Effects of interleukin 1 receptor antagonist alone and in combination with methotrexate in adjuvant arthritic rats.
OBJECTIVE
To determine the benefit of combination treatment with the interleukin 1 receptor antagonist (IL-1ra) and methotrexate (MTX) in adjuvant arthritic rats.


METHODS
Rats with adjuvant arthritis were treated by continuous sc infusion with IL-1ra (5 mg/kg/h). Effects of IL-1ra treatment alone were compared to treatment with daily oral MTX (0.048, 0.06, or 0.075 mg/kg) or MTX in combination with IL-1ra. Efficacy was monitored by sequential caliper measurement of ankle joints, final paw weights, and histologic evaluation with particular emphasis on bone lesions.


RESULTS
Treatment with IL-1ra alone resulted in 6% inhibition of paw swelling assessed by final paw weight. Treatment with MTX (0.075 mg/kg PO) gave 47% inhibition and the combination resulted in an 84% decrease in swelling. Histologic evaluation of ankle joints revealed 53% inhibition of bone resorption with IL-1ra alone, 58% inhibition with MTX alone, and 97% inhibition in combination treated rats. Lower doses of MTX in combination with IL-1ra also provided additive benefit on arthritis variables.


CONCLUSIONS
Combination therapy with IL-1ra and MTX results in additive or synergistic benefit, with excellent inhibition of all arthritis variables. These data support clinical investigation of the use of combination therapy of IL-1ra and MTX in patients with rheumatoid arthritis.
Bendele
A
A
Department of Pharmacology, Amgen Inc., Thousand Oaks, CA 91320-1799, USA.
Sennello
G
G
McAbee
T
T
Frazier
J
J
Chlipala
E
E
Rich
B
B
D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000097:blood; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005528:Foot / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D012795:Sialoglycoproteins / Q000008:administration & dosage* / Q000097:blood
D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D008727:Methotrexate