Abstract: A Distinct Multicytokine Profile Is Associated with Anti-Cyclical Citrullinated Peptide Antibodies in Patients with Early Untreated Inflammatory Arthritis

A Distinct Multicytokine Profile Is Associated with Anti-Cyclical Citrullinated Peptide Antibodies in Patients with Early Untreated Inflammatory Arthritis

CAROL A. HITCHON, PHILIP ALEX, LAWRENCE B. ERDILE, MARK B. FRANK, IGOR DOZMOROV, YUHONG TANG, KENG WONG, MICHAEL CENTOLA, and HANI S. EL-GABALAWY

ABSTRACT.

Objective. Early inflammatory arthritis is clinically heterogenous and biologically-based indicators are needed to distinguish severe from self-limited disease. Anti-cyclical citrullinated peptides (CCP) have been identified as potential prognostic markers in early arthritis cohorts. Since cytokine networks are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, a panel of pro- and antiinflammatory cytokines was measured to identify biologically-based subsets of early arthritis, relating cytokine profiles to clinical measures and to the presence of RA-associated autoantibodies.

Methods. Plasma concentrations of cytokines [interleukin 1ß (IL-1ß), IL-2, IL-4, IL-5, IL-6, IL-7, CXCL8 (IL-8), IL-10, IL-12p70, IL-13, IL-17, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-g (IFN-g), CCL2 (monocyte chemoattractant protein-1, MCP-1), CCL4 (MIP-1ß), and tumor necrosis factor-a (TNF-a)] were measured in patients with early, untreated inflammatory arthritis [symptom duration ≤ 12 months; ≥ 1 swollen joint; RA, n = 41; undifferentiated arthritis (UA), n = 23]. Cytokine expression patterns were determined using cluster analysis.

Results. Both pro- and antiinflammatory cytokines were elevated in patients over controls (n = 21). RA clustered into subgroups based solely on cytokine profiles. The "mild" RA subgroup (n = 23) had higher CCL4 (MIP-1ß), CXCL8 (IL-8), IL-2, IL-12, IL-17, IL-5, and IL-10 levels, lower IL-6, IFN-g, GM-CSF, and IL-4 levels, less CCP positivity (52% vs 82%; p < 0.05), and lower CCP titers [71 (78) vs 153 (94); p < 0.01], but similar erythrocyte sedimentation rate, C-reactive protein, and joint counts compared to the "severe" RA groups. CCL4 (MIP-1ß), IL-13, IL-12, TNF-a, and IL-4 best distinguished the groups. Combining UA with RA samples preserved cytokine subgroups and strengthened the autoantibody associations. Fewer UA patients in the "mild" cluster (n = 16) were RF-positive (24% vs 100%; p < 0.002) or CCP-positive (24% vs 66%; p < 0.08) compared to the "severe" group.

Conclusion. Early untreated inflammatory arthritis can be categorized into distinct subgroups based on cytokine profiles. These subgroups are associated with CCP and RF autoantibodies. Integration of cytokine profiles with autoantibody status may assist prognostication and treatment decisions in these patients. (J Rheumatol 2004;31:2336-46)

Key Indexing Terms:

CYTOKINES
CHEMOKINES
RHEUMATOID ARTHRITIS
ARTHRITIS
CITRULLINE
AUTOANTIBODIES

From the Arthritis Centre, University of Manitoba, Winnipeg, Manitoba, Canada; and the Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

Supported by the Manitoba Medical Services Foundation, the Canadian Arthritis Network, the US National Institutes of Health, grant numbers P20 RR15577 and P20 RR16478, and the Fund for Arthritis and Inflammatory Research.

C.A. Hitchon, MD, FRCPC, Assistant Professor, Arthritis Centre, University of Manitoba; P. Alex, MD, PhD, Graduate Student, Oklahoma Medical Research Foundation; L.B. Erdile, PhD, Arthritis Centre, University of Manitoba; M.B. Frank, PhD, Research Assistant Member; I. Dozmorov, PhD, Associate Member; Y. Tang, PhD, Senior Research Scientist, Oklahoma Medical Research Foundation; K. Wong, BSc, Arthritis Centre, University of Manitoba; M. Centola, PhD, Assistant Member, Associate Professor, Oklahoma Medical Research Foundation; H.S. El-Gabalawy, MD, FRCPC, Professor, Arthritis Centre, University of Manitoba.

Address reprint requests to Dr. C.A. Hitchon, Arthritis Centre, University of Manitoba, RR149, 800 Sherbrook Street, Winnipeg, Manitoba R3A 1M4, Canada.

Submitted March 24, 2004; revision accepted June 28, 2004.