Biomarkers for IL-6 inhibition therapy

Abstract

IL-6 is one of the major pro-inflammatory cytokines involved in the regulation of local and systemic immune responses. IL-6, which is produced by various cells in inflammatory lesions and has various functions during the immune response, is deeply involved in the etiology of immune disorders such as rheumatoid arthritis（RA）. Accumulated evidence indicates that IL-6 is an important therapeutic target for various immune disorders. Since IL-6 plays a key role in the synthesis of the acute phase proteins such as CRP in hepatocytes, the administration of IL-6 inhibitors results in normalization of serum CRP levels in RA patients. In addition, IL-6 inhibitors suppress serum amyloid A（SAA）induction, and are expected to be used for the therapy of secondary amyloidosis. Since IL-6 promotes the antibody production in B lineage cells, its inhibition may lead to suppression of hypergammaglobulinemia and autoantibody production. In addition, since IL-6 is involved in the differentiation of Th17 and Tfh subsets, IL-6 inhibitors may improve the immunopathology by modulating the adoptive immune response. These pharmacological actions are unique to IL-6 inhibitors and probably explain the reason why IL-6 inhibitors are applied to a wide range of immune disorders. However, like other biologics, not all patients can benefit from IL-6 inhibitors. Possible biomarkers for predicting the effects of IL-6 inhibitors have been proposed so far, but there are currently no established markers. Another problem with the use of IL-6 inhibitors is that existing biomarkers such as CRP are normalized during the therapy, making it difficult to assess disease activity and detect complications such as infection. Leucinerich α2 glycoprotein（LRG）, newly identified by our group as an inflammatory biomarker, is useful for evaluation of inflammation that is difficult to evaluate by CRP. LRG may be applicable as an inflammatory biomarker during treatment with IL-6 inhibitors.