Background In rheumatoid arthritis (RA) immune activation and leukocyte migration to the joints precede clinical onset of disease. Early inhibition of inflammation is the main aim of treat-to-target strategy, but the mechanisms and time course for restoration of the immune system remains poorly understood. The family of CD18 integrins is central in the inflammatory response by allowing leukocytes to bind ICAM-1 and migrate to inflammatory foci. We have demonstrated a soluble form of CD18 (sCD18), which is shed to the systemic circulation by monocytes and increased following stimulation with TNFα. sCD18 competes with the cell-expressed receptors for binding to ICAM-1 and thus may function by limiting leukocyte adhesion to ICAM-1.(1) Recently, we found that plasma levels of sCD18 are decreased because of binding to inflammation induced ICAM-1 and associate inversely with disease activity in chronic spondyloarthritis.(2)
Objectives To characterize the profile and regulation of plasma sCD18 levels in patients with early rheumatoid arthritis before and during a treat-to-target strategy (the OPERA regimen).
Methods The level of sCD18 in plasma was analyzed with a time-resolved immunoflourometric assay (TRIFMA) in a study population of 152 patients with early treatment naïve RA (the OPERA cohort) at baseline and after 3, 6, and 12 months of treatment with methotrexate + placebo (PLA) or methotrexate + adalimumab (ADA) and matched healthy controls (HC). In vitro, synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) from 9 RA patients were cultured with or without adalimumab (5μg/ml) for 48 hours.
Results Plasma levels of sCD18 were decreased in early RA patients at baseline (median=958mU/ml, IQR=766-1243mU/ml) compared with HC (median=1001mU/ml, IQR=872-1355mU/ml) (P<0.05). The sCD18 plasma levels further decreased after 3 months of treatment (median=858.9mU/ml, IQR=729-1076mU/ml) compared with baseline (P<0.05). Only after 12 months of treatment (median=1018mU/ml, IQR=830-1346mU/ml) the levels were similar to HC (P=0.6). RA patients with an ACR70 response or EULAR DAS response after 3 months of treatment had a greater increase in sCD18 plasma levels from baseline to 12 months (both P<0.05). There was no significant difference in these changes between patients treated with PLA or ADA. In vitro, both supernatants from RA SFMC and RA PBMC cultures had decreased levels of sCD18 after incubation with adalimumab (P<0.05 and P<0.005 respectively).
Conclusions The decreased plasma levels of sCD18 could be part of the deregulated immune system in early RA. Interestingly, sCD18 exhibited a biphasic course during a treat-to-target strategy with an initial decline followed by a gradual increase to HC levels. In vitro, adalimumab decreased the CD18 shedding explaining the initial decrease in sCD18 plasma levels. The late increase found especially in the patients with an early ACR70 response or EULAR DAS response could reflect latency in restoration of the normal immune system, pointing to sCD18 as a marker for such restoration.
Gjelstrup LC et al., J. Immunol., 2010 Oct.
Kragstrup TW et al., Arthritis Res Ther, 2014 Jan (accepted).
Disclosure of Interest : None declared
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