BOTTOM LINE

IgG4-RD is an immune-mediated fibroinflammatory disorder characterized by inflammatory pseudotumours and/or strictures. Nearly any organ can be involved, but common presentations may include 1) autoimmune pancreatitis with sclerosing cholangitis, 2) retroperitoneal fibrosis with peri/aortitis, 3) Orbital pseudotumor, sinusitis, atopy, thyroiditis, or 4) Submandibular swelling, pulmonary fibrosis, serositis, and tubulointerstitial nephritis. Investigations should include bloodwork and imaging to broadly screen for end-organ involvement. Elevated serum IgE and IgG4 may be seen, but are not elevated as a rule and are not specific for IgG4-RD on their own. Biopsy should always be sought when feasible and it often reveals characteristic lymphoplasmacytic infiltration with storiform fibrosis, obliterative phlebitis, tissue eosinophilia, and high numbers and proportions of IgG4-positive cells. IgG4-positive cells on biopsy are, in isolation, not diagnostic for IgG4-RD and must be considered in clinical context. IgG4-RD mimics — including ANCA vasculitis, malignancy, and infection — must be ruled out. Treatment of IgG4-RD usually requires induction with steroids and often an immunosuppressant like rituximab combined with induction or added later for maintenance. Relapses are common.
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EPIDEMIOLOGY

• Exact epidemiology is challenging: rare disease, evolving definition and recognition
• Reported prevalence of IgG4-RD 1:100,000 (Japan); may be underestimate of true disease prevalence
• Patient Profile
  • Patient profile varies depending on phenotypic sub-group of IgG4-RD (see below)
  • Age:
    • ~50-65 years-old
  • Sex:
    • Slight male predominance (M:F, 1.5-4.0:1.0)
    • Sex-differences (not consistently shown in literature)
      • Males: older, more GI and visceral manifestations (pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis)
      • Females: younger, more atopy/allergy history, more salivary/lacrimal glands, orbit, sinus and skin manifestations
  • Ethnicity:
    • Unclear if more prevalent in certain ethnicities; all ethnicities affected.
    • Asians may present older with higher baseline serum IgG4 and more head/neck disease.
• Risk factors
  • Genetic: Associations with HLA-DRB1 and FCGR2B; various other Non-HLA susceptibility loci described
  • Exposure: smoking, occupational exposure to solvents and industrial gases, infections (TB, S. aureus, H. pylori)

CLINICAL MANIFESTATIONS

• IgG4-RD can affect nearly any organ; >75% of patients have 2 or more organs involved.

Certain manifestations may occur more commonly together in 4 phenotypic groups; though patients can have overlapping features across groups

Group 1: Pancreato-hepato-biliary (31%)	More common in older Caucasian, male patients
Group 2: Retroperitoneum and aorta (24%)	Typically higher inflammatory markers
Group 3: Head and neck-limited (24%)	More common in younger, Asian, female patients
Group 4: Mikulicz and Systemic (22%)	Typically higher serum IgG4 and IgE

GROUP 1: PANCREATO-HEPATOBILIARY IgG4-RD

Group 1 IgG4-RD: more often male, older, caucasian. More likely to have higher serum IgG4 and IgE. Co-existent autoimmune pancreatitis and cholangitis is very suggestive of IgG4-RD.

—PANCREAS

• Clinical
  • Acute: may have pain, obstructive jaundice, pancreatic mass (most common)
  • Chronic: Pancreatic atrophy, calcifications, ductal dilatation; can be painless.
    • May develop low Vitamin A/D/E/K, Mg, zinc, Ca, Fe, hemoglobin, albumin, pre-albumin
  • Steroid responsive
• Serology
  • More likely to have serum IgG4 >2x upper-limit-normal, high IgE
• Imaging (Pancreatic CT, MRI)
  • Parenchymal enlargement: diffuse or segmental/focal
  • “Sausage-like” shape pancreas
  • Peripancreatic edematous rim
  • Main pancreatic duct narrowing without upstream dilatation
• Histology:
  • Endoscopic-ultrasound guided biopsy with 19G needle: aids diagnosis and excludes pancreatic carcinoma
    • Periductal lymphoplasmacytic infiltrate without granulocytic infiltration
    • Storiform fibrosis, Obliterative phlebitis
    • >10 IgG4+ cells/HPF ; >50 cells/HPF in samples from surgical biopsy specimens
    • IgG4/IgG ratio >40%
• DDX
  • Pancreatic cancer, cholangiocarcinoma

—HEPATO-BILIARY

• Clinical
  • Painless jaundice, weight loss, abdominal pain; fever if co-existing bacterial cholangitis.
  • Can develop progressive liver fibrosis and liver cirrhosis.
  • Possible occupational exposure association: oils, solvents, industrial gases (asphalt workers, truck drivers, painters, carpenters)
  • Steroid responsive
• Imaging (Biliary)
  • Narrowing of extra-hepatic, perihilar, and intra-hepatic bile ducts; usually affects lower part of common bile duct
  • Versus primary sclerosing cholangitis (PSC):
    • IgG4-RD causes long-segment band-shaped extra-hepatic duct narrowing
    • PSC causes well-defined circumscribed short-segment extra-hepatic duct narrowing
• Histology
  • Similar to IgG4-RD pancreatitis
  • Diffuse plasmacytic infiltration
  • Marked interstitial fibrosis with storiform fibrosis and obliterative phlebitis.
  • >10 IgG4+ cells/HPF; IgG4/IgG ratio >40%

GROUP 2: RETROPERITONEAL/AORTITIS IgG4-RD

Group 2 IgG4-RD: more often male, older, with normal or slightly elevated serum IgG4; slightly elevated ESR and CRP

—RETROPERITONEAL FIBROSIS (RPF)

• Epidemiology
  • Prevalence of RPF in the IgG4-RD population: ~3–20%
  • Prevalence of IgG4-RPF in the RPF population: 30–60%
• Clinical
  • Asymptomatic; non-specific symptoms could include low-back, abdominal, flank pain, oliguria, peripheral edema.
  • Can cause hydronephrosis or renal atrophy.
  • ~50% have extra-retroperitoneal IgG4 lesions
  • Location of fibrosis:
    • Often infra-renal peri-aortic or peri-iliac
    • Can also be pericaval, pre-sacral, retro-vesicular, peri-rectal
• Serology
  • Normal or slightly elevated serum IgG4
  • May have elevated ESR/CRP
• Histology
  • Storiform fibrosis, tissue eosinophilia obliterative phlebitis on biopsy
  • >30 IgG4+ cells/HPF; IgG4/IgG ratio >40% (lower cut off than peri/aortitis)

—PERI-AORTITIS

• Epidemiology
  • Prevalence ~20–35% of IgG4- RD patients
• Clinical
  • Fibrotic inflammation of tissues surrounding aorta
  • Abdominal aorta more often involved than thoracic aorta
    • Especially infra-renal and iliac arteries
  • Non-specific symptoms of low back, abdominal or flank pain; other organs involved in majority of patients (often kidney and/or urinary tract).
  • ~30% have aortic dilatation/aneurysm.
  • Association with atopy (i.e.: allergic rhinitis, asthma, atopic dermatitis)
• Serology
  • Usually elevated serum IgG4 and ESR/CRP
  • Serum IgG4 usually lower in peri-aortitis compared with other IgG4-RD phenotypes
• Histology
  • Storiform fibrosis, tissue eosinophilia obliterative phlebitis on biopsy
  • >50 IgG4+ cells/HPF; IgG4/IgG ratio >50%

—AORTITIS

• Epidemiology
  • Prevalence of aortitis in IgG4-RD population: ~8%
  • Prevalence of IgG4-RD aortitis in non-infectious aortitis patients: 7-9%
• Clinical
  • Vasculitis of the aorta and major branches with vessel wall thickening and dilatation/aneurysms
  • Thoracic aorta involved twice as often as abdominal aorta
  • Thoracic wall thickening usually milder than abdominal wall thickening
  • Association with atopy (i.e.: allergic rhinitis, asthma, atopic dermatitis)
• Serology
  • Usually elevated serum IgG4 and ESR/CRP
  • Serum IgG4 usually lower in aortitis compared with other IgG4-RD phenotypes
• Histology
  • Storiform fibrosis, tissue eosinophilia obliterative phlebitis on biopsy
  • >50 IgG4+ cells/HPF; IgG4/IgG ratio >50%

—OTHER GROUP 2 IgG4-RD MANIFESTATIONS

• Cardiac:
  • Constrictive pericarditis, Coronary artery disease
• Thoracic:
  • Compression of local mediastinal structures from fibroinflammatory pseudotumor

—IMAGING IN GROUP 2 IgG4-RD

Vascular imaging is crucial since biopsy is not always possible in peri/aortitis

• CT
  • May show thickening of vessels or mass-like homogenous circumferential enhancement of aorta.
  • Stenoses are less characteristic of IgG4-RD and may suggest alternate diagnosis.
  • Wall thickening on CT may persist after immunosuppressive treatment
• PET
  • Reveals active peri/aortitis or RPF (or other affected organs).
  • Can also uptake in atherosclerotic plaque
• MRI
  • May show high intensity signal and late GAD-enhancement in T1- and low intensity T2- weighted images in active peri/aortitis and RPF

GROUP 3: HEAD AND NECK LIMITED IgG4-RD

Group 3 IgG4-RD: more often female, Asian, younger; atopy history.  More likely elevated serum IgG4; normal ESR/CRP and IgE.

—OPTHALMIC

• Motor
  • “Inflammatory orbital pseudotumour”; painless eyelid swelling (unilateral or bilateral), restricted ocular movement, exophthalmos, ptosis, diplopia
  • Caused by inflammation of lacrimal gland (dacroadenitis), extraocular muscles
• Sensory
  • Decreased vision due to inflammation of infra/supraorbital nerves or optic nerve
• Other
  • Scleritis, uveitis: eye pain, redness, epiphora, corneal ulceration
  • Sicca
• Histology
  • Lymphocytic and plasmacytic infiltration; sometimes fibrosis. Germinal centre frequently observed.
  • >50 IgG4+ cells/HPF, IgG4/IgG ratio >40%

—SINONASAL

• Atopy:
  • Sinusitis, rhinitis: nasal crusting, rhinorrhea, post nasal drip, nasal polyposis, nasal obstruction, anosmia
• Other:
  • Hearing loss, mastoiditis, otitis media, laryngeal

—THYROID

• Thyroiditis: subclinical hypothyroidism; can present with goiter and local compression (dyspnea, dysphagia, hoarse)
• Ultrasound of thyroid shows diffuse low echogenicity; may have positive anti-thyroglobulin, anti-thyroid peroxidase 
• Formerly called “Riedel’s thyroiditis”

—PITUITARY

• Rare but reported involvement of pituitary gland (hypophysitis) causing hypopituitarism and/or diabetes insipidus
• MRI of brain shows enlargement of anterior pituitary and/or stalk

—NEUROLOGICAL

• Meninges
  • Hypertrophic pachymeningitis (localized or diffuse thickening of cranial or spinal cord dura)
  • Manifests as headache, cranial nerve palsies, vision disturbance, motor weakness, limb numbness, deafness, seizures
• Cranial nerves
  • Cranial neuropathy caused by adjacent inflammatory tumoral masses, pachymeningitis, mastoiditis, or spinal nerve roots (paravertebral mass)

GROUP 4: MIKULICZ SYNDROME AND SYSTEMIC IgG4-RD

Group 4 IgG4-RD: more often male, older, with high serum IgG4 and IgE

—GLANDULAR

• Lacrimal gland:
  • Dacroadenitis resulting in inflammatory orbital pseudotumour and sicca as in Group 3 IgG4-ID
• Salivary gland:
  • Chronic sclerosing sialenditis causes sicca from inflammation of submandibular, parotid, sublingual, minor salivary glands. More often unliateral, but can be bilateral
• “Mikulicz Syndrome”:
  • Historic name for IgG4-RD manifesting as head/neck glandular enlargement  

—PANCREATIC

• Type 1 Autoimmune pancreatitis, like in Group 1 IgG4-RD

—PULMONARY

• Parenchymal
  • Interstitial lung disease: asymptomatic or presenting as cough, hemoptysis, dyspnea
  • CT may show bronchial wall thickening, consolidation, nodule/mass, ground glass, interlobular thickening and fibrosis
• Pleural
  • Pleural thickening or pleural effusion: asymptomatic or presenting as dyspnea, pleurisy, chest pain
• Mediastinal
  • Lymphadenopathy, sclerosing mediastinitis
• Histology
  • Lymphoplasmacytic infiltration of peribronchovascular sheath, interlobular septal wall, and/or pleura
  • Obliterative phlebitis or arteritis
  • Storiform fibrosis
  • >10 IgG4+ cells/HPF, and/or IgG4/IgG-positive cell ratio >40%

—RENAL

• Tubulointerstitial nephritis:
  • Hypocomplementemia, active urinary sediment, with or without decreased renal function
• Histology:
  • Storiform fibrosis surrounding “nests” of lymphocytes and/or plasma cells
  • >10 IgG4+ cells/HPF and/or IgG4/IgG ratio >40%

DISEASE METRIC

IgG4-RD Responder index: Disease activity score, typically for research purposes

• Sub-score given for Degree of disease Activity in past 28 days for different organs/sites
• Sub-score given for Serum IgG4 concentration
• Total Activity Score: [Organ-site score, x2 if urgent] + Serum IgG4 Score

INVESTIGATIONS

• CBC
  • Eosinophilia ~30%; if peripheral eosinophilia >3000×10⁶/L begin to consider alternate diagnoses (ex: EGPA)
• ALT, ALP, bilirubin
  • Elevated if hepato-biliary involvement
• Cr, urinalysis
  • Abnormal if tubule-interstitial nephritis (TIN): microscopic hematuria/proteinuria with or without decreased renal function
• C3, C4
  • Low C3, C4, especially if TIN
• ESR, CRP
  • ESR can be moderately elevated; CRP usually normal except if retroperitoneal fibrosis or peri-aortitis (slightly ↑CRP)
  • If markedly elevated, consider alternate diagnosis (ex: ANCA vasculitis, multicentric Castleman disease, infection)
• IgE
  • ↑ IgE ~30%; higher baseline associated with greater risk of relapse
• Serum IgG4
  • ↑ IgG4 in 55-97% of patients, especially Asians.
    • Higher baseline associated with male sex, older age, Mikulicz’s; higher risk of relapse
    • Lower baseline associated with retroperitoneal fibrosis
  • Correlated with disease activity and number of organs involved (IgG4RD Responder Index)
  • 2x upper-limit-normal:
    • Sensitivity 63% (60.0% to 66.0%)
    • Specificity 94.8% (94.1% to 95.4%)

Serum IgG4 can be elevated in broad spectrum of neoplastic, infectious, and autoimmune diseases

• Serology
  • ANA and RF: Not generally associated with ANA or RF, but may have low-titre ANA or RF by chance
  • Negative ANCA, dsDNA, SSa/Ro, SSB/La, RNP, smith; if positive, consider alternate diagnosis
• Other
  • Males tend to have higher peripheral eosinophils, CRP and IgG4
• Imaging
  • Based upon clinical manifestations
  • Baseline PET scan or CT neck/chest/abdomen/pelvis for disease staging and planning biopsy targets
• Biopsy
  • IgG4-RD is a clinical diagnosis, but histology is a critical to evaluate for malignancy or other IgG4-RD mimics.
  • Obtain biopsy whenever possible. Send a second sample in Michel’s solution for immunofluorescence
  • Classic findings
    • Marked lymphoplasmacytic infiltration with fibrosis and without granulocytic infiltration
    • Storiform fibrosis
    •  Obliterative phlebitis
    • Abundant >30 cells/HPF IgG4-positive cells, IgG4/IgG ratio >40%
      • Different cut-offs have been suggested for different organs (see above)

An isolated biopsy finding of an increased IgG4 plasma cell count is NOT diagnostic for IgG4-RD. IgG4-RD is a clinical diagnosis.

Neutrophilic or other granulocytic infiltration and granulomata suggest alternate diagnosis

DIAGNOSIS

IgG4-RD is a clinical diagnosis based on characteristic clinical, serologic, radiographic, and histopathological findings. Consider IgG4-RD particularly in patients with auto-immune pancreatitis, sclerosing cholangitis, salivary/lacrimal gland enlargement, retroperitoneal fibrosis, periaortitis, orbital pseudotumor or other mass-like pseudotumor or stricturing elsewhere. Atopy and high IgE is common in certain groups of IgG4-RD. Serum IgG4 may be elevated (ex: >2-5x ULN), but it is not elevated as a rule and is not diagnostic of IgG4-RD in isolation. Biopsy should be sought whenever possible with second sample sent in Michel’s solution for immunofluorescence. Common histopathological findings include lymphoplasmacytic infiltration, storiform fibrosis, tissue eosinophilia, obliterative phlebitis, and high numbers and proportions of IgG4-positive cells on immunofluorescence. IgG4+ cells on biopsy is not diagnostic in isolation and must be considered in clinical context.

—DIAGNOSTIC CRITERIA

• Various Comprehensive and Organ-Specific diagnostic criteria have been proposed, based on expert opinion.
• Different cut-offs for IgG4/IgG ratio and IgG4-positive cells/HPF proposed for different specific organs (see above)

Comprehensive Diagnostic Criteria (Umehara 2017)
1. Diffuse/localized swelling or masses in single or multiple organs
2. High serum IgG4 (>135 mg/dl)
3. Histopathological study shows the following two findings (i) Light microscopy: Marked lymphocyte and plasmacyte infiltration and fibrosis (ii) immunofluorescence: IgG4/IgG-positive cell>40% and IgG4-positive plasma cells/HPF >10

Diagnostic certainty	Criteria Score
Definite diagnosis	1 + 2 + 3 are fulfilled
Probable diagnosis	1 + 3 are fulfilled
Possible diagnosis	1 + 2 are fulfilled

—DIFFERENTIAL DIAGNOSIS

By Organ System

CLASSIFICATION CRITERIA

IgG4-RD is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

—STEP 1: ENTRY CRITERIA (YES or NO)

Characteristic* clinical or radiologic involvement of a typical organ (e.g., pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland [Riedel’s thyroiditis]) OR pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs

—STEP 2: EXCLUSION CRITERIA (Yes or NO)

• Clinical
  • · Fever >38⁰C
  • · No objective response to glucocorticoids
• Serologic
  • Leukopenia and thrombocytopenia NYD
  • Peripheral eosinophilia >3000 x10⁶/L
  • Positive ANCA (specifically against PR3 or MPO)
  • Positive SSA/Ro or SSB/La antibody
  • Positive dsDNA, RNP, or Sm antibody
  • Other disease-specific autoantibody
  • Cryoglobulinemia
• Radiologic
  • Known radiologic findings suspicious for malignancy or infection that have not been sufficiently investigated
  • Rapid radiologic progression
  • Long bone abnormalities consistent with Erdheim-Chester
  • Splenomegaly
• Pathologic
  • Cellular infiltrates suggesting malignancy that have not been sufficiently evaluated
  • Markers consistent with inflammatory myofibroblastic tumor
  • Prominent neutrophilic inflammation
  • Necrotizing vasculitis
  • Prominent necrosis
  • Primarily granulomatous inflammation
  • Pathologic features of macrophage/histiocytic disorder
• Known diagnosis of
  • Multicentric Castleman’s disease
  • Crohn’s disease or ulcerative colitis (if only pancreatobiliary disease is present)
  • Hashimoto thyroiditis (if only the thyroid is affected)

If meets entry criteria and but not any exclusion criteria, proceed to step 3.

—STEP 3: INCLUSION CRITERIA

• Histopathology
  • 0: Uninformative biopsy
  • +4: Dense lymphocytic infiltrate
  • +6: Dense lymphocytic infiltrate and obliterative phlebitis
  • +13: Dense lymphocytic infiltrate and storiform fibrosis with or without obliterative phlebitis
• Immunostaining; 0–16, as follows#:
  • 0:       
    IgG4/IgG+ is 0-40% or indeterminate**, and         IgG4+ cells/HPF is 0-9.
  • 7:
    If 1) IgG4/IgG+ is ≥41%, and
    IgG4+ cells/HPF is 0-9 or indeterminate;
    Or 2) IgG4/IgG is 0-40% or indeterminate, and
    IgG4+ cells/hpf is ≥10 or indeterminate.
  • 14:
    If 1) IgG4/IgG+ is 41–70% , and
    IgG4+ cells/hpf is ≥10;
    Or 2) IgG4/IgG+ is ≥71%, and
    IgG4+ cells/hpf is 10–50.
  • 16:     
    If IgG4/IgG+ is ≥71%, and
    IgG4+ cells/hpf is ≥51
• Serum IgG4
  • 0: Normal or not checked
  • +4: <2× upper limit of normal
  • +6: 2-5x upper limit of normal
  • +11: >5x upper limit of normal
• Glands: Bilateral lacrimal, parotid, sublingual, and submandibular glands
  • 0: No set of glands involved
  • +4: One set of glands involved
  • +14: Two or more sets of glands involved
• Chest
  • 0: Not checked or neither of the items listed is present
  • +4: Peri-bronchovascular and septal thickening
  • +10: Paravertebral band-like soft tissue in the thorax
• Pancreas, biliary tree
  • 0: Not checked or none of the items listed is present
  • +8: Diffuse pancreas enlargement (loss of lobulations)
  • +11: Diffuse pancreas enlargement and capsule-like rim with decreased enhancement
  • +19: Pancreas (either of above) and biliary tree involvement
• Renal
  • 0: Not checked or none of the items listed is present
  • +6: Hypocomplementemia
  • +8: Renal pelvis thickening/soft tissue
  • +10: Bilateral renal cortex low-density areas
• Retroperitoneum
  • 0: Not checked or neither of the items listed is present
  • +4: Diffuse thickening of the abdominal aortic wall
  • +8: Circumferential or anterolateral soft tissue around the infrarenal aorta or iliac arteries

—STEP 4: TOTAL INCLUSION POINTS

A case meets the classification criteria for IgG4-RD if the entry criteria are met, no exclusion criteria are present, and the total points is ≥20.

*	Refers to enlargement or tumor-like mass in an affected organ except in 1) the bile ducts, where narrowing tends to occur, 2) the aorta,    where wall thickening or aneurysmal dilatation is typical, and 3) the lungs, where thickening of the bronchovascular bundles is common.
¶	Only the highest-weighted item in each domain is scored.
#	Biopsies from lymph nodes, mucosal surfaces of the gastrointestinal tract, and skin are not acceptable for use in weighting the immunostaining domain
**	“Indeterminate”: pathologist is unable to clearly quantify the number of positively staining cells within an infiltrate yet can still ascertain that the number of cells is at least 10/HPF (ex: due to quality of immunostain)

TREATMENT

GENERAL PRINCIPLES

Management of IgG4-RD is based on expert opinion and small retrospective/prospective studies.  Risk factors for relapse should be evaluated when considering choice of induction and maintenance therapy.  Patients may be grouped into those with minimal/asymptomatic presentations who could be monitored versus severe disease requiring induction and maintenance therapy.

• Risk factors for relapse
  • Multiorgan disease, involvement of proximal bile ducts, or a history of relapse, Group 3 IgG4-RD phenotype
  • Elevated pre-treatment serum IgG4, IgE, and peripheral eosinophilia
  • IgG4-RD responder index >9
• Minimal Disease
  • Asymptomatic single organ involvement with low likelihood of organ dysfunction, no risk factors for relapse
  • Ex: minimal lymph node involvement or asymptomatic submandibular gland enlargement
  • Watchful waiting may be reasonable in select cases with minimal disease
• Severe Disease
  • Symptomatic organ involvement or with a high likelihood of organ dysfunction and risk factors for relapse
  • Examples:
    • Aortitis +/- aneurysm or ischemia
    • Retroperitoneal fibrosis +/- obstructive uropathy
    • Tubulointerstitial nephritis +/- renal injury
    • Symptomatic pachymeningitis
    • Orbital disease causing optic nerve compression
    • Pancreato-biliary involvement +/- jaundice
    • Coronary artery or pericardial involvement
  • Induction and maintenance therapies are needed for severe disease

INDUCTION

• Glucocorticoids
  • Prednisone 0.4-0.6mg/kg/day x 4 weeks, then taper to <7.5mg/d over 12-14 weeks (ex: taper 5mg q2 weeks)
  • Consider starting Prednisone at 1mg/kg/day for very severe presentations
  • Induction and taper of steroids can be personalized depending on disease-specific or patient-related factors
• Additional Agents
  • Consider adding up-front immunosuppressives to prednisone if severe disease with risk factors for relapse or if unfavorable patient factors for prolonged glucocorticoid exposure (ex: osteoporosis, diabetes).
  • Rituximab 2g IV (divided over 2 weeks)
  • Inebilizumab 300mg IV Days 1, 15 and week 26
  • Mycophenolate mofetil 1-1.5g/BID
  • Azathioprine 2mg/kg/day
  • Methotrexate 20-25mg/week
  • Leflunomide 10-20mg/d
  • Thalidomide 25 mg/day, increased to no more than 75 mg/day within a week based on tolerance
  • Cyclophosphamide

If no response to induction: reconsider the diagnosis; add/change steroid-sparing agent and re-induce with glucocorticoids

MAINTENACE

• Agents
  • Prednisone ≤5-7mg/d or taper off completely if steroids combined with background immunosuppressive agent
  • Rituximab, inebilizumab, mycophenolate mofetil, azathioprine, methotrexate, thalidomide, or leflunomide
• Duration
  • Consider for at least 2-years; optimal duration unknown

Relapses are frequent. If relapse: reconsider the diagnosis; add/change steroid-sparing agent and re-induce with glucocorticoids

NON-PHARMACOLOGIC TREATMENT

• Stenting
  • May be required as adjunctive bridging in select cases of severe organ dysfunction from obstructive processes
  • Ex: Cholangitis from biliary obstruction, obstructive uropathy from retroperitoneal fibrosis. 
• Surgery
  • Surgical debulking of highly fibrotic “burnt out” disease in rare instances as adjunctive therapy
  • Ex: symptomatic fibrosclerotic encasement of organ, fibrotic orbital pseudotumor, sclerosing mesenteritis

PROGNOSIS

• Natural history of IgG4-RD not yet well defined
• Relapses frequent: 40-60% across various case series
• Prognosis may vary be IgG4-RD Group
  • Group 1 (Pancreato-hepato-biliary): more frequent emergency room visits compared to other groups
  • Group 3 (Head and neck limited): higher relapse rate and more frequent use of ritixumab
  • Group 4 (Mikulicz and Systemic): higher disease activity by IgG4-RD Responder Index

REFERENCES

Brito-Zerón, P., Ramos-Casals, M., Bosch, X., & Stone, J. H. (2014). The clinical spectrum of IgG4-related disease. Autoimmunity reviews, 13(12), 1203–1210. https://doi.org/10.1016/j.autrev.2014.08.013

Carruthers, M. N., Stone, J. H., Deshpande, V., & Khosroshahi, A. (2012). Development of an IgG4-RD Responder Index. International journal of rheumatology, 2012, 259408. https://doi.org/10.1155/2012/259408

Floreani, A., Okazaki, K., Uchida, K., & Gershwin, M. E. (2020). IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. Journal of translational autoimmunity, 4, 100074. https://doi.org/10.1016/j.jtauto.2020.100074

Hao, M., Liu, M., Fan, G., Yang, X., & Li, J. (2016). Diagnostic Value of Serum IgG4 for IgG4-Related Disease: A PRISMA-compliant Systematic Review and Meta-analysis. Medicine, 95(21), e3785. https://doi.org/10.1097/MD.0000000000003785

Johnston, J., & Allen, J. E. (2018). IgG4-related disease in the head and neck. Current opinion in otolaryngology & head and neck surgery, 26(6), 403–408. https://doi.org/10.1097/MOO.0000000000000487

Kamisawa, T., Zen, Y., Pillai, S., & Stone, J. H. (2015). IgG4-related disease. Lancet (London, England), 385(9976), 1460–1471. https://doi.org/10.1016/S0140-6736(14)60720-0

Khosroshahi, A., Wallace, Z. S., Crowe, J. L., Akamizu, T., Azumi, A., Carruthers, M. N., Chari, S. T., Della-Torre, E., Frulloni, L., Goto, H., Hart, P. A., Kamisawa, T., Kawa, S., Kawano, M., Kim, M. H., Kodama, Y., Kubota, K., Lerch, M. M., Löhr, M., Masaki, Y., … Second International Symposium on IgG4-Related Disease (2015). International Consensus Guidance Statement on the Management and Treatment of IgG4-Related Disease. Arthritis & rheumatology (Hoboken, N.J.), 67(7), 1688–1699. https://doi.org/10.1002/art.39132

Lanzillotta, M., Mancuso, G., & Della-Torre, E. (2020). Advances in the diagnosis and management of IgG4 related disease. BMJ (Clinical research ed.), 369, m1067. https://doi.org/10.1136/bmj.m1067

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