Arthritis patients who take a particular drug to reduce symptoms are at much greater risk of developing tuberculosis, according to research led by an Irish scientist in Boston. His study showed that the drug lowers the resistance of patients with latent TB infection, making them more susceptible to the disease.
Dr Joseph Keane, assistant professor of medicine at Boston University School of Medicine, is involved in the university's pulmonary centre and tuberculosis control programme. The results of his research are published today in the New England Journal of Medicine.
The drug in question, infliximab, is sold by manufacturers Centicor under the brand name, Remicade. It is available in the Republic; in fact, one of the patients studied was treated in a Dublin hospital, according to Dr Keane.
"Infliximab is a remarkably effective drug for the treatment of rheumatoid arthritis," says Dr Keane. However, his discovery now makes it essential that any patient prescribed the drug must first be screened for latent TB. Currently, 147,000 people have taken the drug, 26,000 of them outside the US. Dr Keane's team reviewed data from the US Food and Drug Administration's Adverse Event Reporting System, looking for tuberculosis disease following infliximab therapy.
They discovered that patients who took the drug and who had an undetected, symptomless TB infection were more at risk of having an active TB flare-up afterwards.
The team also found that if the disease arose, its appearance was unusual. Most TB is seen in the lungs but in these cases it showed up in other tissues, including the spine, brain, bladder and lymph nodes. Many of the cases examined involved "disseminated tuberculosis", where the disease occurs in several tissue types. Normally only two per cent of cases are disseminated, but 24 per cent of the cases post-infliximab were disseminated, says Dr Keane. Asked whether this confirmed the connection, he said: "The data is highly, highly suggestive." It was certainly enough to encourage doctors to check for latent TB infection before prescribing the drug. "You have to be an infected person before you are at risk of reactivation of the disease," says Dr Keane. "The important thing is before prescribing the drug, the clinician has to check if the person is infected."
Having a TB infection but remaining unaware of it is not unusual, particularly given the high incidence of the disease world-wide. One in three people has the disease, says Dr Keane. "It is one of the single most common bacterial infections and it is also one of the biggest bacterial killers, with three million deaths world-wide a year. We don't know how many people are infected in Ireland."
DR Keane is a specialist in the body's immune response to tuberculosis. He studied lung tissues and, in particular, a white blood cell in the lungs called a macrophage. "It acts as a sentry against things that infect the lung, such as tuberculosis." This work gave him important clues about what was happening after infliximab therapy. "We don't know why this happens but I have spent the last six or seven years studying why this might happen." A patient may have TB but it remains latent because the macrophages successfully hold it in check. They are helped by the release of a protein called tumour necrosis factor (TNF), an important element of the immune response.
Rheumatoid arthritis is one of a number of related auto-immune diseases where the body's immune system becomes overactive and begins to attack healthy tissues. Used in arthritis patients, infliximab works to lower TNF levels and reduce immune damage to joints. But if the patient has latent TB, reduced TNF levels allows the TB to become active. The macrophages can no longer keep the disease at bay.
This finding represented "a large bone thrown to the researchers studying TNF", says Dr Keane. It will provide much new information about the role of this protein.
Dr Keane is due to return to the Republic after more than eight years in the US. He has accepted a post at St James's Hospital and Trinity College as a consultant respiratory physician. He is originally from Lisdoonvarna, Co Clare, and studied at Trinity and University College, Dublin.