Background/Purpose:

An atypical subgroup of patients with seropositive rheumatoid arthritis (RA) has been identified with confirmed synovitis but normal levels of the acute phase protein C-reactive protein (CRP), often considered an accurate marker of disease activity. We questioned whether this presentation was associated with delayed diagnosis and/or relative under treatment, risking worse disease outcome, and whether there were distinct immunological features.

Methods: 48 RA patients with active synovitis confirmed on Power Doppler ultrasound were recruited; 30 had normal (n)CRP (≤5mg/L) and 18 had high (h)CRP (>5mg/L) levels. In all other measures, disease activity was equivalent between the two groups.

Results: Time to diagnosis and time to first disease modifying anti-rheumatic drug (DMARD), were both significantly longer in the nCRP cohort. One and two year follow-up revealed that nCRP patients needed escalation to biologics significantly earlier in their disease. Serum Interleukin (IL)-6, IL-1β, and tumour necrosis factor (TNF)-α, were appropriately elevated in both patient groups compared to healthy donors (HCs), but while IL-6 expression was positively correlated with other pro-inflammatory cytokines and acute phase reactants in hCRP patients, this synergy was lost in nCRP patients. Moreover, nCRP patients had an anti-inflammatory immune cell phenotype with significantly increased regulatory T-cell (Treg) frequencies and elevated Treg IL-10 production compared to hCRP patients. Proteomics identified differential expression of complement components in serum from hCRP compared to nCRP patients; specifically a significant upregulation of alternative complement pathway factors (eg Factors I, H and B) was seen in hCRP patients and an upregulation of kallistatin, an inhibitor of the alternative pathway in nCRP patients. Complement activation measured by serum C3 cleavage product was similarly elevated in both patient groups compared to HCs (P<0.01 HC vs nCRP, p<0.05 HC vs hCRP). However, a strong positive correlation was observed between C3 cleavage product and levels of anti-CCP antibodies (R²=0.53, p<0.05) in nCRP patients but not hCRP patients. Finally, analysis of complement activation pathways revealed that nCRP patients preferentially activated complement via Classical and Mannose Lectin pathways compared to hCRP patients suggesting that nCRP and hCRP patients have an altered disease pathogenesis.

Conclusion: Patients with normal CRP during flares of RA had an altered immunological profile and altered activation of complement pathways compared to hCRP patients, experienced diagnostic delays and appeared to respond less well to conventional treatment.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/patients-with-seropositive-rheumatoid-arthritis-who-do-not-mount-a-crp-response-when-they-have-synovitis-are-immunologically-distinct-and-are-poorly-served-by-current-management-strategies/