Haemostatic changes and bleeding with anti-IL-6 directed therapy in autoimmune diseases

Anti-IL-6 directed therapy, especially tocilizumab (TCZ), is widely used for the treatment of autoimmune diseases such as rheumatoid arthritis, giant cell arteritis and systemic juvenile idiopathic arthritis. Next to being a master regulator of inflammation, IL-6 also is an important regulator of haemostasis. Although generally well tolerated, increasing clinical experience has associated TCZ treatment with rare, yet clinically significant, bleeding complications. These complications reflect disruption of IL-6-regulated hepatic fibrinogen synthesis, thrombopoiesis and possibly FXIII expression and local wound healing, although the precise mechanisms remain incompletely defined. The purpose of this narrative review is to detail the current knowledge of haemostatic effects and bleeding complications associated with anti-IL-6 therapeutics in autoimmune diseases. This review encompasses delineating the incidence, clinical characteristics and severity of haemostatic disruptions, discussing the proposed underlying mechanisms and providing a summary of possible management strategies. Bleeding can present across a spectrum, from subtle bruising or gingival bleeding to severe haematomas, and possibly diffuse intravascular coagulation. Routine coagulation parameters such as prothrombin time and activated partial thromboplastin time are frequently normal, masking significant hypofibrinogenaemia or FXIII deficiency. Recent cohort studies demonstrate that hypofibrinogenaemia is common, occurring in more than half of treated patients in some series, although often without overt bleeding. By contrast, acquired FXIII deficiency is rare. In light of the expanding use of anti-IL-6 therapeutics, this review underscores the importance of early recognition of bleeding complications, targeted laboratory monitoring and individualised perioperative and haemostatic management.