Inhibition of tumor necrosis factor-alpha (TNF-alpha) in patients with early rheumatoid arthritis results in acute changes of bone modulators

Objective: Dicckopf-1 (Dkk-1) is a potent inhibitor of the Wnt canonical pathway. In rheumatoid arthritis (RA), Dkk-1 is upregulated by tumor necrosis factor-alpha (TNF). Certolizumab pegol (CMZ) is a biologic TNF-inhibitor (TNFi) effective in RA and slows radiographic progression. Data on the immediate effects (<= 1-8 weeks) of TNFi on Wnt modulators are lacking. This study investigated the acute influence of TNFi treatment on Wnt modulators (Dkk-1 and sclerostin) and bone turnover markers (BTM), including intact N-terminal propeptide of collagen type I (PINP) and C-terminal telopeptide of type I collagen (CTX-I). Methods: This longitudinal, uncontrolled study involved female RA patients with inadequate response to conventional methotrexate who underwent treatment with CMZ. ESR, Dkk-1, sclerostin, BTM, parathyroid hormone (PTH), and 250H-vitamin D levels were evaluated at baseline, week 1, week 4, and week 8. Radiographs of the hands and feet were obtained at baseline and the total and erosion scores were assessed using the Simple Erosion Narrowing Score method (SENS). Results: Seventeen patients were enrolled. Dkk-1 and CTX-I significantly decreased after one week of treatment with CMZ (-49.1 +/- 17.1% and -25.0 +/- 20.6%, respectively, p < 0.01), whereas PINP increased (+ 43.2 +/- 31.5%, p < 0.01). These changes persisted at week 4 and 8. Conclusions: Our study showed that TNF-alpha inhibition with CMZ promptly results in a rapid decline of serum Dkk-1 levels, alongside decreased bone resorption and increased bone formation.