IgG4-related disease

IgG4-related disease
Low power view of IgG4-related prostatitis Low power view of IgG4-related prostatitis. The prostatic stroma shows a dense inflammatory infiltrate and fibrosis (H&E, 100x)
Classification and external resources
Specialty	Immunology/Rheumatology
ICD-10	M35
Patient UK	IgG4-related disease
Orphanet	284264

IgG4-related disease (IgG4-RD) is a chronic inflammatory condition characterised by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and a prompt response usually to oral steroids.

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.

The disease, which was formerly also known as IgG4-related systemic disease, is so named because plasma cells producing the antibody subtype IgG4 are present in large amounts on tissue samples from involved organs, and because serum IgG4 concentrations are elevated in approximately 60–70% of people during an acute phase.

Inflammation resulting in fibrosis, the deposition of connective tissue, in affected anatomical sites can lead to organ dysfunction, or even organ failure, 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.

Nomenclature

Names previously used for IgG4-RD:
IgG4-related systemic disease (IgG4-RSD) IgG4-related sclerosing disease IgG4-related systemic sclerosing disease IgG4-related autoimmune disease IgG4-associated multifocal systemic fibrosis IgG4-associated disease IgG4 syndrome Hyper-IgG4 disease Systemic IgG4-related plasmacytic syndrome IgG4-positive multiorgan lymphoproliferative syndrome

Prior to 2011, IgG4-RD used to get mentioned in the medical literature under various different names.

At the 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 tumours 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 IgG4, as its role in pathogenesis is questionable and the use of serum IgG4 concentrations as a biomarker is unreliable.

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, retroperitoneal fibrosis, mediastinal fibrosis, Riedel's thyroiditis, Mikulicz's disease, Küttner's tumor and inflammatory pseudotumor are now regarded as forms of IgG4-RD.

Nomenclature for individual organ involvement

Organ or site	Preferred names	Previously used names
Head and neck
Salivary gland	IgG4-related sialadenitis	Chronic sclerosing sialadenitis, Küttner's tumour (submandibular glands), Mikulicz's disease (salivary and lacrimal glands)
Lacrimal gland	IgG4-related dacryoadenitis	Mikulicz's disease (salivary and lacrimal glands)
Orbit	IgG4-related ophthalmic disease (IgG4-ROD)	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 or 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 periaortitis.
Branches of the aorta (including coronary, renal or iliac arteries)	IgG4-related periarteritis
Pericardium	IgG4-related pericarditis
Mediastinum	IgG4-related mediastinitis	Fibrosing 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), IgG4-related membranous glomerulonephritis	Idiopathic 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.

Radiologic evidence suggestive of involvement of the superior vena cava and seminal vesicle has been reported in confirmed cases of IgG4-RD.

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 the 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 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:

System	Uncommon 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, angina, sudden cardiac death
Respiratory	Airway obstruction, pleural effusion
Gastrointestinal	Esophageal obstruction, bowel obstruction
Urological	Renal failure, hydronephrosis, testicular pain

Histology

Whatever area of the body is involved, the hallmark histopathological features of IgG4-RD are:

1. 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.
2. 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)'.
3. 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) lymphocytic infiltration
• Stage 2: Diffuse lymphocytic infiltration and severe periductal fibrosis (scarring)
• Stage 3: Prominent lymphocytic infiltration, atrophy of parenchyma (functional area), and periductal sclerosis (hardening due to scarring)
• Stage 4: Marked loss and sclerosis (hardening) of the parenchyma - similar to the process involved in cirrhosis where there is shrinkage and loss of functional areas of the liver

This may reflect the fibroinflammatory process in other organs involved in IgG4-RD.

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.

Although not validated yet in clinical trials, the common induction regime is prednisolone 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. Steroid-sparing agents that have been used include rituximab, azathioprine, methotrexate, and cyclophosphamide, 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 maintenancy therapy is prednisolone 2.5–5 mg per day, or use of a steroid-sparing agent instead.

Relapse

Relapses 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 rituximab 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 cause obstruction of the bile duct, it may be necessary to insert a biliary stent to allow the bile to drain freely.

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

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.

External links

• Overview of IgG4-related disease - UpToDate's article on IgG4-related disease.
• DermNet NZ entry
• International Symposium on IgG4-Related Diseases & Associated Conditions