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In a recent paper in the Annals of the Rheumatic Diseases, Furst et al proposed preliminary consensus guidelines, elaborated during the “Advances in targeted therapies IV” meeting 2002, for diagnosis and treating latent tuberculosis in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) blockers.1 Such guidelines cannot be universal and must take into account the prevalence of tuberculosis, the type of immigrants, and the prevalence of vaccination with BCG (bacille Calmette-Guerin) in the country where they are proposed. A multidisciplinary French cooperative group termed RATIO (Recherche sur Anti-TNF et Infections Opportunistes), including specialists in infectious diseases, pneumology, gastroenterology, and rheumatology, recently proposed such guidelines adapted for France,2 which have been validated by the French agency for healthcare product safety (AFSSAPS). These guidelines are intended to help doctors detect and manage tuberculosis in their patients before and after TNF blocker therapy. Moreover, they are now mandatory for all doctors and have to be implemented in addition to the labelling recommendations. They differ in several points from the preliminary consensus guidelines.
Definition of latent tuberculosis and of patients at risk
These patients are defined by the presence of one of the following items:
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A history of tuberculosis treated before 1970, including at least two months with the rifampicin-pyrazinamide combination, or not treated for at least six months
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A weal larger than 10 mm in diameter or a blister in response to an intradermal tuberculin test done more than 10 years after the last BCG vaccination, with no history of correct treatment for active tuberculosis
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Residual radiographic tuberculous lesions larger than 1 cm3 in size with no certainty that eradicating treatment was received.
The small differences between the previous recommendations are:
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The date of the BCG, which is frequently performed in Europe and mandatory in France where 95% of the children are vaccinated by age 6, is taken into account
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Interpretation of the PPD test: choice of a single threshold of 10 mm to consider the test positive in order to simplify the doctor’s practice.
Management of latent tuberculosis
Before starting TNF blocker therapy, antituberculous chemoprophylaxis should be initiated in all patients who are at risk of tuberculous reactivation, as defined above.
Three regimens can be used for chemoprophylaxis:
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Rifampicin (Rifadine) 10 mg/kg/day and pyrazinamide (Piriléne) 20 mg/kg/day, each in a single daily dose, for two months. However, the efficacy of this regimen for prophylactic treatment has been validated only in HIV infected patients.3
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Rifampicin (Rifadine) 10 mg/kg/day in a single daily dose and isoniazid (Rimifon) 4 mg/kg/day for three months.
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Isoniazid alone for nine months in very elderly patients and in patients with hepatic toxicity or cirrhosis.
The main difference with the previous recommendations is the preferred choice of two drugs including pyrazinamide when possible. This drug may have hepatic toxicity but interest in use of the combination of rifampicin and pyrazinamide for two months has been recently emphasised in immigrants with resistant BK coming from Asia and Africa.4
Chemoprophylaxis should be started at least three weeks before the first infusion of TNF blockers. If latent tuberculosis is diagnosed, it is recommended that gastric aspirates are obtained. If Mycobacterium tuberculosis is recovered from the gastric aspirates, the patient should be switched from the prophylactic regimen to a curative regimen.
Management of active tuberculosis diagnosed before or during TNF blocker therapy
Curative treatment includes triple combination therapy with rifampicin (10 mg/kg/day in a single dose), isoniazid (4 mg/kg/day), and pyrazinamide (20 mg/kg/day in a single dose), after which the pyrazinamide is stopped and the two other drugs continued in combination. Ethambutol (20 mg/kg/day) should be added during the first two months if there is a relapse or a suspicion of drug resistance (patient from an endemic area).
It is not advisable to start the treatment in hospital departments where other patients with TNF blocker associated immune deficiency are seen.
Can TNF blocker therapy be resumed?
In the absence of prospective data, resumption of TNF blocker therapy is not recommended. If the clinical value of TNF blockers is considered large, the drug should be started no sooner than two months after the end of the antituberculous treatment. It is essential to make sure that there is no clinical or radiographic evidence of active tuberculosis and that tests for the tubercle bacillus are negative.
Current knowledge suggests that isoniazid alone, or with rifampicin, should be given as long term treatment to patients who resume TNF blocker therapy. Careful monitoring by a multidisciplinary team is essential.
Prescription of systemic or local glucocorticoid therapy in patients with tuberculosis receiving TNF blockers
There is no contraindication to intra-articular or systemic glucocorticoid therapy. Glucocorticoid therapy is recommended in patients with tuberculous miliary, meningitis, or pericarditis. Because rifampicin accelerates the breakdown of glucocorticoids, the glucocorticoid dose should be increased by 40%.
Such recommendations, adapted in every country, should substantially reduce the frequency and severity of tuberculosis occurring during TNF blocker therapy. However, many issues remain unsettled, and changes in these recommendations are likely to occur in the near future.