Ig G4 Related DiseasesPresenter – Dr. Shubhanshu ChawlaModerator – Prof. Reshma Kaushik

 Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized immune-mediated condition comprised of a collection of disorders that share specific pathologic, serologic, and clinical features.

AIP – Auto Immune Pancreatitis is considered the prototype IgG4-RD.

Introduction and Definition

The commonly shared features include Tumor-like swelling of involved organs A lymphoplasmacytic infiltrate enriched in

IgG4-positive plasma cells A variable degree of fibrosis that has a

characteristic “storiform” pattern, and obliterative phlebitis

Elevated serum concentrations of IgG4 ( in 60-70 % of the patients)

Response to glucocorticoids, particularly in early stage of the disease.

The disease was not recognized as a systemic condition till 2003, when extra pancreatic manifestations were identified in patients of AIP.

AIP had been linked to elevated serum IgG4 levels as early as in 2001.

AIP is now considered the prototype IgG4-RD, and majority of the research regarding these diseases has been done on AIP.

IgG4-RD has been described in virtually every organ system: the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin.

The histopathological features bear striking similarities across organs, regardless of the site of disease.

IgG4-RD is therefore analogous to sarcoidosis, another systemic disease in which diverse organ manifestations are linked by the same histopathological characteristics.

The preferred name for the overall condition is IgG4-related disease. However, multiple names have been employed to describe this entity. These include:

●IgG4-related disease ●IgG4-related systemic disease ●IgG4-syndrome ●IgG4-associated disease ●IgG4-related sclerosing disease ●IgG4-related systemic sclerosing disease ●IgG4-related autoimmune disease ●IgG4-positive multiorgan lymphoproliferative

syndrome ●Hyper-IgG4 disease ●Systemic IgG4-related plasmacytic syndrome ●Systemic IgG4-related sclerosing syndrome ●Multifocal fibrosclerosis ●Multifocal idiopathic fibrosclerosis

The hallmarks of IgG4-RD are lymphoplasmacytic tissue infiltration with a predominance of IgG4-positive plasma cells, usually accompanied by fibrosis, obliterative phlebitis, and elevated serum levels of IgG4.

A sizeable minority of patients (less than 40 percent) have normal serum IgG4 concentrations despite the presence of the classic histopathological changes in tissue.

The fibrosis associated with IgG4-RD has a characteristic “storiform” pattern, typified by a cartwheel appearance of the arranged fibroblasts and inflammatory cells. Modest tissue eosinophilia is also common.

Histology

IgG4-RD generally occurs most commonly in middle-aged and older men. This is certainly true for conditions such as AIP, retroperitoneal fibrosis, IgG4-related tubulointerstitial nephritis (TIN), and many other organ manifestations.

However, the sex distribution differs somewhat with regard to patients with involvement of organs of the head and neck. As examples, in patients with IgG4-related sialadenitis and IgG4-related ophthalmic disease, males and females appear to be affected more equally.

Beyond these general statements, the epidemiology of IgG4-RD requires further definition. Initially, study of the condition suffered from a lack of definitions, incomplete nomenclature, and underrecognition among clinicians and pathologists. These deficits are gradually being overcome and should facilitate more complete understanding of the disease epidemiology.

Epidemiology

The pathogenesis of IgG4-RD is poorly understood; findings consistent with both an autoimmune disorder and an allergic disorder are present. IgG4 has been postulated to have a role in tolerance to allergens and in responses to certain infectious agents, but its physiologic role is poorly understood. A specific autoantigenic target has not been identified, and it is not clear whether the IgG4 antibodies are pathogenic.

An emerging consensus holds that the IgG4 antibodies in this disease are not pathogenic, but rather represent a down-regulatory response to another primary process(es).

Elevations in serum and tissue IgG4 concentrations are not specific to IgG4-RD; they are also found in disorders such as multicentric Castleman’s disease, allergic disorders, the Churg-Strauss syndrome and sarcoidosis.

Pathogenesis

Findings in IgG4-RD suggesting autoimmunity have been particularly evident in patients with type 1 (IgG4-related) AIP, the prototypic IgG4-related disorder.

Evidence for an allergic response includes elevated levels of Th2 cytokines in affected tissues and increased amounts of serum IgE. In addition, patients with IgG4-RD have an increased prevalence of allergic rhinitis and bronchial asthma

Pathogenetic Mechanismsin IgG4-Related Disease and Clinical Implications.Autoimmunity and infectious agents are potential immunologic triggers in IgG4-related disease (Panel A). Interleukins 4, 5, 10, and 13 and transforming growth factor β (TGF-β) are overexpressed through an immune reaction in which type 2 helper T (Th2) cells predominate, followed by activation of regulatory T (Treg) cells (Panel B). These cytokines 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 results in organ damage (Panel C).The inflammatory-cell infiltrate leads to tumefactive enlargement of the affected sites and organ dysfunction (Panel D).

Clinical Features

IgG4-RD can involve one or multiple organs. Patients can present with

1) Subacute development of a mass in the affected organ (eg, an orbital pseudotumor, a renal mass resembling renal cell carcinoma, nodular lesions in the lung) or

2) Diffuse enlargement of an organ (eg, the pancreas) Multiple organs are affected in 60 to 90 percent of patients

with IgG4-RD. The affected tissues share specific pathologic, serologic, and clinical features, regardless of the organ involved, in a manner analogous to the systemic involvement of sarcoidosis, another disorder with shared histopathologic features in the different tissues that are affected.

Lymphadenopathy is common, and symptoms of asthma or allergy are present in approximately 40 percent of patients.

IgG4-RD is often recognized incidentally based upon a radiologic finding or histopathologic examination of a tissue specimen.

The relatively commonly studied IgG4-RD include the following Type 1 (IgG4-related) AIP IgG4-related sclerosing cholangitis Mikulicz’s disease (IgG4-related dacryoadenitis and sialadenitis) Sclerosing sialadenitis (Küttner’s tumor, IgG4-related submandibular

gland disease) Inflammatory orbital pseudotumor (IgG4-related orbital inflammation or

orbital inflammatory pseudotumor) Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-

related dacryoadenitis) Idiopathic retroperitoneal fibrosis (Ormond’s disease) Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or

periaortitis) Riedel’s thyroiditis (IgG4-related thyroid disease) IgG4-related interstitial pneumonitis and pulmonary inflammatory

pseudotumors (IgG4-related lung disease) IgG4-related kidney disease (including tubulointerstitial nephritis [TIN]

and membranous glomerulonephritis [GN] secondary to IgG4-RD) IgG4-related hypophysitis IgG4-related pachymeningitis IgG4-related midline destructive disease

Type 1 (IgG4-related) AIP is the prototypical form of IgG4-RD. The prevalence of this condition in Japan has been estimated to be 0.82 per 100,000 persons, but this is likely to be an underestimate as clinical recognition of this disorder is growing .

AIP has been estimated to account for 2–6 %percent of patients with chronic pancreatitis. It often presents as a pancreatic mass or as painless obstructive jaundice and can be mistaken for pancreatic cancer.

Some patients with type 1 AIP exhibit acute, recurrent, or chronic pancreatitis, and AIP is frequently associated with diabetes mellitus.

Most patients have another concomitant IgG4-related condition, such as IgG4-related sclerosing cholangitis, lymphadenopathy, or salivary or lacrimal gland involvement

The differentiation of AIP from adenocarcinoma of the pancreas is sometimes difficult on the basis of clinical presentations. Painless jaundice, for example, is common to both. Many patients have undergone Whipple procedures out of concern for pancreatic cancer.

AIP

A form of sclerosing cholangitis that is clinically distinct from primary sclerosing cholangitis may occur as part of the IgG4-RD.

IgG4-related sclerosing cholangitis is the most frequent extrapancreatic manifestation of type 1 AIP (IgG4-related), present in over 70 percent of such patients. It very rarely occurs in the absence of pancreatitis.

Distinctions between primary sclerosing cholangitis and IgG4-related sclerosing cholangitis are crucial because of the drastically different prognoses in these conditions.

Unfortunately, the clinical distinction between primary sclerosing cholangitis and/or cholangiocarcinoma and IgG4-related sclerosing cholangitis can be difficult because biopsies performed via endoscopic retrograde cholangiopancreatography (ERCP) are seldom deep enough to define the histopathological features of IgG4-RD.

IgG4 related Sclerosing Cholangitis

Although clearly defined diagnostic criteria for IgG4 sclerosing cholangitis are lacking, differentiation from primary sclerosing cholangitis is based upon

1. Tissue biopsy with infiltrates of IgG4+ plasma cells and severe interstitial fibrosis

2. Increased IgG4 serum levels3. Characteristic responsiveness to

glucocorticoids.4. The presence of clinical manifestations of

IgG4-RD in extra-biliary organs can also be an important clue to the presence of IgG4-RD

Asymptomatic IgG4-related lymphadenopathy is common, occurring in 80 percent of patients with AIP; it is usually observed together with other clinical or laboratory manifestations of the syndrome, but may be the initial or only manifestation.

Symptoms occasionally occur due to mass effect of the enlarging nodes; individual nodes are typically no more than 2 centimetres in diameter but may range up to 5 centimetres.

Multiple groups of lymph nodes are usually involved; the mediastinal, hilar, intraabdominal, and axillary are most common.

The lymphadenopathy is generally non-tender and the nodes themselves are rubbery rather than hard.

IgG4 Related Lymphadenopathy

Patients with lymphadenopathy may exhibit elevated serum IgG4, serum IgG and IgE, polyclonal hypergammaglobulinemia, and elevations in the erythrocyte sedimentation rate (ESR).

The differential diagnosis in patients with generalized lymphadenopathy includes sarcoidosis, multicentric Castleman disease, infection (eg, tuberculosis), and lymphoma or other malignancy.

IgG4-related lymphadenopathy is distinguished from these conditions by the modest lymph node enlargement, histologic distinctions on biopsy, lack of constitutional features, and the usually striking clinical response to glucocorticoids

Salivary gland involvement is a common feature of IgG4-RD. Patients may either present with

1. enlargement of lacrimal and salivary glands (parotid and/or submandibular), previously referred to as Mikulicz disease, or with

2. Chronic sclerosing sialadenitis and unilateral or bilateral submandibular gland enlargement, previously referred to as Küttner’s tumor.

These diseases were initially considered to be a part of the spectrum of SS.

Salivary and Lacrimal Glands

Nearly 40 percent of patients with IgG4-related pancreatitis also have salivary or lacrimal gland involvement, while AIP may be seen in only 17 percent of patients presenting with sialadenitis.

Patients with salivary and lacrimal involvement include comparable numbers of both men and women.

The pathologic findings are typical of those in other patients with IgG4-RD, including the lymphoplasmacytic infiltrate with IgG4-positive cells, sometimes with obliterative phlebitis and fibrosis.

Increased IgG4 and IgE serum levels are also present. These histopathologic and laboratory findings

distinguish IgG4-related sialadenitis from SS.

The clinical features that characterize IgG4-related sialadenitis and also help to distinguish it from SS include :

●Fewer patients with dry mouth, dry eyes, or arthralgias .

●A higher frequency of allergic rhinitis and bronchial asthma .

●A higher frequency of AIP and interstitial nephritis.

●Low frequencies of autoantibodies.

Previously known as Ormond’s disease, Retroperitoneal fibrosis is now considered a part of the IgG4-RD spectrum.

A variable proportion of patients with idiopathic retroperitoneal fibrosis exhibits histologic and serologic changes consistent with IgG4-RD.

In some cases, the syndrome is responsive to glucocorticoids.

All of the published cases of IgG4-related retroperitoneal fibrosis exhibited involvement of other organs, including the pancreas, salivary glands, lymph nodes and the pituitary gland.

Retroperitoneal Fibrosis

Aortitis and periaortitis — IgG4-RD has been recognized as one of the causes of noninfectious aortitis.

Thyroid disease — Two forms of thyroid involvement in IgG4-RD have been described, including Reidel’s thyroiditis (IgG4-related thyroid disease) and the fibrous variant of Hashimoto’s thyroiditis.

 Multiple reports have documented IgG4-related pulmonary disease, which may be asymptomatic or present with cough, hemoptysis, dyspnea, pleurisy, or chest pain.

Pseudotumors and interstitial pneumonia have been associated with AIP.

The affected tissues exhibit characteristic lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells, interspersed with abundant storiform fibrosis.

Obliterative arteritis is more common in the lung than in other organs affected by IgG4-RD.

Lung and Pleural Disease

Renal involvement in patients with IgG4-RD; the most common finding is tubulointerstitial nephritis (TIN).

Affected patients are primarily middle-aged and older men, and histopathology and other laboratory characteristics are similar to those observed in patients with AIP.

The histologic findings include lymphoplasmacytic infiltration of the renal interstitium and the presence of fibrosis.

Nodular lesions mimicking renal carcinoma may be seen. IgG4-related membranous nephropathy is much less

frequent than IgG4-related TIN, and these sometimes occur together.

Renal Disease

Other involved organs and tissues — Involvement of other organs and tissues by IgG4-RD:

●Skin disease, including a subset of cutaneous pseudolymphoma.

●IgG4-hepatopathy, resembling autoimmune hepatitis. ●Lymphoplasmacytic gastritis. ●Sclerosing mastitis and inflammatory pseudotumors of

the breast ●Hypopituitarism with IgG4-related hypophysitis ●Pachymeningitis ●Prostatitis ●Constrictive pericarditis ●Nasopharyngeal disease ●Midline-destructive lesion

 The diagnosis of IgG4-RD is based upon biopsy findings demonstrating the characteristic histopathologic findings and immunohistochemical staining.

These findings include lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and lymphocytes, accompanied by fibrosis that has storiform features and often by obliterative phlebitis.

Modest tissue eosinophilia. Serum IgG4 levels should be measured, and isolated

elevated levels are a significant aid in diagnosis, although they are not diagnostic.

The histopathological and immunohistochemical staining features of IgG4-RD are strikingly similar in different tissues, regardless of the organ or tissue involved

Diagnosis

Indications for diagnostic evaluation  Patients at high risk for having IgG4-RD are

those with any of the following: ●Pancreatitis of unknown origin ●Sclerosing cholangitis ●Bilateral salivary and/or lacrimal gland

enlargement ●Retroperitoneal fibrosis ●Orbital pseudotumor or proptosis The likelihood of IgG4-RD for patients

presenting with at least one of these conditions is significantly increased if high serum levels of IgG4, allergic symptoms, and/or other fibrotic processes are also present.

1.Tissue biopsy – A core needle biopsy is

often adequate, but fine-needle aspirates do not provide adequate tissue. In the presence of abnormal histopathology characteristic of the syndrome, we generally do not perform additional biopsies of other organs, particularly if improvement in these other areas has occurred with glucocorticoid treatment.

 

Diagnostic studies — 

The serum IgG4 level was elevated above the upper limit of normal (>135 mg/dL) in 60-70 % of the patients. The degree of IgG4 elevation correlates imperfectly with the degree of disease activity, but is often a useful parameter to follow in individual patients. The serum IgG4 concentration tends to increase with the number of organs involved and usually decreases after treatment with glucocorticoid. 

2. Serum IgG4

Blood plasmablast concentrations may be a better biomarker than the serum IgG4 concentration, both for the purposes of diagnosis and following disease activity. Plasmablasts were identified through flow cytometry of peripheral blood.

These studies of circulating plasmablasts confirm that these cells are elevated to dramatically high levels in patients with active IgG4-RD, even in patients with normal serum IgG4 concentrations. Plasmablast counts therefore are a potentially useful biomarker for diagnosis, assessing response to treatment, and determining the appropriate time for retreatment.

3. Blood plasmablasts as biomarkers

Well-defined diagnostic criteria had previously been proposed only for AIP. The histopathological findings of a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis are critical features for establishing the diagnosis . The presence of these findings, often together with mild tissue eosinophilia, is strongly suggestive if accompanied by increased numbers of IgG4-positive plasma cells.

The number of IgG4-positive plasma cells per high-power field (HPF) that is regarded as consistent with or suggestive of IgG4-RD varies somewhat from tissue to tissue.

Diagnostic Criteria

The diagnosis cannot be predicted entirely upon the number of IgG4-positive plasma cells.

Similarly, the diagnosis of IgG4-RD cannot be based upon serum concentrations of IgG4 alone.

Thus, confirmation of the diagnosis by biopsy of an involved organ whenever this is possible is advised.

Blood plasmablast concentration measurements, particularly those for IgG4+ plasmablasts, are not widely available

Imaging studies – Computed tomography (CT) scan of the chest, abdomen, and pelvis in patients diagnosed with IgG4-RD, because of the frequency of subclinical disease.

Markers of allergic disease – Markers of allergic disease such as serum IgE concentrations and the peripheral eosinophil count, should be tested.

Postdiagnostic evaluation

 The optimal treatment for IgG4-RD has not been established.

A growing number of reports support the efficacy of B cell depletion with Rituximab in this condition.

However, no randomized trials have evaluated approaches to the treatment of IgG4-RD.

Treatment

Most patients respond to glucocorticoids within several weeks, typically with symptomatic improvement, reductions in the size of masses or organ enlargement, improvement in organ function, and often a decrease in serum levels of IgG4.

However, some require a few months to respond, and there are some patients who relapse and others who respond less well or not at all initially.

Those who respond poorly may include patients with more advanced fibrotic changes.

Glucocorticoids

Patients who are symptomatic from their organ involvement at the time of the diagnosis often benefit from treatment.

By contrast, for a subset of patients such as those who have mild lymphadenopathy or incidentally-detected lung nodules, watchful waiting may be appropriate.

The currently recommend protocol suggests beginning treatment with Prednisolone, usually at a dose of approximately 40 mg/day.

A response is frequently seen within two to four weeks and often sooner.

Once a significant response is clinically evident in the affected organ system, it is recommended to gradually taper the dose of glucocorticoids, with a planned reduction over a two-month period, as tolerated.

The tapering should be done with a goal of discontinuing the medicine completely.

In patients who are resistant to glucocorticoids or who are unable to have their dose reduced sufficiently (usually to below 10 mg/day) to avoid adverse effects of the medication due to chronic use, the preferred drug is Rituximab.

The recommended dosage is 1 gram IV every fifteen days for a total of two doses.

Rituximab

B cell depletion leads to the targeted reduction, often swiftly, of serum IgG4 concentrations, with relative preservation of the concentrations of other immunoglobulins and immunoglobulin subclasses.

Rituximab also leads even more swiftly to steep declines in blood plasmablast concentrations.

If Rituximab is not available, either Azathioprine (2 mg/kg/day) or Mycophenolate mofetil (up to 2.5 g/day as tolerated) are reasonable choices for second-line agents that have potential as glucocorticoid-sparing therapies.

However, the effects of these glucocorticoid-sparing medications in IgG4-RD have not been evaluated adequately to clearly define their role relative to other agents.

The natural history of IgG4-RD has not been well-defined.

A minority of patients improve at least temporarily without treatment, but the majority of these relapse and most patients have chronic disease that progresses at variable rates.

Causes of significant morbidity and mortality in untreated patients include cirrhosis and portal hypertension; retroperitoneal fibrosis; complications from aortic aneurysms, including dissection; biliary obstruction and diabetes mellitus.

Prognosis

A subset of patients have subacute constitutional symptoms marked by fatigue and weight loss that may be substantial over months, on the order of 20 or 30 pounds.

Sustained benefit may be observed in treated patients, but relapses are common after discontinuation of therapy.

Additional studies of long term prognosis are needed.

Several types of cancers have been reported in individual case studies, in relation to IgG4-RD.

Non-Hodgkin’s Lymphoma, gastric carcinoma, salivary duct carcinoma, pancreatic carcinoma, pulmonary adenocarcinoma, small cell carcinoma of the lung, and prostate carcinoma have been reported.

Risk of Malignancy

None of these documented patients experienced relapse of their IgG4-related disease after successful treatment of their cancers, raising the question as to whether IgG4-RD may occur as a paraneoplastic syndrome in these patients.

Additional study is required to determine the degree, if any, of increased risk for malignancies in patients of IgG4-RD.

Immunoglobulin G4-related systemic disease (IgG4-RD) is an increasingly recognized syndrome of unknown etiology, most often occurring in middle-aged and older men, which is comprised of a collection of disorders that share specific pathologic, serologic, and clinical features.

Several of the manifestations typically occur in the same patient.

Conclusion

The commonly studied IgG4-RD include the following.1. Type 1 autoimmune pancreatitis (AIP) and IgG4-related

sclerosing cholangitis2. Mikulicz’s disease and sclerosing sialadenitis (Küttner’s

tumor), inflammatory orbital pseudotumor, and chronic sclerosing dacryoadenitis.

3. Idiopathic retroperitoneal fibrosis.4. Chronic sclerosing aortitis and periaortitis.5. Riedel’s thyroiditis and a subset of Hashimoto’s thyroiditis.6. IgG4-related interstitial pneumonitis and pulmonary

inflammatory pseudotumors.7. IgG4-related renal disease, particularly tubulointerstitial

nephritis.

The hallmarks of IgG4-RD are lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and small lymphocytes, which may be accompanied by fibrosis, obliterative phlebitis, and, in the majority of patients, elevated serum levels of IgG4.

Patients often present with subacute development of a mass in the affected organ or diffuse enlargement of an organ.

Lymphadenopathy is common, and symptoms of asthma or allergy may be present.

A good initial therapeutic response to glucocorticoids is also characteristic

The diagnosis of IgG4-RD is based upon biopsy findings demonstrating the characteristic histopathology.

Serum IgG4 levels should be measured, and isolated elevated levels are a significant aid in diagnosis, although they are not diagnostic.

Additional organ involvement may be identified.

It is currently recommended to begin treatment with glucocorticoids. Therapy is usually initiated with Prednisolone (40 mg/day), which is then tapered as tolerated over a two-month period.

Responses are characterized by symptomatic improvement, reductions in the size of masses or organ enlargement, improvement in organ function, and often a decrease in serum levels of IgG4.

In patients who do not respond to up to 40 mg/day of prednisolone, or who cannot be tapered to less than 10 mg daily, Rituximab can be used.

The natural history and prognosis are not well-described.

Spontaneous improvement can be seen, but disease often recurs without treatment.

Most patients respond initially to therapy with glucocorticoids, but relapses are common following discontinuation of therapy.

Significant organ dysfunction may arise from uncontrolled and progressive inflammatory and fibrotic changes in affected tissues.

The possibility of increased risk of malignancy in patients with IgG4-RD requires further study.

Thank You.