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PatientPlus articles are written for doctors and so the language can be technical. However, some people find that they add depth to the articles found in the other sections of this website which are written for non-medical people.

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.

Traffic light scheme for prescribing

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.

Types of DMARDs4,5

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.
  • Azathioprine (amber) acts in a similar manner to methotrexate but is usually reserved as second-line due to its toxicity.7
  • 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) agents8

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.
  • 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.9 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.

Contraindications10
(These are main contraindications - see individual drug monographs for full list of contraindications and precautions)

Drug

Contraindications

Gold - auranofin and sodium aurothiomalate Severe liver disease, severe kidney disease
Bone marrow aplasia, history of blood disorders
Exfoliative dermatitis
Necrotising enterocolitis
Porphyria
Systemic lupus erythematosis
Pulmonary fibrosis
Penicillamine Moderate to severe kidney disease
Systemic lupus erythematosus
Sulfasalazine Salicylate hypersensitivity
Chloroquine and hydroxychloroquine Pre-existing retinopathy
Methotrexate Hepatic impairment
Pregnancy (a woman or man should avoid conception
for at least three months after stopping medication)
Breast-feeding
Active infection
Immunodeficiency syndromes
Azathioprine Hypersensitivity to azathioprine
Breast-feeding
Ciclosporin Renal impairment
Uncontrolled hypertension
Uncontrolled infections
Malignancy
Leflunomide Severe immunodeficiency
Serious infection
Liver dysfunction
Severe hypoproteinaemia
Pregnancy (significant teratogenic risk - effective contraception essential during treatment and for at least 2 years after treatment in women and at least 3 months after treatment in men)
Breast-feeding
Infliximab Severe infections
Pregnancy
Breastfeeding
Etanercept Active infection
Pregnancy
Breastfeeding
Initiation of treatment11

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.

Investigations prior to starting a DMARD

Drug(s)

Investigations

Gold -
auranofin or
sodium aurothiomalate
Urine testing for protein and blood
Full blood count (FBC) with WCC (white cell count) differential and platelets
Urea and electrolytes (U&Es)
Liver function tests (LFTs)
Penicillamine Urine testing for protein and blood
FBC and platelets
U&Es
Sulfasalazine FBC
U&Es
LFTs
Chloroquine
and
hydroxychloroquine
U&Es
LFTs
Optometry assessment if visual impairment or eye disease
(can cause retinopathy12)
Methotrexate FBC
U&Es
LFTs
Urine testing for protein and blood
Azathioprine FBC and platelets
Ciclosporin U&Es on two occasions
Serum creatinine on two occasions
LFTs
Urine testing for protein and blood
Blood pressure measurement
Leflunomide Pregnancy test
FBC
LFTs
BP measurement
Infliximab Exclude active or latent tuberculosis (tuberculin skin test and chest x-ray)
Etanercept Exclude active or latent tuberculosis (tuberculin skin test and chest x-ray)
FBC if history of blood dyscrasia suspected

Monitoring13

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:

Penicillamine and Gold
(auranofin or sodium aurothiomalate)
Check FBC, including platelets and stick test urine for blood and protein weekly until dose stable, then every 1-3 months.
Chloroquine and hydroxychloroquine Patients should be regularly asked about visual symptoms and monitored for visual acuity.
If long term treatment required, follow up by optometrist/ophthalmologist is desirable.
Sulfasalazine FBC, LFTs every 1–2 weeks for 2 months; then 3-monthly for a year; then 6-monthly.
Methotrexate FBC should be checked on initiating treatment, every week for 6 weeks thereafter, and 1 week after any dose change, and if aspirin or a NSAID is introduced.
Check every month when on established regime.
LFT should be checked at 3 monthly intervals.
FBC, U&Es, LFTs, urine dipstick for blood and protein, weekly until dose stable; then every 1–3 months.
Patients should be advised to report symptoms suggestive of pulmonary toxicity (cough, dyspnoea, fever).
Azathioprine FBC every 2 weeks until dose stable; then every 1–3 months.
Ciclosporin FBC, U&Es every 2 weeks until dose stable; then monthly.
Leflunomide FBC, LFTs 2–4 weekly for the first 6 months; then every 8 weeks.
Infliximab 1st 2 hours - monitor for acute hypersensitivity reactions (e.g. chest, pain fever, hypotension, pruritis).
Monitor for latent tuberculosis during treatment and for six months after.
Etanercept Advise patients to report the development of any symptoms of tuberculosis or blood dyscrasias after treatment.
Complications and reasons to discontinue drugs5

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 for further details).

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

Symptoms of Myelosuppression

  • Sore throat
  • Fever and other signs of infection
  • Unexpected bleeding or bruising
  • Purpura and rashes
  • Mouth ulcers
  • Cough or breathlessness


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 2 years). Rheumatology (Oxford). 2006 Jul 13;.
  2. Management of early rheumatoid arthritis, SIGN (2004)
  3. Rotherham Healthcare Traffic Light Sytem; Rotherham PCT 2007
  4. Akil M, Amos RS; ABC of rheumatology. Rheumatoid arthritis--II: Treatment. BMJ. 1995 Mar 11;310(6980):652-5.
  5. Rheumatoid arthritis, Clinical Knowledge Summaries (2005)
  6. 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]
  7. Azathioprine (GPN)
  8. Management of Early Rheumatoid Arthritis; SIGN Guidance Chapter 48 Section 4: Pharmacological Management 2000
  9. 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]
  10. Hosie G Field M; Shared Care For Rheumatology 2002
  11. Tests Before Initiation of Treatment; East Cambs and Fenland PCT 2001
  12. Fraenkel L, Felson DT; Rheumatologists' attitudes toward routine screening for hydroxychloroquine retinopathy.; J Rheumatol. 2001 Jun;28(6):1218-21. [abstract]
  13. Monitoring people on disease-modifying drugs (DMARDs), Clinical Knowledge Summaries (2005)

Internet and further reading AcknowledgementsEMIS is grateful to Dr Laurence Knott for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2007.
DocID: 533
Document Version: 2
DocRef: bgp24874
Last Updated: 23 Nov 2007
Review Date: 22 Nov 2008






















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