Unlike first-line drugs, which are prescribed mainly to reduce pain and inflammation, second-line drugs are given in an attempt to modify the condition or to stop arthritis from progressing. Mainly prescribed for rheumatoid arthritis, this category is variously referred to as either DMARDs (disease-modifying antirheumatic drugs) or SAARDs (slow-acting antirheumatic drugs). Both refer to the same broad-brush group that includes: antimalarials and gold injections; synthetic agents such as methotrexate and sulphasalazine; anti-tumour necrosis factor agents (TNF blockers), such as etanercept and infliximab, which suppress the body’s response to tumour necrosis factor, part of the inflammatory response; even powerful cytotoxic (cell-killing) immunosuppressant drugs, such as drugs developed for chemotherapy. Although not classified as ‘disease-modifying’, even corticosteroids (usually just referred to as steroids) – which regulate immune response and inflammation – get thrown at rheumatoid arthritis and polymyalgia rheumatica.
Unsurprisingly, these drugs too have had their problems, particularly with patients at risk of infection, and there have been reports of ‘rare neurological and haematological events’ (side effects related to the brain, nerves or blood).1
The use of all these types of drugs is based on the theory that arthritis is a malfunction of the immune system. Accordingly, doctors look to drugs that block basic immune-system processes to attempt to thwart or at least arrest the condition.
Second-line treatments, such as gold, methotrexate and sulphasalazine, are traditionally prescribed to rheumatoid arthritis sufferers once the disease is advanced. It is thought – or at least hoped – that these drugs can stop whatever autoimmune destruction is going on. Every case, however, is a decidedly hit-and-miss affair, with doctors coming upon something that seems to work in the course of treating something else. This treatment may slow down the progress of the disease, but also brings with it a host of side effects, including ulcers and life-threatening gastrointestinal problems. Many of the drugs the medical profession throws at sufferers are powerful immunosuppressants and cell-blockers developed to treat more serious and life-threatening conditions such as cancer.
Because first-line treatments like NSAIDs can only ease the pain, many specialists are now pushing SAARDs to the front, using them to slow the progress of rheumatoid arthritis and help to prevent damage to the joints.
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 make them stop the treatment.2 In fact, gold is considered so dangerous that many specialists are turning to methotrexate as a safer option.3
Common among the side effects of most SAARDs are nausea, vomiting, abdominal pain and diarrhoea. Yet, even after suffering these reactions, the patient may be no better off. Benefits have been either observational or studied for only a short period of time. One double-blind study to test the second-line treatments against a placebo among 3,439 arthritis patients concluded that the benefits of the drugs were uncertain.4
Lack of research into long-term effects means that the patient has to play a game of Russian roulette to discover whether he or she will develop symptoms worse than their original condition. Fortunately, with gold treatment at least, an intolerance can usually be quickly spotted when the patient develops mouth sores or rashes.
Specialists don’t understand how SAARDs work – if and when they do – but accept that they can be highly toxic and even life-threatening.5 The overall impression is a stumble in the dark. As two American rheumatologists, Joseph Cash and John Klippel, concluded: ‘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’.6
The traditional and favoured SAARD, gold has even been described by some rheumatologists as the ‘gold standard’, a surprising title for a highly toxic treatment that can lead to fatal bone marrow suppression.7
Although gold has been in use as a treatment for arthritis since the 1920s, there has never been a long-term trial to test for reactions.
However, even over the short term, more than a third of patients find the side effects intolerable and stop treatment.8
Gold 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 that arthritis was an infection, the theory was that gold could treat it.
Gold can be administered either as an injection, which was formerly the most common course, or in tablet form. The usual dose by injection is 50mg a week for 18 months, although the patient needs to be monitored carefully for early side effects, such as skin rash and mouth sores.
More serious adverse effects include kidney problems and bone marrow suppression. It is because of these concerns that gold in tablet form was developed.
Methotrexate is fast becoming the most popular second-line therapy in the USA, as it has been found to be less toxic than gold in one Scottish study, an astonishing discovery for a powerful drug developed to treat cancer. In that study, average weekly dosages were 10mg/week and 1,460mg/week for methotrexate and gold, respectively.9 The usual dose is 5–15mg a week, and improvement has been noted in 30–70 per cent of patients.10
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. In the wrong hands, methotrexate is a potential killer, causing liver and kidney damage, lung disease and bone marrow suppression. Not surprisingly, the Physicians’ Desk Reference reports deaths among arthritis patients taking the drug. The PDR stresses that the drug should be given only by ‘physicians whose knowledge and experience includes the use of antimetabolite [the term refers to substances that fundamentally change the body’s metabolism] therapy’.
This already powerful drug can form a lethal cocktail when taken with other drugs. Some rheumatologists are combining methotrexate with NSAIDs, which, on their own, account for thousands of deaths in Britain every year. Damage to the liver and lungs has been reported.11
It’s long been known that methotrexate is a potential killer. Back in the 1990s, the National Patient Safety Agency announced that methotrexate, used for both arthritis and psoriasis, had led to 25 deaths and 26 cases of serious harm over a period of 10 years. Around the same time, reports came in about liver and kidney damage, lung disease and bone marrow suppression.12 And researchers have warned of death among arthritis patients taking high doses, especially when taken daily instead of weekly.13
Sulphasalazine belongs to the family of cytotoxic drugs that block the growth of cells. Serious side effects include bone marrow suppression, an increased risk of infection, infertility, cancer and defects in the embryo.14 The drug was originally developed to treat ulcerative colitis and Crohn’s disease. Its beneficial effects can be swift, usually apparent within two to three months.15 In one study, a daily 2g dose achieved partial or complete remission from arthritis symptoms in 30 out of 59 patients.16
However, other studies show that, while sulphasalazine is better than a placebo, it has ‘significant side effects’ and is ‘similar in efficacy to gold, but with lesser and milder toxicity’.17
As the name suggests, penicillamine is a component of penicillin, 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 125–250mg 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, in which case the treatment should be stopped immediately. The blood disorder thrombocytopenia is common and can be severe.18
These are antimalarial 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 World War Two.
A common side effect is visual impairment that may even lead to blindness. The drugs may cause lesions in the eye with doses greater than 6mg a day.19 Other effects include tinnitus, insomnia, hyperactivity and anaemia.
This immunosuppressant, originally developed to stop the body from rejecting a transplanted organ, has become another current ‘flavour of the month’ in medicine, used to treat every disease doctors otherwise don’t know how to manage. It acts by reducing numbers of 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 are azathioprine and cyclophosphamide, both of which come with the same high risks. Common side effects are kidney dysfunction, high blood pressure and stomach problems.
Leflunomide, a pyrimidine synthesis inhibitor, works by inhibiting an enzyme involved in the synthesis of a protein on the membrane of the mitochondria – the ‘energy power pack’ – of cells. This drug has been linked to six times more cases of fatal liver toxicity and 13 times more reports of hypertension than methotrexate, even though five times more prescriptions had been written for methotrexate. Marketed as Arava, leflunomide, which treats rheumatoid arthritis, has been linked to 12 deaths in the USA alone. The FDA has received at least 130 reports of severe liver toxicity from people taking the drug since it hit the market in 1998. Of these, 56 were treated in hospital and 12 died. Two of those who died were in their 20s.
Similar reactions to leflunomide have been reported in Europe, and the European Agency for the Evaluation of Medicinal Products issued an urgent warning to patients and doctors about the drug’s toxicity after learning of 296 cases, 129 of which were serious, including liver failure. Public Citizen, a consumer watchdog group, petitioned the FDA to remove the drug from the marketplace. The drug was also linked to 12 cases of Stevens-Johnson syndrome (SJS), a serious systemic skin condition – an adverse reaction not seen with methotrexate.
Other side effects of leflunomide include diarrhoea, nausea, vomiting and anorexia, headache, dizziness, hair loss, eczema, dry skin, jaundice, anxiety, ruptured tendons and anaemia.
The link with possibly fatal liver toxicity was suspected at the time of licensing. Nevertheless, efforts to get the drug banned failed because an advisory panel to the FDA recommended that its benefits outweigh its ‘rare’ side effects.
TNF blockers, which include Amgen and Wyeth’s Enbrel, Abbott’s Humira and Centocor’s Remicade, are biologically engineered to relieve the worst and most painful symptoms of several forms of arthritis. Also called ‘biological response modifiers’, TNF blockers curtail the overproduction of TNF, an inflammation-regulating protein (TNF-alpha) that medical scientists believe is behind the inflammatory response seen in rheumatoid arthritis and other autoimmune disorders. As with many other drugs, TNF blockers act indiscriminately, crushing the immune response against any foreign agents TNF plays a major part in dealing with.20
Not long after the development and release of TNF blockers on the market, an FDA advisory panel met to determine whether they were behind some 170 cases of lymphoma that occurred among users of these drugs over a five-year period. The advisory panel issued several stiff warnings about these products, and the FDA asked manufacturer Centocor, a subsidiary of Johnson & Johnson, to revise its warnings in the prescribing information for bestselling arthritis TNF-blocking drug Remicade (also used to treat Crohn’s disease), following evidence that it may cause cancer.
In more recent studies of all TNF-blocking agents, patients taking these drugs for arthritis were found to have three times the incidence of lymphoma than was usual among arthritis patients. Centocor itself admitted that in all its controlled trials their drug had a six-times higher incidence of this cancer than expected. Those most at risk included those with Crohn’s disease and RA – the very population being prescribed the drug, many of whom were also frequently taking immunosuppressant drugs at the same time.
The FDA has advised all manufacturers producing TNF-blocking drugs to add to their product information a ‘black box’ warning (which the agency uses to highlight a drug’s adverse effects) about the drug’s potential to cause malignancy. The black box warning was a huge blow for companies such as Remicade’s manufacturer Centocor. Remicade, a synthetically bio-engineered antibody (infliximab), was a top-selling intravenous drug in 2003, with sales of $1.5 billion in the USA alone. This drug can cause potentially fatal blood conditions such as leukopenia, neutropenia and pancytopenia (where the number of white blood cells capable of fighting infection is radically decreased), and inflammation and thickening of blood vessels. So far, there have been a number of deaths among people taking Remicade in combination with other drugs worldwide, although the FDA says it can’t prove a direct causal link. Remicade is also implicated in numerous cases of pericardial effusion (fluid in the heart tissue).
Humira (adalimumab), a TNF blocker manufactured by Abbott Laboratories, is used to reduce symptoms in patients with moderate-to-severe rheumatoid arthritis, as well as to prevent bone damage and improve physical functioning in patients who haven’t responded well to any other arthritis medication. Usually administered by injection every two weeks, Humira is also used to treat juvenile arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis, and is also prescribed in the treatment of Crohn’s disease.
Like etanercept (Enbrel) and infliximab (Remicade), it’s associated with numerous dangerous side effects – specifically anaphylactic reactions and serious blood disorders such as pancytopenia and aplastic anaemia. And again like Enbrel and Remicade, Humira is also linked to an increased rate of tuberculosis (TB), serious fungal infections (endemic mycoses) and intracellular bacterial infections, even when used only for short periods of time.21
Previously, Humira’s side effect profile and immunosuppressant action limited its use for only moderate-to-severe cases of RA in adults who failed to respond to other DMARDs. But now it’s indicated as a go-to drug against all cases of RA, and its approval for ankylosing spondylitis (arthritis of the spine) is not far off.22
As for Humira’s use for psoriatic arthritis, paradoxical effects have been reported. In one instance, five patients developed psoriatic skin lesions six to nine months after starting TNF-blocker drugs such as Humira. The lesions disappeared with topical treatment or on discontinuing the drug treatment.23
Some researchers question Humira’s efficacy altogether, as placebo-controlled trials suggest that it’s only moderately effective on its own, and that there’s no point in continuing the drug for more than three months if it hasn’t worked by then. The best results have been achieved in combination with another drug such as methotrexate, which of course has its own raft of side effects, including depressed bone marrow function.24
One of the most harmful side effects of TNF blockers is that they have contributed to the resurgence in tuberculosis, since they damage pro-inflammatory agents that nevertheless help to maintain TB in the latent phase. Anti-TNF medications appear to reactivate latent TB. They also disrupt calcified lung tissue containing live but dormant Mycobacterium tuberculosis, the bacteria that causes TB.25
So far several hundreds of cases of TB, in the lungs and in other organs, many of them fatal, have been associated with TNF-blocking agents.26 The brain, lymph nodes and digestive tract may be involved, and there’s even been a case of tonsillar TB in a 61-year-old RA patient after eight months of Humira treatment.27
Neither the FDA nor the various pharmaceutical manufacturers of this class of drugs are certain whether or not they reactivate latent tubercular infection or actually cause new infection. Nevertheless, Wyeth Pharmaceuticals, which makes Enbrel, has admitted that some patients who tested negative for latent TB prior to receiving the drug went on to develop active TB later.
In its own information leaflets, Wyeth also claims that as many as 7 per cent of patients given Enbrel with another drug for six months went on to develop serious infections, including bacterial pneumonia, cellulitis (bacterial skin infection), pulmonary fibrosis and fatal pneumonia. One patient with pulmonary fibrosis and pneumonia died as a result of respiratory failure. Of all the patients given the drug, nearly twice as many will go on to develop upper respiratory infections as those given a placebo.
Besides lung infections, TNF blockers have been found to cause viral, bacterial, fungal and protozoal infections in all organs, whether taking the drug alone or with other immunosuppressants. Those particularly susceptible include diabetics, those at risk of recurrent infections or those with open wounds. And as these types of infections have been implicated in arthritis, this raises the question of whether the ‘cure’ is actually worse than the disease.
There are also questions about TNF blockers’ long-term effects, including documented side effects such as congestive heart failure, a lupus-like syndrome, lymphomas, blood-cell deficiencies and a multiple-sclerosis type of neurological disease. The most common, ‘non-threatening’ side effects are injection site reactions, and a skin rash is sometimes seen.28
At present, the FDA is especially concerned about the possible association between TNF blockers and lymphoma and other cancers in children and young adults after receiving around 30 reports of cancer in this population group between 1998 and April 2008.
The reports describe the development of cancer in children and young adults taking TNF blockers when they were under 18 years of age. Approximately half the cancers were lymphomas – both Hodgkin’s and non-Hodgkin’s types. The FDA has also received reports of other cancers in children and young adults, including leukaemia, melanoma and organ cancers, while taking the TNF blockers.
All this, and yet there’s no real evidence that more is better when it comes to second-line treatments. Researchers carried out a meta-analysis of 101 studies of people with rheumatoid arthritis, which either compared a number of DMARDS against TNF-blocking drugs head to head or followed at least 100 patients on a single DMARD for 12 weeks or more. The researchers concluded that, on their own, all the tested drugs have a similar therapeutic effect, along with similar side effects. Combining two drugs seemed to help a little, especially when just one of the drugs on its own was having little effect, but there was insufficient data to assert categorically that this was the better approach.29
TNF blockers can cause:
After the immunosuppressants, steroids are the most controversial – and possibly most damaging – treatments available for arthritis. Steroid overuse in the 1950s for arthritis and the horrors resulting from this have 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.
Steroids – such as cortisol, cortisone, prednisone and dexamethasone – are the oldest group of anti-arthritis drugs. Injected in large doses, they can reduce inflammation of the joints, and so reduce the pain of arthritis. They are closely related to cortisol, a hormone produced by the adrenal gland that helps the body to regulate its salt and water balance, as well as the metabolism of carbohydrates, fat and proteins. Steroids block the production of such chemical substances as prostoglandins, which trigger allergic and inflammatory reactions – since in arthritis conditions, these reactions occur in an out-of-control cascade. Steroids also interfere with certain functions of the immune system and the production of white blood cells designed to destroy foreign bodies and infection.
Unfortunately, this interference with white blood-cell function creates numerous side effects as well as an increased susceptibility to infection.
Most doctors work on the assumption that steroids are safe if taken over a short period of time, and regularly prescribe them for any inflammatory or allergic reaction including skin and back problems, asthma, eczema, arthritis and bowel problems such as ulcerative colitis. Steroids have even been used as a replacement for baby’s gripe water. The shots usually include a local anaesthetic and in many cases can be administered in your doctor’s surgery. But research suggests that serious adverse reactions can happen right after treatment has started.
The side effects of steroids are many and various, including, in the words of a 2013 study, ‘growth retardation in children, immunosuppression, hypertension, hyperglycaemia, inhibition of wound repair, osteoporosis, metabolic disturbances, glaucoma, and cataracts’ and ‘psychiatric’ effects such as ‘catatonia, decreased concentration, agitation, insomnia, and abnormal behaviours’.30
As one report concluded, ‘The anti-inflammatory effects of corticosteroids cannot be separated from their metabolic effects’,31 which means that these drugs affect all cells of the body.
Long-term use of steroids can lead to loss of bone mineral density and can cause spinal fractures. One major study found that patients in the Netherlands suffered permanent damage to the bone mineral density in the lower spine after just 20 weeks of taking prednisone for rheumatoid arthritis.32 In another case, nine-year-old Lexi McConnell was dead within five weeks of starting steroids to treat toxoplasmosis in the eye. Steroids can also stop the pituitary glands from producing ACTH, a hormone that regulates the adrenals, needed by the body during stress and to fight infections. Adrenal suppression (and therefore not enough cortisol) due to high-dose inhaled corticosteroids can even result in death, especially in children with asthma.33 Steroids can even cause bone cell death (osteonecrosis), requiring complete joint replacement in some cases.34
Oral steroid use increases the risk of acute pancreatitis by 70 per cent, which can be a life-threatening problem in up to 20 per cent of cases.35