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Leflunomide

A Review of its Use in Active Rheumatoid Arthritis

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Summary

Abstract

A77 1726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active rheumatoid arthritis. Because A77 1726 has a long half-life (≈2 weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg once daily for 3 days and continued with 20mg once daily.

Results of large randomised, double-blind, multicentre trials of up to 24 months’ duration have shown that leflunomide is significantly superior to placebo and at least as effective as sulfasalazine in improving primary outcome measures, such as tender joint counts, swollen joint counts and physicians’ and patients’ global assessment, in adult patients with active rheumatoid arthritis. Whereas improvement in all primary outcome measures with leflunomide was similar to or significantly less than that with methotrexate after 12 months, the efficacy of both agents was similar after 24 months. The therapeutic effect of leflunomide appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and reduction from baseline values in functional disability was significantly greater with leflunomide than with sulfasalazine, methotrexate or placebo at end-point. Leflunomide was at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease.

The most common adverse events reported in patients receiving leflunomide in randomised double-blind, placebo-controlled trials were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of serum hepatic enzyme levels is recommended in patientsreceiving leflunomide. The drug is not recommended in female patients who are or may become pregnant. Drug treatment should be discontinued, and hastened drug elimination procedure should be considered, in male patients wishing to father a child. 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of leflunomide in 76 000 patients to date.

Conclusions: Leflunomide is a disease-modifying antirheumatic drug which reduces the signs and symptoms of inflammatory arthritis and delays the radiological progression of disease in adult patients with active rheumatoid arthritis. The drug appears to be as effective and as well tolerated as sulfasalazine or methotrexate, and represents a suitable alternative to these agents in adult patients with active rheumatoid arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is maintained for durations of up to 24 months.

Pharmacodynamic Properties

Leflunomide is an immunomodulatory prodrug which is rapidly converted to its active metabolite, A77 1726, possibly in the gut wall, plasma and in the liver. A77 1726 inhibits cell proliferation in activated lymphocytes in patients with rheumatoid arthritis but its precise mechanism of action is unclear. In vitro data indicate that the drug inhibits dihydro-orotate dehydrogenase activity and protein tyrosine kinase activity in actively dividing cells. Additional pharmacodynamic effects of the drug, such as inhibition of nuclear factor κB activation and nuclear factor KB-dependent reporter gene expression and inhibitory effects on oxygen radical, immunoglobulin (Ig)G and IgM production and interleukin (IL)-Iβ and IL-2 levels, may also contribute to the immunomodulatory effects of A77 1726.

Treatment with oral leflunomide 5 to 35 mg/kg/day decreased signs and symptoms of arthritis and histological evidence of joint damage in rodent models of rheumatoid arthritis and ankylosing spondylitis.

The effects of leflunomide are at least additive with other disease-modifying antirheumatic drugs (DMARDS) such as cyclosporin and sirolimus (rapamycin) in vitro and in vivo.

Pharmacokinetic Properties

After oral administration, leflunomide is rapidly metabolised to its active metabolite, A77 1726, possibly in the gut wall, plasma and in the liver. Peak plasma A77 1726 concentrations are reached 6 to 12 hours after oral administration of leflunomide. In patients with rheumatoid arthritis, A77 1726 reaches steady-state plasma concentrations of 18 and 63 mg/L after administration of oral leflunomide 10 and 25 mg/day.

A77 1726 is 99.38% bound to plasma proteins and has an apparent volume of distribution of 0.13 L/kg. The drug undergoes enterohepatic circulation and biliary recycling may contribute to its long elimination half-life (≈2 weeks). Because of the long elimination half-life, treatment with leflunomide should be initiated with a loading dose of 100mg once daily for 3 days to hasten attainment of steady-state plasma concentrations.

48% of the administered dose is excreted in the faeces and 43% in the urine. The drug was cleared at a rate of 0.031 L/h after intravenous administration and smokers tend to clear the drug at a faster rate than nonsmokers. Age and gender do not have any consistent effect on the pharmacokinetics of A77 1726. Plasma A77 1726 free fraction concentrations were higher in patients with rheumatoid arthritis and in patients chronic renal insufficiency than in healthy volunteers. A77 1726 is not dialysable. The effects of hepatic dysfunction on the pharmacokinetics of A77 1726 are unknown.

Oral cholestyramine 8g 3 times a day for 24 hours or activated charcoal 50g every 6 hours for 24 hours are reported to rapidly decrease plasma A77 1726 concentrations (by 49 to 65% and 48%, respectively, after 48 hours). Coadministration of rifampicin (rifampin) increases peak plasma A77 1726 concentrations by ≈40%. No pharmacokinetic interactions have been reported after coadministration of leflunomide with triphasic oral contraceptives, methotrexate or cimetidine. Since A77 1726 inhibits cytochrome P450 (CYP) 2C9 in vitro, the drug may have potential for interaction with other drugs which are metabolised by this enzyme, such as diclofenac, ibuprofen and tolbutamide.

Therapeutic Efficacy

Once daily oral leflunomide 20mg (after a loading dosage of 100mg once daily for 3 days) was effective in the treatment of adult patients with active rheumatoid arthritis in large randomised, double-blind, multicentre trials. Significant benefit with leflunomide was evident after 4 weeks’ and the drug had a faster onset of action than sulfasalazine or methotrexate. Improvement with leflunomide in all primary outcome measures, such as tender joint count, swollen joint count, physicians’ and patients’ global assessment of disease severity, and in American College of Rheumatology (ACR) 20 criteria were similar to those with sulfasalazine 2 g/day after 6 months. However, improvements from baseline in physicians’ and patients’ global assessment and ACR 20 responder rates were significantly better with leflunomide than with sulfasalazine after 24 months.

The efficacy of leflunomide was broadly similar to that of methotrexate 7.5 to 15 mg/week. Improvement in all primary outcome measures with methotrexate was significantly better than with leflunomide after 12 months’ treatment in 1 trial, but there was no difference between the treatment groups in another trial of similar duration. Change from baseline in tender joint, patient’ global assessment and the ACR 20 responder rate were similar in leflunomide- or methotrexatetreated patients after 24 months. Furthermore, leflunomide was reported to be equivalent to methotrexate in an area-under-the-curve analysis of the ACR 20 responder rate.

Leflunomide reduced functional disability to a significantly greater extent than sulfasalazine or methotrexate. Significantly greater benefit on functional disability with leflunomide than with sulfasalazine was evident after 6 months and was maintained over a period of up to 24 months. Leflunomide was significantly better than methotrexate in 5 of the 6 methods used to assess functional disability and quality of life in another trial of 12 months’ duration.

Leflunomide is at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. Radiological progression of disease over 24 months was significantly slower with leflunomide or sulfasalazine than with placebo in 1 trial. Whereas radiological disease progression in leflunomide recipients was significantly less than that in patients receiving methotrexate or placebo in one 12-month trial, there was no difference in treatment-related delay in radiological disease progression after 12 and 24 months’ treatment with leflunomide or methotrexate in another trial.

Preliminary data indicate that a combination of leflunomide with methotrexate is effective in patients with active rheumatoid arthritis refractory to methotrexate alone. However, the relative risks and benefits of using leflunomide with another DMARD have not been adequately evaluated.

Tolerability

Leflunomide was as well tolerated as sulfasalazine or methotrexate in adult patients with active rheumatoid arthritis over durations of up to 24 months. The most common adverse effects (in ≥5% of recipients) with leflunomide were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic transferases (10%), dyspepsia (10%) and alopecia (9%), which were similar in intensity and severity to those with sulfasalazine or methotrexate. Of an estimated 76 000 patients who have received treatment with leflunomide, 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of the drug.

The incidence and severity of increased serum hepatic enzymes with leflunomide (in up to 4.4% of recipients) were similar to those with sulfasalazine (3.8%) or methotrexate (2.7%). Although human data are lacking, animal data indicate that exposure to leflunomide during pregnancy has teratogenic and fetotoxic effects. The potential for male-mediated fetal toxicity with leflunomide has not yet been evaluated. However, male patients wishing to father a child should discontinue drug treatment should and hastened drug elimination procedure with cholestyramine or activated charcoal should be considered.

Dosage and Administration

Treatment with leflunomide should be initiated with a loading dose of 100mg administered once daily for 3 days and continued at a dosage of 20 mg/day. Dosages >20 mg/day are not recommended and the dosage may be decreased to 10 mg/day in those who cannot tolerate 20 mg/day. Serum hepatic enzymes should be monitored before initiating treatment with leflunomide and then at monthly intervals.

The dosage of leflunomide does not have to be modified in patients >65 years of age, but the drug should be used with caution in patients with renal impairment.

The use of leflunomide is contraindicated in female patients who are pregnant or are not using adequate contraception and in those who are breast-feeding infants. Treatment with leflunomide is not recommended in patients with significant hepatic impairment, positive hepatitis B or C serologies, severe immunodeficiency, bone marrow dysplasia or in those with severe uncontrolled infections.

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References

  1. Choy EH, Scott DL. Drag treatment of rheumatic diseases in the 1990s: achievements and future developments. Drugs 1997 Mar; 53: 337–48

    Article  PubMed  CAS  Google Scholar 

  2. Edmonds JP, Scott DL, Furst DE, et al. Antirheumatic drags: a proposed new classification [editorial]. Arthritis Rheum 1993; 36: 336–9

    Article  PubMed  CAS  Google Scholar 

  3. Group for the Respect of Ethics and Excellence in Science (GREES): Rheumatoid Arthritis Section. Recommendations for the registration of drags used in the treatment of rheumatoid arthritis. Br J Rheumatol 1998 Feb; 37: 211–5

    Article  Google Scholar 

  4. HMR’s Arava launched in US. Scrip 1998 Nov 13; 2387: 19

    Google Scholar 

  5. HMR’s Arava approved in the EU. Scrip 1999; 2471: 22

    Google Scholar 

  6. EMEA safety warning delays Arava. Scrip 1999; 2485: 22

    Google Scholar 

  7. Eckhardt SG, Rizzo J, Hammond L, et al. A phase I and pharmacokinetic (PK) study of the tyrosine kinase inhibitor SU101 in patients with advanced solid tumors [abstract no. 792]. Proceedings of the 33rd Annual Meeting of the American Society of Clinical Oncology, 1997 May 17–20; Denver, 225

  8. Burkhardt H, Kalden JR. Xenobiotic immunosuppressive agents: therapeutic effects in animal models of autoimmune diseases. Rheumatol Int 1997 Sep; 17: 85–90

    Article  PubMed  CAS  Google Scholar 

  9. Metzler C, Löw-Friedrich I, Reinhold-Keller E, et al. Leflunomide, a new, promising agent in maintenance of remission in Wegeners granulomatosis (WG) [abstract]. Clin Exp Immunol 1998 Apr; 112 Suppl. 1:56

    Google Scholar 

  10. Thoss K, Henzgen S, Petrow PK. Immunomodulation of rat antigen-induced arthritis by leflunomide alone and in combination with cyclosporin A. Inflamm Res 1996 Feb; 45: 103–7

    Article  PubMed  CAS  Google Scholar 

  11. Seiffge D, BartlettR, Finkenauer V, et al. Effects of leflunomide on leukocyte adhesion in adjuvant arthritis rats [abstract no. 5]. Proceedings of the Eighth APLAR Congress of Rheumatology; 1996 Apr 21–26; Melbourne: Asia Pacific League of Associations for Rheumatology, P2

  12. Glant TT, Mikecz K, Brennan F, et al. Suppression of autoimmune responses and inflammatory events by leflunomide in an animal model for rheumatoid arthritis. Agents Actions 1994 Aug; 41 Spec. Iss.: C267–70

    Article  Google Scholar 

  13. Rückemann K, Fairbanks LD, Carrey EA, et al. Leflunomide inhibits pyrimidine de novo synthesis in mitogen-stimulated T-lymphocytes from healthy humans. J Biol Chem 1998 Aug 21; 273: 21682–91

    Article  PubMed  Google Scholar 

  14. Cao WW, Kao PN, Aoki Y, et al. A novel mechanism of action of the immunomodulatory drug, leflunomide: augmentation of the immunosuppressive cytokine, TGF-β1, and suppression of the immunostimulatory cytokine, IL-2. Transplant Proc 1996 Dec; 28: 3079–80

    PubMed  CAS  Google Scholar 

  15. Cherwinski HM, Cohn RG, Cheung P, et al. The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther 1995 Nov; 275: 1043–9

    PubMed  CAS  Google Scholar 

  16. Chong AS-F, Rezai K, Gebel HM, et al. Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro. Transplantation 1996 Jan 15; 61: 140–5

    Article  PubMed  CAS  Google Scholar 

  17. Zielinski T, Herrmann M, Muller HJ, et al. The influence of leflunomide on cell cycle, IL-2-receptor (IL-2-R) and its gene expression. Agents Actions 1994 Aug; 41 Spec. Iss.: C204–5

    Article  Google Scholar 

  18. Zielinski T, Muller HJ, Bartlett RR. Effects of leflunomide (HWA-486) on expression of lymphocyte activation markers. Agents Actions 1993; 38 Spec. Iss. CI: C80–2

    Article  PubMed  CAS  Google Scholar 

  19. Dimitrijevic M, Stupar N, Pilipovic N. Leflunomide in the treatment of patients with severe rheumatoid arthritis: influence on immunological parameters [abstract no. 15-B-P]. Clin Exp Rheumatol 1995 Sep–Oct; 13 Suppl. 12: S56

    Google Scholar 

  20. Milenkovic M, Stojic VZ, Arsenovic RN, et al. Spontaneous homotypic aggregation of peripheral blood mononuclear cells in patients with rheumatoid arthritis: influence of leflunomide [abstract no. 4-B-P]. Clin Exp Rheumatol 1995 Sep–Oct; 13 Suppl. 12: S–55

    Google Scholar 

  21. Weithmann KU, Jeske S, Schlotte V. Effect of leflunomide on constitutive and inducible pathways of cellular eicosanoid generation. Agents Actions 1994 May; 41: 164–70

    Article  PubMed  CAS  Google Scholar 

  22. Schorlemmer HU, Kurrle R, Schleyerbach R. Leflunomide’s active metabolite A77 1726 and its derivatives, the malononitrilamides, inhibit the generation of oxygen radicals in mononuclear phagocytes. Int J Immunother 1998; XIV: 213–22

    Google Scholar 

  23. Cao WW, Kao PN, Chao AC, et al. Mechanism of the anti-proliferative action of leflunomide: A77 1726, the active metabolite of leflunomide, does not block T-cell receptormediated signal transduction but its antiproliferative effects are antagonized by pyrimidine nucleosides. J Heart Lung Transplant 1995; 14 (Pt 1): 1016–30

    PubMed  CAS  Google Scholar 

  24. Cherwinski HM, Byars N, Ballaron SJ, et al. Leflunomide interferes with pyrimidine nucleotide biosynthesis. Inflamm Res 1995 Aug; 44: 317–22

    Article  PubMed  CAS  Google Scholar 

  25. Herrmann ML, Frangou CG, Simmonds HA, et al. The primary mode of action of leflunomide in rheumatoid arthritis is inhibition of de novo pyrimidine synthesis [abstract]. Arthritis Rheum 1998 Sep; 41 Suppl.: S35

    Google Scholar 

  26. Déage V, Burger D, Dayer J-M. Exposure of T lymphocytes to leflunomide but not to dexamethasone favors the production by monocytic cells of interleukin-1 receptor antagonist and tissue-inhibitor of metalloproteinasees-1 over that of interleukin-1β and metalloproteinases. Eur Cytokine Netw 1998; 9: 663–8

    PubMed  Google Scholar 

  27. Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factorκB activation and gene expression. J Immunol 1999; 162: 2095–102

    PubMed  CAS  Google Scholar 

  28. Siemasko KF, Chong A-S, Williams JW, et al. Regulation of B cell function by the immunosuppressive agent leflunomide. Transplantation 1996 Feb 27; 61: 635–42

    Article  PubMed  CAS  Google Scholar 

  29. Xu X, Blinder L, Shen J, et al. In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MRL/MpJ-Ipr/Ipr mice. J Immunol 1997 Jul 1; 159: 167–74

    PubMed  CAS  Google Scholar 

  30. Siemasko K, Chong A-SF, Jäck H-M, et al. Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. J Immunol 1998 Feb 15; 160: 1581–8

    PubMed  CAS  Google Scholar 

  31. Elder RT, Xu X, Williams JW, et al. The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. J Immunol 1997 Jul 1; 159: 22–7

    PubMed  CAS  Google Scholar 

  32. Lang R, Wagner H, Heeg K. Differential effects of the immunosuppressive agents cyclosporine and leflunomide in vivo: leflunomide blocks clonal T cell expansion yet allows production of lymphokines and manifestation of T cell-mediated shock. Transplantation 1995 Feb 15; 59: 382–9

    PubMed  CAS  Google Scholar 

  33. Zielinski T, Muller HJ, Schleyerbach R, et al. Differential effects of leflunomide on leukocytes: ihibition of rat in vivo adhesion and human in vitro oxidative burst without affecting surface marker modulation. Agents Actions 1994 Aug; 41 Spec. Iss.: C276–8

    Article  Google Scholar 

  34. Dimitrijevic M, Bartlett RR, et al. Leflunomide, a novel immunomodulating drug, inhibits homotypic adhesion of peripheral blood and synovial fluid mononuclear cells in rheumatoid arthritis. Inflamm Res 1996 Nov; 45: 550–6

    Article  PubMed  CAS  Google Scholar 

  35. Greene S, Watanabe K, Braatz-Trulson J, et al. Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol 1995 Sep 7; 50: 861–7

    Article  PubMed  CAS  Google Scholar 

  36. Fox RI. Mechanism of action of leflunomide in rheumatoid arthritis. J Rheumatol 1998 Jul; 25 Suppl. 53: 20–6

    Google Scholar 

  37. Parnham MJ. Leflunomide: a potential new disease-modifying anti-rheumatic drug. Expert Opin Invest Drug 1995 Aug; 4: 777–9

    Article  CAS  Google Scholar 

  38. Brazelton TR, Morris RE. Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol 1996 Oct; 8: 710–20

    Article  PubMed  CAS  Google Scholar 

  39. Fox RI, Herrmann ML, Frangou CG, et al. How does leflunomide modulate the immune response in rheumatoid arthritis? Biodrugs 1999; 12: 301–15

    Article  PubMed  CAS  Google Scholar 

  40. Knecht W, Löffler M. Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazol and cinchoninic acid derivatives. Biochem Pharmacol 1998 Nov 1; 56: 1259–64

    Article  PubMed  CAS  Google Scholar 

  41. Fox R, Mahboubi A, Green D, et al. Leflunomide inhibits de novo uridine synthesis and is dependent on p53 for arrest in G1 phase of cell cycle [abstract]. Arthritis Rheum 1998 Sep; 41 Suppl.: S137

    Google Scholar 

  42. Silva HT, Cao W, Shorthouse R, et al. Mechanism of action of leflunomide: in vivo uridine administration reverses its inhibition of lymphocyte proliferation. Transplant Proc 1996 Dec; 28: 3082–4

    PubMed  CAS  Google Scholar 

  43. Xu XL, Williams JW, Bremer EG, et al. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide. J Biol Chem 1995 May 26; 270: 12398–403

    Article  PubMed  CAS  Google Scholar 

  44. Xu X, Williams JW, Gong H, et al. Two activities of the immunosuppressive metabolite of leflunomide, A77 1726: inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Biochem Pharmacol 1996 Aug 23; 52: 527–34

    Article  PubMed  CAS  Google Scholar 

  45. Davis JP, Cain GA, Pitts WJ, et al. The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry 1996 Jan 30; 35: 1270–3

    Article  PubMed  CAS  Google Scholar 

  46. Hoechst Marion Roussel. Arava™ (leflunomide) prescribing information. Hoeschst Marion Roussel Incorporated, Kansas City, USA. Sep 1998

  47. Hoechst Marion Roussel. Arava — Pharmacokinetics. Hoechst Marion Roussel (Kansas City). 1998 (Data on file)

  48. Hoechst Marion Roussel. Arava — Drug interactions. Hoechst Marion Roussel (Kansas City). 1998 (Data on file)

  49. Silva HT, Shorthouse R, Morris RE. Single- and multiple-dose pharmacokinetics and pharmacodynamics of leflunomide’s active metabolite A77 1726 in normal Lewis rats. Transplant Proc 1996 Dec; 28: 3092–4

    PubMed  CAS  Google Scholar 

  50. Hoechst Marion Roussel. Arava — washout with cholestyramine and activated charcoal. Hoechst Marion Roussel (Kansas City). 1998 (Data on file)

  51. Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999; 42: 1322–8

    Article  PubMed  CAS  Google Scholar 

  52. Weber W, Harnisch L. Use of a population approach to the development of leflunomide: a new disease-modifying drug in the treatment of rheumatoid arthritis. Conference of the European Commission on European cooperation in the field of scientific and technical research; 1997 Feb 12–14; Geneva, Switzerland, 238–244

  53. Mladenovic V, Domljan Z, Rozman B, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis: results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995 Nov; 38: 1595–603

    Article  PubMed  CAS  Google Scholar 

  54. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Hoechst Marion Roussel (Bridgewater). Nov 2, 1999 (Data on file)

  55. Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med 1999; 159 (In press)

  56. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet 1999 Jan 23; 353: 259–66

    Article  PubMed  CAS  Google Scholar 

  57. Campion G, Löw-Friedrich I, Oed C, et al. Comparison of different dosing regimens of leflunomide in the treatment of active rheumatoid arthritis [abstract]. Scand J Rheumatol 1994 Suppl. 98: 140

    Google Scholar 

  58. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727–35

    Article  PubMed  CAS  Google Scholar 

  59. Smolen JS, Larsen A, Kalden JR, et al. Retardation of structural damage with leflunomide in rheumatoid arthritis assessed by Larsen methodology: 2-year results [abstr. no. 68]. 63rd Annual Scientific Meeting of the American College of Rheumatology; 1999 Nov 13–15; Boston, Massachusetts. Available from http://www.abstracts-on-line.com/scripts/abstracts/ACR/ACR.cfm.37125738 [Accessed 1999 Nov 14]

  60. Fries JF, Spitz P, Guy Kraines R, et al. Measurement of patient outcome in arthritis. Arthritis Rheum 1980; 23: 137–45

    Article  PubMed  CAS  Google Scholar 

  61. Ahern MJ, Chandran G. Category III symptom-modifying antirheumatic drugs: a comparative review. Clin Immunother 1995 Mar; 3: 196–217

    Google Scholar 

  62. Rains CP, Noble S, Faulds D. Sulfasalazine: a review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995 Jul; 50: 137–56

    Article  PubMed  CAS  Google Scholar 

  63. Kalden JR, Schattenkirchner M, Smolen JS, et al. Leflunomide vs sulfasalazine in rheumatoid arthritis: 24-month update of a randomised, double-blind study [abstr no. 1202]. 63rd Annual Scientific Meeting of the American College of Rheumatology 1999 Nov 13–15; Boston, Massachusetts; [1 page]. Available from http://www.abstracts-on-line.com/scripts/abstracts/ACR/ACR.cfm.37125738 [Accessed 1999 Sep 27]

  64. Emery P, Breedveld F, Lemmel EM. A phase III, randomized, double-blind study of leflunomide versus methotrexate in rheumatoid arthritis [abstract no. 399]. XIV European League Against Rheumatism Congress: Rheumatic diseases — from genes to therapy; 1999 Jun 6–11; Glasgow, Scotland, 103

  65. Strand V, Tugwell P, Bombardier C, et al. Function and health-related quality of life, results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Arthritis Rheum 1999; 42: 1870–8

    Article  PubMed  CAS  Google Scholar 

  66. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 1996 May; 39: 713–22

    Article  Google Scholar 

  67. Markham A, Faulds D. Methotrexate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in rheumatoid arthritis and other immunoregulatory disorders. Clin Immunother 1994 Mar; 1: 217–44

    Google Scholar 

  68. Pope RM. Rheumatoid arthritis: pathogenesis and early recognition. Am J Med 1996 Feb 26; 100 Suppl. 2A: 3S–9S

    Article  PubMed  CAS  Google Scholar 

  69. Sharp JT, Strand V, Leung H, et al. Treatment with leflunomide slows radiographic progression of RA: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999 (In press)

  70. Giovagnoni A, Valeri G, Burroni E, et al. Rheumatoid arthritis: follow-up and response to treatment. Eur J Radiol 1998; 27: S25–30

    Article  PubMed  Google Scholar 

  71. Larsen A, Emery P, Loew-Friedrich I, et al. Comparison of radiographic endpoints in rheumatoid arthritis patients treated with leflunomide or methotrexate [abstract no. 86]. XIV European League Against Rheumatism Congress: Rheumatic diseases — from genes to therapy; 1999 Jun 6–11; Glasgow, Scotland, 31

  72. O’Dell J, Rheumatoid Arthritis Investigational Network (RAINS). Combination DMARD therapy for rheumatoid arthritis: apparent universal acceptance [abstract no. 119]. Arthritis Rheum 1997; 40 Suppl.: S50

    Google Scholar 

  73. Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-agent therapy in early rheumatoid arthritis: a randomised trial. Lancet 1999; 353: 1568–73

    Article  PubMed  Google Scholar 

  74. Kremer JM. Methotrexate and leflunomide: biochemical basis for combination therapy in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999; 29: 14–26

    Article  PubMed  CAS  Google Scholar 

  75. Weaver A, Caldwell J, Olsen N, et al. Treatment of active rheumatoid arthritis with leflunomide compared to placebo or methotrexate [abstract no. 593]. Arthritis Rheum 1998 Sep; 41 Suppl.: S131

    Google Scholar 

  76. Georgescu L, Paget SA. Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate. Drug Saf 1999; 20: 475–87

    Article  PubMed  CAS  Google Scholar 

  77. Moreland LW, Fleischmann RM, Leflunomide RA Investigators Group, et al. Efficacy of leflunomide vs placebo vs methotrexate in early and late rheumatoid arthritis [abstract no. 733]. Arthritis Rheum 1998 Sep; 41 Suppl.: S155

    Article  Google Scholar 

  78. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996 May; 39: 723–31

    Article  Google Scholar 

  79. Davis M. Hepatic disorders. In: Davies DM, Ferner RE, de Glanville H, editors. Davies’s texbook of adverse drug reactions. 5th ed. London: Chapman & Hall Medical, 1998: 275–338

    Google Scholar 

  80. Callahan LF. The burden of rheumatoid arthritis: facts and figures. J Rheumatol 1998 Jul; 25 Suppl. 53: 8–12

    Google Scholar 

  81. Buckley CD. Treatment of rheumatoid arthritis. BMJ 1997 Jul 26; 315: 236–8

    Article  PubMed  CAS  Google Scholar 

  82. Arnett FC, Edworthy SM, Bloch DA, et al. The 1987 revised American Rheumatism Association criteria for classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–24

    Article  PubMed  CAS  Google Scholar 

  83. McQueen FM, Stewart N, Crabbe J, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months after symptom onset. Ann Rheum Dis 1998; 57: 350–6

    Article  PubMed  CAS  Google Scholar 

  84. Pincus T, Callahan LF. What is the natural history of rheumatoid arthritis? Rheum Dis Clin North Am 1993; 19: 123–51

    PubMed  CAS  Google Scholar 

  85. van der Heijde DMFM. Joint erosions and patients with early rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl. 2: 74–8

    PubMed  Google Scholar 

  86. Pincus T. Long term outcomes in rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl. 2: 59–73

    PubMed  Google Scholar 

  87. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis: a metaanalysis of published clinical trials. Arthritis Rheum 1992; 35: 1117–25

    Article  PubMed  CAS  Google Scholar 

  88. Østensen M. Optimisation of antirheumatic drug treatment in pregnancy. Clin Pharmacokinet 1994; 27: 486–503

    Article  Google Scholar 

  89. Wyeth Laboratories. Methotrexate sodium tablets. Prescribing information. ABPI compendium of data sheets and summaries of product characteristics 1998–99. Datapharm Publications Limited, London

  90. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253–9

    Article  PubMed  CAS  Google Scholar 

  91. Escalante Á, del Rincón I. Etanercept in rheumatoid arthritis [letter]. N Engl J Med 1999; 340: 2000

    Article  PubMed  CAS  Google Scholar 

  92. Arriola ER, Lee NP. Treatment advances in rheumatoid arthritis. West J Med 1999; 170: 278–81

    PubMed  CAS  Google Scholar 

  93. Jarvis B, Faulds D. Etanercept: a review of its use in rheumatoid arthritis. Drugs 1999; 57: 945–66

    Article  PubMed  CAS  Google Scholar 

  94. Fye KH. New treatments for rheumatoid arthritis: available and upcoming slow-acting antirheumatic drugs. Postgrad Med 1999; 106: 82–92

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Amitabh Prakash.

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Prakash, A., Jarvis, B. Leflunomide. Drugs 58, 1137–1164 (1999). https://doi.org/10.2165/00003495-199958060-00010

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