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IgG4-related disease for hematologists
Introduction
Immunoglobulin G4-related disease (IgG4-RD) is a chronic immune-mediated disease that may present with tumefactive lesions, fibrosis, and a polyclonal IgG4-posi- tive (IgG4+) plasma cell-enriched infiltrate in nearly any anatomic site. In many centers, systemic therapy is guided by rheumatologists, yet nearly every medical, surgical and pathology specialty must be aware of this entity and its protean manifestations. Involvement of blood-forming and lymphoid organs, manifesting as lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia, is common and IgG4-RD often mimics other hematologic conditions such as multicentric Castleman disease, lym- phoma, plasma cell neoplasms, and hypereosinophilic syndromes (HES). This review provides an overview of IgG4-RD with a focus on aspects most relevant to clinical hematology practice.
In the early 2000s, while searching for non-invasive bio- markers to distinguish sclerosing (autoimmune) pancreati- tis from pancreatic cancer, Japanese investigators noticed a fast-moving band in the beta-gamma region of the serum protein electrophoresis of patients with sclerosing pancre- atitis. This band represented markedly elevated serum IgG4.1 Subsequently, abundant polyclonal IgG4+ plasma cells were found within a lymphoplasmacytic infiltrate in tissue samples from patients with autoimmune pancreati- tis and in surrounding tissues including the liver and gall- bladder.2 Once this entity was recognized as a distinct dis- ease with characteristic histological features, many histor- ically “idiopathic” and eponymous disorders such as mul- tifocal fibrosclerosis (mediastinal and retroperitoneal fibrosis), Kuttner tumor (chronic sclerosing sialadenitis) and Reidel thyroiditis (woody infiltration of the thyroid) were found to be part of the IgG4-RD spectrum.3 Numerous names were proposed in the early days of its discovery, including “IgG4-related sclerosing disease”, “IgG4-related systemic disease”, “IgG4-related multi- organ lymphoproliferative syndrome” and “systemic IgG4-related plasmacytic syndrome”. An international group of investigators, primarily from Japan, the USA and Europe met in Boston in 2011 and agreed upon uniform nomenclature and diagnostic criteria.3 The accepted name “IgG4-related disease” reflects the universality of the IgG4+ plasma cell infiltration in involved organs as well as the frequency of elevation in serum IgG4 rather than a pathogenic role for IgG4 per se.4 The wide variety of dis- ease manifestations stems not only from multi-organ involvement, but also from the fact that different organs may be involved in a metachronous fashion. Common presentations are major salivary (parotid and submandibu- lar) and lacrimal gland enlargement (Mickulicz disease), lymphadenopathy, orbital pseudotumor, pancreatitis, scle- rosing cholangitis, retroperitoneal fibrosis and tubulointer- stitial nephritis.5
Epidemiology and pathophysiology
Underrecognition has hindered accurate estimates of the epidemiological burden of this disease, but a starting point is the prevalence of autoimmune pancreatitis in Japan, which increased from 2.2/100 000 in 2007 to 4.6/100 000 in 2011. The increase is almost certainly due to increased recognition, and given that pancreatic
involvement is present in about 20-25% of IgG4-RD cases, the true prevalence of the disease is likely much higher. There is a 2:1 male preponderance and the median age of affected patients at diagnosis is in the sixth to sev- enth decade of life. Aside from one case report of identical twins with IgG4-RD,6 evidence of genetic susceptibility is sparse. Pediatric cases are rare, but a recent review identi- fied 25 cases in children, of whom 11 had orbital disease and three had autoimmune pancreatitis.7
At first glance, the presence of IgG4 in serum and IgG4+ plasma cells in tissues, increased IgG4+ plasmablasts in serum, and responsiveness to rituximab suggest that B-cell activation drives the disease.8 However, the IgG4 antibody itself is not thought to be pathogenic since it does not bind complement, does not traditionally form immune com- plexes, and patients with other conditions with markedly elevated serum IgG4, such as IgG4 myeloma, do not develop features of IgG4-RD.9,10 Recent studies have demonstrated that an unconventional population of CD4+SLAMF7+ cytotoxic T lymphocytes is central to the pathogenesis of the disease.11 Histopathologically, poly- clonal B cells are found in clusters near these CD4+ T cells, the latter of which are among the most abundant cells within affected tissues. Oligoclonal expansion of these CD4+ cytotoxic T lymphocytes in peripheral blood may explain the high rates of T-cell clonality positivity deter- mined by polymerase chain reaction analysis.12 These CD4+ T cells produce profibrotic cytokines such as inter- leukin-1, transforming growth factor-beta and interferon- gamma, as well as cytolytic molecules such as granzyme A and B and perforin.13 These cytotoxic T lymphocytes are likely sustained by continuous antigen presentation by B cells and plasmablasts. The responsible autoantigen(s) have not been definitively identified, but annexin A11 and galactin-3 have both recently been implicated in IgG4- RD.14,15 The autoantibody response to galactin-3 is prima- rily of the IgG4 and IgE isotypes, which correlates with the typical immunoglobulin responses seen in IgG4-RD.
Clinical presentation
IgG4-RD can affect nearly any organ except synovial tis- sue. This “fibro-inflammatory” disease presents with tumefactive (puffy) inflammatory infiltrates and fibrosis with a predilection for glandular tissue. Figure 1 illustrates the manifestations of IgG4-RD by organ system. The most common organ manifestations from two large cohorts, one Japanese and one American, are shown in Table 1.16,17 In patients presenting with the better-known features of IgG4-RD, such as autoimmune pancreatitis, orbital disease and major salivary gland involvement, the disease tends to be recognized and histologically con- firmed earlier, but patients referred to hematologists may present with less obvious features of IgG4-RD, and a high index of suspicion is needed to arrive at an accurate diag- nosis. Common reasons for referral to a hematologist include lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia.
Lymphadenopathy
IgG4-related lymphadenopathy is one of the three most common manifestations of IgG4-RD, affecting 30-60% of patients with IgG4-RD in most large cohorts (Table 1).5,16,17 IgG4-lymphadenompathy may be generalized or local-
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