IgG4-related kidney disease: the effects of a Rituximab-based immunosuppressive therapy.

Giacomo Quattrocchio,Giulio Del Vecchio,Giulietta Beltrame,Antonella Barreca,Paola Mesiano,Roberta Fenoglio,Carlo Massara,Cristiana Rollino,Laura Solfietti,Dario Roccatello,Stefano Murgia,Andrea Demarchi,Michela Ferro

doi:10.18632/oncotarget.25095

Giacomo Quattrocchio, Giulio Del Vecchio + Show 11 more

Open Access

https://doi.org/10.18632/oncotarget.25095

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Journal: Oncotarget	Publication Date: Apr 20, 2018
Citations: 26	License type: cc-by

Affiliation: University of Turin, Ospedale San Giovanni Bosco

Abstract

IgG4-related disease (IgG4-RD) is a recently recognized disorder, characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells and storiform fibrosis. Treatment is usually based on steroids, however, relapses and long-term adverse effects are frequent. We prospectively studied 5 consecutive patients with histologically-proven IgG4-RD and renal involvement, treated with an extended Rituximab protocol combined with steroids. Two doses of intravenous cyclophosphamide were added in 4 patients.Five patients with IgG-RD were investigated: three had tubulointerstitial nephritis (TIN), while two had retroperitoneal fibrosis (RPF). In the patients with TIN, renal biospy was repeated after 1 year.In the patients with TIN, estimated glomerular filtration rate (eGFR) at 12 months increased from 9 to 24 ml/min per 1.73 m2; IgG/IgG4 decreased from 3,236/665 to 706/51 mg/dl; C3/C4 increased from 49/6 to 99/27 mg/dl; CD20+ B-cells decreased from 8.7% to 0.5%; Regulatory T-cells decreased from 7.2% to 2.5%. These functional and immunologic changes persisted at 24 months and in two patients at 36 months. A repeat renal biopsy in the patients with TIN showed a dramatic decrease in interstitial plasma cell infiltrate with normalization of IgG4/IgG positive plasma cells. The patients with RPF showed a huge regression of retroperitoneal tissue.In this sample of patients with aggressive IgG4-RD and renal involvement, treatment aimed at depleting B cells and decreasing antibody and cytokine production was associated with a substantial, persistent increase in eGFR, and a definite improvement in immunologic, radiologic and histological parameters.

Highlights

IgG4-related disease (IgG4-RD) is a recently recognized, frequently multi-organ disorder characterized by tumefactive lesions or organ enlargement, elevated serum IgG4 concentrations, and peculiar histological features including dense lymphoplasmacytic infiltrate enriched with IgG4+ plasma cells, a storiform pattern of fibrosis, and obliterative phlebitis [1,2]
CD4+ T cells are abundant within IgG4-RD lesions, and tissue T cell cytokines (IL-4, IL-10 and TGF-β) are upregulated [7]
We previously reported the favourable outcome of a cohort of patients with severe SLE treated with intensive B cell depletion therapy (IBCDT) consisting of a combination of 4 plus 2 infusions of RTX, cyclophosphamide and methylprednisolone pulses [26]

Summary

Introduction

IgG4-related disease (IgG4-RD) is a recently recognized, frequently multi-organ disorder characterized by tumefactive lesions or organ enlargement, elevated serum IgG4 concentrations, and peculiar histological features including dense lymphoplasmacytic infiltrate enriched with IgG4+ plasma cells, a storiform pattern of fibrosis, and obliterative phlebitis [1,2].It predominantly affects middle-aged or elderly men, usually with a mild or subacute clinical presentation and it may mimic various malignant, infectious and inflammatory disorders [3].Laboratory investigations show some very frequent, albeit non specific, abnormalities [4,5,6] including hypergammaglobulinemia (80–90% of cases), elevated (>135 mg/dl) serum IgG4 levels (50–70%), elevated serum IgE levels (60–70%), C3 and/or C4 hypocomplementemia (50–70%), peripheral eosinophilia (35–50%), antinuclear antibodies (30%) and rheumatoid factor (20–30%).Cellular immunity, and T-cells are implicated in disease pathogenesis. IgG4-related disease (IgG4-RD) is a recently recognized, frequently multi-organ disorder characterized by tumefactive lesions or organ enlargement, elevated serum IgG4 concentrations, and peculiar histological features including dense lymphoplasmacytic infiltrate enriched with IgG4+ plasma cells, a storiform pattern of fibrosis, and obliterative phlebitis [1,2]. It predominantly affects middle-aged or elderly men, usually with a mild or subacute clinical presentation and it may mimic various malignant, infectious and inflammatory disorders [3]. Regulatory T-cells likely play a central role in IgG4 and TGF-β production in the interstitium, promoting interstitial fibrosis [10]

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