Background/Purpose:

An atypical subgroup of patients with seropositive rheumatoid arthritis (RA) was identified with active disease (confirmed by Power Doppler ultrasound (PDUS)) but normal levels of the acute phase protein C-reactive protein (CRP). We questioned whether this presentation was associated with altered response to treatment, risking worse disease outcome. Our objective was to investigate whether we could exploit the immunological and clinical phenotype of this patient subgroup to propose a more appropriate treatment algorithm.

Methods:

48 RA patients with active synovitis were recruited, defined by ≥1 joint with positive PDUS, 30 had normal (n)CRP (≤5mg/L) and 18 had high (h)CRP (>5mg/L) levels. Peripheral blood mononuclear cells (PBMC), serum and detailed clinical data were collected. 20 age- and sex-matched healthy donors were also analyzed. Multiparameter flow cytometry was used to perform in-depth PBMC immunophenotyping.

Results:

Pro-inflammatory cytokines IL-6, IL-1β, and TNF-α contribute to RA pathogenesis and are key in triggering CRP production. Despite normal measured CRP levels, all these cytokines were significantly elevated in both patient groups compared to HC (p=<0.001). CRP, SAA and IL-6 all correlated positively with pro-inflammatory cytokines in hCRP patients but not nCRP patients. Conversely, pro-inflammatory cytokine levels positively correlated with markers of disease severity in nCRP patients only. Interestingly, nCRP patients were able to mount a CRP response to infection. Thus the results point to an altered disease mechanism in nCRP compared to hCRP patients. In-depth phenotyping identified unique immune signatures in both patient groups compared to HCs and when compared to each other. Notably, nCRP patients had a significant increase in naïve regulatory T cells (Tregs) and in CD161⁺ Tregs (known to correlate negatively with CRP levels and have increased suppressive capacity) compared to hCRP patients. Furthermore, Treg frequencies correlated significantly with markers of disease progression and serum lipids in the nCRP but not the hCRP patients suggesting that defects in Treg function and potentially lipid metabolism could play a role in disease pathogenesis in nCRP patients.

The immunological differences between the two groups were associated with an altered response to treatment. Disease activity was assessed ≥1 year post recruitment. In nCRP patients 50% still had active disease compared to only 10% in hCRP patients. Also, 50% of nCRP patients had treatment escalated to a biological (b)DMARD compared to only 10% of hCRP patients.

Conclusion:

This study stratifies distinct patient subgroups using detailed, clinical, immunophenotyping and proteomic signatures. We have identified altered immunopathological mechanisms in nCRP patients which could translate to improved patient-specific therapies. Provisional analysis suggested that nCRP patients were less responsive to treatment with conventional DMARDS, needing escalation to biologics earlier in their disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/patients-with-active-rheumatoid-arthritis-but-normal-levels-of-acute-phase-proteins-have-altered-regulatory-t-cell-function-and-rapidly-progress-to-biological-therapies/