Differential efficacy of TNF inhibitors with or without the immunoglobulin fragment crystallizable (Fc) portion in rheumatoid arthritis: the ANSWER cohort study

Rheumatol Int. 2022 Jul;42(7):1227-1234. doi: 10.1007/s00296-021-05086-w. Epub 2022 Mar 10.


Rheumatoid factor (RF) binds to the fragment crystallizable (Fc) portion of immunoglobulin. It could bind to the Fc portion of anti-TNF inhibitors (TNFi) and attenuate the clinical efficacy. We tried to determine whether the therapeutic efficacy of TNFi with Fc might be lower than that of TNFi without Fc in rheumatoid arthritis (RA) patients with high titres of RF. The Kansai Consortium for Well-being of Rheumatic Disease Patients (ANSWER) cohort is an observational multi-center registry of patients with RA in the Kansai district of Japan. RA patients treated with TNFi were included and divided into two groups based on the structural characteristics between TNFi with Fc (infliximab, adalimumab, golimumab, and etanercept) and TNFi without Fc (certolizumab pegol). Patients were classified into 4 groups according to RF titre quartiles. The sequential disease activity score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR) was compared by Mann-Whitney U test between TNFi with and without Fc in each RF titre group. Multiple linear regression analysis was used to analyze the effect of TNFi without Fc for the change of DAS28-ESR adjusted after potential confounders. A total of 705 RA patients were classified into four groups (RF1; RF 0-15.0 IU/mL, RF2; 15.0-55.0, RF3; 55.0-166, RF4; 166-7555). In RF4, RA patients treated with TNFi without Fc had a significantly lower DAS28-ESR than those treated with TNFi with Fc [3.2 (2.3-4.2) vs. 2.7 (2.0-3.0)] after 12 months. This effect of TNFi without Fc for the change of DAS28-ESR after 12 months treatment retained in multivariate analysis in RF4. TNFi without Fc may be more efficacious than TNFi with Fc in RA patients with high RF titres.

Keywords: Arthritis, Rheumatoid; Rheumatoid factor; Tumor necrosis factor inhibitors.

MeSH terms

  • Adalimumab / therapeutic use
  • Antirheumatic Agents* / therapeutic use
  • Arthritis, Rheumatoid* / diagnosis
  • Arthritis, Rheumatoid* / drug therapy
  • Cohort Studies
  • Etanercept / therapeutic use
  • Humans
  • Infliximab / therapeutic use
  • Rheumatoid Factor
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha


  • Antirheumatic Agents
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha
  • Rheumatoid Factor
  • Infliximab
  • Adalimumab
  • Etanercept