Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction.
OBJECTIVE
To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model.


METHODS
Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically.


RESULTS
Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL-1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra.


CONCLUSIONS
Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.
Zwerina
Jochen
J
University of Vienna, Vienna, Austria. georg.schett@akh-wien.ac.at
Hayer
Silvia
S
Tohidast-Akrad
Makiyeh
M
Bergmeister
Helga
H
Redlich
Kurt
K
Feige
Ulrich
U
Dunstan
Colin
C
Kollias
Giorgos
G
Steiner
Günter
G
Smolen
Josef
J
Schett
Georg
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000097:blood*; D002356:Cartilage / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000068800:Etanercept; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D000069285:Infliximab; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000473:pathology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D012795:Sialoglycoproteins / Q000494:pharmacology; D013585:Synovitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D002352:Carrier Proteins; D006023:Glycoproteins; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept