"French Guidelines for Pretreatment Screening Inadequate to Determine TB Risk in Patients on Anti-TNFalpha Therapy: Presented at ECCMID-ICC"
By Chris Berrie
MUNICH, GERMANY -- April 10, 2007 -- Current pretherapeutic screening of patients who require treatment with tumour necrosis factor alpha (TNFalpha) inhibitors according to national guidelines in France is not sensitive enough to identify all patients at risk of developing tuberculosis (TB), researchers reported here at the joint 17[th European Congress of Clinical Microbiology and Infectious Diseases and 25th International Congress on Chemotherapy (ECCMID-ICC).
"TNFalpha antagonists are increasingly used to treat rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and several other inflammatory diseases," said principal investigator Dominique Salmon, MD, PhD, professor in infectious diseases, Cochin Hospital, Paris, France. However, their powerful inhibitory effects on the monocyte-macrophage system result in increased risk of infection.
Dr. Salmon presented the study on April 3rd on behalf of the Recherche Axée sur la Tolérance des Biothérapies (RATIO) group.
With a view to preventing TB infections in these patients, various European countries have issued official screening guidelines. In France the guidelines include screening for latent TB, which is defined as previously untreated TB, chest X-ray abnormalities, previous contact with a TB patient, or a positive tuberculin skin test (>5 mm). If indicated, prophylaxis must be started at least 3 weeks before the start of TNFalpha inhibition, Dr. Salmon said.
To assess the effects of the French guidelines on tuberculosis occurrence, Dr. Salmon and colleagues analysed data from the national prospective RATIO registry of patients treated with TNFalpha inhibitor therapy.
This case-control study was performed with the first 38 TB cases declared since the guidelines were released in France, with each case matched with 2 controls according to sex and underlying illness. Cases had a mean age of 61 years (range 19-63 years) and 58% were males. Their underlying illnesses were rheumatoid arthritis (n = 26), ankylosing spondylitis (10), Crohn's disease (1) and Takayashu (1) disease.
Clinical presentations were severe; 55% of patients had pleuropulmonary TB; 45% had extrapulmonary or disseminated TB (55%); 11% were admitted through an intensive care unit; there was 1 death from TB.
Analysis of their concomitant immunosuppressive therapies showed use of methotrexate in 19 patients, leflunomide in 2, azathiprine in 1 and salazopine in 5; 26 were receiving corticosteroids, at a median dose of 7.5 mg/day.
The last specific TNFalpha inhibitor therapy that these cases had received were the chimeric antibody infliximab (19), the humanised antibody adalimumab (17) and the soluble receptor fusion protein etanercept (2), with 5 (13.2%) having received 2 such agents, and 1 (2.6%) having received 3.
Mean delay between initiation of their last anti-TNFalpha treatment and their first TB symptoms was 33 weeks, and after completion of anti-TB prophylaxis, there was no further TB seen in these patients.
Presence of at least 1 classical TB risk factors was seen in 46% of patients, including 2 patients with previous TB (untreated or less than 6 months), 3 with chest X-ray abnormalities, 4 patients who had contact with a TB patient, 8 who were born in or were previously residents of a TB-prevalent country, and 8 (21%) had a positive intradermal tuberculin test >5 mm.
Multivariate analysis comparing cases and controls for TB risk factors found that increasing age was a relatively minor, but significant, factor (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.03-1.07; P = .02). Methotrexate use was protective against TB (OR, 0.28; 95% CI, 0.01-1.08; P = .01). Although they have no clear explanation for this, Dr. Salmon said, "Probably, those patients with methotrexate have had less TNFalpha treatments."
Dr. Salmon said that the risk of TB appears to be higher in patients treated with monoclonal anti-TNFalpha antibodies (infliximab, adalimumab) than with the soluble receptor protein (etanercept), although further analyses will be needed to determine the significance and extent of these outcomes.
He stressed that this case-control study shows that current pretherapeutic screening of patients who require anti-TNFalpha therapy according to current national guidelines in France is not sensitive enough, particularly as only 21% of the TB cases showed positive tuberculin skin tests > 5 mm, and only 46% showed at least 1 current risk factor for TB.
This study was supported by Schering-Plough, Abbott and Wyeth Pharmaceuticals.
[Presentation title: The Risk of Tuberculosis Persists in Patients Treated With Anti-TNFalpha Therapy Despite Prophylactic Guidelines. Identification of Main Risk Factors. Abstract O471]
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