Pharmacological treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) affects around 1 per cent of the population, making it the most common inflammatory arthritis. It typically presents as a symmetrical polyarthritis affecting the small joints of the hands, wrists and feet, with symptoms of joint pain, swelling and early morning stiffness. As it is a systemic condition, many organs can be affected.¹

Laboratory testing should be seen as an adjunct to the clinical diagnosis of RA. Inflammatory markers (ESR, CRP) are typically raised but are normal in around 10 per cent of rheumatoid patients.

A positive rheumatoid factor is present in three-quarters of cases and if this is in conjunction with classical clinical features then the diagnosis of RA is very likely. X-rays of hands and feet may show radiological evidence of erosions.

Negative tests should not however halt further assessment if clinical features are suggestive of RA. In recent guidelines, NICE recommends testing for anti-CCP (anti-cyclic citrullinated peptide) in the context of suspected RA with a negative rheumatoid factor.²

Management plan
In suspected RA simple analgesia and NSAIDs should be offered. Oral steroids such as prednisolone are appropriate in managing the acute disease process.

Immediate referral to a rheumatologist is now accepted practice because evidence clearly indicates that early use of disease-modifying anti-rheumatic agents (DMARDs) can prevent joint damage.

Monitoring for drug toxicity with blood or urine testing, and re-prescription of DMARDs can be undertaken in primary care, usually under a shared care agreement. NICE emphasises the importance of a multidisciplinary approach for RA, which might involve the physiotherapist, occupational therapist and podiatrist. In more advanced joint disease referral to the orthopaedic surgeon may be necessary.

Primary care is also in a position to assess co-morbidities associated with RA. Thus, patients with RA are at increased cardiovascular risk and should be screened for risk factors. Depression should be checked for and consideration given to bone mineral density scanning given the association of RA with osteoporosis, whether or not oral steroids have been used.

NSAIDs are likely to achieve a better response than simple analgesics because of their anti-inflammatory action. An advantage of NSAIDs is their rapidity of action in bringing symptom relief, but it is important to recognise that they do not halt the progress of joint damage in RA and that they carry a real risk of toxicity to several organ systems, especially in the elderly.

NSAIDs and COX-2 inhibitors
If possible, NSAIDs (and COX-2 inhibitors) should be avoided in patients with a history of previous or active peptic ulceration. NICE suggests automatically co-prescribing a proton pump inhibitor (PPI) if an NSAID or COX-2 inhibitor is used. Risks of a gastrointestinal bleed are particularly high if the patient is taking warfarin or oral corticosteroids.

NICE guidance on RA management

Symptom control with NSAIDs/COX-2 inhibitors: - Use lowest dose for shortest possible time. - Co-prescribe with proton pump inhibitor. - Before using, consider individual risk of gastrointestinal/liver/renal and cardiac problems. - Consider alternative analgesia if low-dose aspirin already being used. - Consider alternative DMARD/biological treatment if NSAID/COX-2 inhibitor does not control symptoms. Glucocorticoids: - Offer short term for flare-ups or as part of DMARD combination therapy. - Avoid long-term treatment if possible. DMARDs and biological therapies: - Aim to start treatment within three months of symptom onset. - Start ideally with a combination of DMARDs. - Reduce drug dosage when the disease is controlled. - Increase dose of DMARD to achieve control of disease flare-up.

NSAIDs may aggravate renal failure or heart failure and if their use is unavoidable in these conditions then patients must be carefully monitored. Asthmatic patients should be warned that symptoms may worsen with NSAID use.

Ibuprofen, diclofenac and naproxen are three commonly prescribed NSAIDs in primary care. Ibuprofen generally carries the lowest risk of side-effects but is the weakest anti-inflammatory of the three. Diclofenac and naproxen possess greater potency but naproxen appears to carry a lower risk of thrombotic events (MI and stroke) than diclofenac and high dose ibuprofen.

Adopting the NICE recommendation for PPI gastroprotection with all NSAIDs may mean that the differential gastrointestinal toxicity between various agents (including COX-2 inhibitors) may be rendered less important, placing naproxen as a first choice NSAID because of its reduced cardiovascular toxicity.

Using an NSAID (or COX-2 inhibitor) alongside low dose aspirin may not only increase risk of peptic ulceration but would appear to nullify the cardiovascular benefit of the aspirin. Diuretics and ACE-inhibitors/angiotensin receptor blockers used concomitantly with NSAIDs increase the risk of renal toxicity.

The COX-2 inhibitors are as effective as conventional NSAIDs in relieving symptoms of RA and have a lower propensity to cause upper gastrointestinal problems, although they are not free from these problems and indeed, NICE recommends co-prescription with a PPI if they are to be used.

The Committee on Safety of Medicines has advised avoiding COX-2 inhibitors in ischaemic heart disease, heart failure, cerebrovascular disease and peripheral vascular disease. Because of these cardiovascular concerns there has been a reversion to the use of conventional NSAIDs with gastroprotection, although the increased risk of cardiovascular events with COX-2 inhibitors is probably similar to diclofenac and high dose ibuprofen.

Disease-modifying agents
The aim should be to start DMARDs within three months of onset of symptoms to limit permanent joint damage. Patients need to be warned that it can be several weeks before benefit becomes apparent, but if they do prove effective then the need for NSAIDs should be reduced. In addition to relieving joint symptoms, extra-articular manifestations of RA improve with DMARD treatment.

Monitoring DMARD Therapy
DMARD	Comments	Typical monitoring requirements
Methotrexate	Once weekly treatment; weekly 5mg folic acid. Risk of cirrhosis or pneumonitis.	FBC, U&E, LFT initially fortnightly for two months, then two-monthly when stabilised; chest X-ray in the event of cough or breathlessness.
Sulfasalazine	Reversible oligospermia.	FBC, LFT initially monthly for three months, then three-monthly.
Azathioprine	Useful steroid sparing agent.	FBC, LFT as for methotrexate.
Ciclosporin	Risk of renal toxicity and hypertension.	FBC, U&E, LFT initially fortnightly then monthly; monitor blood pressure.
Leflunomide	Prolonged half-life and long wash-out period (greatly reduced by colestyramine). Need to avoid pregnancy for extended period after treatment.	FBC, LFT initially fortnightly for six months, then two-monthly; monitor blood pressure at same intervals.
Hydroxychloroquine	Small risk of retinopathy; refer to ophthalmology if there are concerns.
Sodium aurothiomalate (intramuscular gold injection)	Risk of immune complex nephritis and pulmonary toxicity.	FBC, urinalysis before each injection.
Penicillamine	Risk of immune complex nephritis; loss of taste.	FBC, urinalysis initially fortnightly for two months, then monthly.

Side-effects vary between drugs but problems that may arise are nausea, rashes, mouth ulcers and bone marrow suppression. Monitoring requirements are listed in the top table. Blood count, renal and hepatic function need to be checked before commencing any DMARD and any subsequent deterioration in these parameters is obviously concerning.

DMARDs should be withheld and the rheumatologist contacted if the patient's white cell count falls below 3.5x109/l, neutrophils below 2x109/l or platelets below 120x109/l. An ALT elevated above twice the upper limit of normal or the persistent finding of greater than 1+ proteinuria or 1+ haematuria should again lead to discussion with the rheumatologist.

Symptoms that might suggest bone marrow suppression include sore throat, persistent infection/fever, easy bruising and breathlessness. NICE recommends CRP as a marker of inflammatory control.

There is evidence that using combinations of DMARDs is superior to monotherapy in RA and NICE recommends this approach, using methotrexate as the anchor drug together with another DMARD and use of short-term corticosteroids.

Biological therapies
TNF-alpha is a key cytokine driving the inflammatory process of RA and biological therapies designed to block its activity are now available and can have a profound effect on reducing joint damage. Response to treatment is relatively quick in comparison with DMARDs, often within days.

 

Biological treatments for RA
Drug	Mode of action	Mode of administration
Infliximab (Remicade)	Monoclonal antibody to TNF	Intravenous infusion, repeated
Etanercept (Enbrel)	TNF receptor fusion protein	Twice weekly subcutaneous injection
Adalimumab (Humira)	Fully humanised monoclonal antibody to TNF	Fortnightly subcutaneous injection
Rituximab (MabThera)	Monoclonal antibody to selectively deplete B cells. An option if response to anti-TNF agents is unsatisfactory.	Intravenous infusion, repeated

Biological therapies are indicated when DMARDs have been ineffective in controlling disease activity. They should be initiated, supervised and monitored in secondary care but GPs should have some knowledge of the potential problems arising from their use.

As they are proteins, these treatments cannot be given orally. They are usually used in combination with methotrexate. The strategy can be to induce remission with an anti-TNF treatment and then provide maintenance with a DMARD. NICE guidance on bilogical therapies has been issued.^3,4

A flu-like illness and injection site reactions are the most common problems associated with use of biologicals, but there is also an increased likelihood of infections, most notably a reactivation of latent TB. Longer-term data are not yet available and there is a concern over potential increased risk of malignancy.

- Dr David Morris is a GP in Shrewsbury, Shropshire and a member of the Midlands Therapeutics Review and Advisory Committee

References

1. Young A. Prescriber 2008; 19(12): 19-28.

2. NICE. Rheumatoid arthritis. CG79. February 2009.

3. NICE. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. TA130. October 2007.

4. NICE. Rituximab for the treatment of rheumatoid arthritis. TA126. August 2007.