B cell targeted therapy for immunoglobulin G4-related disease

Abstract

Glucocorticoids are the first-line drug for the remission induction therapy of immunoglobulin (Ig) G4-related disease. Achieving drug-free remission using glucocorticoids alone is difficult, however, and many patients require maintenance therapy with glucocorticoids and immunosuppressants. Studies have recently found that the number of peripheral memory B cells and plasmablasts is increased in IgG4-related disease and have indicated the efficacy of rituximab, which, in remission induction therapy, rapidly reduces serum IgG4 levels and has the tapering effect of glucocorticoids. Rituximab has been shown to reduce the risk of relapse more than oral immunosuppressants such as azathioprine. However, maintaining drug-free remission is difficult with a single course of rituximab alone, and many cases require maintenance therapy with rituximab. This article outlines the potential of B-cell targeted therapy, focusing on the efficacy, and safety of rituximab for IgG4-related disease.

IgG4-Mediated Neurologic Autoimmunities

“…In IgG4-RD, the risk of relapse tended to be lower with rituximab maintenance, compared with 1 rituximab induction therapy with elevated serum IgG4 considered a risk factor for relapse. 1 , 3 , 50 The value of circulating IgG4 as a biomarker in IgG4-RD is however unclear because IgG4 alone can nonspecifically increase in chronic immune activation. 1 The IgG4 levels also seem irrelevant in IgG4-ND; in 39 patients with CIDP, including several with IgG4-nodal antibodies, the IgG4 concentration was normal (<1,350 mg/L, the limit for active IgG4-RD [Dalakas et al unpublished observations]).…”

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

“…The IgG4 antibodies arise after chronic antigenic exposure late in the immune response and, after undergoing several rounds of affinity maturation and somatic hypermutation, they exhibit very high affinity for their target antigen [5,11]. In contrast to IgG4-RD however which have a broad and heterogeneous multi-organ clinicopathology with tumefactive lesions and IgG4 + plasma cell infiltrates in multiple tissues [2][3][4], the IgG4-ND exhibit distinct signs of antigen-specific CNS or PNS neuro-autoimmunities characterized by neural cell-specific antibodies exerting pathogenic effects on their targeted antigens. Most importantly, in IgG4-ND, the antibodies do not cause an inflammatory-mediated tissue destruction as the IgG1-3 subclass of antibodies do, but inhibit cellular adhesion, block enzymatic activity, or disrupt protein-protein interactions affecting signal transduction pathways [1,5,11].…”

“…Most importantly, in IgG4-ND, the antibodies do not cause an inflammatory-mediated tissue destruction as the IgG1-3 subclass of antibodies do, but inhibit cellular adhesion, block enzymatic activity, or disrupt protein-protein interactions affecting signal transduction pathways [1,5,11]. This is also in contrast to the IgG4-RD where only a few of the IgG4 antibodies are potentially pathogenic, mostly the anti-M-type phospholipase A2 receptor 1 and thrombospondin type-1 in membranous nephropathy, the anti-desmoglein in pemphigus vulgaris, and the antimetalloprotease ADAMTS13 in thrombotic thrombocytopenic purpura [1][2][3][4][5]11]. The main IgG4-ND include [1] :…”

“…The IgG4 subclass of autoantibodies has been associated with a broad spectrum of more than 12, multisystemic or fibroinflammatory autoimmune disorders, referred to as IgG4-related diseases (IgG4-RD). These disorders, insidiously and sometimes subclinically, affect lacrimal and salivary glands, thyroid, lungs, bile ducts, kidneys, pancreas, aorta, retroperitoneum, and orbits in a form of orbital myositis [1][2][3][4][5]. They are generally poorly understood because only a few of them, like pemphigus vulgaris, membranous nephropathy, and thrombotic thrombocytopenic purpura, are characterized by disease and tissue-specific autoantibodies [1,5].…”

“…In contrast to their IgG1-3-associated counterparts, the IgG4-ND exhibit most of the times poor long-term response to IVIg and inadequate long-term response to steroids or plasmapheresis, but excellent response to anti-B cell therapies, like rituximab [1,4]. It has now become apparent that many of these patients clinically present similarly to their IgG1-3-associated identical syndromes and they are almost always treated with conventional immunotherapies of steroids, IVIG, plasmapheresis, and oral immunosuppressants until recognized in retrospect that they do not adequately respond, questioning not only the diagnosis but also the associated autoimmunity [1].…”