Anti-interleukin-1 and anti-tumor necrosis factor-alpha synergistically inhibit adjuvant arthritis in Lewis rats.
Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) play dominant roles in mediating the progression of many inflammatory joint diseases, including rheumatoid arthritis in humans, collagen-induced arthritis in mice and rats, and adjuvant arthritis in rats. Blockade of either cytokine partially controls these diseases. The present study investigated the value of combination anti-cytokine therapy in arthritis: the efficacy of IL-1 receptor antagonist (IL-1ra) and 30 kDa polyethylene glycol (PEG)-conjugated soluble TNF receptor type I (PEG sTNF-RI) given together was assessed in Lewis rats with adjuvant arthritis. Administration of either IL-1ra or PEG sTNF-RI partially alleviated joint inflammation, loss of bone mineral density, and loss of body weight. In contrast, combination of these anti-cytokine treatments exhibited a synergistic capacity to inhibit these changes, even when combining doses of IL-1ra and PEG sTNF-RI that did not affect lesion severity when used alone. Statistical analysis of these adjuvant arthritis data using the isobologram method proved that IL-1ra and PEG sTNF-RI were clearly synergistic in inhibiting inflammation, loss of bone mineral density, loss of body weight, and histopathologic parameters of inflammation and joint destruction. These results suggest that treating autoimmune arthritic diseases with combinations of anti-IL-1 and anti-TNF molecules will achieve superior efficacy compared to the use of a single class of anti-cytokine agent and may allow for dose reductions that could prove useful in minimizing potential side effects.
Feige
U
U
Department of Pharmacology/Pathology, Amgen, Thousand Oaks, California 91320-1789, USA. ufeige@amgen.com
Hu
Y L
YL
Gasser
J
J
Campagnuolo
G
G
Munyakazi
L
L
Bolon
B
B
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000473:pathology / Q000517:prevention & control*; D015519:Bone Density; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008297:Male; D011092:Polyethylene Glycols; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins / Q000627:therapeutic use*; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D015431:Weight Loss
D018501:Antirheumatic Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D011092:Polyethylene Glycols