IgG4-Related Disease - Causes, Pathology, Symptoms, and Treatment

Introduction

IgG4-related disease is an immune condition that results in various immunologic diseases across multiple organs. An IgG4 dysfunction affects the pancreas, bile ducts, orbits, lungs, kidneys, and retroperitoneum. The condition can present itself in a solitary organ or as a multi-organ disease affecting anywhere between two and six organs, and sometimes more, in a single patient.

Who Is Susceptible to IgG4-Related Disease?

The exact prevalence of IgG4-related disease is still under question as the recognition of the condition is under investigation; also, it lacks an official International Statistical Classification of Diseases and related health problems (ICD-10) code which makes epidemiological studies a challenge. In Japan, where it was first recognized, the approximate prevalence stands at 0.28 to 1.08 per 100,000 individuals, which might be an underestimation. The condition shows a slight predilection for middle-aged and old individuals than for their female counterparts. The males dominate females with a ratio of 2:1. The prevalence increased from 2.2 to 4.6 per 100,000 population between 2007 to 2011 in Japan. The median age of patients was between the sixth and the seventh decade. Pediatric cases were rare. Pancreatic involvement was observed in 20 to 25 percent of the cases.

What Causes IgG4-Related Disease?

The exact etiology of IgG4-related disease is still controversial. The current idea suggests the infiltration of IgG4 immunoglobulins into various tissues is etiologic to the condition. Such infiltration is mediated by an autoimmune response that creates auto-antibodies against the body’s natural non-pathogenic cells. IgG4 has anti-inflammatory and tolerance-inducing effects, which get inaccurately targeted against normal cells.

What Is the Pathophysiology of IgG4-Related Disease?

The pathophysiology of IgG4-related disease has an autoimmune base with significant roles attributed to both B and T cells, especially CD4+ and T-follicular helper cells (Tfh). IgG4 immunoglobulin is not pathogenic by itself but rather acts as an epiphenomenon with an anti-inflammatory role. The condition is not triggered by a single antigen. Evidence reports galectin-3, laminin 111, and annexin A11 proteins as autoantigenic. As a result of an immune response, various cytokines get produced, which then recruit the IgG4 immunoglobulins. The immunoglobulins are not specific to this condition but are also found in several other rheumatic disorders.

CD4+ cytotoxic cells are abundantly found in the affected tissues and are dispersed throughout the IgG4-related disease lesions. The expanded population of CD4+ cytotoxic T lymphocytes in both the peripheral blood and fibrotic lesions suggests a more central role of these cells in the condition. Circulating Tfh cells facilitate B-cell proliferation and differentiation. T-follicular regulatory cells and Tfh cells regulate the germinal center formation and B-cell class switching. These cells, along with CD4+ cytotoxic T cells, orchestrate the condition and are sustained by continuous antigen presentation by cells of the B lymphocyte lineage.

What Are the Microscopic Findings of IgG4-Related Disease?

Histopathological studies of IgG4-related disease show dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, multifocal chronic fibrosing inflammation, tissue infiltration with IgG4, and positive plasma cell infiltration.

Five histological variants of the disease have been reported:

• Type I – Multicentric Castleman disease-like.

• Type II – Follicular hyperplasia.

• Type III – Interfollicular expansion.

• Type IV – Progressive transformation of germinal center-like.

• Type V – Nodal inflammatory pseudotumor-like.

What Are the Signs and Symptoms of IgG4-Related Disease?

IgG4 infiltration is seen in various organs from tip to toe in almost all organ systems. The patients often present with a subacute mass development in the affected organ resembling a tumor mass. Lymphadenopathy is one of the common symptoms seen in approximately 30 to 60 percent of patients. A majority of patients lose up to 14 kgs (kilograms) of weight before a definitive diagnosis which is indicative of a probable pancreatic failure. About 40 percent of the patients present with peripheral blood eosinophilia (increase in peripheral blood eosinophils to more than 600 cells per microliter, asthma, and atopy (immune problems making one prone to allergies).

1. Neurological Manifestations:

• Seizures.

• Paralysis.

• Hemiparesis (one-side paralysis).

• Cranial nerve palsies (paralysis or non-functioning cranial nerves).

• Headaches.

• Speech dysfunction.

• Swallowing dysfunction.

• Eye movement dysfunction.

• Sensorineural hearing loss.

• Pituitary hormone deficiencies.

• Painful neuropathy of limbs.

2. Optic Manifestations:

• Vision loss.

• Extraocular muscle control dysfunction.

• Proptosis (bulging of the eyes).

3. Cardiovascular Manifestations:

• Constrictive pericarditis.

• Heart block.

• Ruptured aortic aneurysm.

• Aortic dissection.

• Carotid artery dissection.

• Intracranial aneurysm.

• Angina.

• Sudden cardiac death.

4. Pulmonary Manifestations:

• Airway obstruction.

• Pleural effusion.

5. Gastrointestinal Manifestations:

• Esophageal obstruction.

• Bowel obstruction.

6. Urological Manifestations:

• Renal failure.

• Hydronephrosis (stretched and swollen kidneys due to urine accumulation).

• Testicular pain.

Manifestations of IgG4-Related Disease by Organ System:

1. Head and Neck:

• Orbital pseudotumors (swelling of the tissue behind the eye).

• Hypophysitis (inflammation of the pituitary gland).

• Hypertrophic pachymeningitis (inflammatory thickening of the dura mater).

• Mikulicz disease (enlargement of glands in head and neck), Kuttner tumor (chronic inflammatory swelling of the salivary gland).

• Tracheal stenosis (narrowing of the trachea).

• Riedel thyroiditis (chronic inflammation and fibrosis of the thyroid gland).

• Allergy, atopy, nasal polyps, and eosinophilic angiocentric fibrosis.

2. Skin:

• Erythematous papules (red pimple-like growth).

• Flesh-colored papules (skin-colored pimple-like growth).

3. Thorax:

• Asthma.

• Interstitial pneumonitis.

• Inflammatory pseudotumor of lungs and breasts.

• Pleural disease.

4. Abdomen:

• Autoimmune pancreatitis type 1.

• Sclerosing cholangitis or cholecystitis.

• Inflammatory mesenteritis (inflammatory disease affecting the mesentery).

• Gastritis.

5. Heart:

• Peri-aortitis.

• Coronary arteritis.

6. Mediastinal:

• Retroperitoneal fibrosis (RPF-abnormal fibrous tissue behind the peritoneum).

7. Renal:

• Tubulointerstitial nephritis (inflammation of kidney tubules and surrounding tissues).

• Membranous glomerulonephropathy (immune systems attacking the kidney’s filtering membranes).

• Obstructive uropathy from RPF (urine fails to drain due to RPF).

• Pyelitis (inflammation of the membrane of the pelvis and calyces of the kidney).

• Hydronephrosis.

8. Lacrimal Gland:

• Enlargement of the gland.

• Dacryoadenitis (inflammation of the lacrimal gland).

9. Salivary Glands:

• Enlargement of the parotid, submandibular, and sublingual glands.

• Xerostomia (dry mouth).

10. Thyroid Gland:

• Riedel’s thyroiditis (chronic inflammation and fibrosis of the thyroid gland).

• Airway compromise.

11. Pancreas:

• Painless jaundice.

• Exocrine failure of the pancreas.

• Substantial weight loss

• Diabetes mellitus.

12. Bile Duct:

• Cholangiocarcinoma (cancer that starts from the bile duct).

How to Diagnose IgG4-Related Disease?

The diagnosis of IgG4-related disease is primarily made through a complete medical history, and physical examination and secondarily may progress with various serological, imaging, and biopsy studies.

A. Serological Studies:

• Eosinophilia (increased eosinophil count).

• Polyclonal hypergammaglobulinemia (overproduction of multiple classes of immunoglobulins).

• Increased plasma levels (more than 135 mg/dl, milligrams per decilitre).

• Decreased complement factor (C3 and C4).

• Plasmablasts (greater than 2000 cells/ml, milliliter).

• Moderately high CRP (C-reactive protein).

• Serum IgG4 (greater than 5 g/L, grams per liter).

• IgG4:IgG (greater than 0.2).

• Autoantibodies.

• Albuminuria (too much albumin in the urine).

• Elevated lipase (increased amount of lipase-a type of digestive enzyme).

• Glucose intolerance (higher than normal glucose levels).

• Hepatitis (liver inflammation).

B. CT (Computed Tomography):

Pancreas:

• Hypodense, peri-glandular halo comprising an inflammatory infiltrate.

• Sausage pancreas (diffuse infiltration and loss of fatty lobulation).

• Delayed homogenous enhancement.

• Peripheral capsule-like rim.

• Irregular narrowing of the main pancreatic duct.

• Pancreatic duct diameter of less than 5 mm (millimeter).

Biliary Tree:

• Stricture of the distal common bile duct.

• Diffuse intrahepatic structures.

• Extrahepatic duct strictures.

• Hilar and distal common bile duct strictures.

• Solitary hilar strictures.

• Gallbladder wall thickening.

Glands:

• Bilateral and diffused enlargement.

• Symmetric enlargement and homogenous enhancement.

Arterial System:

• Aortic wall thickening.

• Homogenous enhancement.

• Circumscribed lesions.

• Periaortic inflammation.

• Aneurysmal dilatation.

• Accelerated atherosclerotic changes.

Retroperitoneum:

• Infiltrating IgG4 plasma cells.

• Soft tissue thickening.

• Preferential perivascular and periureteric involvement.

• Retroperitoneal fibrosis

• Periureteric plaque-like mass.

Renal:

• Peripheral cortical nodules.

• Round or wedge-shaped regions.

• Large solitary mass.

• Diffuse patchy parenchyma.

Lungs:

• Solitary pulmonary mass or nodule greater than 1 cm (centimeter).

• Round-shaped ground glass opacity.

• Thickening of the broncho-vascular bundles.

• Interlobular septal thickening.

Meninges:

• Thickening of the dura.

Pituitary:

• Focal mass or enlargement.

Lymph Nodes:

• Diffuse marked enhancement.

• Retroperitoneal, peripancreatic, mesenteric, mediastinal, hilar, and cervical lymphadenopathy.

C. MRI (Magnetic Resonance Imaging):

• MRI results of the pancreas scan are similar to that of CT scan results.

• Biliary tree MRI shows a thick symmetrical rind of enhancing soft tissue surrounding the strictures.

• A salivary gland scan shows homogenous low to intermediate signal intensity on T1 and T2 weighted images with a homogenous enhancement of the involved area.

• Lacrimal gland reports are isointense on T1-weighted MRI and hypointense on T2-weighted MRI.

• MRI reports of retroperitoneum are proportional to the degree of fibrosis and active inflammation, with low-intermediate signal intensity on T1-weighted imaging and variable signal intensity on T2-weighted and postcontrast imaging.

• Renal lesions are isointense on T1-weighted images, and hypointense on T2-weighted images and show progressive enhancement following intravenous gadolinium administration.

• On T2-weighted MRI in focal disease, the dura is thickened and hypointense with scattered foci of hyperintensity in the meninges.

• On post-contrast, T1-weighted MRI of the pituitary gland, homogenous enhancement is seen.

D. Ultrasound

Ultrasound study is only diagnostic in the salivary gland, where it shows focal involvement as hypoechoic hypervascular areas within the affected gland.

How to Treat IgG4-Related Disease?

Some symptoms, like asymptomatic lymphadenopathy or mild submandibular gland enlargement, may recede without any intervention. Some serious manifestations, like pachymeningitis may require urgent treatment.

• Initial Therapy: Glucocorticoid monotherapy as an initiation therapy had good response rates. The efficacy of the protocol was lower in American patients than in Asians. Initial therapy should be maintained for two to four weeks and gradually tapered over three to six months. A steroid-sparing agent like Prednisone should be added to therapy and cannot be tapered off. Other drugs include Methotrexate, Azathioprine, Mycophenolate, 6-Mercaptopurine, and Cyclophosphamide. Rituximab monotherapy has promising results in remission.

• Maintenance Therapy: Maintenance therapy with a small glucocorticoid dosage. A steroid-sparing agent with Rituximab can also be prescribed for maintenance.

Other treatment regimes include disease-modifying anti-rheumatic drugs (DMARDs), B-cell-targeted therapy, plasmablast-directed therapy, CD4+ CTL-directed treatments, and anti-fibrosis therapies.

What Is the Prognosis of IgG4-Related Disease?

The IgG4-related disease is capable of causing morbidity and mortality if the condition remains undiagnosed and untreated.

What Is the Differential Diagnosis of IgG4-Related Disease?

• Lung cancer.

• Inflammatory myofibroblastic tumor.

• Sarcoidosis.

• Granulomatosis with polyangiitis (GPA).

• Castleman disease.

• Lymphomatoid granulomatosis.

• Interstitial pneumonia.

What Are the Complications of IgG4-Related Disease?

• Cerebral aneurysm.

• Renal failure.

• Pancreatic cancer.

• Lung cancer with pleural dissemination.

• Type 1 autoimmune pancreatitis.

Conclusion

IgG4-related diseases are to be closely observed by a team of physicians concerned with persisting symptoms, adjunct to a rheumatologist. Although the condition presents with a fatality, most of the symptoms can be managed, with currently available medications and induce remission. The condition tends to relapse frequently, so maintenance therapy is essential.