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Abstract Objective To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists. Methods Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years. Results Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre-OR) and 2 began treatment after the recommendations were issued (post-OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre-OR, the active TB rate in BIOBADASER patients was 20.9-fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6- and 6.2-fold higher than the background and EMECAR populations, respectively.
The presence of comorbidities (renal failure, peripheral vascular disease, ejection fraction, and atrial fibrillation), the need for conversion to surgery, and at least moderate aortic regurgitation after transcatheter aortic valve implantation were identified as independent predictors of in-hospital and mid-term mortality. RAUI GUTIERREZ SAENZ MIRODUCdON A I A.
Post-OR, 324 patients with a tuberculin skin test result ≥5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post-OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03–0.88; P = 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02–8.2).
There were no INH treatment–related hospitalizations or deaths. Conclusion Strategies to treat latent TB infection that are tailored to the at-risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists. • Active tuberculosis (TB) that, in most instances, is the result of reactivation of latent TB infection has been associated with treatment with tumor necrosis factor (TNF) antagonists in patients with rheumatoid arthritis (RA) and Crohn's disease (). Different recommendations for targeting patients with latent TB infection have been proposed worldwide by scientific organizations, health authorities, and other experts to decrease the risk of active TB (,, ), but, to date, the effectiveness of these recommendations has yet to be confirmed. In February 2000, the Spanish Society of Rheumatology (SER) launched a registry (the Database on Biologic Products, or BIOBADASER; see ) that records data on patients with rheumatic conditions who are being treated with TNF antagonists.
The primary objective of this database is to monitor the safety of such treatment. Over the past 4 years, more than 4,000 patients from 95 hospitals have been included in the registry and are followed up regularly (). An extremely high rate of active TB was detected in the first 2 years of this program, and these observations have been reported previously (). Having been made aware of the problem, authorities from the Spanish National Health Service, in collaboration with the SER, advocated a set of recommendations in March 2002 for the management of latent TB infection in those patients receiving TNF antagonists () (details available at the SER Web site at ). It is recommended that patients in any of the following categories should be treated for 9 months with isoniazid (INH): 1) history of untreated or partially treated TB, or exposure to an active case of TB; 2) chest radiograph showing residual changes indicative of prior TB infection; and 3) reaction of ≥5 mm in diameter on the purified protein derivative of tuberculin skin test (TST) or on the 2-step TST procedure with an interval of 7–10 days between steps ().
Based on the information from the BIOBADASER, we provide, in this present report, an account of the effectiveness of these recommendations in a Spanish population of patients with rheumatic conditions who are at high risk of active TB. PATIENTS AND METHODS A description of the BIOBADASER has been published previously (). In brief, the BIOBADASER is a database that was established in February 2000 for the purpose of actively following up the long-term safety of biologic response-modifiers in patients with rheumatic diseases. The registry, which is supported by the SER and funded partially by the Spanish Medicines Agency, notes relevant adverse events that occur during treatment. All hospital and community-based rheumatology units in Spain were invited to participate in setting up the project. The SER has a policy of maximum dissemination of information to all Spanish rheumatologists.
Patients registered in the BIOBADASER are those with rheumatic diseases being treated with any of the currently approved biologic response-modifiers, as well as those who were treated before the database was created but for whom retrospective data are available. The earliest records date back to January 1999. Patients treated with infliximab, etanercept, and adalimumab have been entered into the database. Data analyzed in the present study span the time period from the start of the registry up until April 2004.
Infliximab was made available for clinical use in August 1999, etanercept in April 2003, and adalimubab in February 2004. The guidelines of the SER do not propose different criteria for prescribing any of the TNF inhibitors. To guarantee confidentiality, the BIOBADASER does not include data that can possibly identify individual patients.
Every patient has a lifetime alpha-numeric code randomly assigned among the participating centers. The database is physically located at the SER headquarters, where access is restricted and controlled by the scientific steering committee (a detailed description of the database is available at the Web site ). Up until March 2002, the data were collected by participating physicians and information was recorded on standard forms, which were then faxed or sent by electronic mail to the SER headquarters. Since then, data have been reported by an electronic system. The following data are collected systematically: 1) identification of center, department, or unit, including contact person details; 2) data on patients, including sex, date of birth, diagnosis, and date of diagnosis; and 3) data on treatment, including type of treatment, start and discontinuation dates, and reason for treatment discontinuation, if applicable. Commencing on March 1, 2002, results from the TST and findings on the chest radiograph, as well as type of TB therapy, have been registered. The quality of our database is ensured by a clear definition of its aim, an optimized number of variables, and an easy method of data collection that allows for checks on consistency (see the above-mentioned BIOBADASER Web site).
Completeness and agreement of data with patients' charts were assessed on site by an audit of 15% of patient's records between December 2003 and March 2004. The audit indicated 21% incompleteness of relevant data (absence of communication of treatment discontinuation or of a relevant adverse event, and absence of information regarding date of diagnosis, TST results, and chest radiograph findings in TB cases), and complete agreement was observed in 100% of the data when the patient's record was directly compared with that contained in the BIOBADASER.
All errors were accordingly corrected in our database. Thus, we expect that ∼18% of the data reported herein are incomplete. Minor errors not affecting our analyses, such as errors in the date of diagnosis, date of chest radiograph, or data regarding the input center, were also found in ∼40% of the data, and these were corrected accordingly. For the purpose of the present study, a patient was classified as having active TB when Mycobacterium tuberculosis was isolated in any biologic specimen from an individual patient, in conjunction with an appropriate clinical picture. When necessary, physicians who reported a TB case were asked to provide information regarding the clinical presentation of the patient, results of the TST, health status according to the chest radiograph prior to commencing therapy, previous treatment of latent TB infection, and concomitant medications at the time of active TB infection.
National TB rates (in 2001, 25 cases per 100,000 residents of Spain) were communicated directly from the Committee on Tuberculosis and Respiratory Infections of the Spanish Society of Pneumology and Chest Surgery. The number of TB cases was confirmed in 2 ways: 1) by on-site monitoring, and 2) by contrasting our data with the Division of Pharmacoepidemiology (Med Watch system) of the Spanish Medicines Agency. According to the available information, there were no TB cases in the participating hospitals other than those reported to the BIOBADASER.
TB rates in patients with RA who have not been treated with TNF antagonists were obtained from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study, comprising a cohort study funded by the SER. The EMECAR cohort was assembled in 1999 by random sampling from the clinical databases of 34 established rheumatology units (, ) and is currently in its fifth year of followup. The sample includes 788 patients with RA from whom data on clinical presentation, activity of the disease, progression of the disease, and comorbidities are prospectively collected.
EMECAR patients are representative of the RA population of Spain and cover the whole spectrum of disease severity. The incidence rate of TB (per 100,000 patient-years) and 95% confidence intervals (95% CIs) were calculated. For the analysis, incidence rates were divided into the rate of active TB prior to the official recommendations issuance date of March 1, 2002, at which time recommendations were disseminated among physicians, and the rate on or after March 1, 2002 in patients treated with TNF antagonists, and these were compared with the rates in the background Spanish population and in the EMECAR cohort. RESULTS A total of 2,729 female and 1,373 male patients, with a mean ± SD age of 50 ± 15 years, were registered in the BIOBADASER between January 2000 and April 2004.
Of the registered patients, 69% have a diagnosis of RA (Table ), 10% have ankylosing spondylitis, 10% have psoriatic arthritis, 4% have juvenile idiopathic arthritis, and the remaining 7% have a variety of other chronic inflammatory rheumatic conditions. There were 394 patients treated with more than one TNF antagonist, and 1,578 of the treatments commenced after March 1, 2002. The total treatment exposure rate was 7,825 patient-years (Table ), and this was higher for infliximab (6,328 patient-years) than for etanercept (1,375 patient-years) or for adalimumab (122 patient-years). In RA patients the rate of exposure to TNF antagonists was 5,829 patient-years (Table ), and was 1,996 patient-years in non-RA patients. Table 1. Characteristics of the 2,833 rheumatoid arthritis patients treated with tumor necrosis factor (TNF) antagonists in the BIOBADASER registry Pre-OR Post-OR • * The pre-OR (prior to official recommendations to prevent reactivation of latent tuberculosis infection) time period is defined as before March 2002, while post-OR (after official recommendations) is on or after March 1, 2002. BIOBADASER = Spanish Society of Rheumatology Database on Biologic Products.
• † Some of the patients (n = 394) were treated with more than one TNF antagonist. Of patients 1,690 1,143 Women,% 78 78 Age, mean ± SD years 54 ± 13 50 ± 15 Disease duration, mean ± SD years 11 ± 8 10 ± 8 TNF antagonist, no. (%) Infliximab 1,648 (87.6) 579 (46.7) Etanercept 233 (12.4) 506 (40.8) Adalimumab 0 (0) 154 (12.5). • 1 Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor -neutralizing agent. N Engl J Med 2001; 345: 1098– 104.
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