Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis

INTRODUCTION — Leflunomide (LEF) is a nonbiological disease-modifying antirheumatic drug (DMARD) that has antiinflammatory and immune modulatory characteristics. LEF is approved by the US Food and Drug Administration (FDA) to treat rheumatoid arthritis (RA). Worldwide, LEF is used as a cost-effective strategy for multiple indications, including psoriatic arthritis and systemic lupus erythematosus [1-3].

The mechanism of action, pharmacology, dosing, and adverse effects of LEF, particularly in the context of its use in RA, will be reviewed here. The general approach to the management of RA and the use of LEF in the treatment of active disease are presented separately. (See "General principles and overview of management of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

The use of LEF in other conditions, including psoriatic arthritis, juvenile idiopathic arthritis, dermatomyositis, and systemic lupus erythematosus, and the use of teriflunomide, its active metabolite, in multiple sclerosis are discussed separately. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Leflunomide' and "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Treatment of arthritis' and "Management of refractory cutaneous dermatomyositis in adults", section on 'Other systemic medications' and "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Teriflunomide'.)

MECHANISM OF ACTION — Leflunomide (LEF) is an oral drug that is rapidly absorbed from the gastrointestinal tract; it acts as an immunomodulatory and immunosuppressive agent largely through inhibition of pyrimidine synthesis [4,5].

Inhibition of DHOD and rUMP synthesis — LEF is an isoxazole derivative that prevents pyrimidine synthesis. Once absorbed, LEF is converted to its active form (A77-1726), a malononitrilamide known as teriflunomide (figure 1) [6]. The metabolite inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHOD) [5]. The major action of teriflunomide at the doses given for rheumatoid arthritis (RA) is inhibition of the synthesis of a pyrimidine known as ribonucleotide uridine monophosphate pyrimidine (rUMP). This effect is particularly toxic to activated lymphocytes, which depend on de novo synthesis of uridine.

LEF decreases the synthesis of rUMP through inhibition of the mitochondrial enzyme DHOD. Inhibition of DHOD leads to inability of activated cells to move from G1 to the S phase by activating the p53 pathways of apoptotic selection. This enzyme is essential for the proliferation of T lymphocytes. While additional mechanisms of action have been noted, the inhibition of rUMP synthesis is thought to be the primary mechanism of the antiinflammatory and immunomodulatory effects of LEF at the levels of drug reached in most patients taking the recommended doses [7,8].

The structure of the enzyme DHOD and the binding site for teriflunomide have been determined by x-ray crystallography [9]. Human DHOD has two domains: an alpha-helical domain that forms the opening of a channel leading to the active site and an alpha/beta-barrel domain that contains the active site. Teriflunomide binds within the channel of the alpha-helical domain to exert its inhibitory effect on the enzyme.

Patients with the haplotype DHOD5 have a better response to LEF than patients with other haplotypes [10].

Effects on immune cells in vitro — LEF impacts many components of the immune-inflammatory response, some of which may be relevant to its mode of action in RA [4,5]. These include:

●Inhibition of leukocyte adhesion to vascular endothelial cells [11-16]

●Preferential inhibitory effects on self-reactive memory B cells [17]

●Interference with dendritic cell function, disrupting antigen presentation [18]

●Blocking two steps essential for nuclear factor (NF)-kappa B activation, including degradation of the inhibitor of kappa B alpha and the subsequent translocation of the p65 subunit to the nucleus, blocking the proinflammatory consequences of NF-kappa B activation [19]

●Inhibition of receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclast differentiation [20,21]

●Inhibition of the protein tyrosine kinases Janus kinase (Jak)1 and Jak3, which influence signaling through cytokine receptors [22,23] and of mitogen-activated protein kinase kinase kinase 2 (MAP3K2) [23]

●Decreasing the response to interleukin (IL)-4 by B cells [24-26], inhibiting IL-10 and IL-11 secretion, and reducing IL-2 synthesis [27,28]

●Increasing synthesis of transforming growth factor (TGF)-beta [29]

●Altering the pyrimidine metabolism, leading to a shift from Th1 to Th2 cells [30,31]

Effects on inflammatory markers in patients — Multiple effects on various mediators of inflammation and joint injury have been observed after administration of LEF:

●Clinical evidence of antiinflammatory effects of leflunomide – Findings in a randomized trial involving 38 patients with active RA treated with LEF or methotrexate (MTX) and using synovial biopsies at baseline and four months revealed similar antiinflammatory effects on cells and molecules involved in joint destruction in both treatment groups [32]:

•Reduced numbers of macrophages and T cells

•Decreased synovial infiltration of lymphocytes and type I synoviocytes with reduced vascular inflammation, including intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) expression, and metalloproteinase production (perhaps decreasing radiographic progression [33])

•In the subset of patients fulfilling the 20 percent response criteria of the American College of Rheumatology (ACR20), a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1b, and matrix metalloproteinase 1 (MMP-1; collagenase) was found compared with the nonresponders

●Influence on proinflammatory mediators in RA patients – Differential effects of LEF and MTX have been seen in studies of mediators in patients with RA [34]; LEF reduced serum levels of interferon gamma without a change in IL-6 levels, while both interferon gamma and IL-6 levels were reduced after MTX treatment.

●Influences on serum metalloproteinases – Patients with RA treated with LEF demonstrated decreases in serum levels of MMP-1, the activity of MMP-9, the degradation marker, cartilage oligomeric matrix protein (COMP), and the acute phase protein, serum amyloid A [35].

LEF, either directly or through its active metabolite, A771726, inhibits the accumulation of prostaglandin PGE2 at serum concentrations lower than those required to inhibit the induction of cyclooxygenase 2 (COX-2) protein. It does, however, appear unlikely that LEF could be antiinflammatory in vivo by mechanisms that include inhibition of COX-2 or inducible nitric oxide synthase (iNOS) [36].

DOSING

Administration — Leflunomide (LEF) is available in oral tablets and comes in the following dosages: 10 mg, 20 mg, and 100 mg. LEF is generally administered at 20 mg daily without a loading dose [37].

Role of loading dose — A loading dose of 100 mg daily for three days was used in some early clinical studies of LEF. However, use of a loading dose is associated with a higher likelihood of side effects, particularly diarrhea and other gastrointestinal disturbances. Thus, one of the authors (RF) and many experts prefer to begin LEF, starting at 20 mg daily, without a loading dose [38,39]. The other author (SH) and some experts prefer to use a loading dose of 100 mg daily for the first three days at the start of therapy or once weekly for three weeks, while taking the regular daily dose on other days in an effort to more quickly reach a therapeutic effect.

There are very limited data available regarding the relative benefits and risks of a loading dose, although one randomized trial involving a total of 120 patients found no advantage to use of a loading dose (100 mg daily for three days) compared with initiating therapy at a fixed dose (20 mg daily), with adverse events occurring earlier in the loading-dose group [37].

Ongoing daily dose — The usual dose of LEF is 20 mg, administered orally once daily, regardless of whether a loading dose was used. A 10 mg daily dose can be tried in patients with gastrointestinal intolerance of the usual dose, and the lower dose is sometimes used in patients treated with a combination of methotrexate (MTX) and LEF. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Leflunomide'.)

Limited information is available concerning dosing in patients with kidney function or hepatic impairment. Results of single-dose studies in patients with chronic kidney disease indicate that LEF is not removed by continuous ambulatory peritoneal dialysis or by hemodialysis due to its high degree of protein binding [40,41].

PHARMACOKINETICS, DRUG ELIMINATION, AND GENETIC FACTORS

Pharmacokinetics — Leflunomide (LEF) is well absorbed following oral administration. The serum half-life of teriflunomide, the active metabolite of LEF, is approximately 15 days, but it undergoes extensive enterohepatic recirculation, and plasma levels of this active metabolite above 0.02 mg/L may persist for up to two years. Normally, drug elimination of teriflunomide is achieved through the kidneys and gastrointestinal tract in an approximately equal ratio [40]. Teriflunomide is excreted in the urine as a glucuronide conjugate.

Drug metabolism is affected by the activity of CYP2C19, a liver enzyme that acts on at least 10 percent of drugs in clinical use, notably clopidogrel, omeprazole, and diazepam. CYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk-benefit ratio when using this drug [42].

Studies in adults have not revealed differences in the pharmacokinetics of the drug based upon gender or age. However, clearance of LEF is increased 38 percent in smokers compared with nonsmokers [43].

Other genetic factors may influence drug effects. One study has suggested that polymorphisms in the estrogen receptor allele, estrogen receptor 1 (ESR1), may be associated with differences in efficacy among women treated with LEF [44]. Another has suggested that a genetic polymorphism of CYP1A2, but not total or free teriflunomide concentrations, was associated with increased risk of discontinuing LEF due to side effects in patients with RA [45].

Drug interactions — The metabolic pathways used by LEF affect its interactions with other drugs:

●Warfarin – LEF has been reported in some patients to potentiate the action of warfarin as a result of its mutual competition at the level of cytochrome metabolism [46,47]. However, both increases and decreases in the effects of warfarin can be seen, and close monitoring is required in patients using both of these agents. (See 'Patients receiving vitamin K antagonists' below.)

●Cholestyramine – Elimination of LEF is rapidly increased by this drug, which binds to bile salts and prevents enterohepatic recirculation [40] (see 'Treatment to accelerate drug elimination' below).

●Other agents and cytochrome polymorphisms – Theoretically, LEF administration in patients with cytochrome 2C9 polymorphisms might alter levels of tolbutamide, glipizide, celecoxib, and fluvastatin as it has been noted to cause such changes at higher levels in rodent models [48]. In one study, a genetic polymorphism of CYP1A2 (but not total LEF or teriflunomide concentrations) predicted adverse reactions and intolerance in patients with RA [45].

Treatment to accelerate drug elimination — Accelerated elimination of the drug (eg, to prevent fetal risk during pregnancy due to potential drug exposure) can be achieved through the administration of cholestyramine (8 g orally three times daily for 11 days) [7]; this is effective because the drug's persistence depends upon enterohepatic circulation of the active metabolite. (See 'Pregnancy and lactation' below.)

This approach can be used if LEF is inappropriately taken during pregnancy, if the patient inadvertently becomes pregnant while taking LEF, or if a women of child-bearing age wishes to become pregnant and if levels persist from prior treatment.

Serum concentrations <0.02 mg/L should be verified by two separate tests performed at least 14 days apart. If serum concentrations are >0.02 mg/L, additional cholestyramine treatment can be employed.

As an alternative to cholestyramine, the Canadian labeling recommends that activated charcoal may be used to enhance drug elimination.

ADVERSE EFFECTS — A range of potential adverse effects may occur in patients using leflunomide (LEF); major concerns include hypertension, especially in patients on nonsteroidal antiinflammatory drugs (NSAIDs), diarrhea and nausea, hepatotoxicity, and risk of fetal and neonatal toxicity. The risks of LEF use during conception, pregnancy, and lactation are reviewed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Leflunomide'.)

The risk of adverse effects may be affected by specific gene polymorphisms. Observational studies indicate that cytochrome P450 (CYP1A2) and dihydroorotate dehydrogenase (DHODH) gene polymorphisms can influence the risk of adverse effects, but such testing is not available for routine clinical use [49,50]. Adverse effects may also occur due to drug-drug interactions. (See 'Drug interactions' above.)

●Gastrointestinal – Diarrhea and nausea occur in 10 to 15 percent of patients taking LEF. These side effects are seldom severe enough to lead to drug discontinuation. Diarrhea may be more severe when a loading dose is used [38]. Symptoms usually occur soon after starting therapy but may occur over time with chronic drug use. In rare cases there may be unexplained weight loss [51].

●Hepatic – Threefold elevation of serum aminotransferases have been noted in up to 13 percent of patients treated with LEF [7,38]. Careful monitoring of LEF has been thought to allow it to be used with a level of safety comparable with that of methotrexate (MTX) [52]. (See 'Warnings and monitoring for liver disease' below.)

The changes in liver function are generally reversible with dose reduction or discontinuation of the drug. However, infrequently, hepatoxicity can be severe. Between August 2002 and May 2009, 49 cases of severe liver injury, including 14 cases of fatal liver failure, were reported to the US Food and Drug Administration (FDA) [53].

Most patients who experience transaminase elevation have one or more comorbidities that might contribute to hepatotoxicity, including concomitant NSAID or MTX therapy, previous or concurrent alcohol abuse, nonalcoholic steatohepatitis, or viral or autoimmune hepatitis. The FDA issued a warning based upon these observations [53]. Estimates of the risk of transaminase elevations vary:

•In one practice-based study in Australia involving 2975 patients with rheumatoid arthritis (RA), the overall incidence of adverse effects was similar among patients receiving MTX alone, LEF alone, or a combination of the two agents [54]. The frequency of patients with abnormal hepatic aminotransferases in these groups was 12, 16, and 19 percent, respectively.

•Another study of a practice-based cohort of 1953 patients with RA and 151 with psoriatic arthritis found that the risks of elevated hepatic aminotransferase levels above the upper limit of normal were greater with the combination of LEF and MTX compared with monotherapy with either agent or with the use of neither agent (31 percent versus 17 to 22 percent versus 14 percent, respectively) [55].

Elevations of aminotransferase levels of greater than twice the upper limit of normal occurred in 1 to 2 percent of patients on LEF or MTX alone compared with 5 percent of patients on the combination. The risk appeared to be higher in patients with psoriatic arthritis and in those on higher doses of MTX.

●Hypertension – A small percentage of patients with RA develop hypertension when taking LEF [56,57]. Concurrent therapy with NSAIDs is a risk factor. The proposed mechanism is the displacement of NSAIDs from albumin by teriflunomide, thereby increasing NSAID activity [57]. Blood pressure monitoring is recommended during the first months of treatment and is also recommended if NSAID therapy is begun at a later date. (See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)

●Pulmonary – LEF treatment has been reported to be associated with an increased risk of interstitial lung disease. However, it is not clear whether this is a true effect or whether this is the result of "channeling bias," in which patients with preexisting interstitial lung disease are more likely to be treated with LEF than MTX, which is known to cause this complication [58]. A 2016 systematic review and meta-analysis of randomized trials failed to demonstrate increased pulmonary toxicity with LEF use [59].

We generally obtain a chest radiograph prior to therapy with LEF and avoid the use of LEF in patients with known interstitial lung disease or a history of MTX-induced lung toxicity. (See "Methotrexate-induced lung injury" and "Drug-induced lung disease in rheumatoid arthritis", section on 'Leflunomide'.)

●Neurologic – Peripheral neuropathy has been reported in patients receiving LEF [60,61], with partial improvement after drug removal with cholestyramine [62]. A review of 80 cases reported to the FDA noted that symptoms of peripheral nerve dysfunction, typically characterized by axonal polyneuropathy, began a mean of six months after beginning the drug [63]. Discontinuation of LEF within 30 days of the onset of symptoms was associated with a better outcome than discontinuation at a later time. In another study, 5 of 50 RA patients treated with LEF developed symptoms of peripheral neuropathy, but all improved after stopping the drug [60].

Similarly, a case of aseptic meningitis that improved with drug removal has also been reported [64].

●Dermatologic – Rash and alopecia occur in 10 to 15 percent of patients taking LEF. These side effects are typically mild and seldom lead to drug discontinuation. Stevens-Johnson syndrome has been reported in a patient with systemic lupus erythematosus who was receiving LEF [65].

●Hematologic – Leukopenia occurs very infrequently; estimates of incidence in patients taking LEF alone ranged from 1 in 3698 to 1 in 4582 patients exposed; for patients also taking MTX, the estimates ranged from 1 in 575 to 1 in 822 [40]. Otherwise, hematologic toxicity primarily results from an interaction between LEF and other drugs. LEF may enhance the bone marrow toxicity of MTX, possibly leading to pancytopenia, agranulocytosis, or thrombocytopenia.

LEF can potentiate the anticoagulant effect of warfarin [47]. As a result, the international normalized ratio (INR) should be more carefully monitored after initiation of LEF in patients taking warfarin. (See "Warfarin and other VKAs: Dosing and adverse effects".)

In addition, there was a report in 2010, but not since, of contamination with commercial solvents during the manufacturing process in some generic preparations of LEF used in Asia [66].

MONITORING

Routine laboratory monitoring — In most patients, we obtain the following routine testing during treatment with leflunomide (LEF): a complete blood count (CBC), aminotransferases, and creatinine every two to four weeks for the first three months or, after increasing the dose, every 8 to 12 weeks for months three to six, then every 12 weeks. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug monitoring and prevention of drug toxicity'.)

Closer monitoring is advised in patients receiving methotrexate (MTX) and LEF in combination. As an example, we obtain a CBC, creatinine, albumin, and transaminases every two to four weeks for the first three months (or following a dose increase), every four weeks for the next three months, then every three months subsequently. Some experts prefer that patients receiving MTX and LEF concurrently be monitored monthly for at least the first year, then increase the monitoring interval to only every two months [67].

Warnings and monitoring for liver disease — Patients receiving LEF should be closely monitored for signs of liver disease. LEF can be prescribed in patients with a history of previously abnormal liver function tests (LFTs) from MTX therapy and whose values subsequently normalize. This approach is consistent with the American College of Rheumatology (ACR) recommendations for LEF, which indicate that LEF should not be used in patients with significant prior liver disease suggestive of cirrhosis (Child-Pugh scale A or greater) but allow use in patients with prior elevated LFTs that have returned to normal [68]. Patients with acute or chronic infection with hepatitis B or C should be treated prior to initiating LEF. In patients with hepatitis C who have been treated, caution and close clinical and laboratory follow-up needs to be used after initiation of LEF [69].

The 2010 US Food and Drug Administration (FDA) warning based upon review of the cases of liver injury described above states [53]:

●Patients with preexisting liver disease should not receive LEF.

●Patients with elevated liver enzymes (alanine aminotransferase [ALT] greater than two times the upper limit of normal) should not receive LEF.

●Caution should be used in patients who are taking other drugs that can cause liver injury.

●Liver enzymes should be monitored at least monthly for three months after starting LEF and at least quarterly thereafter.

●If the ALT rises to greater than two times the upper limit of normal while the patient is on LEF, LEF should be stopped, cholestyramine washout should be begun to speed the removal of LEF from the body, and follow-up LFTs should be conducted at least weekly until the ALT value is within normal range.

These FDA recommendations for monitoring frequency are consistent with those of the 2008 ACR recommendations on the use of LEF in rheumatoid arthritis (RA) as well as subsequent ACR guidelines [68,70].

Patients receiving vitamin K antagonists — In patients taking warfarin and related agents, the international normalized ratio (INR) should be more carefully monitored after initiation of LEF because concomitant use of the drugs may affect the INR in either direction. (See 'Drug interactions' above and "Warfarin and other VKAs: Dosing and adverse effects".)

CONTRAINDICATIONS — Leflunomide (LEF) is contraindicated in pregnant and nursing women and in patients with preexisting liver disease. Live vaccines should not be administered to patients being treated with LEF. (See 'Pregnancy and lactation' below and 'Adverse effects' above.)

PREGNANCY AND LACTATION — Women of reproductive potential should not receive therapy until pregnancy has been excluded, they have been counseled concerning fetal risk, and reliable contraceptive measures have been confirmed. Following treatment, pregnancy should be avoided until undetectable serum concentrations (<0.02 mg/L) are verified. However, a report of data from a Canadian registry did not find statistically increased incidence of birth defects or spontaneous abortions in their cohort of 72 pregnancies and births exposed to LEF [71]. Nonetheless, caution remains warranted given the relatively small number of exposed women identified in this study.

Despite the prolonged half-life of the active metabolite, the drug and its metabolites can be relatively rapidly removed from the body by one of several measures, most commonly use of cholestyramine treatment. (See 'Treatment to accelerate drug elimination' above.)

The risks of leflunomide (LEF) use during conception, pregnancy, and lactation are reviewed in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Leflunomide'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Leflunomide (LEF) achieves its antiinflammatory effects through the inhibition of a mitochondrial enzyme termed dihydroorotate dehydrogenase (DHOD), leading to a decrease in the synthesis of ribonucleotide uridine monophosphate pyrimidine (rUMP). (See 'Mechanism of action' above.)

●Dosing – A starting dose of 20 mg daily of LEF is appropriate for most patients for whom LEF therapy is indicated. A loading dose is no longer commonly used, as it is associated with an increased risk of gastrointestinal side-effects. In patients with gastrointestinal tolerance, the dose may be lowered to 10 mg daily, with or without the addition of methotrexate (MTX). (See 'Pharmacokinetics, drug elimination, and genetic factors' above and 'Role of loading dose' above.)

●Adverse effects – LEF has a side effect profile comparable with that of MTX. Diarrhea and nausea are the most common adverse events. Transaminase elevation occurs in 13 percent of patients and generally reverses with drug cessation. Rash is also commonly observed but generally does not require drug cessation. (See 'Pharmacokinetics, drug elimination, and genetic factors' above and 'Adverse effects' above.)

●Monitoring – We advise monthly monitoring of liver function tests (LFTs) for the first three months of therapy, followed by testing at least every three months when LEF is used as a single agent. In patients who receive LEF in combination with MTX, liver function should be monitored more closely (eg, monthly for at least the first 6 to 12 months). (See 'Monitoring' above.)

●Pregnancy and lactation – Pregnancy and breast feeding should not be considered until serum concentrations of LEF are undetectable. Because of its long half-life, special measures may be required to eliminate LEF prior to pregnancy. (See 'Pregnancy and lactation' above and 'Treatment to accelerate drug elimination' above.)