IgG4-Related Disease — Viva

Long Case Viva Defence

Candidate's opening statement (model answer)

"Mr Robert Chen is a 62-year-old retired engineer presenting with six weeks of painless obstructive jaundice, three months of progressive painless enlargement of both submandibular glands, and intermittent flank discomfort with a rising creatinine. He has mild asthma and allergic rhinitis. His main problems are: [1]

1. IgG4-related disease with multi-organ involvement — type 1 autoimmune pancreatitis, IgG4-related sclerosing cholangitis, Mikulicz syndrome, IgG4-related kidney disease and early retroperitoneal fibrosis — the active inflammatory phase, supported by the avid FDG uptake and the marked IgG4 elevation.
2. Obstructive jaundice from the pancreatic and biliary involvement, with a common bile duct stricture.
3. Renal impairment from bilateral ureteric obstruction by the periaortic rind — the urgent, potentially reversible problem.
4. The exclusion of pancreatobiliary malignancy, which the radiology and the tumour markers favour against but which tissue must confirm.
5. The treatment-related risks of glucocorticoids and rituximab in a 62-year-old.
6. The psychosocial impact of a new multisystem diagnosis on a man in retirement. [1]

My integrated plan is to decompress the ureteric obstruction first, exclude malignancy with adequate tissue, confirm the clinicopathological diagnosis with the histopathology triad and the 2019 ACR and EULAR criteria, induce remission with prednisolone 35 mg daily, and plan rituximab as the steroid-sparing maintenance strategy, with bone and infection prophylaxis and coordinated multi-specialty follow-up." [1]

Problem list and integrated plan (model answer for probing)

The examiner will press for a prioritised problem list and a plan that addresses each. Lead with the answer: decompress first, exclude malignancy in parallel, then treat the inflammation, then plan the maintenance. The ureteric obstruction with a rising creatinine is the only immediately reversible organ threat — bilateral ureteric stents or nephrostomy today. The pancreatic mass and the bile duct stricture are then characterised with endoscopic ultrasound-guided core biopsy (with sufficient tissue for histology, IgG4 immunostaining and flow cytometry) and biliary drainage if the cholestasis or cholangitis risk demands it. Once the diagnosis is histologically secure, prednisolone 35 mg daily induces remission, and a planned rituximab course provides the steroid-sparing maintenance, having screened for hepatitis B and tuberculosis [1][3][4].

Probing questions and model answers

Examiner: How confident are you that this is not pancreatic cancer? [1]

"Moderately confident on the pattern, but not enough to omit tissue. The features favouring type 1 autoimmune pancreatitis are the diffusely enlarged, capsule-rimmed, sausage-shaped pancreas rather than a focal mass; the absence of vascular encasement; the normal CA19-9; the marked IgG4 elevation (more than twice the upper limit); and the other-organ involvement (the submandibular glands, the renal lesions, the periaortic rind). Against this, cancer can elevate IgG4 mildly in 10 to 15 per cent of cases, and a focal pancreatic head cancer can coexist with an unrelated IgG4 elevation. I will therefore obtain adequate tissue before any immunosuppression, and I will not rely on a radiological steroid response to make the diagnosis, because lymphoma and even cancer can shrink transiently on steroids." [1][3]

Examiner: Tell me about the histopathology you expect. [1]

"The diagnostic triad is a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform (cartwheel-like) fibrosis, and obliterative phlebitis with veins occluded by the infiltrate while arteries are spared. Immunostaining shows an IgG4 to total IgG plasma cell ratio above 40 per cent, with organ-specific cell-count thresholds (above 30 per high-power field for pancreas). Two cautions: the count is organ-specific because IgG4-positive cells occur in normal and inflamed tissue, and the count is not diagnostic in isolation — lymphoma, Castleman disease and some cancers can have IgG4-positive cells. I read the histology with the clinical pattern and the imaging, not alone." [1][2]

Examiner: What is the role of the serum IgG4, and does a normal value exclude the disease? [1]

"Serum IgG4 is supportive, not diagnostic. It is elevated above 135 mg per decilitre in 60 to 70 per cent of IgG4-related disease, falsely elevated in pancreatobiliary cancer, primary sclerosing cholangitis, asthma and atopy, and normal in 20 to 30 per cent of biopsy-proven type 1 autoimmune pancreatitis. A normal IgG4 does not exclude the disease, and an elevated IgG4 does not confirm it. In Mr Chen it is markedly elevated, which supports the diagnosis, but the diagnosis rests on the clinicopathological pattern." [1]

Examiner: How do you use the 2019 ACR and EULAR criteria here? [1]

"The criteria are a three-step process. The entry criterion is characteristic organ involvement, which he meets. The exclusion criteria screen for malignancy, infection and alternative diagnoses — he has a normal CA19-9, no cachexia, no granulomas, no fever, so no exclusion criterion applies. The weighted inclusion score across eight domains (clinical, serological, radiological, pathological) totals 20 points or more to classify the case as IgG4-related disease. His multi-organ pattern, the marked IgG4, the characteristic imaging and the diagnostic histology would score well above 20. The criteria are a classification tool, but they are the framework I use to justify the diagnosis." [2]

Examiner: Walk me through the treatment. [1]

"Immediate: decompress the ureteric obstruction with stents or nephrostomy, because the renal recovery depends on the duration of obstruction. Induction: prednisolone 35 mg daily for two to four weeks, then taper over three to six months, with bone protection and pneumocystis prophylaxis. Maintenance: because this is multi-organ disease and relapse is expected in 40 to 50 per cent, I plan a course of rituximab (375 mg per square metre weekly for four doses, or 1 g on days 1 and 15) after screening for hepatitis B and tuberculosis and updating vaccinations. I will monitor the serum IgG4, the B-cell count, the renal and hepatic function, and the imaging, and I will use a planned rituximab maintenance schedule rather than treating only flares." [3][4]

Examiner: What is the role of the fibrotic phase in your management? [1]

"The disease has an early inflammatory, steroid-responsive phase and a late fibrotic, steroid-resistant phase. The ureteric obstruction has a mechanical component that needs stenting regardless of the inflammatory activity, and a mature retroperitoneal rind or a chronic biliary stricture will not respond to escalating immunosuppression. I treat the complications mechanically and reserve the immunosuppression for the metabolically active, FDG-avid lesions. Escalating steroids for a burnt-out fibrotic lesion adds toxicity without benefit — a classic trap." [1][3]

Communication and shared decision-making

"I would frame this as a treatable but relapsing multisystem disease. Mr Chen will want to know whether this is cancer, and I will explain directly that we have actively excluded cancer by tissue and that the disease responds to treatment. I will explain the steroid burden honestly — osteoporosis, diabetes, infection — and the rationale for rituximab as the steroid-sparing strategy. I will name the lead clinician coordinating rheumatology, gastroenterology, nephrology and ophthalmology, and I will set up a structured surveillance plan. Finally, I will address the practical and psychological impact of a chronic relapsing illness on a man in retirement." [3]

Short Case Discussion — Salivary and lacrimal gland examination for Mikulicz syndrome

Instruction: "Examine this patient's head, neck and relevant general systems. The patient has noticed gradual enlargement of the glands in the neck." [1]

Examination routine (model answer): [1]

"I would begin at the end of the bed, observing for the facial fullness of parotid or submandibular enlargement and any proptosis. I would examine the lacrimal glands first, everting the upper eyelid and palpating the superolateral orbit; then the parotid glands bilaterally, inspecting and palpating both lobes and noting any ductal discharge; then the submandibular glands by bimanual palpation, feeling intra-orally; and then the cervical, supraclavicular and axillary lymph nodes. I would assess for sicca (Schirmer test for dry eyes, oral dryness, dental caries) and perform a general systemic screen — chest for pleural effusion, abdomen for organomegaly, skin for excoriation from pruritus, and a focused assessment for the multisystem features of IgG4-related disease." [1]

Key signs the patient demonstrates: [1]

Firm, non-tender, bilateral enlargement of the submandibular glands (Kuttner tumour) with lacrimal gland enlargement and firm, mobile cervical nodes, in an older man with minimal sicca. [1]

Presentation to the examiner: [1]

"I found firm, bilateral, non-tender enlargement of the submandibular and lacrimal glands in an older man with minimal sicca. My leading diagnosis is IgG4-related disease causing Mikulicz syndrome. The discriminators from Sjogren syndrome are the male sex, the older onset, the prominent gland enlargement rather than pure sicca, and (on testing) a normal anti-Ro and anti-La with an elevated serum IgG4. I would like to confirm the diagnosis with a serum IgG4 and IgG subclasses, autoimmune serology, cross-sectional imaging and an FDG-PET-CT for extent, and a submandibular gland biopsy for histopathology and flow cytometry to exclude lymphoma." [1]

Discussion questions: [1]

• "The differential is IgG4-related disease versus Sjogren syndrome versus lymphoma versus sarcoidosis. Sjogren is female-predominant, sicca-dominant, anti-Ro and anti-La positive, with a normal IgG4. Lymphoma is asymmetric or rapidly growing and needs flow cytometry. Sarcoidosis has non-caseating granulomas and bilateral hilar lymphadenopathy."
• "The management is glucocorticoids for active inflammatory disease, rituximab for relapsing or multi-organ disease, and surveillance for multi-organ involvement. The single most important lesson is to look beyond the gland for the multi-organ pattern, because the gland enlargement is often the visible tip of a multisystem disease." [1][3]