Disease Modifying Antirheumatic Drugs (DMARDs)

The prevailing guidelines for the management of rheumatoid arthritis (RA) recommend that once the disease has been diagnosed and its impact on the patient's life documented, disease-modifying antirheumatic drugs (DMARDs) should be commenced.¹ DMARDs should be part of an aggressive package of care, which should also include intra-articular steroid injections and parenteral methotrexate, progressing to anti-TNF-α therapy when appropriate. For further details see Management of Rheumatoid Arthritis.

DMARDs either affect the immune response (e.g. gold, penicillamine and chloroquine) or suppress the disease process (e.g. sulfasalazine). As well as improving the symptoms and signs of the arthritis, they may also improve the extra-articular manifestations such as vasculitis in addition to exerting systemic effects.²

Any DMARD that has been prescribed should be recorded in a patient's notes, both written and electronic, so that all doctors prescribing for that patient will be aware of any potential interactions with other drugs.

This has been introduced in many areas to give guidance and clarify the responsibilities and expectations associated with the prescribing of drugs such as DMARDs, usually initiated in secondary care, but which GPs may be called upon to prescribe under some circumstances.³

• “Red” designated drugs: for specialist use in secondary care or by a competent clinician only. These are either only available from hospital pharmacies, require monitoring too complex for Primary Care or have a side-effect profile which requires rigorous monitoring. The patient should obtain supplies of these drugs from hospital.
• “Amber” designated drugs: initiated in secondary care and monitored there until patient stabilised. The GP can agree to take over clinical and prescribing responsibility when shared care arrangements have been established, and protocols developed (and sent to the GP) before the transfer occurs. There is no compulsion for the GP to accept this responsibility, in which case the patient should obtain supplies of the drug from the hospital.
• “Green” designated drugs: which are appropriate for prescribing in primary and secondary care (within the competencies of the prescriber).

The drugs below have been designated as Red/Amber/Green according to the Avon NHS Trust Protocol by way of an example. There may be local variations which should be agreed in protocols drawn up between GPs and with local rheumatologists.

Drugs which suppress the disease process

• Gold (amber) may be given either orally as auranofin or by intramuscular injection as sodium aurothiomalate. Sodium aurothiomalate has a greater toxicity than auranofin, but tends to be more effective and has a faster onset of action. Either drug should be withdrawn if no benefit is seen after six months.
• Penicillamine (amber) has a similar method of action to gold and more patients are able to tolerate it, but side effects occur frequently. The rate of onset of action is slow, improvement may not be seen for three months, but in patients who have shown no benefit after a year of treatment the drug should be discontinued.
• Sulfasalazine (green) also has a similar action to gold, and has slightly more side effects than methotrexate.⁶

Drugs which affect the immune process

• Chloroquine and hydroxychloroquine (both green) may be used in the treatment of systemic lupus erythematosus in addition to rheumatoid disease .They are usually better tolerated than gold or penicillamine.
• Methotrexate (amber) may be used in the treatment of rheumatoid and psoriatic arthritis. It is a disease modifying agent with both anti-inflammatory and immunosuppressant activity.⁷
• Azathioprine (amber) acts in a similar manner to methotrexate but is usually reserved as second-line due to its toxicity.⁸
• Ciclosporin (red) is licensed for the treatment of severe active rheumatoid arthritis when the usual second line therapy is inappropriate or ineffective.
• Leflunomide (red) is used in the treatment of moderate to severe, active, rheumatoid arthritis, often in combination with methotrexate.

Anti-tumour necrosis factor (TNF) agents⁹

Since the original protocol was written, the following have become available:

• Infliximab (red) is a monoclonal antibody given as an intravenous infusion, often in combination with methotrexate.¹⁰
• Etanercept (red) is a TNF receptor fusion protein designed to bind circulatory TNF. It is also often administered with methotrexate. It is given by subcutaneous injection.

Choosing the right DMARD

Current evidence suggests that combinations of DMARDs are more effective, and probably less toxic, than monotherapy.¹¹ Methotrexate is often used as an anchor drug, combined with hydroxychloroquine, sulfasalazine or leflunomide. An anti-TNF-α drug such as etanercept or infliximab may also be used in combination.There is a stronger evidence base for the disease-modifying effects of methotrexate, sulfasalazine, leflunomide and intra-muscular gold than for hydroxychloroquine, penicillamine, oral gold, ciclosporin or azathioprine, although these agents do improve symptoms and some objective measures of inflammation.¹ The choice of first agent or combination of agents should be based on a risk/benefit analysis for individual patients.

Due to their potential toxicity, treatment with these drugs is only initiated by specialist rheumatologists, and it is therefore essential to ensure that all patients and their GPs receive, from the specialist clinic, a clear protocol for any dosage increments and requirements for routine testing. It is also important for the practice staff to have a copy of the protocol, and a system in place for ensuring that it has been adhered to.

The use of DMARDs is limited by potentially serious side effects, and therefore patients who are taking these drugs should be monitored on a regular basis, as follows:

Although some have greater tendency than others, all DMARDs have a potential to cause myelosuppression. Many also cause renal or liver toxicity, skin rash, or gastrointestinal disturbance (see individual drug monographs or summary of product characteristics (SPC) for further details).¹⁰

Patients should be warned to report any warning symptoms or signs as detailed below: