There is an air of desperation surrounding treatment for rheumatoid arthritis (RA). With every new failure to come up with a drug that can reliably prevent progression of the disease, medicine grows bolder, experimenting with ever more powerful—and potentially dangerous—agents.
Many of the latest disease-modifying anti-rheumatic drugs (DMARDS), such as methotrexate, are immunosuppressants; the latest, the monoclonal antibodies, started life as a last-ditch cancer drug.
Before being reinvented as a drug for arthritis, ulcerative colitis, Crohn’s disease and other autoimmune disorders, this class of drugs, also known as anti-tumour necrosis factor (anti-TNF) agents, were used to combat non-Hodgkin’s lymphoma, usually in those patients whose cancer returned after more traditional chemotherapy didn’t work.
Anti-TNF drugs (known as ‘biological DMARDS’) work by neutralizing TNF within the cell and its membranes. These proteins, believed to play a central role in the development of RA, are present in the blood and joints of RA sufferers in excessive amounts, causing inflammation. Anti-TNF agents block the action of TNF and consequently reduce inflammation.
TNF also plays some other major roles in the body, however. It’s well known, at least in animal models, that TNF helps to fight infection in the body. TNF also plays a central role in natural killer cell activity, although, paradoxically, it also has some tumour-promoting effects as well.
Nevertheless, a fairly obvious question remains: wouldn’t turning off the body’s response to infection and its control of tumour growth lead to serious infection or cancer?
A recent major review of all the drug trials of anti-TNF antibody conducted by a number of researchers at the Mayo Clinic in America recently answered with a resounding ‘yes’. The review concluded that anti-TNF therapy at least trebles the risk of malignancies (lymphomas, plus skin, gastrointestinal, breast and lung tumours) and doubles the risk of serious infections (i.e., those requiring antimicrobial therapy and/or hospitalization) in patients with RA. What’s more, the study found a ‘dose-dependent’ effect; the higher the dosage of the drug taken, the more likely the patient was to be adversely affected.
Patients on high doses of the drug were more than four times likely to develop cancer (JAMA, 2006; 295: 2275-85).
The review concerned two of the anti-TNF drugs licensed for clinical use: the unpronounceable infliximab (Remicade) and an even bigger mouthful, adalimumab (Humira).
A third product, etanercept (Enbrel) is also licensed, but has a different binding capability and so was not included in the Mayo study.
Nevertheless, a recent study of etanercept showed a significant increase in the incidence of solid malignancies in patients given the drug (six solid cancers in 89 patients treated with the drug plus cyclophosphamide), compared with no malignancies in the control patients (N Engl J Med, 2005; 352: 351-61)
For the ‘meta-analysis’, a team of researchers from the Mayo Clinic in Minnesota combined the results of all randomized, placebo-controlled trials of the two licensed drugs tested over 12 weeks or more.
This totalled nine such trials, with nearly 3493 patients given the active drug, and approximately 1512 given a placebo. The investigators also inter-viewed the manufacturers of the two licensed drugs.
The actual statistics show even higher risks that those reported in the meta-analysis. Of the 3493 patients given at least 1 dose of an anti-TNF drug, 24 developed malignancies, compared with two in the control group.
Furthermore, the safety data reported to the US Food and Drug Administration showed even larger figures: a total of 37 malignancies among those given the drug, compared with three among the controls.
Nevertheless, the Mayo Clinic investigators chose not to count seven cases of skin cancer, which developed during the study periods but were deemed unrelated to the drug, and six cases of malignant lymphomas, which developed after the study had actually finished. The eventual pooled analysis concluded that patients taking the drug had 3.3 times the risk of developing a malignancy, compared to those given a placebo.
Among those given the drugs, an additional 126 patients developed serious infections, compared with 26 in the control groups.
The main infection risk from this class of drugs has been assumed to be granulomatous infections (like pneumonia or tuberculosis). Nevertheless, only 10 per cent of serious infections were of this variety.
Indeed, a recent Dutch study shows that up to one-quarter of patients taking these drugs develop skin infections, rashes or eczema (Arthritis Research and Therapy, 2005; 7: R666-R676).
The results of the Mayo Clinic meta-analysis are similar to the findings of the German Biologics Register, which showed that patients given infliximab trebled their risk of serious infection (Arthritis Rheum, 2005; 52: 3403-12).
Up until now, the drug companies claimed that malignancies caused by anti-TNF therapy for RA were rare. Only a single drug study of 18,000-plus patients, comparing those receiving methotrexate or anti-TNF agents, found an increased risk of malignancies of the blood in the patients given the monoclonal antibodies (Arthri Rheum, 1994; 50: 1740-51). The results of this meta-analysis put paid to that optimistic view.
The National Institute for Clinical Evidence (NICE), an organization that advises the National Health Service in Britain, is now re-evaluating how widely these drugs should be prescribed. The researchers of the Mayo Clinic suggest that infliximab doses above 3 mg/kg every eight weeks can cause problems. In fact the research shows no additional benefit in taking higher doses.