IgG4 Related Disease

A fibroinflammatory immune mediated condition capable of affecting almost any organ, characterised histologically by dense lymphoplasmacytic infiltrate rich in IgG4 positive plasma cells, storiform fibrosis and obliterative phlebitis. It is a systemic disease masquerading as organ specific pathology, and the diagnostic challenge is recognising that apparently unrelated lesions across different organs and different years in the same patient are one disease.

Pathophysiology

Not a classical antibody mediated process despite the name. IgG4 antibodies are poor complement activators and the pathogenic mechanism is thought to involve CD4 positive cytotoxic T lymphocytes and T follicular helper cells driving plasmablast expansion, fibroblast activation via interleukin 4, interleukin 13 and transforming growth factor beta, and B cell depletion responsiveness that supports rituximab efficacy.

Obliterative phlebitis, in which veins are occluded by the inflammatory infiltrate without arterial involvement, is a specific and diagnostically useful histological feature distinguishing it from other fibrosing conditions.

Organs involved

Pancreas (autoimmune pancreatitis type 1), biliary tree (IgG4 related sclerosing cholangitis, which mimics cholangiocarcinoma and primary sclerosing cholangitis), salivary and lacrimal glands (Mikulicz disease and Küttner tumour of the submandibular gland), orbit (orbital pseudotumour), retroperitoneum (retroperitoneal fibrosis with ureteric obstruction), aorta (periaortitis and inflammatory aortic aneurysm), kidney (tubulointerstitial nephritis), lung, thyroid (Riedel thyroiditis), meninges (hypertrophic pachymeningitis), and lymph nodes.

Epidemiology

Middle aged and older men predominate, typically over 50 years, with a male to female ratio of roughly 3 to 1 outside the head and neck manifestations, where sex distribution is more even. Asian populations, particularly Japanese, have the highest reported incidence, though the disease is now recognised worldwide.

• Painless, subacute swelling of one or more organs over weeks to months, notably without the systemic toxicity (fever, weight loss) typical of malignancy or infection despite the mass effect, which is a genuinely useful discriminator.
• Painless bilateral submandibular and lacrimal gland swelling in Mikulicz disease.
• Obstructive jaundice from biliary or pancreatic head involvement, mimicking pancreatic cancer closely.
• Abdominal or flank pain and renal impairment from retroperitoneal fibrosis with ureteric entrapment.
• Orbital swelling and proptosis from orbital pseudotumour.
• Cough and dyspnoea from pulmonary nodules or interstitial disease.
• Allergic features including asthma, allergic rhinitis and elevated eosinophils occur in a substantial minority and can mislead toward an atopic diagnosis.
• Multiorgan disease develops metachronously in a proportion, so a patient presenting with one lesion may develop another years later, and this pattern itself supports the diagnosis retrospectively.

• Serum IgG4, elevated above 135 mg/dL in the majority, but with meaningful limitations: normal in up to 20 to 40 percent of biopsy proven cases, and elevated in a proportion of pancreatic cancer, primary sclerosing cholangitis, and other conditions. It is supportive, not diagnostic alone.
• Histology is the reference standard: dense lymphoplasmacytic infiltrate, storiform ("swirling") fibrosis, obliterative phlebitis, and IgG4 positive plasma cells exceeding 10 per high power field with an IgG4 to IgG ratio above 40 percent.
• Cross sectional imaging (CT/MRI) of the affected organ, with characteristic diffuse pancreatic enlargement described as "sausage shaped" in autoimmune pancreatitis, and a capsule-like rim.
• PET-CT is useful for mapping multiorgan involvement and guiding biopsy site selection.
• Exclude malignancy rigorously before committing to the diagnosis, since pancreatic and biliary IgG4 disease mimics adenocarcinoma and cholangiocarcinoma closely; tissue diagnosis or a steroid trial with close surveillance is mandatory before treating a mass lesion as benign.
• Full organ screening once diagnosed: salivary gland ultrasound, renal function and imaging, chest CT, and orbital assessment.

Differential diagnosis: pancreatic and biliary malignancy, primary sclerosing cholangitis, Sjögren syndrome, sarcoidosis, granulomatosis with polyangiitis, Castleman disease, lymphoma, and idiopathic retroperitoneal fibrosis.

• Glucocorticoids are first line: prednisolone 0.6 mg/kg daily (typically 30 to 40 mg) for 2 to 4 weeks, then tapered over 3 to 6 months. Response is often dramatic and rapid, which is itself diagnostically supportive.
• Relapse occurs in 30 to 60 percent on tapering or after cessation, particularly with biliary and retroperitoneal involvement.
• Rituximab 1 g on days 1 and 15, or 375 mg/m² weekly for 4 weeks, is highly effective for induction and for relapsing or steroid intolerant disease, and is increasingly used as first line in place of prolonged steroid exposure.
• Steroid sparing agents (azathioprine, mycophenolate) for maintenance in relapsing disease.
• Manage organ specific complications: biliary stenting for obstruction, ureteric stenting or surgical ureterolysis for retroperitoneal fibrosis, monitoring renal function.
• Screen for and monitor malignancy risk, which appears modestly elevated in IgG4 related disease, particularly pancreatic and lymphoid malignancy.
• Long term follow up with imaging and IgG4 levels to detect relapse and new organ involvement.