Phys · rheumatological
IgG4-Related Disease
Also known as IgG4-related disease · IgG4-RD · IgG4-related sclerosing disease · type 1 autoimmune pancreatitis · lymphoplasmacytic sclerosing pancreatitis · IgG4-related sclerosing cholangitis · Mikulicz syndrome · IgG4-related sialadenitis · IgG4-related dacryoadenitis · Kuttner tumour · IgG4-related kidney disease · IgG4-related tubulointerstitial nephritis · retroperitoneal fibrosis · Ormond disease · IgG4-related aortitis · IgG4-related pachymeningitis · IgG4-related hypophysitis
Consultant-physician-depth guide to IgG4-related disease for FRACP DWE and DCE — the one-disease-many-organs fibroinflammatory concept linking type 1 autoimmune pancreatitis (painless obstructive jaundice, sausage-shaped pancreas, steroid-responsive), IgG4-related sclerosing cholangitis (distinguish from PSC and cholangiocarcinoma), Mikulicz syndrome (sialadenitis and dacryoadenitis, distinguish from Sjögren), IgG4-related kidney disease (tubulointerstitial nephritis), retroperitoneal fibrosis (Ormond disease, ureteric obstruction), aortitis, lung disease, pachymeningitis and hypophysitis; the diagnostic approach built on histopathology (dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, IgG4-positive plasma cells with IgG4 to IgG ratio above 40 per cent), the 2019 ACR and EULAR classification criteria and the 2020 revised comprehensive diagnostic criteria; the correct use and limits of serum IgG4 (elevated in 60 to 70 per cent, falsely positive in pancreatobiliary cancer and asthma, normal IgG4 does not exclude the disease); and the treatment ladder — glucocorticoids first-line, rituximab for relapsing or multi-organ disease, mycophenolate or azathioprine for maintenance, and the critical distinction of the steroid-responsive inflammatory phase from the steroid-resistant fibrotic phase.
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Red flags
- An older man with painless obstructive jaundice, a pancreatic head mass and weight loss that could be pancreatic cancer — check the serum IgG4 and look for other-organ involvement (salivary glands, renal lesions, retroperitoneal rind) before committing to surgery; type 1 autoimmune pancreatitis responds dramatically to steroids
- Bilateral ureteric obstruction with a periaortic mass causing acute kidney injury — retroperitoneal fibrosis; decompress with stents or nephrostomy first, then treat the active inflammation with steroids
- Bilateral, painless, persistent salivary and lacrimal gland enlargement in an older man — Mikulicz syndrome from IgG4-RD until proven otherwise; distinguish from Sjögren syndrome by the male sex, the older onset and the elevated serum IgG4
- New biliary strictures with an elevated IgG4 that could be cholangiocarcinoma — never treat with steroids on serology alone; obtain tissue to exclude cancer first
- Aortic aneurysm or dissection in a patient with known or suspected IgG4-RD — IgG4-related aortitis; control blood pressure strictly and involve vascular surgery
- Hypopituitarism or cranial nerve palsies with dural thickening on imaging — IgG4-related pachymeningitis or hypophysitis; check pituitary axes and give stress-dose steroid for adrenal insufficiency
IgG4-Related Disease
The answer first
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition defined by a characteristic histopathology — a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis — that can appear in almost any organ [1]. The central idea for the exam is one disease, many organs: type 1 autoimmune pancreatitis (AIP), IgG4-related sclerosing cholangitis, Mikulicz syndrome (sialadenitis and dacryoadenitis), IgG4-related kidney disease, retroperitoneal fibrosis, aortitis, lung disease, pachymeningitis and hypophysitis are all the same disease in different locations [1].
Three rules that change outcome [1]:
- Serum IgG4 is a biomarker, not a diagnosis. It is elevated in only 60 to 70 per cent of cases, it is falsely elevated in pancreatobiliary cancer, primary sclerosing cholangitis, asthma and atopy, and a normal IgG4 does not exclude the disease. The diagnosis rests on the clinicopathological pattern, with histopathology as the gold standard [1][2].
- IgG4-RD mimics cancer, and cancer can mimic IgG4-RD. A pancreatic head mass with painless jaundice is pancreatic cancer until proven otherwise. A modest IgG4 elevation occurs in 10 to 15 per cent of pancreatobiliary cancers. Never start steroids on serology alone when malignancy is plausible — obtain tissue and watch the steroid response with suspicion [1][3].
- Glucocorticoids work in the inflammatory phase and fail in the fibrotic phase. Prednisolone 30 to 40 mg daily produces a dramatic response within two weeks for active inflammatory disease, but burnt-out fibrotic lesions (a chronic biliary stricture, a mature retroperitoneal rind) are steroid-resistant — treat those with mechanical relief (stenting, drainage), not escalating immunosuppression [3].
The bedside reasoning moves in three steps. First, recognise the syndrome — is this a pancreatobiliary mass, a salivary or lacrimal gland enlargement, a renal lesion, a periaortic rind, or a dural or pituitary mass, and is there more than one organ involved? Second, confirm the histopathology and exclude the mimic — tissue biopsy for the triad of dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis with IgG4-positive plasma cells and an IgG4 to IgG ratio above 40 per cent, while excluding malignancy, lymphoma and infection. Third, treat by phase and by organ — steroids for active inflammation, rituximab for relapsing or multi-organ disease, and mechanical relief for fibrotic obstruction [3][4][5].
References6ShowHide
- [1]Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease Lancet, 2015.PMID 25481618
- [2]Wallace ZS, Naden RP, Chari ST, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease Ann Rheum Dis, 2020.PMID 31796497
- [3]Khosroshahi A, Wallace ZS, Crowe JL, et al. International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease Arthritis Rheumatol, 2015.PMID 25809420
- [4]Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients Medicine (Baltimore), 2012.PMID 22210556
- [5]Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial Ann Rheum Dis, 2015.PMID 25667206
- [6]Umehara H, Okazaki K, Kawa S, et al. The 2020 revised comprehensive diagnostic (RCD) criteria for IgG4-RD Mod Rheumatol, 2021.PMID 33274670