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- Either drug should be withdrawn if no benefit is seen after six months.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-indications[16]
| (These are main contra-indications - see individual drug monographs for full list of contra-indications and precautions) | |
|---|---|
Drug |
Contra-indications |
| 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 (SLE) Pulmonary fibrosis |
| Penicillamine | Moderate-to-severe kidney disease SLE |
| 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 Breast-feeding |
| Etanercept | Active infection Pregnancy Breast-feeding |
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.
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 white cell count (WCC) 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 retinopathy) |
| 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 (BP) measurement |
| Leflunomide | Pregnancy test FBC LFTs BP measurement |
| Infliximab | Exclude active or latent tuberculosis (TB) (tuberculin skin test and chest X-ray) |
| Etanercept | Exclude active or latent TB (tuberculin skin test and chest X-ray) FBC if history of blood dyscrasia suspected |
Monitoring[6][17]
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. [18]
| Rapid falls or consistent downward trends in any parameter are as equally important as absolute values |
|---|