Emerging Treatment Models in Rheumatology: IgG4‐Related Disease: Insights Into Human Immunology and Targeted Therapies
Authors: Cory A. Perugino, Hamid Mattoo, Vinay S. Mahajan, Takashi Maehara, Zachary S. Wallace, Shiv Pillai, John H. Stone
Journal: Arthritis & Rheumatology (2017)

IgG4-related disease (IgG4-RD) is a systemic, multi-organ disorder with heterogeneous clinical features but distinctive presentations.1, 2 The classic onset of this disease is subacute, taking the form of tumor-like lesions that develop gradually. These lesions are generally identified either on physical examination (e.g., salivary gland enlargement) or imaging (e.g., a renal, lung, or pancreatic mass), frequently at a time when the patient feels well. In the first years following recognition of IgG4-RD, the diagnosis was often made by pathologists in the complete absence of clinical suspicion for the disease. More recently, because of growing familiarity with typical IgG4-RD presentations and the use of blood IgG4 testing, presumptive diagnoses are often rendered by clinicians before the performance of diagnostic tests. Biopsy confirmation of the diagnosis remains important in most cases.

IgG4-RD is not a new disease. Cases of the disease are well documented in medical history going back at least to the late 1800s3 , but the individual organ manifestations were considered to be distinct disease entities for more than a century, each confined to single organs and given eponymic designations: e.g., Riedel’s thyroiditis (circa 1883), Kuttner’s tumor (dacryoadenitis involving the submandibular gland, circa 1896), and Ormond’s disease (circa 1960).4, 5, 6 In 2001, Hamano, Kawa, and colleagues demonstrated that an elevated serum IgG4 level was useful in distinguishing “sclerosing pancreatitis,” now termed type 1 (IgG4-related) autoimmune pancreatitis, from other diseases of the pancreatic and biliary tract.7

In 2003, Kamisawa and Nakajima recognized similar pathology findings in extra-pancreatic organs of patients with sclerosing pancreatitis.8 They described a disease typified by elevated serum IgG4 levels, responsiveness to glucocorticoids, multi-organ involvement, and a fibroinflammatory infiltrate. The name “IgG4-related autoimmune disease” was given to this disorder initially because of the abundance of IgG4-expressing plasma cells within affected tissues, thereby unifying seemingly disparate conditions. The involvement of bile ducts, major salivary glands, lymph nodes, and retroperitoneal tissue was also described in this original case series. Since that time, IgG4-RD has been reported to affect virtually every organ in the body. The lacrimal gland, lung, and kidney are other common sites of disease involvement [Figure 1, A–B].2 The aorta, pachymeninges, and bile ducts comprise exceptions to the tumefactive clinical presentation, presumably because of their tubular structures and/or thin walls.9, 10, 11




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Figure 1


(A) Head and neck illustration highlighting involvement of the lacrimal and major salivary glands. Lacrimal and salivary gland enlargement is most often bilateral in distribution. (B) Abdomen illustration highlighting typical organ involvement including the pancreas, bile ducts, kidneys, and retroperitoneal tissue. Radiographically, the retroperitoneal fibrosis often extends inferiorly to encase the iliac vessels. Not depicted here, the aorta and lung are other common sites of disease involvement.