TNF Blockers: A trigger for TB?

Just when the drug companies thought they’d found an alter-native to COX-2 drugs for arthritis, deemed responsible for at least 60,000 deaths, it now looks as if the replacements—called tumor necrosis factor (TNF)-blocking drugs—are equally as dangerous.

These drugs are being used to treat rheumatoid arthritis, psoriatic arthri-tis and ankylosing spondylitis. But they’ve now been linked to a range of potentially fatal infections, including tuberculosis (TB).

Earlier this year, the US Food and Drug Administration (FDA) requested that the TNF-blocker Enbrel (etaner-cept) be given a black-box warning stating: “Infections, including serious infections leading to hospitalization or death, have been observed . . . Infections have included bacterial sepsis and tuberculosis.” 

Neither the FDA nor the other manufacturers of this class of drugs are certain whether the drug is react-ivating latent TB infection or causing new infection. Nevertheless, Wyeth, which makes Enbrel, has admitted that patients who tested negative for latent TB prior to receiving the drug went on to develop active TB later.

The warning comes after studies of more than 20,000 and 15,000  patients in whom TB rates were 0.01 and 0.007 per cent, respectively. In its own datasheets, Wyeth claims that up to 7 per cent of patients using Enbrel and another drug for six months developd serious infections, including bacterial pneumonia, bacterial skin infections, pulmonary fibrosis and fatal pneumonia. One patient with pulmonary fibrosis and pneumonia died of respiratory failure. Among patients taking the drug, nearly twice as many develop upper respiratory infections compared with a placebo.

Besides lung infections, TNF block-ers can also cause viral, bacterial, fungal and protozoal infections in all organs, whether taken alone or with other immunosuppressants. Those particularly at risk include diabetics or those at risk of recurrent infections or open wounds.

Immunosuppression 

One obvious reason for the link with infections is that these drugs suppress the immune system. TNF blockers also include Abbott’s Humira (adalim-umab) and Centocor’s Remicade (infliximab), which are ‘biological res-ponse modifiers’ that block the production of TNF, an inflammation-regulating protein that medicine believes is behind the inflammatory response seen in rheumatoid arthritis and other autoimmune disorders.

Like many other drugs, TNF block-ers act indiscriminately, crushing the immune response against any foreign agents in which TNF plays a major part (APLAR J Rheumatol, 2006; 9: 165–9).

Although this is being treated as a new finding, the link between these drugs and TB was noted in October 2004 by Health Canada, the Canadian watchdog counterpart of the US FDA. At that time, it published a summary of 1233 cases of adverse reactions to infliximab and etanercept reported between January 2000 and May 2004, which included a number of serious infections such as TB.

The cancer connection

In fact, this is the second blow to be suffered by this class of drugs. A few years after TNF blockers came onto the market to enormous fanfare, the FDA began uncovering a tie between TNF drugs and lymphoma—cancer of the lymphatic network, part of the immune system. TNF drugs now contain warnings against this cancer following trials showing that patients taking infliximab have a sixfold higher incidence of lymphoma than is to be expected.

At present, the FDA is especially concerned about the possible asso-ciation between TNF blockers and lymphoma and other cancers in children and young adults after receiv-ing around 30 reports of cancer in this population subgroup between 1998—just after the approval of the first TNF blocker—and April 2008.

The reports describe the develop-ment of cancer in children and young adults taking TNF blockers when they were still under 18 years of age. About half the cancers were lymphomas, including both Hodgkin’s and non-Hodgkin’s types. The FDA has also received reports of other cancers, including leukaemia, melanoma, and solid organ cancers in children and young adults while taking the drugs.

TNF blockers entered the market-place in 2002 and quickly rushed to the top of the bestseller list just as Vioxx’s star waned. Clearly, the applause was premature.

Lynne McTaggart

For a safer way to treat arthritis, see The Arthritis Manual, which is now available either in paper form or as a download from www.wddty.com .

If you don’t get cancer or TB . . .

  Besides leaving you open to infection and lymphomas, TNF blockers can also cause:

-           lupus-like symptoms               -            abdominal pain

-            peripheral oedema                   -            dyspepsia

-            respiratory disorders                -            sinusitis

-           rhinitis                                       -            vomiting

-            pharyngitis (sore throat)            -            mouth ulcers

-           cough                                       -            hair loss

-           asthenia (loss of strength)            -            nausea.