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.

Lynne McTaggart

One reader, a retired pharmacist, adds to the confusion by pointing out that methotrexate is available only as a 2.5 mg and 10 mg tablet. And it gets curiouser and curiouser. The dosage recommended in the British Formulary is from 7.5 mg to 20 mg a week for arthritis treatment.

Is this one more example of a miscommunication between drug manufacturers and doctors, with the patient, yet again, at the sharp end? We feel we should be told.

The study, conducted by the University of Oslo, enlisted 53 patients with classic rheumatoid arthritis, then allocated27 of them to a four week stay at a health farm. The study group were then put on a near total fast using only herbal teas, garlic, vegetable broth and juice extracts from carrots, beets and celery. The fast did not allow fruit juices.

After the fast, the patients were allowed to reintroduce a new food every other day. If they reported an increase in pain or joint swelling up to two days after ingesting the new item, they omitted it again for another week.

For three and a half months, they were asked to avoid gluten, meat, fish, eggs, dairy products, refined sugar, citrus fruits, alcoholic beverages, tea, coffee, salt strong spices and preservatives.

After three and a half months, the patients were allowed to reintroduce dairy products and gluten so long as they did not react to them.

A control group spent four weeks at a home eating an unrestricted diet.

After four weeks, those on the restricted diet showed significant improvements in joint tenderness and swelling, pain, morning stiffness and grip strength. These benefits carried on for a year, leading the researchers to concludes that “a substantial reduction in disease activity can be obtained by fasting followed by an individually adjusted vegetarian diet”.

These results caused the ordinarily conservative Lancet to begrudgingly admit:”It is already clear . . . that every rheumatology department needs a dietitian, if not a health farm.”

Yet, despite ever more health concerns – and legal claims for injury and death – surrounding Arava, the drug is still being prescribed daily.

In the UK, the drugs watchdogs have done nothing, even though the lead regulator, the European Agency for the Evaluation of Medicinal Products, issued an urgent warning about the drug over two years ago, and claimed that the drug was responsible for 12 deaths in Europe.

In the US, the Food and Drug Administration (FDA) has done as close to nothing as it’s possible to do. In its customary flair for the dramatic, it added a warning to the prescribing information last November. It is now pointing out that Arava patients can suffer serious liver damage, which may be fatal. The new datasheet also reports that some patients have suffered severe infections, including sepsis, that have sometimes proved fatal.

Arava was approved in 1998 as an alternative to the standard arthritis drug methotrexate. But even though five methotrexate prescriptions are written for every one for Arava, the new drug has generated six times more reports of liver damage than methotrexate. The death rate is also 33 times higher than for methotrexate. It can also cause Stevens-Johnson syndrome, a serious systemic skin condition that is never seen with methotrexate.

Problems with Arava could be even worse than the statistics suggest. The drug stays in the body for a long time, and many serious cases of adverse effects have been reported six months after stopping therapy – making it difficult to point an accusing finger at Arava.

The very low incidence of RA in preindustrial Europe has been put down to the use of copper cooking utensils and plates (Rainsford KD, in Sorensen JRJ [ed], Inflammatory Diseases and Copper, Humana Press, 1982). Supplemental copper may, however, be better for some. Its anti-inflammatory effect is due to copper’s ability to create antioxidants (J Int Acad Prev Med, 1980; 7-21).

This is why practitioners of nutritional medicine sometimes advocate replacing conventional medicine’s high-dose aspirin therapy with a copper-salicylate supplement. In a study of more than 1000 RA patients given this copper-salicylate complex, 89 per cent showed better joint mobility, less joint swelling and normal red blood cell levels for an average of three years (Inflammation, 1977; 2: 217-38).

It was such a wonder drug, in fact, that sufferers in Canada were lobbying doctors to prescribe it, and patients with psoriasis were praying for the day when it would be approved for their use as well.

This was an amazingly warm reception for a drug that could bring on TB among the susceptible – and that welcome may go down to gas mark one with the news that Remicade can also cause fatal blood and nerve disorders.

These latest effects were included in a letter sent to health professionals in the US, at the insistence of the FDA, the US drugs watchdog. Any patient taking the drug who develops a persistent fever should seek immediate medical attention, the manufacturer urges.

Next wonder drug, please (www.fda.gov/opacom/7alerts.html; August 2004).

Researchers reviewed the findings of six studies that involved a total of 656 patients and found that it was far more effective a pain-reliever than a placebo, or sugar pill. They also thought it was a useful therapy for those who get no relief from standard painkillers.

Capsaicin, which is derived from chilli peppers, is typically used to relieve pain from neuralgia, diabetic neuropathy, osteoarthritis and rheumatoid arthritis.

It’s not without its side-effects, however, which include sensations of burning, stinging, and respiratory irritation if inhaled.

(Source: British Medical Journal, 2004; 328: 991-4).

Similarly, an NSAID cream fared no better than a placebo.

In contrast, 40 rheumatoid-arthritis sufferers were helped by a form of meditation called ‘mindfulness’. As they reduced their stress levels, so did their pain decrease (Ann Rheum Dis, 2004; 63: 923-30; BMJ, 2004; 329: 324-6; MSNBC News, 13 September 2004 [online]).