Elsevier

The Lancet

Volume 385, Issue 9976, 11–17 April 2015, Pages 1460-1471
The Lancet

Review
IgG4-related disease

https://doi.org/10.1016/S0140-6736(14)60720-0Get rights and content

Summary

IgG4-related disease is a protean condition that mimics many malignant, infectious, and inflammatory disorders. This multi-organ immune-mediated condition links many disorders previously regarded as isolated, single-organ diseases without any known underlying systemic condition. It was recognised as a unified entity only 10 years ago. Histopathology is the key to diagnosis. The three central pathology features of IgG4-related disease are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The extent of fibrosis is an important determinant of responsiveness to immunosuppressive therapies. IgG4-related disease generally responds to glucocorticoids in its inflammatory stage, but recurrent or refractory cases are common. Important mechanistic insights have been derived from studies of patients treated by B-cell depletion. Greater awareness of this disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and even death. Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.

Introduction

IgG4-related disease is a multi-organ immune-mediated condition that mimics many malignant, infectious, and inflammatory disorders.1, 2, 3 The diagnosis links many conditions once regarded as isolated, single-organ diseases without any known underlying systemic condition (panel 1). IgG4-related disease, unrecognised as a unified disease for well over a century, has been likened to a “black crow flying through the dark night”.4 The disease has many similarities to sarcoidosis and some forms of systemic vasculitis, other protean diseases in which the histopathological findings are consistent across a wide range of organ systems.

Two introductory points deserve emphasis. First, awareness of IgG4-related disease is essential because the disorder is treatable. The therapeutic approaches contrast starkly with those of some of the disorders in the differential diagnosis (panel 2), especially malignant disorders but also autoimmune diseases, such as Sjögren's syndrome, granulomatosis with polyangiitis, and membranous nephropathy. Second, knowledge of the immune dysregulation associated with IgG4-related disease explains much about the human immune system. Progress in elucidation of the basis of IgG4-related disease has been swift.

Section snippets

Epidemiology

Understanding of the epidemiology of IgG4-related disease is hampered by insufficient awareness of the diagnosis, because the disease did not appear in medical publications until 2003.5, 6 Definitive diagnosis generally necessitates a biopsy, insightful interpretation of the pathology, and rigorous clinicopathological correlation. Although the overall prevalence of type 1 (IgG4-related) autoimmune pancreatitis in Japan has been estimated as 2·2 cases per 100 000 population,7 the pancreas is

Histology features

Histopathology is the key to diagnosis of IgG4-related disease. Three central pathology features are lymphoplasmacytic infiltration, obliterative phlebitis, and storiform fibrosis (figure 1).14 The lymphocytes and plasma cells are polyclonal. Eosinophils are also commonly present and extreme examples can resemble eosinophilic organopathy, but neutrophilic infiltration is rare in IgG4-related disease. Necrosis, discrete granulomata, and xanthogranulomatous changes are atypical and, when present,

Pathophysiology

Two parallel processes could underlie the observed pathological features in IgG4-related disease. The first is the induction of a polarised CD4-positive T-cell population, yet to be conclusively characterised, which activates innate immune cells, including macrophages, myofibroblasts, and fibroblasts to drive fibrosis. This process could involve the collaboration of activated B-lineage cells, possibly expanded plasmablasts that enter the damaged tissue along with activated CD4-positive T cells.

Diagnosis

Tissue biopsy is the gold standard for diagnosis in most settings. Review of archived pathology samples can confirm the diagnosis of IgG4-related disease on histological findings alone, if large specimens such as submandibular gland resections are available. Even with supporting histopathological evidence, however, clinicopathological correlation is needed to confirm the diagnosis.

Imaging is an important part of the diagnostic approach in many organs. Under some circumstances, the imaging

Serology

High serum IgG4 concentrations are neither sufficiently sensitive nor specific for diagnosis. Serum IgG4 concentrations are useful for screening but are unreliable as a single diagnostic marker. About 20% of patients with type 1 autoimmune pancreatitis have normal serum IgG4 concentrations at presentation.35, 36 The proportion with normal concentrations can be somewhat lower among patients with multi-organ disease,37 but many diagnoses can be associated with high serum IgG4 concentrations. In

Constitutional and musculoskeletal symptoms

The presentation of IgG4-related disease is typically subacute, with symptoms and organ dysfunction evident for months or even years before diagnosis. Disease can progress haltingly, with occasional spontaneous improvements (generally temporary) or long plateaus of disease quiescence in a specific organ. In such cases, disease recurrence in an organ known to be affected or the emergence of new organ involvement can lead to diagnosis.

Weight loss of 5–10 kg can occur over months, but fevers and

Glucocorticoids

Most clinical manifestations of IgG4-related disease respond to glucocorticoids. These agents are the first-line, standard-of-care approach for most patients.43, 99 However, no randomised treatment trials have been done, and few large retrospective examinations have been reported. One treatment approach uses a starting prednisolone dose of 0·6–1·0 mg/kg daily.30, 43 After 2–4 weeks, the dose is tapered by 5 mg every 1–2 weeks according to clinical responses (eg, clinical manifestations, blood

Future perspectives

In only 10 years since the recognition of extrapancreatic features in patients with autoimmune pancreatitis signalled a systemic, multi-organ disease, substantial progress has been achieved in IgG4-related disease. The disease has been identified in nearly every organ system and most of its clinical features have been mapped. Nomenclature has been standardised, and a consensus has been achieved about the major and minor pathological manifestations.3, 14 Effective treatments have been identified

Search strategy and selection criteria

Data for this Review were identified by searches of Medline, PubMed, and references from relevant articles with the search terms “IgG4”, “IgG4-related”, and “autoimmune pancreatitis”. We focused on publications since the year 2000, since the multiorgan nature of IgG4-related disease was not recognised until 2003. We also cited other important publications from earlier years pertaining to conditions now recognised as part of the IgG4-related disease spectrum.

References (106)

  • Y Zen et al.

    Retroperitoneal and aortic manifestations of immunoglobulin G4-related disease

    Semin Diagn Pathol

    (2012)
  • T Saeki et al.

    Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis

    Kidney Int

    (2010)
  • T Saeki et al.

    The clinical course of patients with IgG4-related kidney disease

    Kidney Int

    (2013)
  • MP Alexander et al.

    Membranous glomerulonephritis is a manifestation of IgG4-related disease

    Kidney Int

    (2013)
  • RP Sah et al.

    Differences in clinical profile and relapse rate of type 1 versus Type 2 autoimmune pancreatitis

    Gastroenterology

    (2010)
  • K Hirano et al.

    Endoscopic evaluation of factors contributing to intrapancreatic biliary stricture in autoimmune pancreatitis

    Gastrointest Endosc

    (2010)
  • VS Mahajan et al.

    IgG4-related disease

    Annu Rev Pathol

    (2014)
  • H Umehara et al.

    A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

    Mod Rheumatol

    (2012)
  • JH Stone et al.

    Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations

    Arthritis Rheum

    (2012)
  • S Kawa et al.

    IgG4-related disease: an overview

  • T Kamisawa et al.

    A new clinicopathological entity of IgG4-related autoimmune disease

    J Gastroenterol

    (2003)
  • A Kanno et al.

    Nationwide epidemiological survey of autoimmune pancreatitis in Japan

    Pancreas

    (2012)
  • JH Stone et al.

    IgG4-related disease

    N Engl J Med

    (2012)
  • Y Zen et al.

    IgG4-related disease: a cross-sectional study of 114 cases

    Am J Surg Pathol

    (2010)
  • M Ota et al.

    Polymorphism in the KCNA3 gene is associated with susceptibility to autoimmune pancreatitis in the Japanese population

    Dis Markers

    (2011)
  • T Umemura et al.

    Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients

    Am J Gastroenterol

    (2008)
  • M Ota et al.

    Two critical genes (HLA-DRB1 and ABCF1)in the HLA region are associated with the susceptibility to autoimmune pancreatitis

    Immunogenetics

    (2007)
  • T Umemura et al.

    Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients

    Gut

    (2006)
  • Y Zen et al.

    IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases

    Am J Surg Pathol

    (2009)
  • H Hamano et al.

    Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis

    Lancet

    (2002)
  • T Kamisawa et al.

    Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis

    Gut

    (2003)
  • JD Strehl et al.

    Numerous IgG4-positive plasma cells are ubiquitous in diverse localised non-specific chronic inflammatory conditions and need to be distinguished from IgG4-related systemic disorders

    J Clin Pathol

    (2011)
  • Y Zen et al.

    IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?

    Am J Surg Pathol

    (2004)
  • RC Aalberse et al.

    Immunoglobulin G4: an odd antibody

    Clin Exp Allergy

    (2009)
  • Y Zen et al.

    Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis

    Hepatology

    (2007)
  • H Mattoo et al.

    Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy

    Allergy

    (2014)
  • E Della Torre et al.

    Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease

    Allergy

    (2014)
  • H Tsuboi et al.

    Analysis of IgG4 class switch-related molecules in IgG4-related disease

    Arthritis Res Ther

    (2012)
  • C King et al.

    T follicular helper (TFH) cells in normal and dysregulated immune responses

    Annu Rev Immunol

    (2008)
  • A Khosroshahi et al.

    Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease

    Arthritis Rheum

    (2010)
  • A Khosroshahi et al.

    Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients

    Medicine (Baltimore)

    (2012)
  • M Ebbo et al.

    Usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography for staging and evaluation of treatment response in IgG4-related disease: a retrospective multicenter study

    Arthritis Care Res (Hoboken)

    (2014)
  • T Shimosegawa et al.

    International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology

    Pancreas

    (2011)
  • H Ohara et al.

    Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012

    J Hepatobiliary Pancreat Sci

    (2012)
  • M Kawano et al.

    Proposal for diagnostic criteria for IgG4-related kidney disease

    Clin Exp Nephrol

    (2011)
  • Y Masaki et al.

    IgG4-related diseases including Mikulicz's disease and sclerosing pancreatitis: diagnostic insights

    J Rheumatol

    (2010)
  • H Umehara et al.

    Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011

    Mod Rheumatol

    (2012)
  • RP Sah et al.

    Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis

    Curr Opin Rheumatol

    (2011)
  • MN Carruthers et al.

    The diagnostic utility of serum IgG4 concentrations in patients with potential IgG4-related disease

    Ann Rheum Dis

    (2014)
  • A Ghazale et al.

    Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer

    Am J Gastroenterol

    (2007)
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