Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a fascinating condition recognised as a systemic disease in 2003 . The first link between autoimmunity affecting the pancreas, elevated serum IgG4 concentrations and large numbers of IgG4-positive plasma cells in pancreatic tissue was described only 2 years earlier . Since then, many diseases that have long been viewed organ-specific are now considered within the spectrum of IgG4-RD. Practically any organ can be affected, having in common a key pathological feature consisting in dense lymphocyte and plasma cell infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and often an elevated serum IgG4 concentration. While good clinical response to steroid therapy is observed, immunosuppressive or B-cell depleting therapy can be required. It is important to distinguish the IgG4-RD from traditional organ-specific autoimmune disease to guide therapy.
What we know about immunoglobulin G4
Many terms have been used to describe immunoglobulin G4 related disease (IgG4-RD), including IgG4-related sclerosing disease, IgG4-related autoimmune disease, systemic IgG4 plasmacytic syndrome (SIPS), IgG4-related multiorgan lymphoproliferative syndrome (IgG4-MOLPS) and IgG4-associated multifocal systemic fibrosis . IgG4 is the common factor of all these names, although its contribution as a specific pathogenic molecule is uncertain (reviewed in Refs. ). IgG4 has been long viewed as an anti-inflammatory immunoglobulin, and although an increase of IgG4+ plasma cells is critical for the diagnosis of these conditions, increased levels of IgG4 could be an epiphenomenon rather than an effector molecule.
IgG4 is a unique antibody in both structure and function, and the least common of the four subclasses of IgG. It accounts for only 3–6% of total IgG in normal serum, and IgG4 concentrations are normally stable. The IgG4 subclass was distinguished early on from the other IgG subclasses, as it exhibits negligible binding to the C1q protein complex and is unable to activate the classical complement pathway. IgG4 also has greatly reduced binding to the low-affinity Fc-gamma receptors (FcgRIIa and FcgRIIIa) and a 10-fold reduction in binding to the high-affinity FcgRI compared with other isotypes. The differences between IgG1 and IgG4 for binding to C1q and Fc receptors have been localised to a few amino acid differences in the CH2 domain, notably P331S for C1q binding and L234F and P331S for Fc receptor binding .
The amino acid sequence of the core IgG4 hinge is also distinct from other IgGs, which increases susceptibility of the two core hinge inter-heavy chain disulfide bonds to chemical reduction . This change allows the heavy chain to separate and recombine randomly, so that asymmetric antibodies with two different antigen-combining sites can be formed. This unique characteristic of IgG4 is called half-antibody exchange reaction . The resulting bispecific IgG4 molecules are unable to crosslink antigen, thus losing the ability to form immune complexes.
Other characteristics of the IgG4 subclass are that can bind the Fc portion of other IgG antibodies, particularly other IgG4 molecule. IgG4 and IgG interaction occurs between Fc constant domains and might contribute to the molecule’s anti-inflammatory function. Also, IgG4 is a T-helper cell 2-dependent isotype that plays a significant role in allergic reactions, as physiologic IgG4 response can be induced by repeated antigen exposures. Thus, autoimmunity and infectious agents are potential immunologic triggers in IgG4-related disease. Th2 cytokines such as interleukins 4, 5, 10, and 13 and transforming growth factor β (TGF-β) contribute to the eosinophilia, elevated serum IgG4 and IgE concentrations, and progression of fibrosis that are characteristic of IgG4-related disease. Massive infiltration by inflammatory cells leads to enlargement of the affected sites and results in organ damage . Finally, IgG4 tends to have relatively low-affinity for target antigens .
The antigen specificity for IgG4 antibody in IgG4-RD has not been defined. It is important then to distinguish this syndrome from certain immune-mediated conditions in which autoreactivity plays a central role. In these diseases, IgG4 antibodies recognise a specific antibody and they are distinct from IgG4-RD, including clinical and pathological manifestations . Examples of these disorders are IgG4 antibodies against desmoglein 1 in patients with pemphigus vulgaris and foliaceus; the M-type phospholipase A2 receptor expressed in podocytes in patients with idiopathic membranous glomerulonephritis; the metalloproteinase ADAMTS13 in patients with thrombotic thrombocytopenic purpura; MuSK protein in myasthenia gravis; and IgG4-containing immune complexes damage renal glomeruli in a subset of childhood membranous glomerulonephritis.
Epidemiology of the IgG4-RD
IgG4-RD affects mostly middle-aged and elderly men. This marked male predominance, with the possible exception of those patients with predominantly head and neck involvement, in whom the male and female ratio is balanced, contrasts with other autoimmune diseases that mimic IgG4-RD such as Sjögren’s syndrome (SS) and primary biliary cirrhosis (PBC), which have female predominance .
Few data exist on the incidence and prevalence of IgG4-RD. Many medical conditions that have long been viewed as conditions affecting individual organs are now considered as a part of the spectrum of IgG4-RD ( Table 1 ). Most epidemiologic studies come from Japan and focus on autoimmune pancreatitis. The estimated prevalence of autoimmune pancreatitis is 0.8 cases per 100,000 persons in Japan. The incidence of this disease throughout Japan was estimated to be 0.28–1.08/100,000, with 336–1300 patients newly diagnosed per year and approximately 6700–26,000 patients who developed IgG4-RD over the past 20 years .
| Disease | Organ |
|---|---|
| Mikulicz’s syndrome | Salivary and lachrymal glands |
| Kuttner’s tumour | Submandibular glands |
| Riedel’s thyroiditis | Thyroid |
| Hashimoto’s thyroiditis | Thyroid |
| Autoimmune pancreatitis | Pancreas |
| Eosinophilic angiocentric fibrosis | Orbit and upper respiratory tract |
| Multifocal fibrosclerosis | Orbit, thyroid, retroperitoneum, mediastinum |
| Inflammatory pseudotumor | Orbit, lungs, liver, kidneys |
| Mediastinal fibrosis | Mediastinum |
| Retroperitoneal fibrosis | Retroperitoneum |
| Interstitial pneumonitis | Lungs |
| Inflammatory aortic aneurysm | Abdominal aorta |
| Idiopathic hypocomplementemic tubulointerstitial nephritis | Kidney |
| Periaortitis and periarteriris | Aorta |
| Autoimmune hypophysitis | Hypophysis |
| Cutaneous pseudolymphoma | Skin |
| Rosai-Dorfman disease | Glands |
Epidemiology of the IgG4-RD
IgG4-RD affects mostly middle-aged and elderly men. This marked male predominance, with the possible exception of those patients with predominantly head and neck involvement, in whom the male and female ratio is balanced, contrasts with other autoimmune diseases that mimic IgG4-RD such as Sjögren’s syndrome (SS) and primary biliary cirrhosis (PBC), which have female predominance .
Few data exist on the incidence and prevalence of IgG4-RD. Many medical conditions that have long been viewed as conditions affecting individual organs are now considered as a part of the spectrum of IgG4-RD ( Table 1 ). Most epidemiologic studies come from Japan and focus on autoimmune pancreatitis. The estimated prevalence of autoimmune pancreatitis is 0.8 cases per 100,000 persons in Japan. The incidence of this disease throughout Japan was estimated to be 0.28–1.08/100,000, with 336–1300 patients newly diagnosed per year and approximately 6700–26,000 patients who developed IgG4-RD over the past 20 years .
| Disease | Organ |
|---|---|
| Mikulicz’s syndrome | Salivary and lachrymal glands |
| Kuttner’s tumour | Submandibular glands |
| Riedel’s thyroiditis | Thyroid |
| Hashimoto’s thyroiditis | Thyroid |
| Autoimmune pancreatitis | Pancreas |
| Eosinophilic angiocentric fibrosis | Orbit and upper respiratory tract |
| Multifocal fibrosclerosis | Orbit, thyroid, retroperitoneum, mediastinum |
| Inflammatory pseudotumor | Orbit, lungs, liver, kidneys |
| Mediastinal fibrosis | Mediastinum |
| Retroperitoneal fibrosis | Retroperitoneum |
| Interstitial pneumonitis | Lungs |
| Inflammatory aortic aneurysm | Abdominal aorta |
| Idiopathic hypocomplementemic tubulointerstitial nephritis | Kidney |
| Periaortitis and periarteriris | Aorta |
| Autoimmune hypophysitis | Hypophysis |
| Cutaneous pseudolymphoma | Skin |
| Rosai-Dorfman disease | Glands |
Clinical manifestations of the IgG4-RD
IgG4-RD can affect almost any organ, and its symptoms are referable to involvement of the specific target organ, often in the form of mass lesion . IgG4-RD usually presents subacutely, and most patients do not have constitutional symptoms. The condition usually comes to clinical attention due to organ swelling or damage. The disorder is also often identified incidentally through radiographic findings or unexpectedly in pathological specimens. However, sometimes IgG4-RD causes major tissue damage and organ failure, such as destructive bone lesions that mimic granulomatous polyangiitis (formerly Wegener’s granulomatosis) or tumours in the sinuses, head and middle ear, although less aggressive lesions are typical in most organs.
The commonest sites of involvement are pancreas, hepatobiliary tract, salivary gland, orbit, and lymph node. Other sites of involvement are retroperitoneum, aorta, mediastinum, soft tissue, skin, central nervous system, breast, kidney, prostate, lung, upper airway and thyroid.
In rare cases, disease may remain localised in a single site. These lesions may precede, coexist with, or develop subsequent to the pancreatic lesion, or even occur in the absence of pancreatitis. Additional sites of involvement often appear with time, sometimes after many years ( Table 2 ). For instance IgG4-related sclerosing pancreatitis (AIP) is frequently associated with extrapancreatic lesions (49%–80% of cases). Hilar lymphadenopathy occurs in 80.4%, extrapancreatic bile duct lesions in 73.9%, lachrymal and salivary gland lesions in 39.1%, kidney lesions in 30%, hypothyroidism in 22.2%, pulmonary complications in 13.3% and retroperitoneal fibrosis in 12.5% .
| ORGAN/LOCAT | SYMPTOM / SIGN (US, CT, MRI, PET) | Imaging |
|---|---|---|
| Thyroid | Hypothyroidism | Thyroid nodule/mass |
| Lung | Cough, dyspnoea | Lung nodule/mass, interstitial pneumonia, pulmonary fibrosis, pleural changes |
| CNS | Headache, cranial nerve palsies Visual or endocrine abnormalities | Meningeal enhancement pituitary mass |
| Orbit | Proptosis | Orbital mass |
| Lagrimal gland | Swelling | Gland mass |
| Bile duct and liver | Abnormal liver tests | Hepatic mass |
| Kidney | Urinalysis abnormalities | Kidney mass |
| Skin | Nodular lesions | |
| Lymph nodes | Lymphadenopathy | |
| Salivary glands | Swelling, sicca syndrome | Gland mass |
| Prostate | Lower urinary symptoms | Prostate enlargement |
| Aorta | Abdominal pain | Aortic aneurysm, aortic dissection, wall thickening |
| Retroperitoneum | Ureteral stenosis, SVC syndrome | Mass lesion |
| Pancreas | Obstructive jaundice | Pancreatic mass, diffuse inflammation. |
IgG4-related pancreatitis
A substantial portion (40–60%) of autoimmune pancreatitis cases represents the pancreatic manifestation of the IgG4-RD . The non-IgG4-RD autoimmune forms of pancreatitis are associated with neutrophilic infiltrates and (occasionally) epithelioid cell granulomas, both of which are generally inconsistent with the diagnosis of IgG4-RD . IgG4-related pancreatitis most commonly affects middle-aged and elderly men with a mean age of 59–68 years and a male-female ratio of 4-to 7.5/1. It is characterised by mild abdominal symptoms, usually without acute attacks of pancreatitis, diffuse enlargement of the pancreas with a capsule-like low-density rim, narrowing of pancreatic duct and painless obstructive jaundice that sometimes may mimic adenocarcinoma of the pancreas. Systemic symptoms are rare, and new-onset type II diabetes mellitus and steatorrhoea are seen in some cases .
Imaging studies typically show enlargement of the pancreas, predominantly at the pancreatic head, and endoscopic retrograde cholangiopancreatography (ERCP) shows irregular narrowing of the pancreatic duct with striking mimicry of pancreatic cancer on clinical and radiological grounds. The disease responds well to steroid therapy, although relapses can occur on cessation of treatment .
Lymph node
Lymphadenopathy is detected in up to 80% of patient with IgG4-related pancreatitis . Lymphadenopathy can develop subsequent to a diagnosis of extranodal IgG4-RD, although sometimes lymphadenopathy is the initial presentation of IgG4-RD. Multiple lymph nodes are usually involved, the commonest being mediastinal, intraabdominal and axillary. Can be asymptomatic or produce mass effects. They are usually non-tender and discovered incidentally on imaging of patient with known IgG4-RD.
When lymphadenopathy is generalised the clinical impression is often that of lymphoma, sarcoidosis, multi centric Castleman’s disease, or disseminated malignancy . In contrast with these entities, the lymph nodes are generally not very large, constitutional symptoms such as fever and weight loss are usually absent, and lactate dehydrogenase level is normal or only minimally raised . In those cases, specific stains for IgG4 are required performed in order to determine the diagnosis, as lymph node biopsies in most cases are reported as ‘reactive follicular hyperplasia’. Features against lymphoma include absence of lymphoepithelial lesions, lymphoid cells reminiscent of monocytoid B-cells, diffuse sheets of CD20+ cells, light chain restriction, aberrant immunophenotype and clonal immunoglobulin gene rearrangements.
Thyroid
IgG4-related thyroiditis is considered as a subtype of Hashimoto thyroiditis, and it is characterised by lymphoplasmacytic infiltration, fibrosis, increase of IgG4-positive plasma cell in the thyroid and high IgG4 level in the serum . It is often accompanied by circulating antithyroglobulin antibody. In patients with autoimmune pancreatitis, 26.8% show biochemical evidence of hypothyroidism.
From a clinical aspect, IgG4 thyroiditis differs from non-IgG4 thyroiditis, with the former being associated with lower female-male ratio, rapid progression, subclinical hypothyroidism, higher levels of circulating antibodies (antithyroglobulin and peroxidase) and diffuse low echogenicity . Riedel’s thyroiditis (also termed invasive fibrous thyroiditis) is also a member of the IgG4-RD spectrum .
Hepatobiliary system
Biliary tract involvement (IgG4-related cholangitis) is found in 50%–90% of patients with IgG4-related pancreatitis, manifesting as obstructive jaundice or fever. In one study, 73% of patients with AIP showed wall thickening or sclerosing changes in extrapancreatic bile ducts on endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS), though only 26% of patients with AIP demonstrated sclerosing changes by ERCP . Rarely it occurs in the absence of pancreatic lesion. It mainly affects the extrahepatic segment particularly the intrapancreatic portion of the bile duct. The main differential diagnosis is primary sclerosing cholangitis, which is progressive disease that requires liver transplantation, whereas IgG4-related cholangitis responds favourably to steroid in most cases . Involvement of the gall bladder, manifesting as diffuse acalculous cholecystitis is found in up to 25% of patients with IgG4-related pancreatitis . Concurrent IgG4-reated cholangitis is common.
The hepatic manifestation is most frequently in the form of mass lesions designated as inflammatory pseudotumour. The lesion usually involves the hepatic hilum and is centred on the bile ducts. Sclerosing cholangitis is almost invariably present . Hepatic involvement may present with abnormal liver function tests. Liver biopsy shows lymphoproliferative infiltrate with a number of IgG4+ plasma cells increased, sclerosis and obliterative phlebitis that contrast with other pathologies that affects liver such as autoimmune hepatitis, primary biliary sclerosis and chronic viral hepatitis.
Orbit, including lachrymal glands, and salivary gland
Lachrymal glands and the orbital soft tissue are commonly involved by IgG4-RD and may represent the first manifestation of the syndrome. Patients typically present with unilateral or bilateral, painless orbital swelling with no significant impairment of visual acuity or keratoconjunctivitis sicca symptoms . IgG4-RD appears to cause approximately half of the cases of ‘idiopathic orbital inflammation’.
The submandibular glands are frequently involved in IgG4-RD. It also known as chronic sclerosing sialedenitis or Kuttner tumour, in which patients present with unilateral or bilateral submandibular hard masses . The parotid glands are sometimes involved alone or together with the submandibular glands.
Bilateral lachrymal, parotid and salivary glands can be involved simultaneously and is sometimes called Miculicz disease (MD) . Although considered a subtype of SS in the past, chronic dacryoadenitis and sialadenitis, which show symmetrical, persistent swelling of the lachrymal and salivary glands, are now part of the spectrum of IgG4-RD. Differences between MD and SS have been clarified . For example, the gender distribution is quite different, in that MD occurs equally in men and women, whereas SS occurs mainly in women. In addition, patients with MD have relatively mild xerostomia and xerophthalmia, despite significant enlargement of their lachrymal and salivary glands. MD is accompanied by more complications, such as AIP. Patients with MD show a better response to glucocorticoid therapy than patients with SS. Finally, it has become clear that MD is related to elevated serum IgG4 concentrations and infiltration of IgG4-positive cells . ( Table 3 ). Although IgG4-RD and SS show marked lymphocytic infiltration, IgG4-RD is characterised by the formation of lymphoid follicles but lower levels of lymphocytic infiltration into the salivary ducts, such that their structure remains intact. Therefore, the absence of lymphoepithelial lesions in patients with IgG4-RD, in contrast to SS, might explain the lower rate of dryness in the former, despite the marked swelling of lachrymal and salivary glands.
| IgG4-RD MD (%) | SS (%) | p | |
|---|---|---|---|
| Clinical symptoms/signs | |||
| Swelling | 100 | 10 | <0.001 |
| Dry eye | 32.8 | 93.5 | <0.001 |
| Dry mouth | 37.5 | 87.1 | <0.001 |
| Arthralgia | 15.6 | 48.4 | <0.001 |
| Interstitial pneumonia | 9.4 | 32.3 | n.s. |
| Interstitial nephritis | 17.2 | 6.5 | n.s. |
| Autoimmune pancreatitis | 17.2 | 0 | <0.05 |
| Immunological findings | |||
| ANA | 23.4 | 90.3 | <0.01 |
| RF | 26.6 | 87.1 | <0.01 |
| SSA/SSB | 1.6 | 100 | <0.001 |
| Low CH50 | 57.8 | 48.4 | n.s. |
| IgG (mg/dl) | 2963 | 2473 | <0.05 |
| IgM (mg/dl) | 63 | 147 | <0.01 |
| IgA (mg/dl) | 194 | 389 | <0.01 |
| IgE (mg/dl) | 307 | 15.3 | <0.005 |
| IgG1 (mg/dl) | 1153 | 1437 | <0.05 |
| IgG2 (mg/dl) | 798 | 566 | <0.05 |
| IgG3 (mg/dl) | 57 | 81 | <0.05 |
| IgG4 (mg/dl) | 697 | 23 | <0.001 |
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