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.
ReviewIgG4-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
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