Individualization of Leflunomide Dosing in Rheumatoid Arthritis Patients

Ashley M Hopkins; Catherine E O'Doherty; David JR Foster; Richard N Upton; Susanna M Proudman; Michael D Wiese


Personalized Medicine. 2014;11(4):449-461. 

In This Article

Place in Therapy

Early effective treatment of RA is essential for minimizing joint damage that once established, is generally considered to be irreversible.[2–4] Conventional DMARDs are the mainstay of initial therapy and include a number of medications with multiple mechanisms of action that have the overall effect of reducing the synovial and systemic inflammation associated with RA.[2–4,12–13] Recommendations from both the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) recognize methotrexate as the 'anchor' drug of DMARD therapy, and that it should be added at the earliest possible time point in those with 'active' RA.[2–4] DMARD combinations with methotrexate (for example in combination with sulfasalazine and hydroxychloroquine) may result in increased efficacy in those failing to adequately respond to methotrexate monotherapy.[2–4] Two broad treatment strategies ('step-up' or 'step-down') are commonly used. 'Step-up' uses methotrexate monotherapy, and if disease remains active despite maximal doses, additional agents are added until disease remission is achieved. 'Step-down' (also referred to as parallel intensive therapy) uses an initial combination of DMARDs and agents may be withdrawn slowly if sustained remission is achieved. Debate concerning the most appropriate treatment strategy continues, leaving the individual clinician to base the choice on assessment of patient prognosis and prior experience.[2–4]

Meta-analysis has shown that leflunomide has comparable efficacy to methotrexate,[14,15] although a more recent clinical trial by Ishaq et al.[16] reported that methotrexate was more efficacious, while leflunomide is marginally more expensive. As such, leflunomide is most commonly used as a second line option, added when optimal doses of methotrexate (used either alone or in combination with other DMARDs) are unable to induce or maintain remission.[2–4] Furthermore, leflunomide is a suitable monotherapy option in those in whom methotrexate is contraindicated.[2–4]

In those who do not adequately respond to conventional DMARDs, biological DMARDs (e.g., tumour necrosis factor (TNF) antagonists) are considered.[2–4] In addition to being associated with an increased incidence of some cancers and serious infections,[17] these agents are expensive. In Australia, the cost of these agents is between AUD$15,000 and 25 000 per patient per annum, compared with just $150 for methotrexate or $1400 for leflunomide (currency in Australian dollars). Hence, under governmental subsidy schemes such as the Australian Pharmaceutical Benefit Scheme (PBS), strict restrictions are in place, and patients are generally unable to fund treatment themselves.[2–3,13] Therefore, the development of cheap, effective treatment strategies is essential. One such option is the individualisation of leflunomide dosing to improve efficacy and tolerability. This may be achieved by tailoring treatment according to inherent genetic variability (pharmacogenomics), and subsequently by measuring plasma drug concentrations (therapeutic drug monitoring (TDM)), and adjusting drug doses accordingly.

Recently, oral teriflunomide (Aubagio®), the active metabolite of leflunomide was registered by the US FDA for treating relapsing forms of multiple sclerosis (MS). Although there are no studies of teriflunomide in patients with inflammatory arthritis, it is likely to be just as effective as leflunomide for these indications, and potentially has benefits over its predecessor with respect to adverse effects, which will be discussed further below.