Rheumatology

In this review of recent advances in rheumatology I focus on treatment. This is not because our understanding of the pathogenesis or other aspects of rheumatology has progressed little but because there have been some particularly important changes in treatment (particularly of rheumatoid arthritis) that need to be communicated to a wider medical audience. Rheumatoid arthritis is usually an aggressive disease that needs to be treated forcefully if subsequent deformity and disability are to be reduced. Referring patients to a specialist rheumatology unit that can implement new treatment regimens at an early stage is therefore important.

Methods

I scanned the major rheumatology journals for articles on the treatment of rheumatoid arthritis and on advances in non-steroidal anti-inflammatory drug treatment. I also reviewed the abstracts of major rheumatology conferences that took place in 1996 and 1997.

Non-steroidal anti-inflammatory drugs

Although non-steroidal anti-inflammatory drugs are the mainstay of treatment for rheumatic diseases, they are being used less worldwide. This is particularly true in Australia, where the prescribing of these drugs has fallen by about 25%—probably as a result of an educational campaign directed at general practitioners and the public that highlighted adverse reactions to these agents.¹ The box lists factors in the reduced use of non-steroidal anti-inflammatory drugs.

Cyclo-oxygenase inhibitors

It is now understood that the cyclo-oxygenase enzyme system that produces prostaglandins consists of at least two basic isoforms—cyclo-oxygenase 1 and cyclo-oxygenase 2.⁵ The cyclo-oxygenase 1 enzyme performs “housekeeping” duties, maintaining a normal gastrointestinal mucosa and renal blood flow. Cyclo-oxygenase 2 (the inducible form) is seen in inflammation, the brain, and colon cancer cells. Description of the structure of human recombinant cyclo-oxygenase 2 and its interaction with non-steroidal anti-inflammatory drugs has enabled highly specific inhibitors to be developed.⁶ The effectiveness and low incidence of gastrointestinal or renal side effects of drugs such as the preferential cyclo-oxygenase inhibitor meloxicam or the highly specific MK 966 or celecoxib have already been shown in clinical trials in osteoarthritis.⁷,⁸

Recent advances

• Dosage of non-steroidal anti-inflammatory drugs can be reduced by prescribing paracetomol at the same time

• Specific cyclo-oxygenase 2 inhibitor drugs are effective and have a low incidence of gastrointestinal side effects in early studies

• Early use of antirheumatic drugs reduces long term disability in rheumatoid arthritis

• Combinations of antirheumatic drugs seem better than single agents

• Early trials of biological agents for rheumatoid arthritis show good immediate responses

• High dose chemotherapy with stem cell rescue may benefit patients with severe disease

Cardiac side effects

Although it has long been recognised that adverse gastrointestinal events are relatively common with non-steroidal anti-inflammatory drug treatment, recent studies suggest that hospital admissions for congestive cardiac failure are also increased appreciably in people taking these drugs. In a case-control study of patients admitted to hospital with their first episode of congestive cardiac failure, Henry et al showed a relative risk of 2.3 (95% confidence interval 1.2 to 4.4) in users of non-steroidal anti-inflammatory drugs (defined as use in the previous 7 days).⁹ Since congestive cardiac failure is relatively common in elderly people, the public health effects of this are disturbing. In the United Kingdom around 30 000 admissions to hospital and 300 deaths in patients with congestive cardiac failure could be directly attributable to treatment with non-steroidal anti-inflammatory drugs.

Factors in reduced use of non-steroidal anti-inflammatory drugs

• Greater appreciation that adverse effects are important, particularly in elderly people

• Finding that many people with osteoarthritis can be treated adequately with analgesics such as paracetomol alone²

• Co-prescribing paracetomol so that the dosage of non-steroidal anti-inflammatory drugs can be reduced³

• More aggressive and early use of antirheumatic drugs⁴

Non-steroidal anti-inflammatory drugs commonly cause a slight increase in blood pressure and may interfere with antihypertensive treatment, particularly in elderly people. Blood pressure should be monitored in elderly and hypertensive patients taking these drugs.¹⁰

Variable risk of gastrointestinal effects

A meta-analysis of variability in the risk of gastrointestinal complications showed clear differences with individual non-steroidal anti-inflammatory drugs (table).¹¹ Twelve studies that examined relative risks of gastrointestinal complications with 14 non-steroidal anti-inflammatory drugs were identified and satisfied inclusion criteria. Results of this meta-analysis are consistent with other studies and suggest a relative risk for serious complications of bleeding or perforation in the order of 3 to 5. Ibuprofen was the drug least likely to be associated with complications, but this may be a reflection of the relatively low dose prescribed (<1.6 g/day for patients). These data suggest that there is a hierarchy of non-steroidal anti-inflammatory drugs inducing gastrointestinal complications. Drugs with a relatively low risk (ibuprofen and diclofenac) should be used initially, the dose should be kept to a minimum, and patients must be informed of the side effects. This last point is important. Wynne and Long have shown clearly that if patients are told about the risks they will tend to reduce the dose if unwanted symptoms occur, thereby reducing appreciably their chance of developing acute gastrointestinal bleeding.¹²

Antirheumatic drugs

Good long term data support the view that antirheumatic drugs reduce long term disability in rheumatoid arthritis. In a study of nearly 3000 patients with rheumatoid arthritis followed for an average of nine years, consistent use of antirheumatic drugs (hydroxychloroquine, sulphasalazine, auranofin, intramuscular gold, d-penicillamine, methotrexate, and azathioprine) was associated with a better long term disability index (determined by the health assessment questionnaire), and this effect occurred over all periods of disease duration.¹³ Non-steroidal anti-inflammatory drugs and, interestingly, prednisone failed to show this reduction in disability. These data suggest that consistent use of antirheumatic drugs may reduce long term disability by up to a 30%. A recent study has shown that if patients whose rheumatoid arthritis is well controlled by disease modifying agents are given placebo instead of their antirheumatic drug, flare up of the disease occurs in a considerable number.¹⁴ This finding emphasises that rheumatoid arthritis remains active, even though it is suppressed by drugs.

Mottonen et al¹⁵ recently showed that early treatment of rheumatoid arthritis, using a “sawtooth” approach to management suggested by Fries,¹⁶ results in a remission rate of about 30%, which is substantially higher than that reported on standard treatment regimens. With the sawtooth approach, combinations of antirheumatic drugs are used from the initial diagnosis, the patient is reviewed at frequent intervals, and treatment goals are established in terms of a reduction in disease activity. If no appreciable reduction in disease activity is noted, corticosteroids or other antirheumatic drugs are added.

Combination treatments

Combinations of anti-rheumatic drugs are now the rule rather than the exception in treating rheumatoid arthritis. Combinations of methotrexate and sulphasalazine have been shown to be better than methotrexate alone¹⁷; cyclosporin A provides additional benefit in patients who do not respond adequately to methotrexate¹⁸; and weekly methotrexate, sulphasalazine, and hydroxychloroquine are better than methotrexate or methotrexate plus sulphasalazine over a two year period without an increase in toxicity.¹⁹

In a recent study, a combination of prednisolone (60 mg daily tapering to 7.5 mg daily at six week intervals), sulphasalazine (2 g daily), and methotrexate (7.5 mg weekly) was shown to be better than sulphasalazine alone over 56 weeks in early rheumatoid arthritis.²⁰ Use of prednisolone in combination treatment is increasing after reports that it reduces erosion rates in rheumatoid arthritis.²¹ However, corticosteroid use is a risk factor for non-steroidal anti-inflammatory drug induced gastrotoxicity and may be associated with increased infection rates in rheumatoid arthritis.²²

Contribution of biological agents

An increasing range of biologics is undergoing trials in the treatment of rheumatoid arthritis. Studies to determine the dosage ranges have been carried out with antibodies to the soluble tumour necrosis factor α receptor²³ and with a recombinant human interleukin 1 receptor antagonist.²⁴ These studies show great promise in rheumatoid arthritis. Some patients showed dramatic responses in terms of a reduction in the swollen and tender joint count and evaluation by medical practitioner, and side effects were relatively mild. Early data from the interleukin 1 receptor agonist study suggest that this treatment may also reduce the progression of erosions and is the first evidence of a true disease modifying effect with a biologic in humans.²⁵ Recently, combinations of biologics have been shown to be safe,²⁶ and these treatments will probably have an important impact on the management of rheumatoid arthritis in the immediate future.²⁷

Stem cell transplantation

One of the most exciting developments in the management of rheumatoid arthritis and some of the other autoimmune diseases is the suggestion that stem cell transplantation might offer the ability to give much higher doses of chemotherapy with the chance of possibly ablating the autoimmune disease completely.²⁸ In several published reports, patients with autoimmune diseases (particularly rheumatoid arthritis) who have also developed a primary haematological disease (neoplasia or aplastic anaemia) have been given an autologous or allogeneic stem cell transplant and have achieved long term remission of their autoimmune disease. Sometimes (particularly in rheumatoid arthritis) the disease has returned quite rapidly.²⁹ However, as mortality from autologous stem cell rescue is around 1%, this treatment can now be considered for patients with severe progressive connective tissue disease. Protocols for the priming and conditioning regimens, entry criteria, and assessment have now been developed and published, but the procedure is only experimental.³⁰

Conclusion

Recent advances in the treatment of rheumatoid arthritis now provide patients and doctors with the opportunity of slowing (arresting) the disease as long as treatment is begun at an early stage. All patients with continuing inflammatory synovitis that has lasted three months or more should be considered for aggressive treatment with continuing follow up for efficacy and adverse reactions. With this approach, joint destruction, deformity, and disability should be reduced.

Table.

Comparative toxicity of non-steroidal anti-inflammatory drugs, using ibuprofen as the reference¹¹

Drug	Pooled relative risk (95% CI)
Ibuprofen	1.0
Fenoprofen	1.6 (1.0 to 2.5)
Aspirin	1.6 (1.3 to 2.0)
Diclofenac	1.8 (1.4 to 2.3)
Sulindac	2.1 (1.6 to 2.7)
Diflunisal	2.2 (1.2 to 4.1)
Naproxen	2.2 (1.7 to 2.9)
Indomethacin	2.4 (1.9 to 3.1)
Tolmetin	3.0 (1.8 to 4.9)
Piroxicam	3.8 (2.7 to 5.2)
Ketoprofen	4.2 (2.7 to 6.4)
Azapropazone	9.2 (4.0 to 21)