving methotrexate have been reported6,7; however, given the paucity of such reports it is likely that methotrexate alone is not a significant risk factor for the development of active TB. There is no evidence that other immune modulating drugs such as penicillamine and leflunomide are associated with TB. Receiving intermittent or low-dose prednisone does not appear to increase the risk of developing active TB; however, receiving a minimum of 15 mg of prednisone over 2–4 weeks will suppress the tuberculin reaction, and receiving a mean prednisone dose of 15 to 20 mg/day/year has been shown to markedly increase the risk of active TB in a high-prevalence population8. This has led the American Thoracic Society to state that the TB risk is "increased" in patients receiving at least this amount of prednisone or equivalent for one month or greater9. Recently the treatment options available for RA and certain other autoimmune diseases have been substantially broadened with the arrival of the tumor necrosis factor-a (TNF-a) inhibitors etanercept and infliximab. While both drugs have been shown in large trials to be effective in treating RA, a growing body of data suggests that both are associated with the development of active TB. That this should occur is perhaps not surprising given that TNF-a is central to the host's ability to control TB infection. The production of TNF-a by alveolar macrophages has been shown to be essential in granuloma formation, chemokine production, leukocyte recruitment, and the killing of intracellular pathogens such as M. tuberculosis10. In mouse models of TB infection, blocking TNF-a production or inhibiting binding of TNF-a to its receptor typically results in an increased burden of organisms, impaired granuloma formation, and host death11-13. Of the 2 agents, the data associating TNF-a inhibition and active TB are greater for infliximab. On a molecular level, infliximab binds more avidly to both membrane-bound and free forms of TNF-a than does etanercept14. Infliximab has also been shown to cause drug-mediated apoptosis of macrophages and monocytes15. The available epidemiologic data also suggest that infliximab use is associated with an increased risk of active TB compared to the general population and that the proportion of extrapulmonary cases is perhaps higher than predicted3. Finally, the development of TB typically occurred within the first few months of infliximab therapy3. Recent abstracts, however, suggest that etanercept use is also associated with an increased TB risk, with a similar proportion of extrapulmonary cases16. What remains unclear is the magnitude of the increased TB risk associated with either of these agents. The case series published to date have relied on passive surveillance, and hence likely under-represent the true magnitude of the association. Further, the underlying TB risk factors of TNF-a exposed and comparator populations, such as receipt of other immunosuppressive therapy (i.e., corticosteroids), world region of origin, age, sex, comorbid illness, recent contact with an active case, and the presence of TB-associated abnormalities on chest radiograph, have not been well defined. Given that corticosteroids and patient age and sex will confound the relationship between RA and TB, these factors should be controlled in any comparison. In this issue of The Journal, Carmona, et al report an increased incidence of active TB in Spanish RA patients compared to an age and sex-matched Spanish population17. These researchers surveyed 788 randomly selected patients from a large cohort of Spanish patients with RA for the presence of active TB over a one year study period. Patients were interviewed and their medical and laboratory records reviewed. The incidence of TB in the Spanish population was determined from the Spanish Network of Epidemiological Surveillance database, which records all pulmonary and meningeal cases of TB in the country. The mean TB incidence in the RA cohort was calculated over a 10 year period and standardized for age and sex using the Spanish population over age 16. The incidence risk ratio of developing TB at any site in the RA cohort was calculated at 4.13 (95% CI 2.59–6.83), while the incidence risk ratio for pulmonary disease was 3.68 (95% CI 2.36–5.92). As this cohort was assembled in 1998–99, this represents the incidence of disease prior to the widespread use of anti-TNF-a inhibitors. Seventy-two percent of the selected patients, however, had received other disease-modifying antirheumatic drugs. These findings are more precise than those reported in a recent American study. Wolfe, et al calculated the annual incidence of TB in 10,782 American RA patients to be 6.2 per 100,000 per year, similar to the 6.8 per 100,000 rate reported for the general US population18. However, only one case was identified over the 18 month study period, resulting in wide 95% confidence intervals (0.2 to 34.4 per 100,000), making it difficult to accurately estimate the true incidence risk ratio. By actively seeking out TB cases rather than relying on passive surveillance, the error due to missed cases is likely less significant in the Carmona study than in previous studies. Also, the large sample size and relatively increased tuberculosis rate in the Spanish population versus other developed countries also allowed for a more accurate estimation of risk. By not using a case-control design, however, the researchers recognize that they were unable to control for known TB risk factors other than age and sex. It is thus impossible to determine the relative risk afforded by the disease itself versus immunosuppressive therapy (i.e., corticosteroids). Further, their calculated rate may over-represent the true TB incidence rate in patients with RA, as only pulmonary and meningeal cases are reportable in Spain, yet all types of TB were recorded in the RA patients. The authors attempted to correct for this by assuming that 20% of total TB cases are extrapulmonary. Using this correction, the incidence risk rate decreased somewhat, yet remained more than 4-fold higher than the general population. Despite these limitations, the results presented by Carmona, et al suggest that a typical population of patients with RA receiving standard therapy involving different immunosuppressive drugs, yet excluding TNF-a inhibitors, are at increased risk for developing active TB. It is interesting that the 4-fold increased risk found by these researchers is of similar magnitude to the increased risk attributed to infliximab and possibly etanercept in American patients3,16. However, as stated, these studies likely underestimate the risk afforded by these therapies. The results of this study suggest that the risk of developing TB in patients with RA is high enough to warrant consideration of screening and possible therapy to prevent TB. While it is difficult to recommend TB screening for all RA patients, the evidence suggests that patients receiving prolonged corticosteroids with epidemiologic risk factors for TB are at increased risk. Such patients should be screened for latent infection by Mantoux testing and considered for preventive therapy if positive. Preventive therapy has been a key component of TB control programs for almost half a century. The effectiveness of isoniazid has been confirmed in randomized controlled trials, and can afford up to 93% protection if complied with for 9 months or more19. Other preventive therapies are available, and clinicians are referred to existing guidelines for details regarding regimens, monitoring, and possible complications of therapy9,19. Patients receiving TNF-a inhibitors are likely at even greater risk of developing TB. A significant proportion of patients in this and other immunocompromised populations (i.e., HIV infected) may be anergic; however, studies of anergy testing in HIV positive individuals to aid in the prevention of TB have failed to show a benefit20. Given that the relative risk of developing active TB is highest with HIV coinfection, it is reasonable to assume that anergy testing would also fail to provide benefit in RA patients receiving TNF-a inhibitors. Recommendations for the interpretation of Mantoux skin tests in patients receiving TNF-a inhibitors have recently been published10. As the probability of anergy increases, the decision to provide preventive therapy becomes more reliant on epidemiologic risk factors, and should be made in consultation with a TB specialist. As long as a global TB epidemic exists and potent immunosuppressive therapies are used to treat RA and other autoimmune diseases, the threat of TB will not fade. By considering TB prevention early in the management of patients with RA, active disease can be avoided in the vast majority of cases. 1. Dye C, Scheele S, Dolin P, Pathania V, Raviglione MC. Global burden of tuberculosis. Estimated incidence, prevalence and mortality by country. JAMA 1999;282:677-86. [MEDLINE] 2. Njoo H, Long R. The epidemiology of tuberculosis in Canada. In: Long R, editor. Canadian tuberculosis standards. Ottawa: Government of Canada. Canadian Lung Association; 2000:3-14. 3. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104. [MEDLINE] 4. Bouza E, Moya JG, Munoz P. Infections in systemic lupus erythematosus and rheumatoid arthritis. Infect Dis Clin North Am 2001;25:1900-7. [MEDLINE] 5. Menzies D, Pourier L. Diagnosis of tuberculosis infection and disease, In: Long R, editor. Canadian tuberculosis standards. Ottawa: Government of Canada. Canadian Lung Association; 2000. 6. Smith JD, Knox JM. Mycobacterium tuberculosis infection in patients with systemic rheumatic disease. Rheumatology Oxford 1971;40:341-2. 7. Binymin K, Cooper RG. Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis. Rheumatology Oxford 2001;40:341-2. [MEDLINE] 8. Kim HA, Yoo CD, Baek HJ, et al. Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient population. Clin Exp Rheumatol 1998;16:9-13. [MEDLINE] 9. Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society. MMWR Recomm Rep 2000 9;49 RR-6:1-51. [MEDLINE] 10. Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003;3:148-55.[MEDLINE] 11. Ehlers S, Benini J, Kutsch S, Endres R, Rietschel ET, Pfeffer K. Fatal granuloma necrosis without exacerbated mycobacterial growth in tumor necrosis factor receptor p55 gene-deficient mice intravenously infected with Mycobacterium avium. Infect Immun 1999;67:3571-9. [MEDLINE] 12. Mohan VP, Scanga CA, Yu K, et al. Effects of tumor necrosis factor alpha on host immune response in chronic persistent tuberculosis: possible role for limiting pathology. Immunol 2001;102:248-53. [MEDLINE] 13. Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995;2:561-72. [MEDLINE] 14. Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther 2002;301:418-26. [MEDLINE] 15. Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology 2001;121:1145-57. [MEDLINE] 16. Manadan AM, Mohan AK, Cote TR, Siegel JN, Sequeira W, Block JA. Tuberculosis and etanercept treatment [abstract]. Arthritis Rheum 2002;46 Suppl:S166. 17. Carmona L, Hernández-García C, Vadillo C. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003;30:1436-9. 18. Wolfe F, Flowers N, Anderson J, Urbansky K. Tuberculosis rates are not increased in rhematoid arthritis [abstract]. Arthritis Rheum 2001;44 Suppl:S105. 19. Hoeppner V, Marciniuk D, Hershfield E. Treatment of tuberculosis disease and infection. In: Long R, editor. Canadian tuberculosis standards. Ottawa: Government of Canada. Canadian Lung Association; 2000:3-14. 20. Anergy skin testing and tuberculosis [corrected] preventive therapy for HIV-infected persons: revised recommendations. Centers for Disease Control and Prevention. MMWR Recomm Rep 1997;46 RR-15:1-10. [MEDLINE] |
