IgG4-related disease

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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

IgG4-related disease (IgG4-RD), formerly also known as IgG4-related systemic disease, is an emerging fibroinflammatory disease entity characterised by: a tendency to tumefactive, or mass forming, lesions in multiple sites; a characteristic histopathological appearance; an often elevated serum IgG4 concentrations during the acute phase; and usually a prompt response to steroid therapy.[1][2]

The 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 IgG4 antibody levels in the bloodstream are often elevated. Inflammation results in fibrosis, the deposition of connective tissue, in affected anatomical sites which can lead to organ dysfunction, or even organ failure, if not treated.[3]

Early detection is important to avoid organ damage and potentially serious complications.[4]


At the 2011 International Symposium on IgG4-Related Disease, the consensus name of IgG4-related disease was endorsed for the condition.[1] This name had already been agreed upon as a consensus name among Japanese investigators,[1][2] 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.[5] 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.[1]

Prior to this, the condition used to get mentioned in the medical literature under various different names:[1][5]

  • IgG4-related disease (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 (SIPS)
  • IgG4-positive multiorgan lymphoproliferative syndrome (IgG4-MOLPS)

Individual organ manifestations[edit]

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.[6][7]

Nomenclature for individual organ involvement
Organ or site Preferred names[1][8] Previously used names[1]
Head and neck
Salivary gland IgG4-related sialadenitis Chronic sclerosing sialadenitis,
Mikulicz's disease (salivary and lacrimal glands),[9]
Küttner's tumour (submandibular glands)
Lacrimal gland IgG4-related dacryoadenitis Mikulicz's disease (salivary and lacrimal glands)[9]
Orbit IgG4-related ophthalmic disease (IgG4-ROD):
IgG4-related orbital inflammation (orbital soft tissue),
IgG4-related orbital myositis (extraorbital muscle),
IgG4-related pan-orbital inflammation
Idiopathic orbital inflammatory disease
Paranasal sinuses[10]   Chronic sinusitis
Eosinophilic angiocentric fibrosis (orbits and upper respiratory tract)
Pharynx IgG4-related pharyngitis[11]  
Thyroid gland IgG4-related thyroid disease Riedel's thyroiditis
Central Nervous System
Pituitary gland IgG4-related hypophysitis  
Dura mater IgG4-related pachymeningitis Idiopathic hypertrophic pachymeningitis
Chest and abdomen
Pancreas IgG4-related pancreatitis Type 1 autoimmune pancreatitis
Lung IgG4-related lung disease
Pleura IgG4-related pleuritis  
Liver IgG4-related hepatopathy  
Bile duct IgG4-related sclerosing cholangitis  
Gallbladder IgG4-related cholecystitis  
Aorta IgG4-related aortitis/periaortitis[12] Inflammatory aortic aneurysm
Branches of the aorta
(including coronary,[10] renal or iliac arteries)
IgG4-related periarteritis[12]  
Pericardium IgG4-related pericarditis  
Mediastinum IgG4-related mediastinitis Fibrosing mediastinitis
Retroperitoneum IgG4-related retroperitoneal fibrosis Retroperitoneal fibrosis (Ormond disease)
Mesentery IgG4-related mesenteritis Sclerosing mesenteritis
Breast IgG4-related mastitis  
Kidney IgG4-related kidney disease (IgG4-RKD):
IgG4-related tubulointerstitial nephritis (IgG4-TIN),
IgG4-related membranous glomerulonephritis
Idiopathic tubulointerstitial nephritis
Prostate IgG4-related prostatitis  
Scrotum IgG4-related paratesticular pseudotumor,[8]
IgG4-related epididymo-orchitis[8]
Paratesticular fibrous pseudotumor
Lymph nodes IgG4-related lymphadenopathy  
Skin IgG4-related skin disease Cutaneous pseudolymphoma
Nerve IgG4-related perineural disease[8]  

This is not a complete list, as IgG4-RD can involve any site in the body. Other affected sites, confirmed by histology to be manifestations of IgG4-RD, include: ureter, bladder, adrenal gland,[13] uterus and seminal vesicle.[12]


Whatever area of the body is involved, the hallmark histopathological features of IgG4-RD are:[2][6][7]

  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[2] 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.[2]

Other histopathological features associated with IgG4-RD are:


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.[3][14] 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[edit]

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.


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.


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.

Other interventions[edit]

When organ involvement causes local mechanical problems, further interventions may be necessary. For example, when tumefactive lesions cause obstruction of the bile ducts, it may be necessary to insert a biliary stent to allow the bile to drain freely.


  1. ^ a b c d e f g John H. Stone, Arezou Khosroshahi, Vikram Deshpande et al. (October 2012). "Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations". Arthritis & Rheumatism 64 (10): 3061–3067. doi:10.1002/art.34593. PMID 22736240. 
  2. ^ a b c d e f g Vikram Deshpande, Yoh Zen, John H. Stone et al. (18 May 2012). "Consensus statement on the pathology of IgG4-related disease". Modern Pathology 25: 1181–1192. doi:10.1038/modpathol.2012.72. PMID 22596100. 
  3. ^ a b Arezou Khosroshahi et al. (2015). "International consensus guidance statement on the management and treatment of IgG4-related disease". Arthritis & Rheumatology. doi:10.1002/art.39132. 
  4. ^ Kamisawa T, Zen Y, Pillai S, Stone JH (11 April 2015). "IgG4-related disease.". Lancet 385 (9976): 1460–1471. doi:10.1016/S0140-6736(14)60720-0. PMID 25481618. 
  5. ^ a b Umehara H, Okazaki K, Masaki Y et al. (2012). "A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details". Mod Rheumatol 22 (1): 1–14. doi:10.1007/s10165-011-0508-6. PMID 21881964. 
  6. ^ a b c Arezou Khosroshahi, John H. Stone (Jan 2011). "A clinical overview of IgG4-related systemic disease". Curr Opin Rheumatol 23 (1): 57–66. doi:10.1097/BOR.0b013e3283418057. PMID 21124086. 
  7. ^ a b John H. Stone, Yoh Zen, Vikram Deshpande (February 2012). "IgG4-Related Disease". New England Journal of Medicine 336 (6): 539–51. doi:10.1056/NEJMra1104650. PMID 22316447. 
  8. ^ a b c d Pieringer H, Parzer I, Wöhrer A, Reis P, Oppl B, Zwerina J. (16 July 2014). "IgG4- related disease: an orphan disease with many faces". Orphanet Journal of Rare Diseases 9: 110. doi:10.1186/s13023-014-0110-z. PMID 25026959. 
  9. ^ a b Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H. (February 2012). "A novel concept of Mikulicz's disease as IgG4-related disease". Auris Nasus Larynx 39 (1): 9–17. doi:10.1016/j.anl.2011.01.023. PMID 21571468. 
  10. ^ a b Guo Y, Ansdell D, Brouha S, Yen A (Jan 2015). "Coronary periarteritis in a patient with multi-organ IgG4-related disease". Radiology Case 9 (1): 1–17. doi:10.3941/jrcr.v9i1.1967. PMID 25926916. 
  11. ^ Carruthers MN, Miloslavsky EM, Stone JH (August 2013). "Reply to "IgG4-related pharyngitis-an addition to the nomenclature of IgG4-related disease: comment on the article by Stone et al."". Arthritis & Rheumatism 65 (8): 2217–2218. doi:10.1002/art.37998. PMID 23666890. 
  12. ^ a b c Inoue D, Zen Y, Abo H, Gabata T, Demachi H, Yoshikawa J, Miyayama S, Nakanuma Y, Matsui O. (Nov 2011). "Immunoglobulin G4–related Periaortitis and Periarteritis: CT Findings in 17 Patients". Radiology 261 (2): 625–633. doi:10.1148/radiol.11102250. PMID 21803920. 
  13. ^ Costa C, Saraiva C, Freitas S (25 September 2013). "Adrenal lesion as first manifestation of IgG4-related sclerosing disease". EuroRad. European Society of Radiology. doi:10.1594/EURORAD/CASE.11230. Retrieved 15 May 2015. 
  14. ^ Walsh, Nancy (1 April 2015). "Experts Weigh In on IgG4 Disease - Diagnosis requires biopsy, and treatment starts with steroids". MedPageToday. Retrieved 8 May 2015. 

External links[edit]

  • Overview of IgG4-related disease - UpToDate's comprehensive article on IgG4-related disease, updated as new evidence becomes available and following the website's peer review process. Access to the IgG4-RD is free at time of listing (May 2015), but may become subscription-based in the future.
  • DermNet NZ
  • John Stone, MD, MPH: "IgG4-Related Disease" - NYU School of Medicine's Medicine Grand Rounds video archive from June 18, 2013. Preceded by a case presentation, at 8 minutes into the video Dr. John Stone begins his 46-minute presentation on IgG4-RD, including a discussion of the role of rituximab in IgG4-RD. [Watching this video requires high data use, possibly more than 1GB]
  • "IgG4-Related Disease of the Orbit" by Elizabeth A. Bradley, M.D. - 10-minute YouTube video from the Mayo Clinic on IgG4-RD involving the eye/orbit, which also includes more general information about IgG4-RD and its treatment.