Rituximab for IgG4-related disease: a prospective, open-label trial

Carruthers, Mollie; Topazian, Mark D.; Khosroshahi, Arezou; Witzig, Thomas E.; Wallace, Zachary S; Hart, Philip; Deshpande, Vikram; Smyrk, Thomas C.; Chari, Suresh T.; Stone, John H.

doi:10.1136/annrheumdis-2014-206605

Cited by 575 publications

(452 citation statements)

References 29 publications

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“…azathioprine, mycophenolate mofetil, methotrexate, cyclophosphamide and bortezomib), with alternate results [59,60] (Table 1). More recently, RTX has been proved to induce swift clinical responses and a selective decline of serum IgG4 subclass concentrations in patients with recurrent or refractory disease [6,7]. Finally, when urgent decompression is needed, as in the case of biliary duct or ureteral strictures, temporary stenting or surgical approaches remain the strategy of choice for preventing serious organ damage.…”

Section: Treatmentmentioning

confidence: 99%

“…In general theory, an antigen-driven immune response is supposed to drive both B cell commitment to IgG4 production and secretion of profibrotic cytokines by activated T lymphocytes. Indeed, rituximab (RTX), an anti-CD20 monoclonal antibody, has been proved to induce rapid clinical responses in patients with IgG4-RD, further suggesting an important pathogenic contribution of the B cell compartment [6][7][8]. Here, we aim to review the clinical and pathophysiological features of IgG4-RD, focusing on the most recent immunological acquisitions in the field.…”

Section: Introductionmentioning

confidence: 99%

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Immunology of IgG4-related disease

Della‐Torre

Lanzillotta

Doglioni

2015

Clinical and Experimental Immunology

188

215

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SummaryImmunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4 1 plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/ regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

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Section: Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunology of IgG4-related disease

Della‐Torre

Lanzillotta

Doglioni

2015

Clinical and Experimental Immunology

188

215

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“…His steroid-refractory biliary disease was treated with rituximab, and remission was successfully achieved [88]. Based on the findings of subsequent studies including a recent phase I/II study, rituximab appears to be effective for inducing and maintaining remission; therefore, it may be worth considering for patients with previous intolerance to high-dose steroids and those at high risk of relapse [87,89,91]. It is important to note there are two protocols for rituximab therapy.…”

Section: Treatment and Outcomementioning

confidence: 99%

IgG4-related sclerosing cholangitis: all we need to know

2016

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Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a ''benign'' disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell-or immunoglobulin-related (Fc-gamma receptormediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.

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“…Wallace et al in their small trial of rituximab for IgG4-RD noted that 6/16 patients experienced disease resolution and 8/16 patients experienced improved symptoms [26]. Other studies have also noted efficacy for rituximab [27,28]. In cases of vision-threatening disease secondary to mass effect, surgical decompression may be able to prevent further vision loss, if only temporarily [26].…”

Section: Igg4-related Diseasementioning

confidence: 99%