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 National Institute for Health and Clinical Excellence (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 by 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 separate article 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.

Traffic light scheme for prescribing

This has been introduced in many areas to give guidance and to 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 the patient is 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.

Types of disease-modifying anti-rheumatic drugs^5,6

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 (RA) 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 RA which has failed to respond to non-steroidal 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 RA, 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 RA 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 RA 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 RA and also for active psoriatic arthritis.
  • It is used in the treatment of moderate-to-severe, active RA, often in combination with methotrexate.

Antitumour necrosis factor or biological agents

The term biological agents encompasses tumour necrosis factor (TNF)-alpha blockers (infliximab, etanercept, and adalimumab) and other agents, including abatacept, anakinra, and rituximab.^2,9,10,11

• A revolution has occurred in treating RA due to the realisation that the proinflammatory 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 multidisciplinary team (MDT) to be aware of how they are used and of 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.¹²
• 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 is very effective in the treatment of RA, both in treatment-naive and methotrexate-resistant patients.¹³
• 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.¹⁴ Methotrexate is often used as an anchor drug, combined with hydroxychloroquine, sulfasalazine or leflunomide. An anti-TNF-alpha 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 intramuscular gold than for hydroxychloroquine, penicillamine, oral gold, ciclosporin or azathioprine, although these agents do improve symptoms and some objective measures of inflammation.¹⁵ The choice of first agent or combination of agents should be based on a risk/benefit analysis for individual patients.

Contra-indications¹⁶

Initiation of treatment

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.

Monitoring^6,18

The use of disease-modifying anti-rheumatic drugs (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 A useful quick reference guide has been produced by the British Society for Rheumatology. ¹⁹

Complications and reasons to discontinue drugs^6,8

Although some have greater tendency than others, all disease-modifying anti-rheumatic drugs (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:

Document references

1. Luqmani R, Hennell S, Estrach C, et al; British Society for Rheumatology and british health professionals in Rheumatology guideline for the management of rheumatoid arthritis (the first two years). Rheumatology (Oxford). 2006 Sep;45(9):1167-9. Epub 2006 Jul 13.
2. Rheumatoid arthritis, NICE Clinical Guideline (February 2009); Rheumatoid arthritis: the management of rheumatoid arthritis in adults
3. Management of early rheumatoid arthritis, SIGN (2004)
4. Rotherham Healthcare Traffic Light Sytem; Rotherham PCT 2007
5. Akil M, Amos RS; ABC of rheumatology. Rheumatoid arthritis--II: Treatment. BMJ. 1995 Mar 11;310(6980):652-5.
6. Disease-modifying anti-rheumatic drugs (DMARDs), Clinical Knowledge Summaries (2008)
7. Felson DT, Anderson JJ, Meenan RF; Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum. 1992 Oct;35(10):1117-25. [abstract]
8. Summary of Product Characteristics - Methotrexate sodium tablets 2.5 mg, Hospira UK Ltd; electronic Medicines Compendium (Jan 2005)
9. Management of Early Rheumatoid Arthritis; SIGN Guidance Chapter 48 Section 4: Pharmacological Management 2000
10. Rheumatoid arthritis - adalimumab, etanercept and infliximab, NICE Technology Appraisal (October 2007); Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis
11. Rheumatoid arthrits (refractory) - rituximab, NICE Technology Appraisal (2007); Rituximab for the treatment of rheumatoid arthritis.
12. Klareskog L, van der Heijde D, de Jager JP, et al; Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial.; Lancet. 2004 Feb 28;363(9410):675-81. [abstract]
13. Venkateshan SP, Sidhu S, Malhotra S, et al; Efficacy of Biologicals in the Treatment of Rheumatoid Arthritis. A Meta-Analysis. Pharmacology. 2008 Oct 28;83(1):1-9. [abstract]
14. Pincus T, O'Dell JR, Kremer JM; Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy. Ann Intern Med. 1999 Nov 16;131(10):768-74. [abstract]
15. Luqmani R, Hennell S, Estrach C, et al; British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of rheumatoid arthritis (after the first 2 years). (Oxford). 2009 Apr;48(4):436-9. Epub 2009 Jan 27.
16. Hosie G, Field M; Shared Care for Rheumatology. Philadelphia:Taylor and Francis; 2002. ISBN 190186510X
17. Fraenkel L, Felson DT; Rheumatologists' attitudes toward routine screening for hydroxychloroquine retinopathy. J Rheumatol. 2001 Jun;28(6):1218-21. [abstract]
18. Guideline for disease-modifying anti-rheumatic drug (DMARD) therapy, British Society for Rheumatology and British Health Professionals in Rheumatology (2008)
19. Quick reference guideline for monitoring of disease-modifying anti-rheumatic drug (DMARD) therapy, British Society for Rheumatology (November 2009); To accompany Disease-modifying anti-rheumatic drug therapy guideline of April 2008
20. Summary of Product Characteristics. Remicade® 100 mg powder for concentrate for solution for infusion. Infliximab. Schering-Plough Ltd. electronic Medicines Compendium. August 2008.

Internet and further reading

• Suarez-Almazor ME, Belseck E, Shea B, et al; Methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2000;(2):CD000957. [abstract]
• Rheumatoid arthritis, Clinical Knowledge Summaries (June 2009)
• Guideline for the management of rheumatoid arthritis (after the first 2 years), British Society for Rheumatology and British Health Professionals in Rheumatology (January 2009)
• Guideline for the management of rheumatoid arthritis (first 2 years), British Society for Rheumatology (July 2006)

Acknowledgements