IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic disease, is a chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and a usually prompt response to oral steroids. In approximately 51–70% of people with this disease, serum IgG4 concentrations are elevated during an acute phase. It is a relapsing-remitting disease associated with a tendency to mass forming, tissue-destructive lesions in multiple sites, with a characteristic histopathological appearance in whichever site is involved. Inflammation and the deposition of connective tissue 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. Laboratory levels of IgG4 greater than 135 mg/dL Moreover, diagnosis is made due to the presence of painless swellings or mass lesions, or due to complications of masses, e.g. jaundice 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, Riedel's thyroiditis, Mikulicz's disease, Küttner's tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis and some cases of retroperitoneal fibrosis.
This is not a complete list, as IgG4-RD can involve any site in the body. Other affected sites, confirmed on histology to be manifestations of IgG4-RD, include: heart; hard palate, esophagus, stomach, small intestine, rectum, adrenal gland, ovary, uterus, ureter, bladder, urachus, 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 and seminal vesicle 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 (lymphocytes and plasma cells) infiltrate rich in IgG4-positive plasma cells. IgG4 immunostaining needs to be specifically requested and performed in order to detect IgG4-positive plasma cells. Fibrosis, 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 [Latin: storea] (of rush or straw)'. Obliterative phlebitis. 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 without obliteration of the lumen. Tissue has increased numbers of eosinophils.
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 fibrosis (scarring around the salivary ducts) Stage 3: Prominent infiltration of lymphocytes, atrophy of parenchyma (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 parenchyma (functional area) - similar to the process involved in cirrhosis where there is shrinkage and loss of functional areas of the liver 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, a comprehensive medical history and physical examination from a physician astute in new and evolving connective tissue diseases such as IgG4-RD. Serum immunoglobulin G4 (IGG4) is often elevated, but this is not always the case. However, IgG4 blood lab levels greater than 135 are considered an evolving diagnostic criterion for disease suspicion
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 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, retroperitoneal fibrosis, proximal biliary strictures, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement and pericarditis.
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