Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

The early use of disease-modifying anti-rheumatic drugs (DMARDs) has been recommended in recent years to reduce disease progression and long term disability.¹ The need for early use of DMARDs is incorporated in new NICE guidance.² Early use requires early referral in part because DMARD initiation is the province of specialists in secondary care. The optimum use of these drugs requires specialist experience and is complicated not only because of their potential toxicity, but also the range and combination of drugs used. There are a number of new 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 DMARDs should be commenced.¹ DMARDs should be part of a range of treatments from different professional disciplines. For further details see Management of Rheumatoid Arthritis.

DMARDs broadly speaking either affect the immune response or suppress the disease process. 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.³

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.⁴

• “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 is licensed for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis.
  • Can be an effective treatment but use is restricted by severe adverse reactions (up to 5% of recipients).
  • 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):
  • It is a chelating agent licensed for the treatment of severe active rheumatoid arthritis, including juvenile forms (and a range of other conditions including Wilson's disease).
  • It 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):
  • It is licensed for the treatment of rheumatoid arthritis which has failed to respond to nonsteroidal anti-inflammatory drugs (NSAIDs).
  • It has a similar action to gold.
  • It has slightly more side effects than methotrexate.⁷

Drugs which affect the immune process

• Chloroquine and hydroxychloroquine (both green)
  • Hydroxychloroquine is an antimalarial agent licensed for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, discoid and systemic lupus erythematosus, and dermatological conditions caused, or aggravated, by sunlight.⁶
  • 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.⁸
  • It is also classified as an antimetabolite cytotoxic agent, and is the most common first-line agent for the early treatment of rheumatoid arthritis in the UK.⁶
• Azathioprine (amber):
  • It is a cytotoxic drug and a prodrug of mercaptopurine.
  • It is used as an immunosuppressant for many autoimmune conditions and to suppress transplant rejection.
  • It acts in a similar manner to methotrexate but is usually reserved as second-line due to its toxicity.
• Ciclosporin (red):
  • It is a powerful immunosuppressant that appears to act specifically on lymphocytes (mainly helper T-cells) resulting in depression of the cell-mediated immune response.
  • Unlike cytotoxic immunosuppressants (such as cyclophosphamide) it has little effect on bone marrow.⁶
  • It is licensed for the treatment of severe active rheumatoid arthritis when the usual second line therapy is inappropriate or ineffective.
• Leflunomide (red):
  • Leflunomide has antiproliferative properties.
  • It is licensed for the treatment of adults with active rheumatoid arthritis and also for active psoriatic arthritis.
  • It is used in the treatment of moderate to severe, active, rheumatoid arthritis, often in combination with methotrexate.

Anti-tumour necrosis factor or biologic agents

The term biologic agents encompasses tumour necrosis factor (TNF)-alpha blockers (infliximab, etanercept, and adalimumab) and other agents, including abatacept, anakinra, and rituximab.^9,10,11,12

• A revolution has occurred in treating RA due to the realisation that the pro-inflammatory cytokine TNF-alpha plays a central role. In the last 10 years several agents have been developed that block this molecule and TNF inhibitors significantly improve symptoms and reduce disease activity and joint inflammation.
• The initiation and monitoring of these drugs is very much the province of the specialist. However it is important for generalists and members of the multi-disciplinary team (MDT) to be aware of the how they are used and monitoring issues.
• Infliximab (Remicade®) and etanercept (Enbrel®) are very effective in reducing the symptoms and signs of RA in patients who fail to respond to DMARDs and both reduce joint swelling, radiological erosions, malaise and fatigue.¹³
• Clinical effectiveness and side-effect profiles are similar for all these drugs. All have rapid onsets of action - days to weeks.
• A meta-analysis has concluded that this group of drugs are very effective in the treatment of RA, both in treatment-naive and methotrexate-resistant patients.¹⁴
• Contra-indications and monitoring - see individual drug monographs.
• Initiation of treatment - patients at risk of infection (those on high-dose steroids or with uncontrolled diabetes), are excluded from treatment. See also individual drug monographs.
• Complications and reasons to discontinue drug. Side-effects are generally minor and tolerable and monitoring is not required to the degree necessary with DMARDs. Severe adverse events are unusual but have been reported. TNF is a key regulator of immunity and opportunistic infections, such as tuberculosis (TB), have been reported. Reactivation of TB, worsening of demyelinating disease, suppression of bone marrow and a variety of unusual idiosyncratic side effects can occur.

Choosing the right DMARD

Current evidence suggests that combinations of DMARDs are more effective, and probably less toxic, than monotherapy.¹⁵ 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.¹⁶ 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 in the table below. Note throughout that whilst absolute values are useful indicators, trends are also important. Hence any rapid fall or consistent downward trend in any parameter warrants extra vigilance.⁶

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).²⁰

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