In a substantial proportion of patients with rheumatoid arthritis (RA), treatment with the DMARD leflunomide fails to halt the progression of bone erosion, despite inhibiting inflammation. A new study reveals that C-reactive protein (CRP)–hypoxia inducible factor 1α (HIF1α) signalling attenuates the response to leflunomide, and suggests that co-administration of a HIF1α inhibitor could improve the therapeutic response to leflunomide in selected patients.

Credit: Springer Nature Limited

“We performed binary logistic regression analysis to determine the relationships between the limited leflunomide response and commonly used clinical factors,” says corresponding author Ge Zhang. “Surprisingly, we revealed that serum CRP concentrations showed predictive value for classifying the patients with RA with limited response to leflunomide.” In patients with RA and high serum concentrations of CRP (CRP-high), leflunomide attenuated bone erosion to a lesser extent than in CRP-low patients; notably, leflunomide had similar immunomodulatory effects in both groups. Rats with collagen-induced arthritis (CIA) had similarly differential responsiveness to leflunomide treatment on the basis of CRP concentrations.

Further experiments revealed that in CRP-low rats, leflunomide induces the interaction of aryl hydrocarbon receptor (AHR) with AHR nuclear transloclator (ARNT) to inhibit hepatic CRP expression and thus attenuate bone erosion. In CRP-high rats, however, CRP upregulates expression of HIF1α, which competes with AHR for ARNT binding and interferes with leflunomide–AHR–CRP signalling, ultimately limiting the response to leflunomide.

Knockdown of HIF1α in vitro and hepatocyte-specific deletion of HIF1α in mice with CIA improved leflunomide–AHR–CRP signalling and, in the mice, inhibited bone erosion. Moreover, combined treatment with leflunomide and acriflavine, an FDA-approved HIF1α inhibitor, prevented bone loss in CRP-high rats with CIA.

combined treatment with leflunomide and acriflavine, an FDA-approved HIF1α inhibitor, prevented bone loss

Together, the results suggest that CRP could have clinical value for prediction of response to leflunomide treatment, and that the combination of leflunomide and acriflavine could be used as precision medicine for CRP-high patients with RA.