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Objective  A subset of patients with seropositive rheumatoid arthritis ( RA ) do not mount a C‐reactive protein ( CRP ) response during flares. We hypothesize that these patients are more likely to experience poor clinical care and less likely to respond to traditional therapy. This study questioned whether this presentation was associated with worse disease outcome and distinct immunological features.    Methods  Using Power Doppler ultrasound, 48  RA  patients with active synovitis were recruited; 30 had normal (n) CRP  (5 mg/L or less) and 18 had high (h) CRP  (more than 5 mg/L) levels. All had equivalent disease burden assessed by other clinical and laboratory parameters.    Results  Time to diagnosis and time to first disease‐modifying antirheumatic drug were significantly longer in  nCRP  compared with  hCRP  patients ( P  < 0.05). Significantly more  nCRP  patients needed escalation to biologics after 2‐year follow‐up ( P  = 0.01). The inflammatory milieu was also different between the two subgroups. Synergy between inflammatory cytokines observed in  hCRP  patients was lost in  nCRP  patients, and  nCRP  patients had significantly increased regulatory T‐cell (Treg) frequencies that correlated positively with predictors of poor disease outcome. Conversely,  hCRP  but not  nCRP  patients demonstrated a significant upregulation of alternative complement pathway factors that correlated negatively with Treg frequency.    Conclusion  Patients with  nCRP  during flares of  RA  had an altered immunological profile compared with  hCRP  patients and experienced diagnostic delays and responded less favorably to conventional treatment.

Characterization of a Subset of Patients With Rheumatoid Arthritis for Whom Current Management Strategies are Inadequate