Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients.
OBJECTIVE
Leflunomide is a novel immunomodulating drug that has recently been approved as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). The aim of this study was to determine the relationship between the clinical effects of leflunomide and neutrophil migration.


METHODS
The effects of leflunomide and methotrexate on neutrophil chemotaxis were studied in 15 RA patients who participated in a prospective, randomized, double-blind clinical trial. When possible, neutrophil numbers were counted in synovial fluid (SF) samples at baseline and after 14 days, 4 months, and 1 year of treatment. The chemotactic properties of peripheral blood neutrophils from RA patients treated with either leflunomide or methotrexate were studied by the Boyden chamber technique, using the activators formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neutrophils from 7 healthy control subjects were also investigated.


RESULTS
Both therapy groups exhibited clinical improvement, including rapid reductions in SF neutrophil counts and reduced joint swelling and tenderness. On day 14, 3 of 7 patients who received leflunomide showed no detectable effusions. There was a significant effect on neutrophil chemotaxis (P < 0.001), which was similar for leflunomide and methotrexate. The direct effects on the neutrophils diminished over time. Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis.


CONCLUSIONS
Leflunomide treatment is beneficial in RA patients. Different mechanisms are operative in various phases of treatment, leading to decreased recruitment of inflammatory cells in the joints.
Kraan
M C
MC
Department of Clinical Immunology and Rheumatology, Academic Medical Center, Amsterdam, The Netherlands.
de Koster
B M
BM
Elferink
J G
JG
Post
W J
WJ
Breedveld
F C
FC
Tak
P P
PP
D000368:Aged; D000814:Aniline Compounds / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003437:Crotonates; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000494:pharmacology; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D009570:Nitriles; D011446:Prospective Studies; D014052:Toluidines
D000814:Aniline Compounds; D018501:Antirheumatic Agents; D003437:Crotonates; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D016209:Interleukin-8; D007555:Isoxazoles; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000077339:Leflunomide; D008727:Methotrexate