Background/Purpose: Inflammation and immune dysregulation appear to significantly contribute to increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The complement system is a key component of the innate immune system, and recent research suggests that it might be involved in pathophysiology of CVD in the general population. However, information regarding complement activation in response to treatment and its importance in the development of premature CVD in RA is limited.

We will examine effects of methotrexate (MTX) and tumor necrosis factor inhibitors (anti-TNF) on complement activation using soluble C5b-9 (sC5b-9) levels in RA; and assess associations between sC5b-9 levels and established inflammatory biomarkers.

Methods: From the observational PSARA study, we assessed 64 RA patients starting with MTX monotherapy (n=34) or anti-TNF with MTX co-medication (n=30) due to active disease. The median age was 57 years, median RA duration was 5.5 years, and 73% were women. All patients starting with anti-TNF had previously been unsuccessfully treated with MTX. ELISA was used to measure sC5b-9 complexes in EDTA plasma immediately prepared and stored at minus 80⁰C. The patients were examined at baseline and after 6 weeks and 6 months of treatment.

Results: At baseline, the median sC5b-9 level was 1.10 CAU/ml [IQR 0.70], and 57 (89%) patients had sC5b-9 above the upper limit of the estimated reference range (< 0.7). sC5b-9 levels were significantly lower at 6-week (median 0.85 CAU/ml [IQR 0.55]) and 6-month (median 0.80 CAU/ml [IQR 0.58]) visits compared to baseline (p< 0.0005 and p=0.014, respectively). There were no significant differences in sC5b-9 levels between patients treated with MTX monotherapy and those treated with MTX combined with anti-TNF treatment from baseline to 6 weeks (p=0.689) and from baseline to 6 months (p=0.901). The changes in sC5b-9 from baseline to 6 weeks and from baseline to 6 months positively correlated with changes in erythrocyte sedimentation rate (ESR; rs= 0.364, p=0.003 and rs= 0.372; p=0.002, respectively), and C-reactive protein (CRP; rs=0.411; p=0.001 and rs= 0.348; p=0.005, respectively). Similarly, baseline sC5b-9 levels were significantly related to baseline ESR and CRP levels.

Conclusion: Patients with active RA had elevated sC5b-9, indicating increased complement activation. sC5b-9 decreased with antirheumatic treatment during the 6-month treatment period. There were no differences between MTX monotherapy and anti-TNF regimens. Further studies are warranted to determine if the well-known cardioprotective effects of antirheumatic drugs might be partly due to their ameliorating actions on complement activation, and whether the complement system might be a target for therapy in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/antirheumatic-therapy-is-associated-with-reduced-complement-activation-in-rheumatoid-arthritis/