Treatment of IgG4-related disease : Current and future approaches

Abstract

IgG4-related disease (IgG4-RD) is capable of causing great morbidity and even mortality if the condition remains undiagnosed or poorly treated, yet is typically a treatment-responsive disorder. Glucocorticoids have not been studied rigorously and practices with regard to dosing and duration of treatment remain largely empiric. In addition, IgG4-RD patients are often particularly susceptible to and intolerant of the deleterious effects of glucocorticoid therapy. B cell depletion with anti-CD20 monoclonal antibodies appears to be a rapid, effective means of obtaining disease control and limiting patients' glucocorticoid exposure, but this option is frequently not available. Other therapies targeting the B cell lineage may also be efficacious, and one is under study. The means by which depletion or inhibition of B cells and their progeny ameliorate IgG4-RD is coming into focus now through careful mechanistic studies of samples from treated patients. The mechanistic understanding of IgG4-RD will bring an array of specific targets for therapeutic intervention. Plasmablast-directed therapy with a CD19 monoclonal antibody is currently in clinical trials. CD4 + cytotoxic T lymphocytes and fibrosis, both observed nearly universally in the tissue of IgG4-RD patients, present two unexploited vulnerabilities in controlling and even reversing the effects of the disease. Further development of such therapies is a major goal of the next few years.

Keywords: Adverse effects; Antirheumatic agents; B-cells; Glucocorticoids; Monoclonal antibodies.

Figure 1. Current model of the immunologic mechanism of IgG4-RD

1.) Antigen presentation, activation of self-antigen detecting naïve T cell and differentiation into follicular helper T cells and CD4 cytotoxic T lymphocytes. 2.) T-B collaboration as follicular helper T cells drive class switching, somatic hypermutation and plasmablast differentiation of activated, self-antigen detecting B cells. 3.) CD4 CTLs and plasmablasts circulate to the site of inflammation. 4.) T-B collaboration in which activated plasmablasts present antigen to CD4 CTLs and drive further clonal expansion. 5.) Activated CD4 CTLs secrete pro-fibrotic cytokines (IL-1β, TGF-β1, IFN-γ) stimulating myofibroblasts to generate storiform fibrosis and cytotoxic molecules (granzyme, perforin) causing tissue damage.