Correlation of a multi-cytokine panel with clinical disease activity in patients with rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder primarily affecting peripheral joints. Left untreated, chronic inflammation leads to cartilage and bone erosions, destroying the joint architecture and causing disability. Disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, and prednisone have been shown to significantly slow joint destruction and reduce or sometimes prevent disability. More recently, various biologic agents, usually in combination with one or more DMARDs, were shown to be even more effective than the DMARDs used alone. The most common biologic agents used in RA are those that target tumour necrosis factor-α (TNF-α), including infliximab (anti-TNF humanized mouse monoclonal antibody), etanercept (recombinant fusion protein containing 2 p75 TNF-R fused to the Fc portion of human IgG1), and adalimumab (recombinant human IgG1 anti-TNF monoclonal antibody).
There is considerable variation in disease activity in treated patients with RA. Strategies employed to assess this variation include identification of genetic factors [1], gene expression studies in peripheral blood cells [2] and synovial tissue [3], synovial cellularity and cytokine expression [4], and circulating levels and/or activity of cytokines [5]. Although all of these approaches have yielded some insights, they have limited use in everyday clinical practice because of the complex methodology involved in their measurements.
In addition, there are many ways in which one could attempt to measure disease activity in RA. Most of the studies mentioned above used simple measures such as joint counts, radiographic damage, or inflammatory markers, which may not capture all aspects of disease activity in RA. For this reason, tools that incorporate several aspects of disease activity, including joint counts, visual analogue scales, questionnaires and inflammatory markers, have been validated for use both in everyday practice and in clinical studies of RA. The five most commonly used tools for measuring disease activity in RA are the Health Assessment Questionnaire (HAQ) [6], standard 28-joint Disease Activity Score (DAS28) [7], DAS28 using C-reactive protein (DAS28-CRP) [8], Clinical Disease Activity Index (CDAI) [9], and Simple Disease Activity Index (SDAI) [10].
Rheumatoid arthritis is driven by a complex interaction of multiple cytokines, with TNF-α and IL-6 as central mediators. In this pilot study we examined plasma levels of an array of 12 cytokines and chemokines in patients with RA on different treatment regimens, including antil-TNF-α agents. We then attempted to correlate the levels of these cytokines with activity of RA as measured by the various standardized measures of disease activity mentioned above. Our aim was to identify patterns of cytokine expression in an attempt to identify potential biochemical markers of disease activity. We also compared expression of the studied cytokines between patients on conventional DMARDs and patients on the biologic agents.
Section snippets
Patient selection
This study was approved by the Ottawa Hospital Research Ethics Board. Rheumatoid arthritis patients treated with DMARDs (e.g. azathioprine, sulfasalazine, and methotrexate) and/or one of biologic agents (abatacept, adalimumab, anakinra, etanercept or infliximab) attending the Arthritis Centre at the Ottawa Hospital, Riverside campus between December 18, 2007 and January 15, 2008, were recruited. A single member of the study group (NM) performed the clinical assessments on all patients.
Demographics
57 patients were recruited. Cytokine analysis data was only available for 47 out of 57 patients, 35 of which were on biologic agents (with or without a DMARD), and 12 on DMARDs alone. Among these 47 patients, 1 patient did not have CRP measured and thus was excluded from the statistical tests involving CRP and DAS28-CRP, and 1 patient did not have ESR and CRP values measured and thus was excluded from analyses involving ESR, CRP, DAS28, and DAS28-CRP, as well as comparisons by EULAR classes
Discussion
We have demonstrated a significant and consistent correlation between plasma level of IL-6 and all studied measures of clinical disease. Importantly, such correlation was found not only for basic measures of disease activity, such as joint counts, global disease activity scores, and acute phase reactants (ESR and CRP), but also for 5 well-validated and widely used composite measures of disease activity (HAQ, DAS, DAS-CRP, CDAI, and SDAI). To our knowledge, the relationship between IL-6 and
Acknowledgment
This study was supported by a grant from the Ottawa Hospital Pathology and Laboratory Medicine Academic Enrichment Fund.
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