Treatment of IgG4-related disease

Published on Jul 18, 2016in Zeitschrift Fur Rheumatologie0.901
· DOI :10.1007/s00393-016-0142-y
Cory A. Perugino6
Estimated H-index: 6
(Harvard University),
John H. Stone70
Estimated H-index: 70
(Harvard University)
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.
  • References (25)
  • Citations (10)
📖 Papers frequently viewed together
8 Citations
1,120 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Hamid Mattoo (Harvard University)H-Index: 16
#2Vinay S. Mahajan (Harvard University)H-Index: 20
Last. Shiv Pillai (Harvard University)H-Index: 55
view all 14 authors...
Background IgG 4 -related disease (IgG 4 -RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4 + T cells constitute the major inflammatory cell population in IgG 4 -RD lesions. Objective We used an unbiased approach to characterize CD4 + T-cell subsets in patients with IgG 4 -RD based on their clonal expansion and ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4 + effector/me...
97 CitationsSource
#1Cory A. PeruginoH-Index: 6
#2Zachary S. WallaceH-Index: 18
Last. John H. StoneH-Index: 70
view all 6 authors...
Objectives: IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect multiple organs and lead to tumefactive, tissue-destructive lesions. Reports have described inflammatory aortitis and periaortitis, the latter in the setting of retroperitoneal fibrosis (RPF), but have not distinguished adequately between these 2 manifestations. The frequency, radiologic features, and response of vascular complications to B cell depletion remain poorly defined. We describ...
44 CitationsSource
#1Emanuel Della-Torre (Harvard University)H-Index: 14
#2Eoin R. Feeney (Harvard University)H-Index: 13
Last. John H. Stone (Harvard University)H-Index: 70
view all 11 authors...
Objectives Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metallopro...
48 CitationsSource
#1Arezou Khosroshahi (Emory University)H-Index: 26
#2Zachary S. Wallace (Harvard University)H-Index: 18
Last. John H. Stone (Harvard University)H-Index: 70
view all 42 authors...
288 CitationsSource
#1Mollie N. Carruthers (Harvard University)H-Index: 15
#2Topazian (Mayo Clinic)H-Index: 3
Last. John H. Stone (Harvard University)H-Index: 70
view all 10 authors...
Objectives To evaluate the efficacy of rituximab (RTX) in IgG4-related disease (IgG4-RD) in an open-label pilot trial. Methods We treated 30 IgG4-RD patients with two doses of RTX (1000 mg each). The participants were either treated with RTX alone (n = 26; 87%) or required to discontinue baseline glucocorticoids (GC) within 2 months (n = 4; 13%). Disease activity was measured by the IgG4-RD Responder Index (IgG4-RD RI) and physician9s global assessment (PGA). Disease response was defined as the ...
222 CitationsSource
#1Zachary S. Wallace (Harvard University)H-Index: 18
#2Hamid Mattoo (Harvard University)H-Index: 16
Last. John H. Stone (Harvard University)H-Index: 70
view all 10 authors...
Objectives We examined the utility of circulating total and IgG4+ plasmablasts as biomarkers of diagnosis and disease activity in IgG4-related disease (IgG4-RD). Materials methods We evaluated patients with active, untreated, biopsy-proven IgG4-RD affecting various organs. Flow cytometry was used to measure total plasmablast and IgG4+ plasmablast counts by gating peripheral blood for CD19lowCD38+CD20−CD27+ cells and CD19lowCD38+CD20−CD27+IgG4+ cells. Serum IgG4 concentrations were measured by ne...
206 CitationsSource
#1Hamid Mattoo (Harvard University)H-Index: 16
#2Vinay S. Mahajan (Harvard University)H-Index: 20
Last. Shiv Pillai (Harvard University)H-Index: 55
view all 9 authors...
Background IgG 4 -related disease (IgG 4 -RD) is a poorly understood, multiorgan, chronic inflammatory disease characterized by tumefactive lesions, storiform fibrosis, obliterative phlebitis, and accumulation of IgG 4 -expressing plasma cells at disease sites. Objective The role of B cells and IgG 4 antibodies in IgG 4 -RD pathogenesis is not well defined. We evaluated patients with IgG 4 -RD for activated B cells in both disease lesions and peripheral blood and investigated their role in disea...
169 CitationsSource
#1Seung Y. ChuH-Index: 17
#2Karen C. Yeter (SC: University of Southern California)H-Index: 5
Last. David E. SzymkowskiH-Index: 25
view all 13 authors...
Objective Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc-engineered antibody, XmAb5871, which coengages FcγRIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871...
24 CitationsSource
#1Terumi KamisawaH-Index: 56
#2Kazuichi Okazaki (Kansai Medical University)H-Index: 63
Last. Tooru Shimosegawa (Tohoku University)H-Index: 65
view all 15 authors...
Background In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese consensus guidelines for managing AIP required revision.
104 CitationsSource
#1Hamid Mattoo (Harvard University)H-Index: 16
#2Emanuel Della-Torre (Harvard University)H-Index: 14
Last. Shiv Pillai (Harvard University)H-Index: 55
view all 5 authors...
IgG4 related disease (IgG4-RD) is characterized by a lymphoplasmacytic infiltrate composed of IgG4+ plasma cells, tumefactive lesions, obliterative phlebitis, and mild to moderate eosinophilia. It has been suggested that IgG4-RD is characterized by allergic manifestations and is potentially driven by enhanced T helper type 2 (Th2) responses. We aimed to investigate the potential contribution of atopy to enhanced Th2 responses in IgG4-RD. Peripheral blood mononuclear cells from 39 patients were i...
65 CitationsSource
Cited By10
#1Takashi Maehara (Kyushu University)H-Index: 16
#2Masafumi Moriyama (Kyushu University)H-Index: 20
Last. Seiji Nakamura (Kyushu University)H-Index: 36
view all 3 authors...
Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related disease (IgG4-RD), which has been recognized as a single diagnostic entity for less than 15 years. Histopathologic examination is critical for diagnosis of IgG4-RD. CD4+ T and B cells, including IgG4-expressing plasma cells, constitute the major inflammatory cell populations in IgG4-RD and are thought to cause organ damage and ti...
#1Maria Quero (University of Barcelona)H-Index: 1
#2Juliana DraibeH-Index: 6
Last. Joan Torras (University of Barcelona)H-Index: 34
view all 9 authors...
#1Bart K. Chwalisz (Harvard University)
#2John H. Stone (Harvard University)H-Index: 70
Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated systemic disease that has a particular predilection for glandular and connective tissue, including orbital adnexa and the pachymeninges. IgG4-RD enters into the differential diagnoses of numerous inflammatory, infectious, and neoplastic disorders and has emerged as a unifying diagnosis for a number of conditions once considered unrelated but now recognized to be linked by consistent histopathological features across all organs aff...
#1Chan Mi Lee (Cleveland Clinic Lerner College of Medicine)
#2Mohamed Alalwani (Cleveland Clinic)H-Index: 1
Last. Carmen E. Gota (Cleveland Clinic Lerner College of Medicine)H-Index: 8
view all 4 authors...
#1Wei Zhang (Baptist Health)
#2Jeffrey H. Glaze (Baptist Health)
Last. David Wynne (Baptist Health)
view all 3 authors...
IgG4-related disease (IgG4-RD) is a newly recognized immune-mediated multisystemic disease characterized by a fibro-inflammatory condition with tissue infiltration of IgG4-positive plasma cells and often associated with elevated serum IgG4 levels. Typical renal involvement of IgG4-RD presents as tubulointerstitial nephritis (TIN), membranous or membranoproliferative nephropathy. We are presenting a case with combined IgG4 membranous nephropathy and TIN, as well as a literature review on pathophy...
#1Agata SebastianH-Index: 4
#2Maciej SebastianH-Index: 3
Last. Piotr Wiland (Wrocław Medical University)H-Index: 16
view all 8 authors...
IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide-ranging and manifested in one or more organs synchronously or metachronously. In the present...
2 CitationsSource
#1Mahmoud A. AbdelRazek (Harvard University)H-Index: 1
#2Nagagopal Venna (Harvard University)H-Index: 16
Last. John H. Stone (Harvard University)H-Index: 70
view all 3 authors...
Summary IgG4-related disease can involve nearly any organ system, including the central and peripheral nervous systems. The pathology findings are consistent from organ to organ, but careful clinicopathological correlation is necessary to establish the diagnosis. Many non-neurological and neurological inflammatory conditions, previously regarded as idiopathic in nature, are now recognised to fall within the spectrum of IgG4-related disease. The condition is highly treatable, but probably remains...
11 CitationsSource
#1Xia Hong (PKU: Peking University)H-Index: 4
#2Yan-Yan Zhang (PKU: Peking University)H-Index: 2
Last. Yu Gy (PKU: Peking University)H-Index: 17
view all 17 authors...
Background Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary g...
5 CitationsSource
#1Cory A. Perugino (MIT: Massachusetts Institute of Technology)H-Index: 6
#2Hamid Mattoo (MIT: Massachusetts Institute of Technology)H-Index: 16
Last. John H. Stone (Harvard University)H-Index: 70
view all 7 authors...
#1Bernardo BaptistaH-Index: 1
#2Alina Casian (Guy's and St Thomas' NHS Foundation Trust)H-Index: 7
Last. Claire M Rice (Southmead Hospital)H-Index: 18
view all 5 authors...
IgG4-related disease (IgG4-RD) is a multisystem inflammatory disorder. Early recognition of IgG4-RD is important to avoid permanent organ dysfunction and disability. Neurological involvement by IgG4-RD is relatively uncommon, but well recognised—hypertrophic pachymeningitis and hypophysitis are the most frequent manifestations. Although the nervous system may be involved in isolation, this more frequently occurs in conjunction with involvement of other systems. Elevated circulating levels of IgG...
13 CitationsSource