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: SystemUncommon symptoms and complications Neurological Seizures, paralysis or hemiparesis, cranial nerve palsies, sensorineural hearing loss, pituitary hormone deficiencies Eye Loss of vision, proptosis Cardiovascular Constrictive pericarditis, heart block, ruptured aortic aneurysm, aortic dissection, carotid artery dissection, intracranial aneurysm, angina, sudden cardiac death Respiratory Airway obstruction, pleural effusion Gastrointestinal Esophageal obstruction, bowel obstruction Urological Renal failure, hydronephrosis, testicular pain
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.
Nomenclature for individual organ involvement Organ or site Preferred names Previously used names Head and neck Salivary gland IgG4-related sialadenitis: IgG4-related submandibular gland disease, IgG4-related parotitis Mikulicz's disease (salivary and lacrimal glands), chronic sclerosing sialadenitis, Küttner's tumour (submandibular glands) Orbit IgG4-related ophthalmic disease (IgG4-ROD) including: IgG4-related dacryoadenitis (lacrimal glands), IgG4-related orbital inflammation (or IgG4-related orbital inflammatory pseudotumor), IgG4-related orbital myositis (extraocular muscles), IgG4-related pan-orbital inflammation Mikulicz's disease (salivary and lacrimal glands), Idiopathic orbital inflammatory disease, orbital pseudotumor Paranasal sinuses Chronic sinusitis, Eosinophilic angiocentric fibrosis (upper respiratory tract and orbit) Pharynx IgG4-related pharyngitis Thyroid gland IgG4-related thyroid disease Riedel's thyroiditis, Riedel's struma Soft tissues of the head and neck Idiopathic cervical fibrosis, sclerosing cervicitis, cervical fibrosclerosis Central Nervous System Pituitary gland IgG4-related hypophysitis: IgG4-related panhypophysitis (all of pituitary gland), IgG4-related adenohypophysitis (anterior pituitary), IgG4-related infundibuloneurohypophysitis (posterior pituitary and pituitary stalk) Autoimmune hypophysitis Meninges IgG4-related pachymeningitis (dura mater),IgG4-related leptomeningitis (arachnoid and pia mater) Idiopathic hypertrophic pachymeningitis Chest and abdomen Pancreas IgG4-related pancreatitis Type 1 autoimmune pancreatitis, lymphoplasmacytic sclerosing pancreatitis, 'chronic pancreatitis with diffuse irregular narrowing of the main pancreatic duct' Lung IgG4-related lung disease Pulmonary inflammatory pseudotumour Pleura IgG4-related pleuritis Liver IgG4-related hepatopathy Bile duct IgG4-related sclerosing cholangitis Gallbladder IgG4-related cholecystitis Aorta(especially the infrarenal portion) IgG4-related aortitis,IgG4-related periaortitis Inflammatory aortic aneurysm,Chronic sclerosing aortitis, chronic periaortitis. Branches of the aorta(including coronary, renal or iliac arteries) IgG4-related periarteritis Pericardium IgG4-related pericarditis Mediastinum IgG4-related mediastinitis Fibrosing mediastinitis, chronic sclerosing mediastinitis Retroperitoneum IgG4-related retroperitoneal fibrosis Retroperitoneal fibrosis, Albarran-Ormond syndrome, Ormond's disease, perirenal fasciitis, Gerota's fasciitis/syndrome, periureteritis fibrosa, sclerosing lipogranuloma, sclerosing retroperitoneal granuloma, non-specific retroperitoneal inflammation, sclerosing retroperitonitis, retroperitoneal vasculitis with perivascular fibrosis. Mesentery IgG4-related mesenteritis (subtypes are: mesenteric panniculitis, mesenteric lipodystrophy and retractile mesenteritis) Sclerosing mesenteritis, systemic nodular panniculitis, liposclerosis mesenteritis, mesenteric Weber–Christian disease, mesenteric lipogranuloma, xanthogranulomatous mesenteritis. Breast IgG4-related mastitis Sclerosing mastitis Genitourinary Kidney IgG4-related kidney disease (IgG4-RKD): IgG4-related tubulointerstitial nephritis (IgG4-TIN), membranous glomerulonephritis secondary to IgG4-related disease, IgG4 plasma cell arteritis IgG4-related renal pyelitis (renal pelvis) Idiopathic hypocomplementemic tubulointerstitial nephritis Prostate IgG4-related prostatitis Vas deferens IgG4-related perivasal fibrosis Chronic orchialgia Scrotum IgG4-related paratesticular pseudotumor,IgG4-related epididymo-orchitis Paratesticular fibrous pseudotumor, inflammatory pseudotumor of the spermatic cord, pseudosarcomatous myofibroblastic proliferations of the spermatic cord, proliferative funiculitis, chronic proliferative periorchitis, fibromatous periorchitis, nodular periorchitis, reactive periorchitis, fibrous mesothelioma Other Lymph nodes IgG4-related lymphadenopathy Skin IgG4-related skin disease Angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma Nerve IgG4-related perineural disease
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: ] (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.
Induction of remission In untreated patients with active disease, the recommended first-line agent for induction of remission is glucocorticoids unless contraindications exist. Glucocorticoids characteristically result in a rapid and often dramatic improvement in clinical features and often a resolution of radiographic 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.