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Immunoglobulin G4-related Sclerosing Syndrome

Course Authors

Peguy Saad, M.D., and Peter Barland, M.D.

Dr. Saad is Medical Resident at Staten Island University Hospital, New York, and Dr. Barland is Professor of Medicine (emeritus), Albert Einstein College of Medicine, Bronx, NY.

Within the past 12 months, Drs. Saad and Barland report no commercial conflicts of interest.

Albert Einstein College of Medicine, CCME staff and interMDnet staff have nothing to disclose.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Discuss the pathological reaction associated with IgG4 immunoglobulin production.

  • List the clinical features of IgG4-associated inflammation in various organs including the salivary and lacrimal glands, thyroid gland, the pancreas and the biliary ducts.

  • Manage the clinical features of the IgG4-associated inflammation in the aorta and retroperitoneal tissues.

 

Immunoglobulin G4-related sclerosing syndrome (IgG4 RSS) is a newly recognized systemic clinicopathological entity. It is characterized by chronic inflammation and multiorgan involvement secondary to tissue infiltration with IgG4 secreting lymphoplasmocytic cells. It is also known for its dramatic response to steroids.

Immunoglobulin G and G4 Isotype

Immunoglobulin G is the most abundant class of immunoglobulins in serum representing 75% of the total circulating immunoglobulins. Immunoglobulin G is secreted by plasmocytes in response to an immunogen and exists in four subtypes (IgG1, IgG2, IgG3 and IgG4) that differ in the structure of their heavy chains and in their function.

The immunoglobulin G4 isotype (IgG4) is the least abundant of the immunoglobulin G subclasses, accounting for approximately 4% of the total IgG in serum of adults and is undetectable in almost 30% of the healthy population. It is classically described as a non-complement fixating antibody (inability to bind C1q complement component) and therefore incapable of activating the classic complement cascade. It is also characterized by a low affinity to antigens.(1)(2) Elevated IgG4 titers are commonly found in serum of allergic patients along with elevated IgE titers.(3)

IgG4 RSS has the potential to affect many different organs.

It is believed that a prolonged exposure to an antigen elicits IgG4 secretion.(4) A recent study showed that IgG4 in vivo undergoes dynamic changes [exchange of Fab (fragment antigen-binding) fragments] with unknown clinical implications.(5) The mechanism by which IgG4 induces chronic inflammation remains unclear but one hypothesis has been proposed. Hamano et al., for example, have demonstrated the presence of elevated levels of immune complexes containing IgG4 in patients with autoimmune pancreatitis that significantly decreased after steroid therapy and suggested a role for these complexes in the pathogenesis of the disease.(6)

Background

The recent identification of IgG4 in the affected tissues of many chronic inflammatory syndromes has led to the recognition of a new clinicopathological entity — IgG4 RSS. Prior to the discovery of IgG4 RSS as a multiorgan disorder, many separate variants of this syndrome were described in the literature under different names, primarily according to the organ involved.

Mikulicz’s disease, for example, was first reported in 1888 by the Polish surgeon Johann Von Mikulicz. It is by definition a bilateral swelling of the lacrimal and salivary glands associated with mononuclear cell infiltration on glandular pathology. Currently, with the availability of immunostaining techniques, Mikulicz’s disease is recognized as one of the glandular variants of IgG4 RSS.(7)

In 1961 the concept of autoimmune pancreatitis was introduced by Sars et al. who reported the first case of pancreatitis with hypergammaglobulinemia.(8) Later, Hamano et al. in 2001 described for the first time the association of autoimmune pancreatitis with elevated serum and tissue levels of IgG4.(6) Currently, autoimmune pancreatitis is considered as the pancreatic manifestation of IgG4 RSS.

In 1999, Erkelens et al. reported four patients with sclerosing pancreato-cholangitis responsive to steroid therapy.(9) The discovery of IgG4 secreting plasma cells in biliary tissues of patients with a similar presentation (along with other criteria) has led to this entity being recognized as the biliary manifestation of IgG4 RSS.(10)

Many other examples and case reports have followed, proving that IgG4 RSS has the potential to affect many different organs. All have in common the infiltration of the involved tissues with IgG4 positive plasma cells and the dramatic response to corticosteroids. Kamisawa et al. in 2003 proposed that these variants were all part of a systemic syndrome.(11) Subsequently, numerous reports supporting this hypothesis have been published and confirmation by many groups has followed.(12)(13)

Clinical Features and Diagnostic Findings In IgG4 RSS

The clinical features and diagnostic findings of this syndrome will be discussed according to the predominant organ involvement:

GI/Hepatobiliary Involvement

Autoimmune pancreatitis is the most studied and best understood manifestation of IgG4 RSS. It affects predominantly middle-aged to elderly men with a male to female ratio of 4:1 (according to certain series).(14)(15) The usual presentation is that of obstructive jaundice with mild abdominal pain and infrequent attacks of clinical pancreatitis. The level of the pancreatic enzymes is usually normal and both exocrine and endocrine functions of the pancreas can be affected.(16) Autoantibodies such as ANA are frequently present and genetic studies suggest association with the HLA DRB1 0405_ DQB1 0401 haplotype.(17)

Mikulicz's disease is characterized by significant enlargement of the lacrimal and salivary glands.

The CT scan shows diffuse swelling and enlargement of the pancreas, especially the head, with irregular narrowing of the pancreatic duct.(18) Based on its presentation, the findings on CT scan and on endoscopic ultrasound, the entity has been frequently mistaken for pancreatic cancer leading to unnecessary surgeries.(19) The diagnosis was often made after retrospective examination of operative specimens.(9) The pathology reveals atrophy and fibrosis of the parenchyma with obliterative phlebitis and lymphoplasmocytic infiltration staining positively for IgG4(18). The disease is suggested by an elevated serum IgG4 level that can be more than 10 times normal.(6)

It is important to mention that pancreatic cancer can also contain plasma cells that stain positively for IgG4 (<10 IgG4 positive cells/high power field) and that careful interpretation taking into consideration the overall clinical presentation should be done.(20) The response to steroids in autoimmune pancreatitis is remarkable, including normalization or significant decrease in serum IgG4 levels, shrinkage of the pancreatic swelling and reversal of clinical symptoms and pathological findings.(6)

The biliary variant of IgG4 RSS, proposed by Ghazal et al. in 2008, is immunoglobulin-associated cholangitis (IAC). It is most often confused with primary sclerosing cholangitis (PSC) and is commonly reported in association with autoimmune pancreatitis (up to 92% in one series).(10) IAC should be strongly suspected in the presence of obstructive jaundice (which is an uncommon initial presentation in PSC) occurring in a male patient.(21) Intrahepatic biliary strictures mimicking PSC (with or without extrabiliary involvement) and cholangiocarcinoma are seen on cholangiography. The diagnosis is suggested by the absence of malignant cells on bile ducts biopsies in the presence of an inflamed mucosa infiltrated by plasma cells staining positively for IgG4.(10) The response to treatment is variable with some strictures resolving completely after steroid therapy.(9)(22) Though presumably caused by the same mechanism, the response of the proximal disease (intrahepatic involvement) tends to be more favorable than the extrahepatic involvement but unfortunately is associated with higher rates of relapse. (10)

Vascular Involvement

Inflammatory aortitis can be one of the manifestations of IgG4 RSS and should be considered in the differential diagnosis of inflammatory aortitis. As suggested by a few case reports, both the ascending and descending aorta can be affected. The clinical presentation can range from asymptomatic aneurysm discovered incidentally to abdominal/back/thoracic pain with or without systemic symptoms. It can be complicated by dissection and rupture. The diagnosis is almost always made retrospectively by examination of operative specimens obtained at the time of aneurismal repair surgery.(23)(24) The pathology shows transmural infiltration of the vascular wall with IgG4-containing plasma cells predominantly in the adventia and media.(25)(26) Steroid therapy stops the expansion of the aneurysm and its early initiation may avert surgery.

Salivary Glandular Involvement

Mikulicz’s disease is characterized by significant enlargement of the lacrimal and salivary glands. The disease was once thought to be a variant of Sjogren’s syndrome but recent data have shown that it is different clinicopathologically, and that its response to treatment differs.

Mikulicz’s disease tends to affect men and women equally, as opposed to the predominant occurrence of primary Sjogren’s syndrome in females, and is often associated with other glandular manifestations of IgG4 RSS such as autoimmune pancreatitis. Patients will complain of mild xerostomia/exophthalmia (as opposed to the more severe symptoms in Sjogren’s syndrome) mainly because of a tendency to spare the glandular ducts. In addition, the submandibular glands are frequently involved in Mikulicz’s disease, while the parotid glands are usually affected in Sjogren’s syndrome. Involved tissues stain positively for IgG4 plasma cells in Mikulicz’s disease but not in Sjogren’s syndrome. Response to steroids is superior in Mikulicz’s disease.(7)

Other glandular involvement includes the thyroid gland(27) and the hypophysis.(13) Li and Al divided Hashimoto thyroiditis into IgG4 and non-IgG4-related according to histopathological findings. Aside from the presence of IgG4-containing plasma cells, they found more sclerosis and follicular degeneration in the IgG4-related group. This is reflected clinically by a rapid progression of the disease in a population composed mainly of men.(27)

Histology is the gold standard for diagnosis and regardless of the tissue involved

Patients with hypophyseal involvement are most often middle-aged to elderly men who present with pituitary dysfunction including hypopituitarism and diabetes insipidus. MRI shows enlargement of the pituitary stalk with or without pituitary tumor that will shrink significantly after corticosteroid therapy.(13)

Renal Involvement

IgG4-related tubulointerstitial nephritis has been reported in combination with autoimmune pancreatitis (28) and Mikulicz’s disease.(29) The kidney pathology shows fibrosis, primarily in the interstitium, and the presence of tubulointerstitial mononuclear plasma cells positive for IgG4. The mechanism of renal injury is still unknown. Most of the case reports, except for very few,(28) have failed to demonstrate the presence of IgG4 or immune complexes at the glomerular basement membrane(30) and the detected IgG4 was only present within the plasma cells.

Pulmonary Involvement

The IgG4 syndrome can also affect the lungs, where it can present as interstitial lung disease occurring alone or in association with other systemic involvement especially autoimmune pancreatitis. IgG4-related interstitial lung disease frequently presents after the diagnosis of autoimmune pancreatitis.

This entity has a male predominance and patients will complain of cough and shortness of breath. Chest CT findings are not specific and include honeycombing, ground glass opacities, pulmonary nodules and bronchiectasis.(31)(32) Lung biopsy reveals thickening of the alveolar septa with infiltration of the tissue by IgG4 positive plasma cells. In addition to interstitial lung disease, pulmonary inflammatory pseudotumor and lymphomatoid granulomatosis(32) have also been described in association with IgG4-containing cellular infiltrates.

Lymphatic and Blood Involvement

Enlarged cervical, thoracic lymph nodes (mimicking sarcoidosis if bilateral) and abdominal lymph nodes have been described in combination with other organ involvement.(14)(31)(33).Markedly elevated serum IgG4 levels have been mentioned in two case reports where IgG4 level was greater than 15g/l. One of these patients suffered from hyperviscosity syndrome that was successfully treated with plasmapheresis.(34)

Retroperitoneal Fibrosis

IgG4 RSS is one of the identifiable causes of retroperitoneal fibrosis, often complicating autoimmune pancreatitis simultaneously or years after the resolution of the pancreatitis. It presents with back pain, fever, malaise and bilateral hydronephrosis. The CT scan shows a retroperitoneal mass surrounding the major blood vessels. The pathology is similar to that of all IgG4 RSS with the presence of IgG4 positive plasma cells with sclerosis and the disease is responsive to steroids.(35)

Diagnosis and Treatment

Histology is the gold standard for diagnosis and regardless of the tissue involved the histopathological findings are similar — tissue infiltration by IgG4 secreting plasma cells with varying amounts of fibrosis. Serum IG4 levels are often elevated, exceeding up to 10 fold the normal range of 8–140 mg/dl and accounting for the frequently observed elevation of total IgG.(24)

The dose and duration of treatment with steroids have not been established.

IgG4 RSS is a great mimicker with a major advantage over the diseases it resembles — its response to steroids. This is why an early diagnosis is important, as steroids will prevent the sclerotic phase (where treatment is less effective) and thus the patient will be able to avoid unnecessary surgeries. A dramatic response to steroids is characteristic and steroid therapy can stop the progression of the disease, reverse the damage to different extent and decrease or normalize the levels of IgG4. When untreated, the syndrome frequently results in progressive scarring and glandular insufficiency or aneurysm formation but spontaneous remissions have been reported.

The dose and duration of treatment with steroids have not been established. A suggested regimen for autoimmune pancreatitis (AIP) is: 40 mg of prednisone daily for four weeks, then a taper of 5 mg per week for eight weeks.(21) While steroids are most effective when used in the prefibrotic stages of the syndrome, they can occasionally reverse biliary strictures. From our review of the literature, it is not clear at what point the fibrotic changes, which characterize all stages of the disease, become irreversible or at least resistant to steroids. Therefore, it may be justified to give almost all patients with IgG4 RSS a therapeutic trial. In one report, rituximab was effective in a patient with autoimmune pancreatitis and biliary strictures not responsive to a combination of 6-mercaptopurine and steroids.(36)

Conclusion

IgG4 RSS is a new clinical entity that affects a variety of organs. Case reports of affected tissues are being published regularly, putting IgG4 RSS on the top of the list of the great clinical mimickers. Many questions remain unanswered: What is the trigger for IgG4 hypersecretion? Is there a direct role of IgG4 in the pathogenesis of the disease? What is the exact mechanism of the tissue injury? What other organs and tissues might also be involved? Could IgG4 RSS account for some of the cases of idiopathic cardiomyopathies?

What is certain is that IgG4 RSS has significantly decreased the number of “idiopathic inflammatory diseases.”


Footnotes

1Ishizaka, T., et al., Biologic activities of aggregated gamma-globulin. 8. Aggregated immunoglobulins of different classes. J Immunol, 1967. 99(1): p. 82-91.
2Doi, T., et al., Analysis of IgG immune complexes in sera from patients with membranous nephropathy: role of IgG4 subclass and low-avidity antibodies. Nephron, 1991. 57(2): p. 131-6.
3Hussain, R., R.W. Poindexter, and E.A. Ottesen, Control of allergic reactivity in human filariasis. Predominant localization of blocking antibody to the IgG4 subclass. J Immunol, 1992. 148(9): p. 2731-7.
4Aalberse, R.C., R. van der Gaag, and J. van Leeuwen, Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4-restricted response. J Immunol, 1983. 130(2): p. 722-6.
5van der Neut Kolfschoten, M., et al., Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science, 2007. 317(5844): p. 1554-7.
6Hamano, H., et al., High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med, 2001. 344(10): p. 732-8.
7Masaki, Y., et al., Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis, 2009. 68(8): p. 1310-5.
8Sarles, H., et al., Chronic inflammatory sclerosis of the pancreas—an autonomous pancreatic disease? Am J Dig Dis, 1961. 6: p. 688-98.
9Erkelens, G.W., et al., Sclerosing pancreato-cholangitis responsive to steroid therapy. Lancet, 1999. 354(9172): p. 43-4.
10Ghazale, A., et al., Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology, 2008. 134(3): p. 706-15.
11Kamisawa, T., et al., A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol, 2003. 38(10): p. 982-4.
12Li, Y., et al., Immunohistochemistry of IgG4 can help subclassify Hashimoto's autoimmune thyroiditis. Pathol Int, 2009. 59(9): p. 636-41.
13Shimatsu, A., et al., Pituitary and stalk lesions (Infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J, 2009. 56(9): p. 1033-41.
14Kamisawa, T. and A. Okamoto, IgG4-related sclerosing disease. World J Gastroenterol, 2008. 14(25): p. 3948-55.
15Notohara, K., et al., Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases. Am J Surg Pathol, 2003. 27(8): p. 1119-27.
16Kamisawa, T., et al., Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy. Pancreas, 2003. 27(3): p. 235-8.
17Kawa, S., et al., HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology, 2002. 122(5): p. 1264-9.
18Chari, S.T., et al., Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol, 2006. 4(8): p. 1010-6; quiz 934.
19Wakabayashi, T., et al., Chronic pancreatitis with diffuse irregular narrowing of the main pancreatic duct. Dig Dis Sci, 1998. 43(11): p. 2415-25.
20Ghazale, A., et al., Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from pancreatic cancer. Am J Gastroenterol, 2007. 102(8): p. 1646-53.
21Montano-Loza, A.J., E. Lalor, and A.L. Mason, Recognizing immunoglobulin G4 related overlap syndromes in patients with pancreatic and hepatobiliary diseases. Can J Gastroenterol, 2008. 22(10): p. 840-6.
22Kojima, E., et al., Autoimmune pancreatitis and multiple bile duct strictures treated effectively with steroid. J Gastroenterol, 2003. 38(6): p. 603-7.
23Qian, Q., K.B. Kashani, and D.V. Miller, Ruptured abdominal aortic aneurysm related to IgG4 periaortitis. N Engl J Med, 2009. 361(11): p. 1121-3.
24Stone, J.H., et al., IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum, 2009. 60(10): p. 3139-45.
25Matsumoto, Y., et al., A case of multiple immunoglobulin G4-related periarteritis: a tumorous lesion of the coronary artery and abdominal aortic aneurysm. Hum Pathol, 2008. 39(6): p. 975-80.
26Ito, H., et al., IgG4-related inflammatory abdominal aortic aneurysm associated with autoimmune pancreatitis. Pathol Int, 2008. 58(7): p. 421-6.
27Lin, Y.T. and S.C. Liao, Hashimoto encephalopathy presenting as schizophrenia-like disorder. Cogn Behav Neurol, 2009. 22(3): p. 197-201.
28Takeda, S., et al., IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant, 2004. 19(2): p. 474-6.
29Aoki, A., et al., A case of Mikulicz's disease complicated with severe interstitial nephritis associated with IgG4. Clin Exp Nephrol, 2009. 13(4): p. 367-72.
30Yoneda, K., et al., Tubulointerstitial nephritis associated with IgG4-related autoimmune disease. Am J Kidney Dis, 2007. 50(3): p. 455-62.
31Tsushima, K., et al., Pulmonary involvement of autoimmune pancreatitis. Eur J Clin Invest, 2009. 39(8): p. 714-22.
32Shigemitsu, H. and M.N. Koss, IgG4-related interstitial lung disease: a new and evolving concept. Curr Opin Pulm Med, 2009. 15(5): p. 513-6.
33Saegusa, H., et al., Hilar and pancreatic gallium-67 accumulation is characteristic feature of autoimmune pancreatitis. Pancreas, 2003. 27(1): p. 20-5.
34Boulanger, E., et al., Polyclonal IgG4 hypergammaglobulinemia associated with plasmacytic lymphadenopathy, anemia and nephropathy. Ann Hematol, 2006. 85(12): p. 833-40.
35Neild, G.H., et al., Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med, 2006. 4: p. 23.
36Topazian, M., et al., Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol, 2008. 6(3): p. 364-6.