What is igg4 disease

Mod Pathol 25 9 , Diagnosis is clinical. Treatment is of the causative disorder. See also Overview of the Lymphatic System. Lymph nodes are present Fever is highly uncommon in IgG4-RD and should prompt consideration of alternative diagnoses. Pancreatic involvement may be painless, sometimes with jaundice if there is an obstructing pancreatic mass, or may cause abdominal pain and nausea if acute pancreatitis Acute Pancreatitis Acute pancreatitis is acute inflammation of the pancreas and, sometimes, adjacent tissues.

Some patients present with a more smoldering and insidious chronic pancreatitis Chronic Pancreatitis Chronic pancreatitis is persistent inflammation of the pancreas that results in permanent structural damage with fibrosis and ductal strictures, followed by a decline in exocrine and endocrine Retroperitoneal fibrosis most often manifests with flank or back pain but is often asymptomatic and identified incidentally on abdominal imaging.

Aortitis is almost always asymptomatic and identified only incidentally by imaging or postoperatively after aortic resection. Salivary and lacrimal gland involvement usually causes painless, bilateral enlargement. Orbital involvement may cause proptosis Proptosis This photo shows a woman's slightly bulging left eye proptosis , caused by a meningioma. Proptosis is protrusion of the eyeball.

Exophthalmos means the same thing, and this term is usually The following other causes of similar manifestations must be considered:. It sometimes causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice but may be asymptomatic The major types are Hodgkin lymphoma and non-Hodgkin lymphoma see table Comparison of Lung involvement: Sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown.

Symptoms and signs develop over months to years and include TB most commonly affects the lungs. Symptoms include productive Pancreatic involvement: Acute or chronic pancreatitis Overview of Pancreatitis Pancreatitis is classified as either acute or chronic.

Acute pancreatitis is inflammation that resolves both clinically and histologically. Chronic pancreatitis is characterized by histologic Symptoms include weight loss, abdominal pain, and jaundice Aortic involvement: Giant cell arteritis Giant Cell Arteritis Giant cell arteritis involves predominantly the thoracic aorta, large arteries emerging from the aorta in the neck, and extracranial branches of the carotid arteries. Symptoms of polymyalgia Retroperitoneal involvement: Lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems.

Lymphadenopathy: Sarcoidosis Sarcoidosis Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. See also Overview of Histiocytic Syndromes Although these criteria are not designed for diagnostic purposes, they do offer a framework for thinking about the disease, including suggested testing and interpretation of the results.

Immunostaining with IgG4 and IgG should be done only if there are at least 2 of the following 3 histopathologic findings: dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Cross-sectional imaging CT, MRI should be done of clinically affected areas eg, of orbits, chest, abdomen and pelvis. Imaging of other areas is often done to screen for asymptomatic manifestations eg, retroperitoneal fibrosis. Chronic allergic conditions are a frequent cause of mild serum IgG4 elevation.

An elevated total IgG level hypergammaglobulinemia or an elevated globulin to albumin ratio indicates the activation of antibody secreting cells that is typical of but not specific to IgG4-RD. The elevation in total IgG likely reflects the accumulation of auto-antibodies. Marked elevations of the total IgE level often 5 to 10 times the upper limit of normal are common in patients with IgG4-RD.

Arthritis Rheumatol 72 1 , Rheumatology Oxford 55 6 , Like most immune-mediated conditions, there is no cure, but IgG4-RD is very treatable. Most of the organ damage in this disease happens prior to diagnosis.

Treatment of IgG4-RD aims to reduce inflammation, induce remission, and preserve organ function. Following the recognition that autoimmune pancreatitis often has other disease associations, it became clear that the disease now known as IgG4-RD unifies many conditions once regarded as single organ diseases.

Some patients with IgG4-RD have disease in only one organ. Others, however, have disease that affects multiple organs at the same time. It is not unusual for disease to affect anywhere between two and six organs, and sometimes more, in a single patient.

Orbits — Also known as the eye sockets, are the muscles that attach to the sides of the eye and move the eye. Lacrimal glands — The glands on the upper outer portion of the eyes that produce tears.

Major salivary glands — The parotid, submandibular, and sublingual glands produce saliva to aid in the digestion of food. Thyroid gland — The thyroid gland produces a hormone that is important in the regulation of normal body metabolism. Lungs — Tissues of the airways and the lung tissue itself may be involved by a wide array of lesions.

Kidneys — Both the kidneys themselves and the ureters — the organs through which they pass urine into the bladder — can be affected.

Pancreas — The pancreas has both an endocrine function makes insulin, which mediates normal blood glucose control and an exocrine function produces digestive enzymes, critical for the digestion of some foods, particularly fats and proteins. Both the endocrine and the exocrine roles of the pancreas may be affected by IgG4-RD.

Bile ducts — The bile ducts are located both within and outside the liver. They are the channel through which the liver, gallbladder, and pancreas provide digestive enzymes and bile to the gastrointestinal tract, aiding in normal metabolism of nutrients.

Because of the many organs that IgG4-RD can affect, the disease can exist in multiple ways associated with many symptoms. A couple of important themes occur, however:. IgG4-RD typically has a subacute onset, meaning many patients have had active disease with no signs or symptoms for months or even years before the diagnosis is made. The result of this subacute onset is that organ damage often occurs even while the patient is feeling well, long before he or she comes to medical attention.

Patients often feel well for long periods of time despite having disease in multiple organs. Fevers are rare to non-existent in IgG4-RD. Fatigue is often a common symptom, but because fatigue can be a common symptom for many conditions, patients often endure this symptom for long periods of time without a diagnosis. Weight loss can be a prominent component of how IgG4-RD presents. The loss of anywhere between 10 and 50 pounds in IgG4-RD is often because of subclinical pancreatic dysfunction.

The damaged pancreas is no longer making the appropriate amount of digestive enzymes. As a result, patients do not absorb nutrients and calories from their food and often experience extreme weight loss that defies diagnosis for an extended period of time. The most common symptoms below are grouped according to organ:. Meninges — Patients with IgG4-RD affecting the meninges often present with headaches or dysfunction of the cranial nerves, which control eye movements, speech, swallowing, hearing, and other critical functions.

Some patients also develop double vision and the inability to move their eyes together in a coordinated fashion because of tethering of the extra-ocular muscles. Lacrimal glands — The lacrimal glands typically become enlarged. Innate immunity and complement Latest studies have cast doubt over the model of IgG4-RD as a primarily T-cell-driven disease. Future prospects Summing up, it appears that the role of innate immunity in IgG4-RD has been underestimated in the past and needs to be further clarified by future research, just like the question, whether IgG4 antibodies represent a causative factor or just a bystander in the disease.

Differential diagnosis All those mentioned signs and symptoms are highly unspecific. Standard laboratory testing Besides renal, pancreatic, and liver manifestations, which may result in organ-specific laboratory findings, there is no standard laboratory parameter that would explicitly mark the presence of IgG4-RD. Histopathology According to most experts, biopsy and histological proof is the gold standard in the diagnosis of IgG4-RD and should be acquired if anyhow possible.

Imaging techniques As IgG4-RD frequently presents itself with organ enlargement and tumefactive lesions, imaging is obviously essential as malignancy is usually the main differential diagnosis. Open in a separate window. Figure 1. Figure 2. Diagnostic criteria In , Japanese investigators proposed comprehensive diagnostic criteria for IgG4-RD, according to which diagnosis should be based on three pillars Table 1.

Therapy Indication for treatment Untreated IgG4-RD in vital organs such as pancreas and kidney can — even if asymptomatic — lead to irreversible organ damage within only months and therefore requires immediate treatment. Initial treatment and maintenance therapy Glucocorticoids GCs have been considered the first-line therapy in IgG4-RD ever since the first description of AIP in , when prompt response to GC treatment was reported as a characteristic finding.

Disease activity IgG4-RD is a chronic, frequently relapsing disease, which often requires long-term maintenance therapy. Future prospects Regardless of the therapy modality ultimately chosen, it seems that relapses happen frequently in IgG4-RD.

Conclusion IgG4-RD is a complex condition with a highly variable clinical appearance that can mimic various inflammatory and neoplastic diseases. References 1. Mod Rheumatol. IgG4-related disease: an orphan disease with many faces. Orphanet J Rare Dis.

IgG4-related disease: dataset of consecutive patients. Medicine Baltimore ; 94 15 :e Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. IgG4-related sclerosing disease incorporating sclerosing pancreatitis, cholangitis, sialadenitis and retroperitoneal fibrosis with lymphadenopa-thy.

Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum. Okazaki K, Umehara H. Are classification criteria for IgG4-RD now possible? The concept of IgG4-related disease and proposal of comprehensive diagnostic criteria in Japan.

Int J Rheumatol. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. The clinical spectrum of IgG4-related disease. Autoimmun Rev. IgG4-related disease: clinical and laboratory features in one hundred twenty-five patients.

Arthritis Rheumatol. A clinicopathologic case study of two patients with pediatric orbital IgG4-related disease.

Research Committee on Intractable Diseases of Pancreas Nationwide epidemiological survey of autoimmune pancreatitis in Japan. Organ correlation in IgG4-related diseases. J Korean Med Sci. Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease. Immunology of IgG4-related disease. Clin Exp Immunol. Risk of malignancies in IgG4-related disease. Risk of cancer in patients with autoimmune pancreatitis. Am J Gastroenterol. Incidence of malignancies in patients with IgG4-related disease.

Intern Med. Synchronous autoimmune pancreatitis and infiltrating pancreatic ductal adenocarcinoma: case report and review of the literature.

Hum Pathol. IgG4-related disease and its pathogenesis-cross-talk between innate and acquired immunity. Int Immunol. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc. Human monoclonal IgG isotypes differ in complement activating function at the level of C4 as well as C1q. J Exp Med.

Immunoglobulin G4: an odd antibody. Clin Exp Allergy. J Thromb Haemost. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease.

J Allergy Clin Immunol. IgG4-related fibrotic diseases from an immunological perspective: regulators out of control? Analysis of IgG4 class switch-related molecules in IgG4-related disease. Arthritis Res Ther. Clin Nephrol. T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease.

Clin Immunol. Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease.

J Gastroenterol. Antibodies to IgG4 hinge can be found in rheumatoid arthritis patients during all stages of disease and may exacerbate chronic antibody-mediated inflammation. Diagnostic approach to the complexity of IgG4-related disease.