Use of Leflunomide in Combination Therapy
Combination DMARD treatment of RA has demonstrated increased effectiveness in preventing joint damage. Leflunomide is used in combination with other conventional and biological DMARDs with some success, presumably due to teriflunomide's unique mechanism of action.
Leflunomide & Methotrexate
The combination of leflunomide and methotrexate is recommended by both the ACR and EULAR as a therapeutic option in those failing to respond adequately to methotrexate monotherapy.[2–4] It is mostly well tolerated and has some efficacy in patients in whom leflunomide was added after inadequate response to at least 6 months' of methotrexate, an ACR20 response rate of 46.2% was observed compared with 19.5% for the methotrexate/placebo group (p<0.001, after 24 weeks).[2–3,8,66]
Methotrexate has multiple mechanisms of action that complement teriflunomide's inhibition of de novo pyrimidine synthesis, including inhibition of purine synthesis, increased release of adenosine, and a decrease in inflammatory cytokines such as interleukins and TNF. Furthermore, methotrexate inhibits thymidylate synthase, which, along with DHODH, is a critical component of the de novo pyrimidine pathway. Figure 4 summaries the differing and interlinking mechanisms of action which have led to the hypothesis of a complementary or synergistic effect between leflunomide and methotrexate.[66,67] The synergistic effect may enable lower teriflunomide concentrations (and therefore lower leflunomide doses) to induce the desired clinical outcome. On the other hand, this could increase the risk of liver toxicity, as reported in some studies of combined leflunomide and methotrexate treatment.[6,30–31] Despite use of the combination in clinical practice, the teriflunomide concentration response relationship in the context of concurrent methotrexate therapy is yet to be investigated.
Comparison of the mechanisms of action of leflunomide and methotrexate in reducing synovial inflammation.
DHODH: Dihydro-oroate dehydrogenase.
Leflunomide & Sulfasalazine
The combination of leflunomide and sulfasalazine is less commonly used clinically than methotrexate and leflunomide, and is consequently less well studied. It tends to be used in patients intolerant of methotrexate, or in combination with methotrexate and hydroxychloroquine when leflunomide is added to triple therapy. In the RELIEF study, Dougados et al. evaluated the efficacy of the sulfasalazine/leflunomide combination compared with sulfasalazine alone in those who had failed to respond adequately to leflunomide monotherapy. The combination appeared more efficacious, with 8.9% of patients achieving an ACR50 response rate compared with 0% for those switching to sulfasalazine alone (p=0.038). The toxicity profiles appeared comparable, albeit the sample size was small.
Similar to methotrexate, the mechanism of action of sulfasalazine is not completely understood, but it appears to have immunomodulatory and anti-inflammatory effects by inhibiting the release of cytokines such as interleukins and TNF. In vitro studies have indicated this partially occurs via inhibition of the NF-κB pathway and increasing osteoprotegrin, thus preventing the stimulation of T-cells.[70,71] This decreased activation of NF-κB may have an overlapping or synergistic effect with leflunomide, which also has inhibitory effects on TNF mediated activation of NF-κB.
Additionally, teriflunomide and sulfasalazine both appear to interact with the ABCG2 transporter, with decreased plasma clearance (i.e., higher plasma concentrations) of teriflunomide and sulfasalazine observed in carriers of the less active A allele of ABCG2 C421A.[60,73] Furthermore, within a T-cell culture medium, exposure to sulfasalazine resulted in increased expression of ABCG2 and conferred resistance to leflunomide, presumably by lowering intracellular leflunomide concentrations. Despite this, teriflunomide is the active moiety in RA and the significance of changes to leflunomide transport are unknown, although both are substrates for ABCG2, have the same molecular weights and similar structures, so the effects are likely to be the same. Therefore it is of interest to determine what effect, if any, the combination of leflunomide and sulfasalazine has on the concentration-effect relationship of teriflunomide in the context of ABCG2 genotypes, and whether increased resistance to therapy occurs clinically.
Leflunomide's use in combination with biological DMARDs is being increasingly studied, although evidence of efficacy and toxicity is at this stage limited. De Stefano et al. conducted a small study involving 120 patients who received anti-TNF therapy (etanercept, infliximab, or adalimumab) in combination with either leflunomide or methotrexate, and found the same probability of achieving significant clinical improvements in each groups, while leflunomide in combination with anti-TNF therapy was better tolerated than methotrexate and anti-TNF therapy. In contrast, Strangfeld et al. found that methotrexate and anti-TNF therapy reduced disease activity more than leflunomide and biological DMARD combinations. More research is required as current clinical guidelines recommend that leflunomide is a suitable option to use in combination with biological DMARDs when methotrexate is contraindicated.[2,4,76]
Personalized Medicine. 2014;11(4):449-461. © 2014 Future Medicine Ltd.