Tocilizumab induced acquired factor XIII deficiency in patients with rheumatoid arthritis

Abstract

Factor XIII is one of the twelve coagulation factors and also known as a fibrin-stabilizing factor. In 2012, we encountered a male RA patient with hemorrhagic factor XIII deficiency who had been treated with tocilizumab for two years. There are few reports regarding the relationship between tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R)) and factor XIII. We measured the factor XIII activity levels in the plasma of 40 RA patients (10 patients treated without biologics, 30 patients treated with biologics (15 patients treated with necrosis factor inhibitors and 15 patients treated with tocilizumab)) and 19 healthy controls. Consequently, the tocilizumab group exhibited lower levels than the other three groups according to the Steel-Dwass test (P<0.01). Furthermore, we compared the plasma factor XIII activity levels and the plasma factor XIII concentrations in the RA patients treated with biologics. Pearson's correlation test was used to assess the relationship between the factor XIII activity levels and the plasma factor XIII concentrations (r=0.449, P=0.019). According to the multiple regression analysis, the treatment with tocilizumab is an independent risk factor for plasma factor XIII reduction in RA patients. In conclusion, RA patients treated with tocilizumab, an IL-6R blocker, are at risk of developing acquired factor XIII deficiency. The mechanisms underlying the reduced factor XIII activity observed in RA patients treated with tocilizumab may result from the quantitative reduction in the plasma. These data imply that IL-6 plays an important role in maintaining the factor XIII activity level.

Figure 1. Pelvic computed tomography of the RA patient with factor XIII deficiency.

The white arrow indicates the intra-pelvic hemorrhage. (a) Transverse plane and (b) coronal plane.

Figure 2. Comparison of the plasma factor XIII activity levels in the healthy controls and RA patients.

** the Steel-Dwass method (P<0.01). MTX, methotrexate; TNFi, tumor necrosis factor inhibitors; TCZ, tocilizumab.

Figure 3. Plasma factor XIII quantitative concentrations in the RA patients treated with biologics.

(a) The relationship between the factor XIII activity levels and plasma concentrations was assessed according to Pearson's correlation coefficient. (r = 0.449, P = 0.019). (b) Comparison of the plasma factor XIII concentrations between the RA patients treated with TNFi and those treated with tocilizumab. * Student's t-test (P<0.05). TNFi, tumor necrosis factor inhibitors; TCZ, tocilizumab.