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Dr Catherine Sullivan outlines the latest treatment options in rheumatoid arthritis
Rheumatoid arthritis (RA) is a common inflammatory arthritis with a prevalence of 1 per cent worldwide. Left untreated it results in irreversible deformity and disability, there is also now ample evidence that delays in diagnosis and treatment results in poorer outcomes. The incidence of RA in women is twice that of men and is most common between the ages of 30 and 50 years. Patients with RA experience higher levels of work disability and unemployment compared to the general population, which has repercussions for mental health as well as ongoing societal costs. In addition to joint damage caused by synovial inflammation, there are significant potential extra-articular complications of RA, which contribute to both morbidity and mortality. As well as the classic textbook lists of extra-articular features it is now well recognised that patients with RA have a higher incidence of cardiovascular disease compared to the general public and that this accounts for their reported increased mortality rate. Ischaemic heart disease, sudden death and cerebrovascular disease are all more common in patients with RA compared to the general population. Thankfully, this mortality gap is beginning to close reflecting recent changes in treatment strategies that prioritise early aggressive treatment with a focus on achieving disease remission rather than treating symptoms. Accompanying this, a reduction in orthopaedic and plastic surgeries has been seen, with fewer joint replacements and tendon surgery required in RA patients.
The classic presentation of RA is that of pain, swelling and stiffness in the small joints of the hands, wrists, ankles and MTPs though it can affect any synovial joint. Occasionally RA presents as a monoarthritis initially and progresses to a polyarticular pattern over time. Pain and stiffness are usually worse in the morning time and early morning stiffness can last for several hours. Symptoms can develop rapidly in which cases the diagnosis is often straightforward; it may be more difficult to identify where the onset is insidious or the presentation asymmetrical. It is important to remember that about 30 per cent of patients will be negative for rheumatoid factor and anti-CCP and so a negative antibody test does not exclude a diagnosis. Additionally, normal inflammatory markers do not outrule RA and patients with normal ESR and CRP should be referred on for specialist assessment if the clinical suspicion is high. Plain x-rays are often normal in patients with RA and specialist review should not be delayed while waiting for these. Patients with RA will frequently complain of fatigue and other systemic features such as weight loss, anorexia or fever.
There is now a wide range of pharmacological treatment options available to treat RA as well as other types of inflammatory arthritis. While NSAIDs and steroids are useful in initial symptom control the mainstay of long-term treatment is disease modifying anti-rheumatic drugs (DMARDs) – both synthetic and biologic. The newer DMARD treatments target specific inflammatory and immune pathways, blocking the action of specific cytokines or binding to cell surface markers.
Methotrexate is a conventional synthetic DMARD with no specific target and is the cornerstone of treatment for patients with RA; it is the first-line synthetic DMARD used when not contraindicated. Methotrexate is taken weekly either orally or as a subcutaneous injection with supplementation with folic acid at a minimum dose of 5mg weekly. Side effects of methotrexate include GI upset, headaches and mouth ulcers. Patients on methotrexate need to have LFTs and FBC checked regularly and should avoid alcohol intake to reduce the risk of hepatotoxicity. Methotrexate is teratogenic and for pre-menopausal women counselling regarding the risk of methotrexate and ensuring adequate contraception are important parts of the consultation. Despite the daunting list of potential side effects and toxicities, methotrexate is generally well tolerated and its evidence-base in RA is robust. Extra folic acid can be used to reduce recurrent side effects if necessary and the subcutaneous route of administration can help to avoid GI intolerance. Previous concerns about lung disease secondary to methotrexate have been largely disproven in recent large meta-analyses.
Plaquinal/hydroxychloroquine can be used as an adjunct to methotrexate or as monotherapy. Taken daily either as a single or twice-daily dose the side effects of most concern is that of retinotoxicity which is now thought to be more prevalent than previously thought with an estimated 7.5 per cent of long-term users potentially affected. It manifests as damage to the retinal pigment epithelium and the development of bull’s eye maculopathy with central visual loss. Plaquinal should be avoided in patients with pre-existing macular disease and, if long-term use is planned, a baseline review by an ophthalmologist should be carried out within six-to-12 months of starting treatment.
Salazopyrin may again be used as part of combination DMARD therapy or as monotherapy. It is taken orally, up to four tablets a day and may be useful in patients who have contraindications to the use of methotrexate. It can result in reversible azoospermia and infertility in men.
Leflunomide is occasionally used but has a significant rate of symptomatic GI side effects.
Azathioprine and cyclosporin are no longer used as first-line treatments of RA.
In patients who have an inadequate response to methotrexate treatment, triple DMARD therapy may be used, that is methotrexate/hydroxychloroquine/salazopyrin. There is, however, a significant pill burden associated with this, which can lead to challenges in compliance compared to injectable biologic agents.
Anti-TNF agents are often the first biologic agents to be used in RA, either in combination with methotrexate or as a monotherapy. These are either monoclonal antibodies to TNF or receptor antagonists and the majority are subcutaneous with one, infliximab, given intravenously. Depending on the drug chosen these are self-administered with pre-filled pen devices weekly, fortnightly or monthly. There is now a large body of safety data for this class of biologic with over 20 years of clinical experience and registry data. TNF inhibitor therapy is contraindicated in patients with TB, decompensated heart failure, active malignancy and demyelination. They are safe to use in early pregnancy but it is recommended that they are discontinued in the third trimester, this is not due to toxicity but rather antibodies transferred across the placenta may render the new-born immunosuppressed. The exception to this is certolizumab, as the pegylated molecule does not cross the placenta. TNF inhibitors are also widely used to treat psoriatic arthritis (PsA).
Tocilizumab is an anti-IL-6 agent delivered subcutaneously once a week and is licensed for the treatment of both RA and giant cell arteritis. Lipid levels, LFTs and WCC need to be monitored and doses may need to be adjusted accordingly.
Abatacept is a T-cell blocking agent that prevents the co-stimulation signals required for T-cell activation. It is also self-administered by subcutaneous injection once a week and is licensed for both RA and PSA. There are some studies to suggest a better safety profile in terms of infection risk and this may be a consideration when treating older patients, or those with co-morbidities such as COPD or diabetes.
Rituximab targets the B-cell pathway via CD 20 in RA and is delivered intravenously every six months; it is also used to treat some forms of vasculitis.
Tofacitinib is a Janus kinase (JAK) inhibitor with is approved for treatment of both RA and PsA where methotrexate therapy has failed or is contraindicated. It is a targeted synthetic DMARD and has a side effect profile similar to that of the biologic DMARDs, in addition there appears to be a modest increase in the risk of developing herpes zoster infections while on treatment. In high-risk patients, vaccination for shingles should be considered prior to commencing treatment.
A full biochemistry profile and FBC should be carried out before starting any DMARD; in addition a viral hepatitis screen and chest x-ray is prudent before commencing methotrexate. A history of chicken pox should be sought and if the patient has no history of infection varicella, titres should be checked to establish immunity. Prior to biologic DMARD treatment, and JAK inhibitors, all patients must be screened for TB with a chest x-ray and Quantiferon test. Patients must be advised of an increased risk of infection on DMARD therapy but reassured that the benefit generally outweighs the risk, however they should be told to seek medical attention if unwell and to discuss with their GP or rheumatologist whether DMARD therapy needs to be held temporarily. All patients on DMARDs should receive the flu and pneumonia vaccination, if not contraindicated, at the recommended intervals. Patients who smoke are known to be at an increased risk of infection and cardiovascular disease, it is now increasingly recognised that cigarette smoking increases the risk of developing RA and may decrease response to therapy and drug survival. Advice and treatment options for smoking cessation should be introduced to the patient early in the diagnosis as an integral part of the treatment pathway. Screening for osteoporosis should also be strongly considered in patients diagnosed with RA, particularly in patients who have other risk factors such as smoking, low BMI, thyroid disease, coeliac disease, family history and women who are post-menopausal.
Ideally, patients with suspected RA should be seen by a specialist within six weeks of symptom onset to optimise outcomes and prevent structural damage. Research has demonstrated a significant reduction in remission rates in patients treated early, representing a window of opportunity for improving long-term health in this patient cohort.
In the early stages of treatment, patients need to be seen regularly to ensure treatment efficacy, particularly those with features which predict a poorer outcome – positive RF or anti-CCP, high CRP, erosive disease and a large number of swollen joints. While the array of pharmacological therapies is better than ever, we have not yet reached the holy grail of personalised medicine and cannot predict which treatment option with work for each patient. As most therapies take a number of weeks, and often months, to reach full efficacy it is important not to discard any particular therapy as failed too early in the course of treatment.
Many factors feed
into the decision about drug treatments in RA; patient factors such as other
chronic illnesses, infection risk, liver function and renal disease and
lifestyle issues such as alcohol intake, family planning and patient preference
need to be considered. Drug cost may also place a significant burden on
patients and their families while the risk of work disability secondary to
untreated disease needs to be factored in. The single best intervention for our
patients with RA is early suspicion of disease, early referral to a specialist