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INTRODUCTION

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IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by a tendency to form tumefactive lesions. The clinical manifestations of this disease, however, are protean, and continue to be defined. IgG4-RD has now been described in virtually every organ system. Commonly affected organs are the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, and retroperitoneum. In addition, IgG4-RD involvement of the meninges, aorta, prostate, thyroid, pericardium, skin, and other organs is well described. The disease is believed to affect the brain parenchyma, the joints, the bone marrow, and the bowel mucosa only rarely (if ever).

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The clinical features of IgG4-RD are numerous, but the pathologic findings are consistent across all affected organs. These findings include a lymphoplasmacytic infiltrate with a high percentage of IgG4-positive plasma cells; a characteristic pattern of fibrosis termed “storiform”; a tendency to target blood vessels, particularly veins, through an obliterative process (“obliterative phlebitis”); and a mild to moderate tissue eosinophilia.

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IgG4-RD encompasses a number of conditions previously regarded as separate, organ-specific entities. A condition once known as “lymphoplasmacytic sclerosing pancreatitis” (among many other terms) became the paradigm of IgG4-RD in 2000, when Japanese investigators recognized that these patients had elevated serum concentrations of IgG4. This form of sclerosing pancreatitis is now termed type 1 (IgG4-related) autoimmune pancreatitis (AIP). By 2003, extrapancreatic disease manifestations had been identified in patients with type 1 AIP, and since then, the manifestations of IgG4-RD in many organs have been catalogued. Mikulicz’s disease, once considered to be a subset of Sjögren’s syndrome that affected the lacrimal, parotid, and submandibular glands, is now considered part of the IgG4-RD spectrum. Similarly, a subset of patients previously diagnosed as having primary sclerosing cholangitis was known to respond well to glucocorticoids, in contrast to the majority of patients with that diagnosis. This steroid-responsive subset is now explained by the fact that such patients actually have a separate disease, i.e., IgG4-related sclerosing cholangitis. In this manner, the understanding of IgG4-RD has extended to include nearly every specialty of medicine.

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CLINICAL FEATURES

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The major organ lesions are summarized in Table 391e-1. IgG4-RD usually presents subacutely, and most patients do not have severe constitutional symptoms. Fevers and dramatic elevations of C-reactive protein are unusual; however, some patients report substantial weight loss occurring over periods of months. Clinically apparent disease can evolve over months, years, or even decades before the manifestations within a given organ becomes sufficiently severe to bring the patient to medical attention. Some patients have disease that is marked by the appearance and then resolution or temporary improvement in symptoms within a particular organ. Other patients accumulate new organ involvement as their disease persists in previously affected organs. Many patients with IgG4-RD are misdiagnosed as having other conditions, particularly malignancies, or their findings are attributed initially to nonspecific inflammation. The disorder is often identified incidentally through radiologic findings or unexpectedly in pathology specimens.

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