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IgG4 Disease

Yamamoto, Motohisa MD, PhD; Hashimoto, Masato MD, PhD; Takahashi, Hiroki MD, PhD; Shinomura, Yasuhisa MD, PhD

Section Editor(s): Biousse, Valérie MD; Galetta, Steven MD

doi: 10.1097/WNO.0000000000000172
State-of-the-Art Review

Abstract: Immunoglobulin (Ig) G4–related disease (IgG4-RD) is a chronic inflammatory disorder characterized by elevated serum level of IgG4 and abundant infiltration of IgG4-bearing plasmacytes and fibrosis in various organs, typically including the lacrimal glands, salivary glands, pancreas, thyroid gland, lungs, and kidneys. Lacrimal and orbital involvements are called IgG4-related ophthalmic disease, often presenting as orbital myositis, perineuritis of the optic and trigeminal nerves, and orbital inflammation. In particular, a characteristic finding is infraorbital nerve enlargement on magnetic resonance imaging. Systemic screening is necessary to establish the diagnosis of IgG4-RD, and it must be distinguished from neoplastic disease. Corticosteroid treatment is effective in inducing remission but some patients may relapse during tapering of pharmacotherapy. This review encompasses the history, clinical profile, diagnostic criteria, treatment, and prognosis of IgG4-RD.

Department of Gastroenterology, Rheumatology and Clinical Immunology (MY, HT, YS), Sapporo Medical University School of Medicine, Sapporo, Japan; and Department of Ophthalmology (HM), Sapporo Medical University School of Medicine, Sapporo, Japan.

Address correspondence to Motohisa Yamamoto, MD, PhD, Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 0608543, Japan; E-mail:

Supported by a Research on Measures for Intractable Diseases Project matching fund subsidy from the Ministry of Health, Labour and Welfare, Japan.

The authors report no conflicts of interest.

Immunoglobulin (Ig) G4–related disease (IgG4-RD) is a chronic inflammatory condition characterized by elevated serum levels of IgG4 and marked infiltration of IgG4-positive plasmacytes and storiform fibrosis in a variety of organs (1,2). Whether this disease is an autoimmune disorder remains unclear, but patients with IgG4-RD often present with systemic organ dysfunction and immunological abnormalities (3). This report provides an overall review of IgG4 disease including neuro-ophthalmic involvement.

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The historical origins of IgG4-RD are found in the clinical descriptions of Mikulicz disease (MD) and autoimmune pancreatitis (AIP). In 1888, Johann von Milulicz-Radecki, a surgeon, described a patient with bilateral, symmetric, and painless swelling of the lacrimal, parotid, and submandibular glands (4). Although tuberculosis and sarcoidosis subsequently were reported as causes of this clinical presentation, idiopathic cases were classified as MD, whereas cases with an identifiable cause were classified as Mikulicz syndrome (5). In the 1930s, Henrik Sjögren, a Swedish ophthalmologist, analyzed cases of keratoconjunctivitis sicca and documented an association with swollen salivary glands (6), leading to the recognition of the Sjögren syndrome (SS). In 1953, Morgan and Castleman (7) proposed that MD and SS were the same type of disorder or MD was a subtype of SS, and MD disappeared from the literature for approximately 50 years. In 2000, Tsubota et al (8) demonstrated that the frequency of apoptosis in the lacrimal glands was lower in MD than in SS. Yamamoto et al (9,10) reported a series of cases of MD and identified elevated serum levels of IgG4 and noted in other patients' infiltration of IgG4-positive plasmacytes within swollen lacrimal and submandibular glands. In 2006, MD was recognized as a clinical and pathological entity distinct from SS (11).

The history of AIP began in 1961 with a case report by Sarles et al (12) of a patient with pancreatitis and hypergammaglobulinemia. In the 1990s, characteristic histological (13) and imaging (14) features of this type of pancreatitis were reported and, soon thereafter, Yoshida et al (15) proposed the concept of AIP. Hamano et al (16,17) found elevated serum levels of IgG4 and infiltration of IgG4-positive plasmacytes in pancreatic tissue in patients with AIP. This established a link between AIP and IgG4. Additional studies led to the designation of AIP associated with IgG4 as Type 1 AIP and AIP associated with neutrophils as Type 2 (18–20).

A series of published reports began to expand the clinical manifestations associated with IgG4. IgG4-related autoimmune disease (21) and IgG4-related sclerosing disease (22) were derived from an analysis of AIP. Systemic IgG4-related plasmacytic syndrome (11,23) and IgG4-positive multiorgan lymphoproliferative syndrome (24) subsequently were reported. It became apparent that unification of disease terminology and establishing diagnostic criteria were required (25). In 2011, comprehensive diagnostic criteria for IgG4-RD were proposed at an international symposium on IgG4-RD (26). That same year, recommendations regarding the nomenclature for IgG4-RD and its individual organ system manifestations (27) and consensus on the pathology of IgG4-RD (28) were published. MD was designated as IgG4-DS in the proposed classification.

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Lacrimal Gland and Orbit (IgG4-Related Dacryoadenitis and IgG4-Related Ophthalmic Disease)

Oshima et al (29) reported that IgG4-related orbital lesions comprise 22.5% of orbital lymphoproliferative disorders. Primary sites of involvement include the lacrimal glands, extraocular muscles, and orbital nerves (2). Patients with lacrimal gland disease often present with swelling of the upper eyelids and bilateral ptosis (Fig. 1A). They also may display swelling of the submandibular salivary glands (IgG4-DS). Keratoconjunctivitis sicca is apparent in a small number of cases with IgG4-related dacryoadenitis. Lacrimal gland echography (30) reveals a low-echogenic swollen gland with partitioning (Fig. 1B), whereas neuroimaging demonstrates lacrimal gland enlargement (Fig. 1C). Evaluating whether a lesion is benign or malignant based solely on imaging findings is difficult, and histopathological examination is required (Fig. 1D). This is particularly true in cases of unilateral involvement and without signs of additional organ dysfunctions (salivary or pancreatic lesions).

Extraocular myositis due to IgG4 disease frequently develops after dacryoadenitis (31,32). Pain on eye movement and diplopia are typical clinical findings. IgG4-related disease must be differentiated from thyroid eye disease, which is characterized by lid retraction and enlargement of multiple extraocular muscles.

IgG4-related disease may affect branches of the ophthalmic (supraorbital) and maxillary (infraorbital) nerves and cause sensory impairment in the area of innervation (Fig. 2A) (29,32,33). The inflammatory response is primarily perineuritis because direct infiltration of nerve fibers is not present (Fig. 2B) (34,35). Optic nerve involvement also has been described and may lead to permanent visual loss (34,36).

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Salivary Glands (IgG4-Related Sialadenitis)

Inflammation of the salivary glands often occurs in IgG4-RD. The submandibular glands are most frequently involved but the parotid, sublingual, and minor salivary glands may be affected (Fig. 3). Kűttner tumor (chronic sclerosing sialadenitis) falls within the spectrum of IgG4-related sialadenitis (37). Salivary gland swelling is usually painless, and dry mouth is not a major clinical symptom (10). Differentiation from lymphoma is important and requires histopathological examination.

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Pancreas and Bile Duct (Type 1 AIP and IgG4-Related Sclerosing Cholangitis)

With pancreatic involvement in IgG4-RD, patients will complain of upper abdominal discomfort and develop obstructive jaundice. Pancreatic endocrine and exocrine dysfunction leads to impaired glucose tolerance (38) and gastrointestinal symptoms. Differentiation from pancreatic cancer is necessary with AIP and from bile duct cancer and primary sclerosing cholangitis in patients with IgG4-related sclerosing cholangitis. Abdominal echography in AIP shows a low-echogenic swollen pancreas, and abdominal computed tomography (CT) reveals diffuse or focal swelling of the pancreas with a capsule-like rim (Fig. 4A) (39). In cases with pancreatic or biliary involvement, endoscopic retrograde cholangiopancreatography often is performed to achieve the correct diagnosis.

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Head and Neck Region (Pituitary Gland, Dura Mater, and Thyroid)

Infrequently, IgG4-RD may involve the pituitary gland (40), dura mater (41), and thyroid gland (42,43). IgG4-related hypophysitis of the anterior pituitary may cause headache, visual field loss, and galactorrhea. Symptoms of hypopituitarism include general malaise and amenorrhea. Riedels thyroiditis and the fibrous variant of Hashimoto thyroiditis show partial overlap with IgG4-related thyroiditis. Thyroidal lesions exhibit focal or diffuse enlargement of the thyroid. Involvement at the posterior pituitary sometimes induces diabetes insipidus. Patients with IgG4-related hypertrophic pachymeningitis often present with chronic headache and cranial nerve dysfunction (visual loss and facial nerve palsy) (41).

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Thoracoabdominal Region (Lung, Kidneys, Retroperitoneal Cavity, and Prostate Gland)

Pulmonary lesions in IgG4-RD are classified as bronchial or alveolar (44). Patients with bronchial lesions often present with asthma-like symptoms. CT reveals thickened bronchial and bronchiolar walls. Patients with alveolar lesions are often asymptomatic. CT detects various patterns suggestive of interstitial or organizing pneumonia. IgG4-related kidney disease mainly takes the form of tubulointerstitial nephritis, sometimes complicated by glomerulonephritis. Postcontrast CT reveals enlarged kidneys with multiple areas of mild enhancement (Fig. 4B) (45). Thickened lesions sometimes occur at the renal hilus. Approximately, one-half of cases with renal involvement develop hydronephrosis because of ureteral obstruction and some develop prostatitis (46). Regions around the thoracic and lumbar spine, aorta and branching arteries, and ureters may be involved. With periaortitis, a relationship to inflammatory abdominal aortic aneurysm has been suggested (47).

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Lymph Nodes

Bilateral hilar lymphadenopathy is often detected in IgG4-RD. Enlargement of regional lymph nodes occurs around any involved organs. Patients with systemic lymphadenopathy due to IgG4 disease must be distinguished from those with Castleman disease. The diagnosis of IgG4-related lymphadenopathy is not difficult when other lesions typical of IgG4-RD are present, but biopsy of enlarged lymph nodes is required in cases with only lymph node lesions involvement (48).

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Common Pathological Findings

When possible, histopathological findings should be obtained to confirm the diagnosis in IgG4-RD. Common findings include abundant infiltration of lymphocytes and IgG4-bearing plasmacytes and storiform fibrosis in the involved organs. Infiltration of eosinophils and obstructive phlebitis are also characteristic but the degree of these findings depends on the specific organ. For example, obstructive phlebitis is easily identified in AIP but rarely apparent in IgG4-related sialadenitis (28). The ratio of IgG4/IgG-positive cells in IgG4-related retroperitoneal fibrosis tends to be lower than the other sites of involvement. In the early stage of IgG4-RD, these findings are observed sporadically in the involved organs. Although inflammation is present, the structure of the organ is retained. With progression, there is diffuse spread of inflammation leading to fibrosis and eventually failure of the organ system (49).

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Diagnosis of IgG4-RD is made on the basis of clinical imaging, serological, and pathological findings. Proposed diagnostic criteria include enlarged or hypertrophic affected organs, elevated serum level of IgG4 (≥135 mg/dL), and pathological findings (ratio of IgG4+ IgG+ cells >40% and ≥10 IgG4+ plasmacytes/high power field (Table 1) (26). Definitive diagnosis requires that all criteria are met, whereas probable diagnosis is determined when the clinical and histopathological criteria are met. Meeting the clinical and serological criteria warrants only possible diagnosis. It is essential to exclude eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) and multicentric Castleman disease because both disorders also may have elevated serum levels of IgG4 (50,51). Histopathologically, infiltration of IgG4-positive plasmacytes is often detected in the lymph nodes of patients with rheumatoid arthritis (52). IgG4-positive plasmacytes may be found in surrounding pancreatic cancer (53), and similar findings may be observed in other carcinomas. In patients with lesions that are difficult to be biopsied, diagnosis may be achieved using organ-specific criteria for IgG4-RD. Diagnostic criteria for IgG4-DS (MD) have been established (Table 2) (30) as well as diagnostic criteria for AIP (54–56), IgG4-related sclerosing cholangitis (57), and IgG4-related kidney disease (58,59).

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Systemic corticosteroids are effective in inducing remission of IgG4-RD. Starting prednisone at a dose of 0.6 mg·kg−1·d−1 is appropriate for single organ failure, increasing to 1.0 mg·kg−1·d−1 for multiple organ failure. The initial dose of prednisone is continued for 2–4 weeks, followed by tapering the dose by 10% every 2 weeks. Enlarged organs improve rapidly, and gland secretions gradually increase with treatment (60). Maintaining prednisone dose at 5–10 mg/d is recommended because of the high relapse rate of IgG4-RD. Approximately, one-half of relapse patients present with lesions in other organ systems (61). With relapse, corticosteroids are increased or another immunosuppressant must be chosen. Rituximab, an anti-CD20 antibody, has been shown to be effective in inducing remission and achieving steroid-sparing effects (62). The prognosis for patients with IgG4-RD is good but the incidence of developing cancer within 3 years of diagnosing IgG4-RD is higher in the general population (63). The cause for this association is unclear but mandates careful patient follow-up.

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IgG4-RD has only been reported since the beginning of the 21st century. Although autoimmune mechanisms have yet been elucidated, specific immunological abnormalities have been identified. Examination for systemic organ failure and screening for underlying malignancy are essential in caring for patients with this disorder and requires involvement of a wide variety of clinicians.

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