Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis.
Treatment with a chimeric mAb to TNF-alpha has been shown to suppress inflammation and improve patient well-being in rheumatoid arthritis (RA), but the mechanisms of action of such treatment have not been fully explored. Here we show that in vivo administration of anti-TNF-alpha Ab, using a longitudinal analysis, results in the rapid down-regulation of a spectrum of cytokines, cytokine inhibitors, and acute-phase proteins. Marked diurnal variation in the serum levels of some of these were detected. These results were consistent with the concept of a cytokine-dependent cytokine cascade, and the degree of clinical benefit noted after anti-TNF-alpha therapy is probably due to the reduction in many proinflammatory mediators apart from TNF-alpha, such as IL-6, which reached normal levels within 24 h. Serum levels of cytokine inhibitors such as soluble p75 and p55 TNFR were reduced as was IL-1 receptor antagonist. Reductions in acute-phase proteins occurred after serum IL-6 fell and included serum amyloid A, haptoglobin, and fibrinogen. The latter reduction could be of importance, as it is a risk factor for atherosclerosis, which is augmented in RA patients.
Department of Rheumatology, Charing Cross Hospital, London, United Kingdom.
P
P
Charles
M J
MJ
Elliott
D
D
Davis
A
A
Potter
J R
JR
Kalden
C
C
Antoni
F C
FC
Breedveld
J S
JS
Smolen
G
G
Eberl
K
K
deWoody
M
M
Feldmann
R N
RN
Maini
D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004311:Double-Blind Method; D006801:Humans; D000069285:Infliximab; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008137:Longitudinal Studies; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000097:blood; D012795:Sialoglycoproteins / Q000097:blood; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D016207:Cytokines; D000069285:Infliximab; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C507763:IL1RN protein, human