Leflunomide and teriflunomide

Mechanism of action

Teriflunomide inhibits dihydro-orotate dehydrogenase, the rate-limiting enzyme in pyrimidine synthesis. It inhibits the proliferation of T and B cells, and probably acts via the production and action of interleukin-2. Besides its immunomodulatory action, teriflunomide also has an anti-inflammatory action by inhibition of nuclear factor kappa B (NFκB), tumor necrosis factor alfa (TNF-α), and interleukin 1 beta (IL-1β), and increased production of transforming growth factor beta-1 (TGF-β1) [ ].

Pharmacokinetics

After oral administration, leflunomide undergoes rapid metabolism in the gut wall, plasma, and liver to A77 1726 (M1), peak plasma concentrations of which are reached after 6–12 hours. Teriflunomide is highly (99%) bound to plasma proteins. Its pharmacokinetics are not affected by food, and dosage requirements are not influenced by age or sex. Enterohepatic recirculation and biliary recycling contribute to the long half-life of 2 weeks. About 90% of a single dose of leflunomide is eliminated, 43% in the urine, primarily as leflunomide glucuronides and an oxalinic acid derivative of teriflunomide, and 48% in the feces, primarily as teriflunomide. Impaired renal function can result in increased plasma concentrations of teriflunomide. Elimination of teriflunomide can be dramatically increased by using colestyramine or activated charcoal [ , ].

Indications and clinical efficacy

Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis and other conditions in randomized, double-blind, placebo-controlled trials and other studies [ ] ( Table 1 ), and it was approved for treatment of adult rheumatoid arthritis in August 1998 [ ]. In three large phase III trials (US301, n = 482; MN301, n = 358; MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo [ ]. These data were confirmed by a meta-analysis [ , ]. Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs. It is effective as monotherapy and in combination with methotrexate or infliximab [ ].

Clinical experience with leflunomide in patients with other autoimmune diseases is limited ( Table 1 ). Extended indications for the use of leflunomide include treatment of Crohn’s disease in patients who are intolerant of standard immunomodulator therapy [ ], chronic sarcoidosis [ ], maintenance therapy of complete or partial remission in Wegener’s granulomatosis [ ], and mild to moderate systemic lupus erythematosus [ ].

Leflunomide has been used as an immunosuppressive agent in kidney and liver transplant recipients to spare calcineurin inhibitors and glucocorticoids and to slow progression of chronic kidney graft dysfunction [ , ] ( Table 1 ).

In animals, leflunomide had excellent antiviral activity against cytomegalovirus (CMV). It is currently indicated as second-line therapy for CMV disease after solid organ transplantation and in recipients intolerant of ganciclovir [ ]. Leflunomide also reduces HIV replication by about 75% at concentrations that can be obtained with conventional dosing [ ] and was intended for treatment of patients with HIV/AIDS refractory to HAART [ ].

Leflunomide is licensed in France for “active psoriatic rheumatism”. Pharmacovigilance studies have confirmed some severe adverse reactions (hepatic, cutaneous, and hematological) and have uncovered other previously unrecognized reactions, such as interstitial pneumonia, hypertension, weight loss, and peripheral neuropathies. In France, leflunomide costs nearly 10 times more than methotrexate and it has been suggested that it should not be used to treat psoriatic arthropathy [ ].

Teriflunomide has been used in the management of multiple sclerosis [ , ] ( Table 1 ).

General adverse effects and adverse reactions

Leflunomide is said to have no myelosuppressive or nephrotoxic adverse effects [ , ]. Major adverse reactions are gastrointestinal symptoms (diarrhea and nausea), abnormal liver function tests, rashes and pruritus, allergic reactions, alopecia, infections, weight loss, and hypertension [ , ]. Minor adverse reactions are musculoskeletal disorders. Rare adverse effects and adverse reactions include pancytopenia and hypertriglyceridemia, sepsis, interstitial lung disease, vasculitis, aseptic meningitis, reversible neuropathy, and serious skin reactions [ , ]. Teriflunomide is presumed to share all of these adverse effects and reactions.

In 3325 patients who took leflunomide, the rate of drug withdrawal was 42% within 33 months after approval by the US Food and Drugs Administration, and was more likely in patients who received a loading dose. The most common causes of discontinuation were inefficacy (30%), gastrointestinal symptoms (29%), non-adherence to therapy or loss to follow-up (14%), and raised liver enzymes (5%) [ ].

However, the rate of adverse reactions associated with leflunomide was significantly lower than with methotrexate and other disease-modifying antirheumatic drugs (DMARDs) in an analysis of 40 594 patients with rheumatoid arthritis [ , ]. The incidences of adverse events per 1000 patient-years were as follows:

• no DMARDs: 383;

• methotrexate: 145;

• leflunomide monotherapy: 94;

• methotrexate + other DMARDs: 70;

• leflunomide + other DMARDs: 59;

• leflunomide + methotrexate: 43;

• other DMARDs: 143.

Leflunomide monotherapy also had the lowest rate of hepatic events in the DMARD monotherapy groups.

Further developments

Synthetic malononitrilamides (MNA) have been derived from teriflunomide. FK778 is the most promising derivative, because of its much shorter half-life. It also blocks replication of herpesvirus in vitro and in vivo. It has therefore been used as part of an immunosuppressive regimen and as an antiviral agent after solid organ transplantation [ ]. FK778 has been investigated in phase II trials after renal transplantation [ , ].

Observational studies

BK virus, which is closely related to the JC virus, is the most frequent polyomavirus. It was first isolated in 1971 from the urine of a kidney-transplant patient. Polyomavirus-associated nephropathy affects 1–10% of kidney transplant recipients, and there is graft failure/loss in about 90%. Treatment with leflunomide, in addition to reduced immunosuppression, improves graft function in such cases. In a single-center study leflunomide was used to treat polyomavirus-associated nephropathy in 11 of 346 kidney transplant recipients [ ]. The initial dose was 100 mg/day for 5 days, followed by 40 mg/day, maintaining serum concentrations at 40–80 mg/l. The median follow-up time was 16 months, after which median serum creatinine concentration was 150 (90–378) μmol/l versus 189 (92–265) μmol/l at baseline and estimated creatinine clearance was 45 (19–95) versus 36 ml/minute. There were no significant increases in liver enzymes. Platelet counts were reduced below 100 × 10 ⁹ /l in only three patients and there were no bleeding events. Four patients developed fungal pneumonia 2 weeks after leflunomide treatment, and were successfully treated with voriconazole.

Comparative studies

In 285 patients with rheumatoid arthritis leflunomide was discontinued after 1 year in 57%, mainly because of adverse drug reactions (42%) [ ]. The discontinuation rate because of toxicity was higher for leflunomide than for other DMARDs studied, while discontinuation for inefficacy was similar.

Cardiovascular

The incidence of hypertension in patients with rheumatoid arthritis taking leflunomide 25 mg/day was 11% in a phase II trial [ ]. During phase III trials, there was new-onset hypertension in 2.1–3.7% [ , ]. Increased sympathetic drive has been implicated in its pathogenesis, because leflunomide-induced hypertension is accompanied by an increased heart rate [ ]. However, this hypothesis remains to be tested.

Pulmonary hypertension has been described in association with leflunomide [ ].

Respiratory

Respiratory symptoms in the MN301, US301, and MN302 trials in patients with rheumatoid arthritis included respiratory infections (21–27%), bronchitis (5–8%), increased cough (4–5%), rhinitis (2–5%), pharyngitis (2–3%), pneumonia (2–3%), and sinusitis (1–5%) [ , , ].

In Japan, acute interstitial pneumonia due to leflunomide has been mentioned as a serious and severe adverse effect, with an incidence of 1.1% and a fatal outcome in 0.36% [ ].

• A 75-year-old woman with rheumatoid arthritis developed rapidly progressive interstitial pneumonia 45 days after starting to take leflunomide and died of respiratory failure [ ]. Autopsy showed a mixed pattern of acute and organizing diffuse alveolar damage.

• A 77-year-old woman with rheumatoid arthritis and a history of methotrexate-induced pneumonitis suddenly developed dyspnea on exertion about 2 months after starting to take leflunomide and died [ ]. For more than 3 weeks after withdrawal of the drug she had a high concentration of an active metabolite of leflunomide.

• A 49-year-old man with rheumatoid arthritis taking methotrexate developed a skin eruption and a severe non-productive cough after taking leflunomide for 17 days [ ]. He died of respiratory failure 128 days after the diagnosis of acute interstitial pneumonia.

• A 54-year-old woman with rheumatoid arthritis developed an interstitial pneumonia 2 weeks after the end of a 6-week course of treatment with leflunomide [ ]. The onset of the pneumonia was preceded by raised serum liver enzymes and hypertension. The acute respiratory failure improved with prednisolone and colestyramine.

However, clinical trials and subsequent observational studies outside Japan have not suggested that leflunomide causes an excess of pulmonary adverse reactions [ ].

Nevertheless, reports of lung damage attributed to leflunomide in patients outside Japan continue to appear For example, the New Zealand Pharmacovigilance Centre (NZPhvC) and the Australian Adverse Drug Reactions Unit (ADRU) have received 14 reports of supposed pneumonitis in patients taking leflunomide, 12 in combination with methotrexate [ ]. In nine of these 12 patients pneumonitis occurred after leflunomide was added to methotrexate, usually within 12–20 weeks. One of two patients who died had possible previous methotrexate-induced pneumonitis. Leflunomide washout with colestyramine was used to treat three patients, one with life-threatening illness, with good results. This report suggests that prompt recognition is important to avoid life-threatening disease and supports the use of colestyramine to remove leflunomide, as has been reported in another case in which oral colestyramine was used [ ].

In a prospective study of 136 patients with active rheumatoid or psoriatic arthritis taking leflunomide 20 mg/day, five developed cavitating pneumonia after the start of leflunomide treatment [ ].

Of 1010 patients who took leflunomide for rheumatoid arthritis for at least 1 month, 10 developed interstitial lung disease; the risk was greater in those with pre-existing lung diseases [ ].

• A 69-year-old woman with rheumatoid arthritis developed acute interstitial pneumonia 3 months after starting to take leflunomide. Methylprednisolone pulse therapy and colestyramine 24 g/day ameliorated her symptoms.

In 62 734 patients with rheumatoid arthritis who had used a DMARD there were 74 cases of serious interstitial lung disease, corresponding to a rate of 8.1 per 10 000 patients per year [ ]. Leflunomide increased the risk of interstitial lung disease (adjusted RR = 1.9; 95% CI = 1.1, 3.6). Among those who had not previously used methotrexate and without a history of interstitial lung disease, the risk associated with leflunomide was not increased (RR = 1.2; 95% CI = 0.4, 3.1), but it was increased among the others (RR = 2.6; 95% CI = 1.2, 5.6). Patients with a history of interstitial lung disease were twice as likely to have taken leflunomide as any other DMARD. Interstitial lung disease associated with the use of leflunomide is probably due to the fact that leflunomide is used in high-risk patients, particularly those who have used methotrexate or have pre-existing interstitial lung disease.

A pulmonary abscess occurred during leflunomide therapy in a patient with rheumatoid arthritis [ ].

• A 43-year-old woman who had had rheumatoid arthritis for 5 years complained of fever, arthralgia/myalgia, and night sweating for 1 month. She had been taking only leflunomide 20 mg/day for 5 months. There was no evidence of active arthritis or vasculitic lesions. Her erythrocyte sedimentation rate was 145 mm/hour and C-reactive protein 1.6 g/l. All cultures were negative. A chest X-ray and CT scan showed a pulmonary abscess. Staphylococcus aureus was grown in the culture of a purulent sample obtained from the abscess under ultrasonography. The leflunomide was withdrawn, and sultamicillin 8 g/day was given for 6 weeks. Four weeks later, she had completely recovered and a CT scan showed significant improvement of the pulmonary abscess.

Pulmonary nodulosis has been associated with leflunomide [ ]. Thoracoscopic biopsy showed fibrinoid necrosis with pallisading macrophages and a few giant cells, suggestive of a rheumatoid nodule; Ziehl–Nielsen staining for mycobacteria was negative. Leflunomide was withdrawn and the pulmonary nodules regressed within 6 months.

Rheumatoid lung nodulosis has been described during leflunomide therapy [ ].

• A 77 year-old man with long-standing active seropositive nodular rheumatoid arthritis had a complete remission during 2 months of leflunomide therapy. After 10 months he developed limb pain associated with intensive bone uptake on a bone scan, consistent with hypertrophic pulmonary osteopathy. After 13 months progressive cavitary nodules, predominantly involving the basal segments of the right lung, were detected on a CT scan. A lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid disease.

• A 66 year-old man with long-standing active seropositive nodular rheumatoid arthritis achieved a complete remission during 2 months of leflunomide therapy. After 3 months he developed a productive cough. After 7 months a CT scan showed progressive cavitary nodules, predominantly involving the basal segments of the right lung. A lung biopsy showed necrosis surrounded by epithelioid mononuclear inflammation with giant cells, consistent with rheumatoid disease.

In both cases withdrawal of leflunomide was followed by arrest in the growth of the lung nodules, resolution of the limb pain, and gradual improvement in the bone scan. The authors suggested that monocytopenia was involved in the pathogenesis of this rare complication.

Pulmonary alveolar proteinosis is an uncommon disorder marked by abnormal accumulation of surfactant in the alveoli. Secondary pulmonary alveolar proteinosis can occur in patients who are immunosuppressed, usually with corticosteroids. Biopsy-proven pulmonary alveolar proteinosis has been reported in a patient taking leflunomide [ ]. Treatment with whole lung lavage and withdrawal of leflunomide produced a good result.

Imaging findings in 26 cases of leflunomide-related acute lung injury were similar to those caused by other drugs, including diffuse or widespread patchy ground-glass opacities and/or consolidation, often accompanied by septal thickening and intralobular reticular opacities [ ]. Of 23 cases 13 had pre-existing interstitial pulmonary disease on chest X-ray or CT scan. The imaging findings were classified into four patterns: diffuse alveolar damage, acute eosinophilic pneumonia, a hyper-reaction, and cryptogenic organizing pneumonia. Those with diffuse alveolar damage had a higher mortality rate, which did not reach conventional statistical significance.

Nervous system

Leflunomide can cause a peripheral reversible neuropathy [ , ]. This neuropathy is usually axonal in nature, affecting multiple sensory or motor nerves of distal extremities. The mean time of onset of peripheral neuropathy was 6 months after the start of leflunomide therapy, with a range of 3 days to 3 years. Neurological improvement was more likely after drug withdrawal within 30 days after the onset of the symptoms of neuropathy compared with continuous administration [ ].

Peripheral neuropathy attributed to leflunomide was observed in two patients [ ].

• A 76-year-old man, with an 18-month history of seropositive rheumatoid arthritis, chronic emphysema, and pulmonary fibrosis, developed polymyalgia and was treated with glucocorticoids and azathioprine. Azathioprine was withdrawn after a rise in aspartate aminotransferase. He was then given leflunomide 100 mg over 3 days followed by 10 mg/day as a maintenance dosage. After 2 weeks, he developed a sensory neuropathy with a stocking distribution up to the malleoli and leflunomide was withdrawn 4 weeks later. During this time he had also been taking prednisolone, tramadol, disodium etidronate, indoramin, and celecoxib, none of which is known to cause neuropathy. Glucose, vitamin B12, serum folate, thyroid function, serum proteins, Bence–Jones protein electrophoresis, cryoglobulins, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies, the Venereal Disease Research Laboratory test, and hepatitis B and C serology were all normal or negative. Nerve conduction was consistent with motor sensory axonal peripheral neuropathy of the lower limbs. On review 3 months after withdrawal of leflunomide, there was clear subjective and objective improvement of the neuropathy, confirmed by repeat nerve conduction studies.

• A 69-year-old woman with a 10-year history of seropositive erosive rheumatoid arthritis, previously treated with gold salts followed by methotrexate, started to take leflunomide and 3 months later reported numbness in the fingertips and feet bilaterally, with a glove-and-stocking sensory neuropathy involving all fingertips and extending to the mid-shins. Leflunomide was withdrawn. Other medications included prednisolone, lansoprazole, simvastatin, losartan, and amiodarone, which she had been taking for a long time without adverse reactions. Screening tests for neuropathy, as in the previous case, were normal or negative. There was no cord or nerve root compression on magnetic resonance imaging of the cervical spine. Nerve conduction studies confirmed a sensory motor peripheral neuropathy. She reported marked improvement in her symptoms 3 months after withdrawal of treatment, and this was confirmed on clinical examination and repeat nerve conduction studies.

Two patients taking leflunomide developed a severe sensorimotor axonal polyneuropathy starting 5 months after the start of leflunomide therapy; the symptoms rapidly improved after withdrawing leflunomide [ ]. Of 12 patients with leflunomide-related neuropathy 10 were older than 60 years. The mean delay to the onset of neuropathy was 9 months. The neuropathy improved after withdrawal in seven patients.

In 32 patients with rheumatoid arthritis taking leflunomide or other disease-modifying antirheumatic drugs, leflunomide was associated with an apparent increase in the symptoms of peripheral neuropathy after 6 months; however, the symptoms did not correlate with neurophysiological studies [ ].

In 16 patients with rheumatoid arthritis taking leflunomide and 16 who were taking disease-modifying anti-rheumatic drugs 54% of the former and 8% of the controls had increased neuropathy symptom scores 6 months into the study [ ]. However, there was no significant difference between the two groups in upper and lower limb sensory and motor amplitudes. One developed both clinical and neurophysiological evidence of a peripheral neuropathy 5 months into the study and improved after withdrawal of leflunomide.

One case of leflunomide-induced aseptic meningitis has been reported [ ].

Sensory systems

Leflunomide can cause cystoid macular edema [ ].

Endophthalmitis associated with leflunomide and adalimumab has been reported [ ].

• A 48-year-old woman taking leflunomide and adalimumab for rheumatoid arthritis developed endophthalmitis caused by Propionibacterium acnes . The diagnosis was confirmed by polymerase chain reaction and positive cultures. She underwent surgical treatment and was given intravitreal vancomycin, but developed retinal fibrosis and untreatable retinal detachment.

This report of endophthalmitis is consistent with previous reports associated with the use of TNF-α inhibitors. Propionibacterium acnes can cause pathological reactions in immunocompromised patients and can cause endophthalmitis, but only after ocular surgery or in intravenous drug users.