Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.
IgG4-related disease
Rheumatology · UK scope · Sources checked 27 Aug 2026 · Clinical review pending
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Obstruction, threatened vision or major-vessel disease
Cholangitis with jaundice, bilateral ureteric obstruction, rapidly declining kidney function, orbital apex or optic-nerve compression, hypertrophic pachymeningitis, aortitis or impending aneurysmal complication requires organ rescue before prolonged diagnostic sequencing.
Action: Admit under the relevant surgical or medical team, drain infected biliary or urinary obstruction and protect vision, neural function or vascular integrity, obtain cancer and infection tissue where safely possible, then begin specialist glucocorticoid or rituximab treatment once diagnostic probability is adequate.
Overview
Recognise the organ patterns of IgG4-related disease, distinguish inflammatory enlargement from cancer and infection, obtain architecture-preserving tissue with expert pathology, and prevent irreversible pancreatic, biliary, renal, orbital, neural and retroperitoneal fibrosis.
IgG4-related disease unifies conditions once managed separately: type 1 autoimmune pancreatitis, IgG4-related sclerosing cholangitis, Mikulicz-pattern lacrimal and salivary disease, orbital pseudotumour, tubulointerstitial nephritis, retroperitoneal fibrosis, inflammatory aortic disease, lung lesions, hypertrophic pachymeningitis and hypophysitis. A single patient may have synchronous organs or sequential relapses years apart.
Take an organ inventory before choosing the biopsy. Ask about painless jaundice, pancreatitis, weight loss, dry mouth, gland swelling, proptosis and diplopia, cough, loin pain, reduced urine, oedema, abdominal or back pain, urinary obstruction, headache, cranial nerves, thirst and libido. Examine glands, nodes, eyes and cranial nerves, blood pressure and pulses, abdomen, oedema and testicular or skin lesions where symptoms indicate.
Practice
Two practice questions
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Question 1 of 2
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RheumatologyOriginal SBA
Pancreatic mass before steroid
A 68-year-old has painless jaundice, a focal pancreatic head mass and serum IgG4 twice the upper limit. There is no other proven organ involvement. Which next principle is safest?
Sources and review status7 sources · checked 27 Aug 2026 · clinical review pending+
Sources
Sources and review status
National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.
Baseline testing includes FBC, CRP or ESR, renal and liver profiles, adjusted calcium, glucose or HbA1c, urinalysis, ACR or PCR, total IgG and subclasses, IgE, eosinophils and C3 or C4. Serum IgG4 more than several times the upper limit strengthens probability, but concentration is neither required nor specific. Prozone interference can rarely produce a falsely low result in very high disease burden and should be discussed with immunology when the phenotype is compelling.
Cross-sectional imaging maps lesions and chooses tissue. CT chest, abdomen and pelvis can show pancreatic enlargement, renal cortical nodules, a periaortic mantle, ureteric encasement, nodes and thoracic disease. Pancreas-protocol CT or MRI and MRCP define duct and biliary anatomy. FDG-PET can identify an occult safer biopsy site and active distribution but cannot distinguish inflammation from lymphoma or other cancer.
The safest representative core specimen is preferred over fine-needle cytology because architecture matters. Pathology searches for dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis, then counts IgG4-positive cells and their proportion among IgG-positive plasma cells using organ-specific thresholds. Eosinophils may support. Lymph-node, bone-marrow and some mucosal specimens often lack the classic triad and require particular caution.
Pancreatic and biliary disease needs a pancreatobiliary MDT. Diffuse sausage-shaped pancreatic enlargement, capsule-like rim and long smooth duct narrowing favour type 1 autoimmune pancreatitis, while an abrupt duct cut-off, focal hypoenhancing mass, vascular invasion or metastasis favours cancer. Obstructed febrile jaundice is cholangitis and needs antibiotics and drainage before steroid. Endoscopic ultrasound core or biliary tissue is selected to preserve a cancer diagnosis.
Head and neck disease includes bilateral lacrimal, parotid or submandibular swelling, extraocular-muscle or infraorbital-nerve enlargement, orbital mass and thyroid disease. Sjögren disease, lymphoma, sarcoidosis, GPA, infection and thyroid eye disease overlap. Acute visual change or optic compression requires urgent orbital imaging and ophthalmology; choose a salivary or lacrimal core when safer than an orbital apex biopsy.
Renal disease often presents with creatinine rise, low complement and multiple cortical low-attenuation lesions from tubulointerstitial nephritis. Urine can be bland or show modest protein; heavy albuminuria suggests concurrent membranous nephropathy. Exclude obstruction from retroperitoneal disease. Kidney biopsy distinguishes immune-complex, interstitial, malignant and vascular disease when treatment intensity depends on mechanism.
Retroperitoneal fibrosis can encase ureters, inferior vena cava and aorta. Ultrasound identifies hydronephrosis, while contrast CT or MRI maps plaque and malignancy clues. Bilateral obstruction is decompressed urgently with stent or nephrostomy; fibrosis may not recede quickly enough with steroid. Periaortitis or aneurysm needs vascular monitoring because reducing inflammatory wall uptake does not eliminate structural rupture risk.
Neurological IgG4 disease causes hypertrophic pachymeningitis, cranial neuropathy, hypophysitis and rare peripheral-nerve or spinal lesions. Contrast MRI identifies thickening but infection, granulomatous disease, lymphoma and other inflammatory meningitides overlap. CSF is nonspecific; biopsy a systemic lesion if safer. Replace pituitary hormones and protect vision or cord function while immune treatment proceeds.
Do not use a casual steroid trial to make the diagnosis. Glucocorticoid can improve oedema around cancer and obscure lymphoma tissue. Once evidence is sufficient, active symptomatic or organ-threatening disease receives prednisolone about 0.6 mg/kg/day for two to four weeks, followed by reduction every one to two weeks toward withdrawal over three to six months. A rapid objective response is expected, and lack of response should reopen diagnosis and irreversible fibrosis.
Relapse risk is greater with multiorgan disease, high IgG4, low complement, eosinophilia and prior relapse, although none decides treatment alone. Rituximab 1 g IV on days 1 and 15 is an off-label induction and relapse option that can avoid repeated glucocorticoid. Azathioprine 1–2 mg/kg/day or mycophenolate mofetil 1 g twice daily is used as maintenance in selected services, but comparative evidence is weaker.
Before rituximab screen HBsAg, anti-HBc and anti-HBs, TB and other infection, immunoglobulins and vaccines; arrange HBV prophylaxis where required. Monitor late neutropenia, hypogammaglobulinaemia and recurrent infection. In obstructed or fibrotic organs, continue stent, enzyme replacement, endocrine replacement and cancer surveillance as needed; remission of inflammation does not reverse all structural care.
Key points
IgG4-related disease is a relapsing fibroinflammatory condition that forms tumefactive lesions in pancreas, bile ducts, salivary and lacrimal glands, orbit, kidneys, retroperitoneum, aorta, lung, meninges and pituitary.
Serum IgG4 supports but does not diagnose disease: mild elevation occurs in allergy, infection and malignancy, and a meaningful minority of biopsy-proven patients have a normal concentration.
First diagnostic priority is to exclude cancer and infection before corticosteroid, especially with a focal pancreatic or biliary mass, destructive lesion, atypical nodes or constitutional decline.
Reference tissue assessment uses organ architecture plus dense lymphoplasmacytic inflammation, storiform fibrosis and obliterative phlebitis, with IgG4-positive cell count and ratio interpreted by an expert organ pathologist.
The 2019 ACR/EULAR criteria classify research cohorts and should not be used as a stand-alone diagnostic or treatment threshold in an individual patient.
Map organs systematically: pancreas and bile ducts, salivary and lacrimal glands, orbit, chest, kidneys and urine, retroperitoneum and hydronephrosis, aorta, nodes and neuroendocrine symptoms.
Drain cholangitis or obstructed kidneys and protect optic, neural or vascular structures before expecting immunosuppression to reverse the mechanical emergency.
Aetiology
01
Immune-regulatory susceptibility
Older men predominate in many systemic phenotypes, while HLA, B-cell, plasmablast and regulatory T-cell pathways contribute without one inherited or environmental cause.
02
Antigen-driven B-cell response
Expanded plasmablast clones and class-switched IgG4-positive plasma cells suggest persistent antigenic stimulation, but the target antigen and pathogenic role of IgG4 remain incompletely defined.
03
Allergic and eosinophilic tendency
Atopy, raised IgE and eosinophilia occur frequently and may amplify tissue inflammation, yet none is required and marked eosinophilia should reopen competing diagnoses.
04
Organ-specific presentation
The same fibroinflammatory process presents as type 1 autoimmune pancreatitis, sclerosing cholangitis, orbital or salivary disease, tubulointerstitial nephritis, retroperitoneal fibrosis or aortitis.
Pathophysiology
1
Lymphoplasmacytic infiltration
Activated B cells, plasmablasts, IgG4-positive plasma cells and T cells accumulate in affected tissue, causing tumefactive enlargement and early organ dysfunction.
2
Storiform fibrosis
Fibroblasts deposit collagen in a cartwheel or woven pattern, progressively replacing active inflammation with scar that responds less completely to immunosuppression.
3
Obliterative phlebitis
Inflammatory fibrosis narrows or closes venous channels within affected organs, forming a characteristic but variably present pathological component.
4
Complement-consuming renal disease
IgG4-related tubulointerstitial nephritis can produce hypocomplementaemia, cortical lesions and reduced filtration, while membranous nephropathy may cause substantial proteinuria.
5
Relapsing multisite biology
Glucocorticoid rapidly suppresses active lesions, but persisting B-cell clones and residual fibrosis permit relapse in the same or a previously silent organ.
Clinical features and red flags
Pancreatobiliary pattern
Painless jaundice, autoimmune-pancreatitis imaging, long smooth duct narrowing and other organ disease supports IgG4-related pancreatitis or cholangitis, but cancer remains the first exclusion.
Lacrimal and salivary pattern
Persistent usually painless bilateral lacrimal, parotid or submandibular enlargement with orbital or systemic lesions differs from episodic infection, while Sjögren and lymphoma overlap.
A periaortic soft-tissue mantle, ureteric encasement, hydronephrosis, inflammatory aneurysm or periarteritis indicates urgent structural mapping.
Orbital and neurological patternRed flag
Proptosis, diplopia, infraorbital-nerve enlargement, optic dysfunction, pachymeningitic headache, cranial neuropathy or pituitary failure can threaten irreversible function.
Malignancy departureRed flag
A solitary invasive mass, necrosis, destructive bone change, atypical nodes or progressive constitutional loss is not explained safely by raised serum IgG4.
Red flags requiring action
Fever, rigors, jaundice, hypotension or a dilated obstructed biliary tree suggests ascending cholangitis and requires antibiotics and urgent drainage before immune suppression.
Investigations
01First-line organ and biochemical mapFirst stepFirst line
Why
Identify active sites, obstruction and a safe biopsy target before treatment.
Interpretation and limitations
Obtain FBC, renal, liver, glucose, urinalysis and protein, IgG subclasses, IgE, eosinophils, complements and CT-directed testing; serology changes probability but never replaces organ evidence.
02Contrast CT or MRI across involved regions
Why
Define tumefactive disease, fibrosis, vascular involvement, hydronephrosis and cancer features.
Interpretation and limitations
Typical multisite disease strengthens coherence, but FDG uptake and enlargement are not specific. Use pancreas protocol, MRCP, orbital or neuro-axis sequences for the organ question.
03Reference core histology with expert IgG4 staining
Why
Confirm fibroinflammatory architecture and exclude malignancy, granulomatous infection and another immune lesion.
Interpretation and limitations
Dense lymphoplasmacytic inflammation, storiform fibrosis and obliterative phlebitis carry greatest weight; IgG4-positive count and ratio use organ-specific cutoffs and cannot diagnose alone.
04Pancreatobiliary EUS or ERCP tissue
Why
Protect a pancreatic or bile-duct cancer diagnosis and define obstruction.
Interpretation and limitations
Core pancreatic architecture is more useful than cytology alone; brushings, biopsy and drainage follow MDT anatomy. Steroid response is not an acceptable substitute for adequate malignancy evaluation.
Differential diagnosis
01
Pancreatic, biliary or other cancer
Pancreatic adenocarcinoma, cholangiocarcinoma, lymphoma and organ-specific malignancies can elevate IgG4 and transiently improve symptomatically on steroid; tissue and imaging sequence is critical.
02
Sjögren disease and lymphoma
Sicca and salivary enlargement overlap, but anti-Ro, lymphoepithelial lesions, clonality and lymphoma architecture differ from storiform IgG4-related sialadenitis.
03
Granulomatous and vasculitic disease
Sarcoidosis, GPA, eosinophilic granulomatosis, infection and inflammatory pseudotumour require granuloma, necrosis, eosinophil, ANCA and microbiological interpretation.
04
Primary sclerosing cholangitis
IBD association, beaded multifocal intrahepatic strictures and characteristic histology favour PSC, while either disease can coexist with cholangiocarcinoma.
05
Idiopathic or malignant retroperitoneal fibrosis
Drug, cancer, infection and histiocytic disorders can encase ureters or aorta; atypical location, bulky nodes and tissue behaviour determine biopsy need.
Management
01First diagnostic sequenceExclude cancer, map organs and preserve tissueFirst stepA pancreatic, glandular, orbital, renal or retroperitoneal lesion raises IgG4-related disease.+
1Stabilise cholangitis, renal obstruction, visual, neurological and vascular threats and obtain cross-sectional imaging of the presenting and common associated organs.
2Measure serum and organ baselines, then select an architecture-preserving core from the safest representative site before glucocorticoid where possible.
3Review radiology and pathology in an IgG4-experienced MDT, explicitly documenting malignancy, infection and organ-specific mimic exclusion.
02Mechanical emergencyDrain or decompress before waiting for steroidBiliary sepsis, bilateral hydronephrosis, optic compression or vascular instability is present.+
1Give antibiotics and urgent biliary drainage for cholangitis, or ureteric stent or nephrostomy for threatened obstructive renal failure.
Complications
01
Irreversible organ fibrosis
Delayed control can leave pancreatic insufficiency, biliary cirrhosis, chronic kidney disease, ureteric obstruction, visual loss, nerve deficit and fixed salivary or orbital damage.
02
Vascular and obstructive emergency
Periaortitis, aneurysm, coronary involvement, cholangitis and bilateral hydronephrosis can threaten life or organ function independently of inflammatory symptoms.
03
Relapse in a new organ
Recurrent disease may appear after steroid withdrawal in pancreas, bile duct, kidney, orbit, nodes, retroperitoneum or other sites not previously recognised.
04
Malignancy misclassification
Assuming a raised serum IgG4 or steroid response proves the diagnosis can delay curative pancreatic, biliary, renal or lymphoid cancer treatment.
05
Immunosuppressive toxicity
Older age, diabetes, obstruction and organ impairment magnify glucocorticoid infection and metabolic harm and rituximab-associated hepatitis, hypogammaglobulinaemia and vaccine failure.
Monitoring and follow-up
At each review repeat the presenting organ measure and ask systematically about pancreas and bile ducts, glands and orbit, chest, renal and urinary, retroperitoneal, vascular and neurological symptoms.
Trend creatinine, eGFR, urinalysis and protein, liver profile, glucose, FBC, complements and serum IgG4 at intervals matched to organ and treatment, interpreting serology only with clinical activity.
Repeat CT, MRI, MRCP, ultrasound or PET only to answer lesion, obstruction, vascular or activity questions and minimise cumulative radiation where MRI or ultrasound suffices.
Keep biliary and ureteric devices under named follow-up and remove only after adequate anatomical recovery; fever or falling drainage output requires urgent infection and obstruction assessment.
During rituximab follow infection, IgG, delayed neutropenia, hepatitis prevention and vaccine timing and record brand, course and any need for antimicrobial prophylaxis.
After remission continue organ surveillance because relapse can occur in a new site and fixed pancreatic, endocrine, renal or neurological impairment still needs replacement and rehabilitation.
Special situations
IgG4 concentration is supporting evidence
Marked elevation is useful in the right phenotype, but allergy and cancer can raise it and tissue-proven disease can have a normal result.
Classification is not diagnosis
ACR/EULAR exclusions and weighted points create homogeneous research cohorts and can omit genuine single-organ or incompletely investigated clinical disease.
Architecture outranks cell count
Many inflammatory and malignant lesions contain IgG4-positive plasma cells; storiform fibrosis and obliterative phlebitis make staining interpretable.
Steroid response can deceive
Cancer-associated oedema and lymphoma can shrink temporarily, so improvement after prednisolone must not retroactively replace protected tissue diagnosis.
Obstruction has its own clock
A bile duct or ureter may require immediate drainage because fibrosis cannot reliably recede quickly enough to protect sepsis or renal function.
Relapse may move organs
A patient whose pancreas remains quiet can later develop orbital, renal, retroperitoneal or vascular disease, requiring whole-person review.
Common pitfalls
01
Diagnosing IgG4-related disease from a mildly raised serum value without tissue, organ coherence or malignancy exclusion.
02
Using the ACR/EULAR classification score as a gold-standard bedside diagnostic test.
03
Starting a steroid trial for a resectable pancreatic or biliary mass before the MDT protects adequate cancer tissue.
04
Waiting for prednisolone to relieve septic biliary obstruction or bilateral hydronephrosis instead of draining promptly.
05
Escalating treatment for serum IgG4 rise alone while imaging, renal, liver and functional measures remain inactive.
06
Calling a persistent retroperitoneal or orbital mass refractory inflammation without separating fixed fibrosis, stent failure, infection and cancer.
Authoring stateComplete draft
Clinical stateAwaiting review
JurisdictionUnited Kingdom
First-line induction for active organ-threatening disease is prednisolone around 0.6 mg/kg daily for two to four weeks, followed by a structured taper over approximately three to six months.
Rituximab is an effective off-label steroid-sparing option for relapsing, refractory or high-risk disease, commonly 1 g IV on days 1 and 15 after HBV, infection, vaccine and immunoglobulin assessment.
Follow the organ that was ill, not serum IgG4 alone. Falling titre without improved obstruction, eGFR, imaging or gland and neurological function is not remission.
Anuria, bilateral hydronephrosis, rapidly increasing creatinine or flank pain from retroperitoneal fibrosis requires immediate urological decompression.
Reduced acuity, colour desaturation, relative afferent pupillary defect, proptosis or painful restricted eye movement suggests optic or orbital compression.
Severe headache, cranial neuropathy, pituitary dysfunction, myelopathy or focal neurology raises pachymeningitis, hypophysitis or another central process.
A focal pancreatic, renal, pulmonary or salivary mass, vascular invasion, constitutional loss or atypical nodes must remain cancer until adequate tissue and multidisciplinary review say otherwise.
Chest, back or abdominal pain with aortic wall disease, aneurysm or periaortitis requires urgent vascular imaging because inflammation and structural rupture risk are separate decisions.
05Renal ultrasound, CT and kidney biopsy
Why
Separate ureteric obstruction, tubulointerstitial nephritis, membranous nephropathy and an infiltrative mass.
Interpretation and limitations
Hydronephrosis requires decompression; cortical lesions with low complement support TIN, while heavy albuminuria or atypical sediment usually requires glomerular histology.
06Orbital and neuro-axis MRI
Why
Identify optic, extraocular-muscle, nerve, meningeal and pituitary threat.
Interpretation and limitations
Enhancement is not specific and infection, sarcoidosis, GPA and lymphoma need exclusion; serial acuity, fields, cranial nerves and hormones measure function.
07FDG-PET for distribution and biopsy selection
Why
Locate active clinically silent organs and choose a less hazardous representative specimen.
Interpretation and limitations
Uptake supports activity and can help monitor difficult disease but cannot distinguish IgG4-related inflammation from cancer and is not routine for every follow-up.
08Serum IgG4 trend
Why
Provide supportive baseline and one component of relapse assessment.
Interpretation and limitations
A mild rise is nonspecific, a normal value does not exclude tissue disease and treatment is not escalated for titre alone without organ activity.
2Protect vision, neural tissue and aortic integrity through ophthalmic, neurosurgical or vascular intervention while diagnostic samples are obtained.
3Begin immune induction once active IgG4-related inflammation is sufficiently supported; retain devices until objective structural recovery allows removal.
03First-line inductionUse glucocorticoid with an objective early checkpointFirst lineActive symptomatic or organ-threatening disease is secure enough for treatment and untreated infection is excluded.+
1Start prednisolone about 0.6 mg/kg daily for two to four weeks with metabolic, bone, gastric and infection safeguards.
2Measure early response in bilirubin or ducts, creatinine and imaging, orbital or neurological function and gland or lesion size, not symptoms or IgG4 alone.
3Taper every one to two weeks toward withdrawal over three to six months, slowing or adding a steroid-sparing plan for high relapse risk.
04Relapse or refractory routeReconfirm activity and deplete B cellsDisease returns, persists or cannot taper because of glucocorticoid toxicity.+
1Distinguish recurrent inflammation from fixed fibrosis, stent dysfunction, infection and malignancy and remap every previously involved organ.
2Use off-label rituximab 1 g IV on days 1 and 15 after hepatitis, TB, vaccine, immunoglobulin and infection assessment.
3Consider azathioprine or mycophenolate maintenance when rituximab is unsuitable, with realistic discussion of weaker evidence and medicine monitoring.
Key medicines and prescribing safety5 treatments · regimens, roles and cautions+
First-line induction after adequate malignancy and infection assessment, with rapid response expected in active non-fibrotic lesions.
Prednisolone
Start approximately 0.6 mg/kg orally once daily for two to four weeks in active disease, then reduce every one to two weeks toward cessation over about three to six months according to organ response and relapse risk.
Monitor diabetes, pressure, mood, eyes, bone, infection and adrenal risk; failure to improve objectively should reopen diagnosis, obstruction and irreversible scar rather than trigger indefinite high dose.
Steroid-sparing induction for relapsing, refractory, multiorgan or high-risk disease and when glucocorticoid toxicity is unacceptable.
Rituximab
Give 1000 mg intravenously on days 1 and 15 under an off-label IgG4-related disease protocol; retreatment is based on organ relapse and immune recovery rather than a fixed automatic cycle.
Screen HBsAg and anti-HBc, TB and active infection, measure immunoglobulins, time vaccines and monitor infusion reaction, late neutropenia and hypogammaglobulinaemia.
Off-label relapse prevention when repeated glucocorticoid is harmful and rituximab is unsuitable or unavailable.
Azathioprine
Use 1–2 mg/kg orally daily as a specialist maintenance option after TPMT or NUDT15 and baseline assessment, with dose adjusted to counts, liver function and interactions.
Evidence is weaker than for induction. Monitor marrow, liver, infection, pancreatitis and skin-cancer risk and reduce drastically with allopurinol only under an experienced protocol.
Off-label steroid-sparing maintenance for selected renal, orbital, neurological or multisystem disease.
Mycophenolate mofetil
Start 500 mg orally twice daily and increase to 1 g twice daily when tolerated and clinically required, with specialist blood and organ monitoring.
Monitor cytopenia, liver, infection and gastrointestinal toxicity; it is teratogenic, requires contraception and must stop at least six weeks before planned maternal conception.
Treats persistent maldigestion after autoimmune pancreatitis even when inflammatory remission is achieved.
Pancreatic enzyme replacement
For pancreatic exocrine failure, give a minimum 50,000 lipase units spread through every main meal and 25,000 units through each snack, then titrate to stool, weight and nutrition.
Check adherence, timing, dose, weight and fat-soluble nutrients; add acid suppression or investigate another cause when a properly used adequate dose fails.