Effects of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) alone and in combination with methotrexate in adjuvant arthritic rats.
OBJECTIVE
To determine the potential combination benefit of treatment with PEG sTNF-RI and methotrexate in adjuvant arthritic rats.


METHODS
Lewis rats with adjuvant arthritis were treated by sc injections of either 3.0 or 0.3 mg/kg PEG sTNF-RI on days 9, 11, and 13 of adjuvant arthritis. The effects of PEG sTNF-RI treatment alone were compared to treatment with daily oral methotrexate (0.075, 0.06 or 0.045 mg/kg) or methotrexate in combination with PEG sTNF-RI. Efficacy was monitored by volume measurement of ankle joints, final paw weights and histologic evaluation with particular emphasis on bone lesions.


RESULTS
Treatment with 3.0 or 0.3 mg/kg PEG sTNF-RI alone resulted in 52% or 28% inhibition, respectively, of paw swelling as assessed by final paw weight. Treatment with methotrexate at either 0.075, 0.06, or 0.045 mg/kg gave 84%, 51% or 18% inhibition and combination treatment resulted in additive inhibitory effects. Histologic evaluation of ankle joints demonstrated 68% or 25% inhibition of bone resorption with PEG sTNF-RI alone at 3.0 or 0.3 mg/kg. Treatment with 0.075, 0.06 or 0.045 mg/kg methotrexate resulted in 98%, 76% or 40% inhibition of bone resorption. Additive benefit was best seen with the lower doses of methotrexate.


CONCLUSIONS
Combination therapy with PEG sTNF-RI and methotrexate results in additive benefit, with the final result being excellent inhibition of all arthritis parameters. Data from these studies supports the clinical investigation of the use of combination therapy of PEG sTNF-RI and methotrexate in rheumatoid arthritis patients.
Bendele
A M
AM
Amgen, Inc., Thousand Oaks, California, USA.
McComb
J
J
Gould
T
T
Frazier
J
J
Chlipala
E
E
Seely
J
J
Kieft
G
G
Edwards
C K
CK
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001835:Body Weight; D004359:Drug Therapy, Combination; D007279:Injections, Subcutaneous; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013163:Splenomegaly; D013643:Tarsus, Animal / Q000473:pathology; D053319:Tumor Necrosis Factor Decoy Receptors
D018501:Antirheumatic Agents; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; C069521:recombinant human tumor necrosis factor-binding protein-1; D011092:Polyethylene Glycols; D008727:Methotrexate