ARTHRITIS:SECOND-LINE TERRORS

Second-line treatments to treat rheumatoid arthritis are being pushed to the front at greater risk to the patient.

Medicine’s response to arthritis and rheumatoid arthritis in particular has been to throw ever more powerful drugs at a condition they don’t understand.

Rheumatologists are beginning to routinely subject sufferers to an alarming range of drugs whose side effects range from death, blindness, cancer and mental disorders.

Many of these drugs are powerful immunosuppressants and cell-blockers, developed to treat more serious and life threatening conditions. Methotrexate, which is fast becoming the treatment of choice in the US for rheumatoid arthritis, was developed as a cancer drug. Penicillamine, a component of penicillin, and several anti-malaria drugs are also being added to the options open to the rheumatologist.

In the wrong hands, methotrexate is a potential killer, causing liver and kidney damage, lung disease and bone marrow suppression. (Physicians’ Desk Reference 1992). Not surprisingly, the PDR, the US’s drugs reference bible, reports deaths among arthritis patients on the drug. It stresses that the drug should be given only by “physicians whose knowledge and experience includes the use of anti-metabolite [substances which fundamentally changes the body’s metabolism] therapy”.

This already powerful drug can form a lethal cocktail when taken with other drugs. Some rheumatologists are combining drugs, such as methotrexate with non-steroidal anti-inflammatory drugs (NSAIDs), which, on their own, account for 4,000 deaths in Britain every year.

Methotrexate is one in a family of drugs called slow-acting antirheumatic drugs (SAARDs) which have been considered as second-line therapies. Traditionally, they have been prescribed to patients with advanced rheumatoid arthritis to slow its progress.

Front-line treatments have included high-dose aspirin, to reduce inflammation in the joints, but continual use has caused stomach bleeding. The newer, front-line treatment are NSAIDs, a group of pain killers which have brought their own host of side-effects such as ulcers and life-threatening gastrointestinal problems (see WDDTY vol 2, no 12).

But because front-line treatment can only ease the pain, many specialists are pushing the SAARDs to the front to slow the progress of rheumatoid arthritis and to help prevent damage to the joints. They are working on the theory that arthritis is a malfunction of the immune system; as such, they are using powerful immunosuppressants, cell-blockers and steroids to arrest the condition.

Favourite among the SAARDs has always been gold, given either as an injection or in tablet form. But it is so toxic that about 35 per cent of patients have suffered side effects bad enough to stop the treatment (Arthritis Rheum 1990: 33; 1449-61).

In fact, gold is considered so toxic that many specialists are turning to methotrexate as a safer option! (New Eng Jrnl of Med, 12 May 1994.)

Common among the side-effects of most of the SAARDs are nausea, vomiting, abdominal pain and diarrhea. Even after suffering these reactions, the patient may be no better off. Benefits have been either observational or studied only over a short period. One of the few double-blind studies which tested the second-line treatments against a placebo among 3,439 arthritis patients concluded that the benefits of the drugs were uncertain. (J Clin Epidemiol 1993; 46(3): 315-21).

Lack of research into long-term effects means the patient has to play a game of Russian roulette to discover whether he will develop symptoms worse than his condition. Fortunately, with gold treatment at least, an intolerance can usually be quickly spotted when the patient develops mouth sores or rashes.

Specialists do not understand how SAARDs work if and when they do but accept they can be highly toxic and even life-threatening (Drug and Therapeutics Bulletin, 1993; 31:18).

The overall impression is a stumble in the dark. As two American rheumatologists Joseph Cash and John Klippel concluded in their recent paper: “. . . substantial advances in the drug treatment of rheumatoid arthritis will require a much better understanding of the processes that propagate the disease and, ultimately, the identification of the factors that cause it.” (New Eng Jrnl of Med, 12 May 1994).

Besides NSAIDS, here are the main orthodox treatments:

Gold

The traditional, and favoured, SAARD, even described by some rheumatologists as “the gold standard”. A surprising title for a highly toxic treatment that can lead to fatal bone-marrow suppression (Drugs and Therapeutics Bulletin, 1993; 31: 18).

As it has been administered since the 1920s, it is staggering that there has never been a long-term trial to test for reactions.

It became the treatment of choice only because researchers misunderstood the causes of arthritis. German bacteriologist Robert Koch had shown that gold and other heavy metals could fight tuberculosis and other infectious diseases. As it was believed arthritis was an infection, the theory was that gold could treat it as well.

It can be administered either as an injection, the most common course, or in tablet form, introduced about seven years ago. The usual dose by injection is 50mg a week for 18 months, although the doctor should be monitoring carefully for early side effects such as skin rashes and mouth sores. More serious side effects include kidney problems and bone marrow suppression. Because of these concerns, gold tablets were developed. Early studies show they cause fewer side effects than injections (Arthritis Rheum 1990; 33: 1449-61), but conversely are also less efficacious (Ann Rheum Dis 1986; 45: 705-11).

Methotrexate

Methotrexate is fast becoming the most popular second-line therapy in the US as it is supposedly less toxic than gold (J Cash and J Klippel, cited above). This is an astounding statement to make about a powerful drug developed to treat cancer and, if true, can apply only at very low dosages.

The usual dosage is between five and 15mg a week, and improvements have been noted in between 30 and 70 per cent of patients (Eur J Rheumatol Inflamm 1991; 11: 148-61).

However, the typical side effects of stomach complaints, nausea and anorexia can worsen dramatically if the dose is increased or the drug mixed with another. Damage to the liver and lungs has been reported (Ann Rheum Dis 1990; 49: 25-7). Death can occur with high doses, especially if the patient takes the dose daily instead of weekly (Drugs and Therapeutics Bulletin, 1993; 31: 18).

Penicillamine

As the name sugggests, penicillamine is a component of penicillin and was originally developed to treat Wilson’s disease (copper accumulation in the liver). For arthritis the daily maintenance dose can be as high as 750mg, although the patient is usually started with between 125 and 250mg to test for adverse reactions.

Common side effects include a skin rash, mouth ulcers and a loss of taste; a more serious reaction is skin eruptions when the treatment should be stopped immediately. The blood disorder thrombocytopenia is common and can be severe (Drugs and Therapeutics Bulletin, 1993; 31:18).

Sulfasalazine

Sulfasalazine is from the family of cytotoxic drugs which block the growth of cells. Serious side effects including bone-marrow suppression, increased risk of infection, infertility, cancer, and defects in the embryo (G W Cannon and J R Ward, Arthritis and Allied Conditions, Lea & Febiger, Philadelphia 1989).

The drug was originally developed to treat ulcerative colitis and Crohn’s disease (ABPI Data Sheet Compendium 1993-4).

Its beneficial effects can be swift, usually within two to three months and, in one study, a daily 2g dose achieved partial or complete remission in 30 of 59 patients (Ann Rhem Dis 1985; 44: 194-8). Nonetheless, it is less effective than gold, although the side effects seem less severe (Lancet 1989; i: 1036-8).

Chloroquine/hydroxychloroquine

These are anti-malaria drugs that, through trial and error, have been found to have some beneficial effects on rheumatoid arthritis. They were used to treat a number of conditions after the Second World War.

A common side effect can be visual impairment, even leading to blindness; the drugs may cause lesions on the eye in doses above six mg a day (Arthritis Rheum. 1979; 22:832). Other effects include tinnitus, insomnia, hyperactivity and anemia.

Cyclosporin

This immunosuppressant, originally developed to stop the body from rejecting transplant organs, is the current flavour of the month in medicine, used to treat every disease doctors otherwise don’t know how to handle. It acts by lowering the immune system T-cells and should be used in treating rheumatoid arthritis only when the condition is life-threatening. Other immunosuppressants that may be recommended include azathioprine and cyclophosphamide, although they come with the same high risks. None are licensed in the UK for treatment of arthritis, although they are being investigated.

A common side effect can be kidney dysfunction, high blood pressure and stomach problems.

Steroids

After the immunosuppressants, steroids are the most controversial and possibly damaging treatments available for arthritis.

Steroid overuse in the 1950s to treat arthritis and the horrors that came from that has put paid to this treatment among those with long enough memories. The Medical Research Council trial in 1960 concluded that the risks outweighed any benefits.

The side effects of the glucocorticoids which include cortisol, cortisone, prednisone and dexamethasone are many and various, and include the suppression of the immune system, osteoporosis, muscular dystrophy, peptic ulcer, psychiatric disorders, infections and eye problems (T W Behrens and J S Goodwin, Arthritis and Allied Conditions, Lea & Febiger, Philadelphia 1989).

!ABryan Hubbard