IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic disease, is a chronic inflammatory condition characterized by tissue infiltration with

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

s and

IgG4 Immunoglobulin G (Ig G) is a Antibody#Classes, type of antibody. Representing approximately 75% of blood plasma, serum immunoglobulins, antibodies in humans, IgG is the most common type of antibody found in Circulatory system, blood circulation. I ...

-secreting

plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...

s, various degrees of

fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

(scarring) and a usually prompt response to oral

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...

s. In approximately 51–70% of people with this disease, ''serum'' IgG4 concentrations are elevated during an

acute Acute may refer to: Science and technology * Acute angle ** Acute triangle ** Acute, a leaf shape in the glossary of leaf morphology * Acute (medicine), a disease that it is of short duration and of recent onset. ** Acute toxicity, the adverse eff ...

phase. It is a relapsing-remitting disease associated with a tendency to mass forming, tissue-destructive

lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

s in multiple sites, with a characteristic

histopathological Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...

appearance in whichever site is involved. Inflammation and the deposition of

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

in affected anatomical sites can lead to organ dysfunction, organ failure, or even death if not treated. Early detection is important to avoid organ damage and potentially serious complications. Treatment is recommended in all symptomatic cases of IgG4-RD and also in asymptomatic IgG4-RD involving certain anatomical sites.

Signs and symptoms

IgG4-related disease has been described as an indolent condition. Although possibly based on opinion rather than on objective assessments, symptoms, if any, are commonly described as mild in the medical literature. This can be in spite of considerable underlying organ destruction. People are often described as being generally well at the time of diagnosis, although some may give a history of weight loss. Pain is generally not a feature of inflammation. However, it may occur as a secondary effect, for example, due to either obstruction or compression. Often diagnosis is made due to the presence of painless swellings or mass lesions, or due to complications of masses, e.g.

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

due to involvement of the pancreas, biliary tree or liver. Symptoms are commonly attributed to other conditions and other diagnoses may have been made years before diagnosis, e.g. urinary symptoms in men attributed to common prostate conditions. Lesions may also be detected incidentally on radiological images, but can be easily misdiagnosed as malignancies. Reported cases do include some significant symptoms or findings however:

Individual organ manifestations

IgG4-RD can involve one or multiple sites in the body. With multiorgan involvement, the sites involved can be affected at the same time (synchronously) or at different unrelated periods (metachronously). Several different diseases that have been known for many years are now considered to be manifestations of IgG4-RD. These include: type 1 autoimmune pancreatitis,

interstitial nephritis Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...

Riedel's thyroiditis Riedel's thyroiditis, is a chronic form of thyroiditis. It is now believed that Riedel's thyroiditis is one manifestation of a systemic disease that can affect many organ systems called IgG4-related disease. It is often a multi-organ disease affect ...

, Mikulicz's disease, Küttner's tumor,

inflammatory pseudotumor According to the WHO classification, three lesional patterns can be observed * Inflammatory myofibroblastic tumour, that can be associated with an ALK gene rearrangement * Plasmocytic pattern (" plasma cell granuloma"), that can be linked to IgG4 ...

s (in various sites of the body), mediastinal fibrosis and some cases of

retroperitoneal fibrosis Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It may present wi ...

. This is not a complete list, as IgG4-RD can involve any site in the body. Other affected sites, confirmed on

histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...

to be manifestations of IgG4-RD, include:

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...

;

hard palate The hard palate is a thin horizontal bony plate made up of two bones of the facial skeleton, located in the roof of the mouth. The bones are the palatine process of the maxilla and the horizontal plate of palatine bone. The hard palate spans ...

esophagus The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...

stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

small intestine The small intestine or small bowel is an organ in the gastrointestinal tract where most of the absorption of nutrients from food takes place. It lies between the stomach and large intestine, and receives bile and pancreatic juice through the p ...

rectum The rectum is the final straight portion of the large intestine in humans and some other mammals, and the Gastrointestinal tract, gut in others. The adult human rectum is about long, and begins at the rectosigmoid junction (the end of the s ...

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...

ureter The ureters are tubes made of smooth muscle that propel urine from the kidneys to the urinary bladder. In a human adult, the ureters are usually long and around in diameter. The ureter is lined by urothelial cells, a type of transitional epit ...

bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters ...

urachus The urachus is a fibrous remnant of the allantois, a canal that drains the urinary bladder of the fetus that joins and runs within the umbilical cord. The fibrous remnant lies in the space of Retzius, between the transverse fascia anteriorly and ...

, and synovium. Approximately 1/3 of cases exhibit increases in blood eosinophil counts, either eosinophilia or hypereosinophilia. Radiologic evidence suggestive of involvement of the

superior vena cava The superior vena cava (SVC) is the superior of the two venae cavae, the great venous trunks that return deoxygenated blood from the systemic circulation to the right atrium of the heart. It is a large-diameter (24 mm) short length vein th ...

and

seminal vesicle The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen. The vesicles are 5� ...

has been reported in confirmed cases of IgG4-RD.

Histology

Whatever area of the body is involved, the hallmark histopathological features of IgG4-RD are: # A dense lymphoplasmacytic (

s and

s) infiltrate rich in IgG4-positive plasma cells. #* IgG4

immunostaining In biochemistry, immunostaining is any use of an antibody-based method to detect a specific protein in a sample. The term "immunostaining" was originally used to refer to the immunohistochemical staining of tissue sections, as first described by A ...

needs to be specifically requested and performed in order to detect IgG4-positive plasma cells. #

Fibrosis Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...

, arranged at least focally in a "storiform" pattern. #* "Storiform" is commonly referred to as meaning 'having a cartwheel pattern', but its literal meaning is the appearance of 'a woven mat '' atin: ' (of rush or straw)'. # Obliterative

phlebitis Phlebitis (or Venitis) is inflammation of a vein, usually in the legs. It most commonly occurs in superficial veins. Phlebitis often occurs in conjunction with thrombosis and is then called thrombophlebitis or superficial thrombophlebitis. Unlike ...

. #* The venous channels are obliterated by a dense lymphoplasmacytic infiltrate, within both the venous walls and the lumen. Other histopathological features associated with IgG4-RD are: *

Phlebitis Phlebitis (or Venitis) is inflammation of a vein, usually in the legs. It most commonly occurs in superficial veins. Phlebitis often occurs in conjunction with thrombosis and is then called thrombophlebitis or superficial thrombophlebitis. Unlike ...

without obliteration of the lumen. * Tissue has increased numbers of

eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

Submandibular gland research

In an article from 1977, histological research into 349 cases of Küttner's tumor (now known as 'IgG4-related sialadenitis') identified four distinct stages of the fibroinflammatory process: * Stage 1: ''Focal'' periductal (around the salivary ducts) infiltration of lymphocytes * Stage 2: ''Diffuse'' infiltration of lymphocytes and severe periductal

(scarring around the salivary ducts) * Stage 3: Prominent infiltration of lymphocytes, atrophy of

parenchyma Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms. Etymology The term ''parenchyma'' is New Latin from the word π ...

(i.e. loss of functional areas due to shrinkage), and periductal sclerosis (scarring resulting in hardening around the salivary ducts) * Stage 4: Marked loss of and sclerosis (hardening) of the

(functional area) - similar to the process involved in

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

where there is shrinkage and loss of functional areas of the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

This may reflect the inflammatory process and development of fibrosis that occurs in other organs involved in IgG4-RD.

Diagnosis

Diagnosis requires tissue biopsy of an affected organ with characteristic histological findings. Serum immunoglobulin G4 is often elevated but this is not always the case.

Treatment

The goal of treatment is the induction and maintenance of remission so as to prevent progression of fibrosis and organ destruction in affected organ(s). An international panel of experts have developed recommendations for the management of IgG4-RD. They concluded that in all cases of symptomatic, active IgG4-RD that treatment is required. Some cases with

asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...

IgG4-RD also require treatment, as some organs tend to not cause symptoms until the late stages of disease. Urgent treatment is advised with certain organ manifestations, such as

aortitis Aortitis is the inflammation of the aortic wall. The disorder is potentially life-threatening and rare. It is reported that there are only 1–3 new cases of aortitis per year per million people in the United States and Europe. Aortitis is most com ...

, proximal biliary strictures,

tubulointerstitial nephritis Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...

, pachymeningitis, pancreatic enlargement and

pericarditis Pericarditis is inflammation of the pericardium, the fibrous sac surrounding the heart. Symptoms typically include sudden onset of sharp chest pain, which may also be felt in the shoulders, neck, or back. The pain is typically less severe when sit ...

Induction of remission

In untreated patients with active disease, the recommended first-line agent for induction of remission is

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

s unless

contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

s exist. Glucocorticoids characteristically result in a rapid and often dramatic improvement in clinical features and often a resolution of

radiographic Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeut ...

features. However, where advanced fibrotic lesions have resulted in irreversible damage, the response to glucocorticoids and other current treatment options may be poor or even absent. Although not validated yet in clinical trials, the common induction regime is

prednisolone Prednisolone is a steroid medication used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthrit ...

30–40 mg per day for 2–4 weeks, then gradually tapered over 3 to 6 months. Recurrences during or after tapering of glucocorticoids are frequent, however. Steroid-sparing immunosuppressive agents might be considered, depending on local availability of these drugs, for use in combination with glucocorticoids from the start of treatment in order to reduce the side-effects of prolonged glucocorticoid usage. Steroid-sparing agents that have been used include

rituximab Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric pa ...

azathioprine Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...

methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...

, and

cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...

, although trials are needed to ascertain the effectiveness of each drug in IgG4-RD.

Maintenance

Following a successful induction of remission, maintenance therapy might be given in some cases, for example when there is a high risk of relapse or in patients with organ-threatening manifestations. Common maintenance therapy is

2.5–5 mg per day, or use of a steroid-sparing agent instead.

Relapse

Relapse In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or ...

s are common, and a previous history of relapse appears to be a strong predictor of future relapse. When relapse occurs while off therapy and there has been a prolonged disease remission following initial glucocorticoid induction, then the relapse can usually be managed successfully with a re-induction strategy using glucocorticoids. Introducing a steroid-sparing agent might also need to be considered for relapses; however, none has been tested in prospective, controlled studies, and evidence for their efficacy beyond that offered by concomitant glucocorticoid therapy is scarce. In one retrospective cohort study, baseline concentrations of serum IgG4, IgE and blood eosinophils were found to be independently predictive of relapse risk following treatment with

with or without glucocorticoids; the higher the baseline values, the greater the relapse risk and the shorter the time to relapse.

Other interventions

When organ involvement causes local mechanical problems, further organ-specific interventions may be necessary. For example, when a tumefactive lesion causes obstruction of the

bile duct A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...

, it may be necessary to insert a biliary

stent In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...

to allow the

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...

to drain freely. Similarly, ureteral or vascular stents, surgical resection or radiotherapy may be considered for various different presenting problems.

Trials

Research is also underway to evaluate the effect and safety of plasmablast-directed therapy with a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

(XmAb5871) which inhibits B-cell function without depleting these immune cells. XmAb5871 targets CD19 with its variable domain and has an Fc domain that has increased affinity to FcγRIIb.

Epidemiology

As recognition of IgG4-RD is relatively recent, there are limited studies on its epidemiology. It is therefore difficult to make an accurate estimation of prevalence. Furthermore, age of onset is almost impossible to estimate; age at diagnosis is frequently misused as the age of onset. A 2011 study estimated the incidence of IgG4-RD in Japan at 2.8–10.8/million population, with a median age of onset of 58 years.

Nomenclature

Prior to 2011, IgG4-RD used to get mentioned in the medical literature under various different names. At th
2011 International Symposium on IgG4-Related Diseases
the consensus name of IgG4-related disease was endorsed for the condition. This name had already been agreed upon as a consensus name among Japanese investigators, notably choosing not to use the term ' systemic' as that might lead to

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

tumour A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s in other organs getting incorrectly diagnosed as being just another manifestation of the IgG4-related condition. However, some experts at the international symposium did express reservations about naming the disease after

, as its role in

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

is questionable and the use of serum IgG4 concentrations as a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

is unreliable. An expanded term, 'Immunoglobulin G4-related disease', has sometimes been used also. However, this term was never referenced in the 2012 recommendations for nomenclature, and its use would appear to be erroneous.

References

External links

Overview of IgG4-related disease
-

UpToDate UpToDate, Inc. is a company in the Wolters Kluwer Health division of Wolters Kluwer whose main product is UpToDate, a software system that is a point-of-care medical resource. The UpToDate system is an evidence-based clinical resource. It includ ...

's article on IgG4-related disease.
DermNet NZ
entry {{DEFAULTSORT:IgG4-related disease Immune system disorders Autoimmune diseases Pancreas disorders Salivary gland pathology Hepatology Steroid-responsive inflammatory conditions