1. IgG4-related disease
호흡기내과
R4 황인경 / pf.박명재

2. Introduction IgG4-related disease (IgG4-RD)
A syndrome of unknown etiology comprised of a collection of disorders that share specific pathologic, serologic, and clinical features
Hallmarks of IgG4-related disease (IgG4-RD)
Tumor-like swelling of involved organs
Lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells and T-lymphocytes
Usually accompanied by fibrosis (‘storiform’ pattern), obliterative phlebitis
Elevated serum IgG4 levels (60-70%)
Good initial therapeutic response to glucocorticoids
Cartwheel apperance of the arranged fibroblasts and inflammatory cells

3. Histopathological features
Dense lymphoplasmacytic infiltrate and obliterative phlebitis (arrow)
Storiform fibrosis
C-D. Nearly all plasma cells are strongly positive for IgG4 on immunoperoxidase staining
Obliterative phlebitis
Lymphocytes, plasma cells, eosinophils, and fibroblast

4. Introduction
IgG4-related disease has been described in virtually every organ system: biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, etc.
IgG4-RD was not recognized as a systemic condition until 2003, when extrapancreatic manifestations were identified in patients with autoimmune pancreatitis
Many medical conditions that have long been viewed as conditions confined to single organs are part of the spectrum of IgG4-related disease
Cartwheel apperance of the arranged fibroblasts and inflammatory cells

5. Introduction IgG4 molecule
Less than 5% of the total IgG in healthy persons
A unique characteristic of IgG4 is its half antibody exchange reaction, also referred to as Fab-arm exchange
IgG4 molecules are unable to crosslink antigens, thereby losing the ability to form immune complexes  contribute to the molecule’s antiinflammatory function
Cartwheel apperance of the arranged fibroblasts and inflammatory cells

6. Epidemiology In a study of 114 patients with IgG4-RD,
Epidemiology remains largely undefined
IgG4-RD is most often occuring in middle-aged and older men
IgG4-related pancreatitis: more often older men Sialadenitis: more equal sex distribution
In a study of 114 patients with IgG4-RD,
the ages of patients in all groups were similar, years
All the groups, except for head and neck involvement, were predominantly men (75-86%)
the group with only head and neck disease was nearly equally divided (48% men)
Am J Surg Pathol Dec;34(12):1812-9

7. Pathophysiological mechanisms
Multiple immune-mediated mechanisms contribute to fibroinflammatory process of IgG4-RD
Potential triggers
Immune reaction
Cellular infiltrate within affected organ
Clinical results
Autoimmunity and infectious agents are potential immunologic
triggers in IgG4-related disease (Panel A).
Interleukins 4, 5, 10, and 13 and transforming growth
factor β (TGF-β) are overexpressed through an immune
reaction in which type 2 helper T (Th2) cells
predominate, followed by activation of regulatory T
(Treg) cells (Panel B). These cytokines contribute to
the eosinophilia, elevated serum IgG4 and IgE concentrations,
and progression of fibrosis that are characteristic
of IgG4-related disease. Massive infiltration by
inflammatory cells results in organ damage (Panel C).
The inflammatory-cell infiltrate leads to tumefactive
enlargement of the affected sites and organ dysfunction
(Panel D). Epithelial damage may result from tissue
inflammation and immune-complex deposition.

8. Pathophysiological mechanisms
Genetic risk factors
HLA serotypes DRB1*0405 and DQB1*0401 in Japanese people
Bacterial infection and molecular mimicry
Substantial homology exists between human carbonic anhydrase II and the α-carbonic anhydrase of H. pylori
In theory, antibodies directed against these bacterial components could behave as autoantibodies by means of molecular mimicry in genetically predisposed persons
Autoimmunity
Serum IgG4 binds to the normal epithelia of the pancreatic ducts, bile ducts, and salivery gland ducts
Antibodies against potential autoantigens at these sites may be related to systemic manifestations of IgG4-related disease
Anti-PBP peptide antibodies — Anti-plasminogen-binding protein (PBP) peptide antibodies may help diagnose patients with AIP. One study that included an initial and a validation cohort detected anti-PBP peptide antibodies in 33 of 35 patients (94 percent) with autoimmune pancreatitis and in no healthy controls [54]. However, these antibodies were also present in 5 of 110 patients (5 percent) with pancreatic cancer. As a result, it cannot be used to distinguish between these two diseases.
Other antibodies — Other antibodies that may be elevated in patients with AIP include antibodies to carbonic anhydrase II antigens (positive in 30 to 59 percent) [55] and lactoferrin (positive in 50 to 76 percent) [56]. Additional antibodies that have been associated with AIP, but that have not been consistently positive, include rheumatoid factor, perinuclear antineutrophil cytoplasmic antibody, antinuclear antibody, antimitochondrial antibody, anti-smooth muscle antibody, and antithyroglobulin [57-59].
Distinction of IAC from PSC — Certain cholangiographic features may help distinguish biliary involvement of AIP (IgG4-associated cholangitis; IAC) from primary sclerosing cholangitis (PSC), which has similar clinical features and, in some patients, elevations in serum IgG4 (though less pronounced than those seen in IAC) [49]. (See 'Serologic testing for IgG4' above.)

9. Pathophysiological mechanisms
Th2 cells and regulatory immune reaction
Th2-cell responses are predominantly activated
Levels of Th2 cytokines, IL-4,5,10,13 are higher than in classic autoimmune conditions
Many lymphocyte, plasma cell are collected
The activation of Treg cell can be produced IL-10, TGF-ß
TGF-ß may play a role in the promotion of fibrosis
Anti-PBP peptide antibodies — Anti-plasminogen-binding protein (PBP) peptide antibodies may help diagnose patients with AIP. One study that included an initial and a validation cohort detected anti-PBP peptide antibodies in 33 of 35 patients (94 percent) with autoimmune pancreatitis and in no healthy controls [54]. However, these antibodies were also present in 5 of 110 patients (5 percent) with pancreatic cancer. As a result, it cannot be used to distinguish between these two diseases.
Other antibodies — Other antibodies that may be elevated in patients with AIP include antibodies to carbonic anhydrase II antigens (positive in 30 to 59 percent) [55] and lactoferrin (positive in 50 to 76 percent) [56]. Additional antibodies that have been associated with AIP, but that have not been consistently positive, include rheumatoid factor, perinuclear antineutrophil cytoplasmic antibody, antinuclear antibody, antimitochondrial antibody, anti-smooth muscle antibody, and antithyroglobulin [57-59].
Distinction of IAC from PSC — Certain cholangiographic features may help distinguish biliary involvement of AIP (IgG4-associated cholangitis; IAC) from primary sclerosing cholangitis (PSC), which has similar clinical features and, in some patients, elevations in serum IgG4 (though less pronounced than those seen in IAC) [49]. (See 'Serologic testing for IgG4' above.)

10. Clinical manifestations
Involve one or multiple organs(60-90% of IgG4-RD)
Subacute development of a mass in the affected or diffuse enlargement of an organ
affected tissues share specific pathologic, serologic, and clinical features, regardless of the organ involved
Lymphadenopathy is common
Symptoms of asthma or allergy are present in about 40% pts, often recognized incidentally based upon a radiologic finding or histopathologic examination of a tissue specimen
a study of patients with autoimmune pancreatitis found frequent extrapancreatic involvement, including hilar lymphadenopathy (80 percent), extrapancreatic bile duct lesions (74 percent), lacrimal and salivary gland lesions (39 percent), hypothyroidism (22 percent), and retroperitoneal fibrosis (13 percent) [28]. In contrast, autoimmune pancreatitis was found in only 17 percent of patients studied with IgG4-related lacrimal, parotid, or submandibular gland disease, and interstitial nephritis (17 percent) and interstitial pneumonitis (9 percent) were also seen among this group

11. IgG4-RD associated disorders
Type 1 autoimmune pancreatitis (IgG4-related pancreatitis)
IgG4-related sclerosing cholangitis
Mikulicz’s disease (IgG4-related dacryoadenitis and sialadenitis)
Sclerosing sialadenitis (Küttner’s tumor, IgG4-related submandibular gland disease)
Inflammatory orbital pseudotumor (IgG4-related orbital inflammation or orbital inflammatory pseudotumor)
Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-related dacryoadenitis)
A subset of patients with “idiopathic” retroperitoneal fibrosis (Ormond’s disease) and related disorders (IgG4-related retroperitoneal fibrosis, IgG4-related mesenteritis)
Chronic sclerosing aortitis and periaortitis (IgG4-related aortitis or periaortitis)
Riedel’s thyroiditis (IgG4-related thyroid disease)
IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors (IgG4-related lung disease)
IgG4-related kidney disease (including tubulointerstitial nephritis and membranous glomerulonephritis secondary to IgG4-RD)
IgG4-related hypophysitis
IgG4-related pachymeningitis

12. IgG4-related lung disease (IgG4RLD)
IgG4-related interstitial pneumonitis and pulmonary inflammatory pseudotumors
Fibroinflammatory entity that has diverse clinical manifestations
IgG4RLD shares the same histopathological features
Storiform fibrosis, obliterative phlebitis are more common
Extrapulmonary manifestations are common
Autoimmune pancreatitis, periaortitis, interstitial nephritis, etc.
Visceral or parietal pleural thickening may occur
lacrimal and salivary gland involvement

13. IgG4-related lung disease
Four patterns of lung involvement on chest CT appearance
Solid nodular
Bronchovascular : thickening of bronchovascular bundle, interlobular septum
Alveolar interstitial (with honeycombing, bronchiectasis, and diffuse ground-glass opacities)
Round-shaped ground-glass opacities
lacrimal and salivary gland involvement

14. Lung biopsy on suspicious malignancy
M/65; dyspnea, LUQ pain
Lung biopsy on suspicious malignancy
Infiltration of plasma cell with immunoreactive for IgG4, fibrosis
Elevated serum IgG4 level (341mg/dl)
Diffuse, low attenuated enlarged pancreas in abdominal CT
Oral prednisolone 40mg/day  pulmonary lesion, lymphadenopathy and Sx were markedly improved; IgG4 71.4mg/dl
Infiltrative shadows were observed along the bronchovascular
bundles of the left lung, and scattered infiltrative shadows
reflecting emphysematous changes were observed
around these bundles. Within these infiltrative shadows, traction
bronchiectasis was observed. Bilateral hilar and mediastinal
lymphadenopathy as well as a pleural effusion on the
left side were also observed. Mild infiltrative shadows were
present directly under the pleura of the right upper lobe.

15. Diagnosis
Biopsy findings (histopathologic + immunohistochemical staining)
lymphoplasmacytic tissue infiltration of mainly IgG4-positive plasma cells and small lymphocytes
accompanied by storiform fibrosis and by obliterative phlebitis
modest tissue eosinophilia is often present
Serum IgG4 levels are a significant aid in diagnosis
Additional organ involvement 여부 확인
Lung biopsy of the pulmonary nodule
Nodular fibrous lesion with immynopositivity for IgG4 in the infiltrating plasma cells (*2)
Plamacytic infiltration of the fibrous lesion(*100)
Occlusive vascular lesion with plasmacytic infiltration (*100)
Immunopositivity for IgG4 in the infiltrating plasma cells (+100)

16. Diagnosis Indications for diagnostic evaluation Diagnostic studies
Patients at high risk for IgG4-RD
Pancreatitis of unknown origin
Sclerosing cholangitis
Bilateral salivary or lacrimal gland enlargement
Diagnostic studies
Tissue biopsy
If the presence of abnormal histopathology of IgG4-RD, do not perform additional biopsy but glucocorticoid treatment
Serum IgG4
Elevated above the normal limit (>135mg/dL) : 60-70%
The degree of IgG4 elevation may correlate with disease activity and the number of involved organs

17. Diagnosis Postdiagnostic evaluation (for the extent of disease)
Imaging studies
CT scan of the chest, abdomen, and pelvis in patients diagnosed with IgG4-RD
PET scan can also be highly effective in determining the extent of disease in selected patients require additional imaging, particularly if orbit is suspected
Urinalysis
asymptomatic proteinuria may be an indication of subclinical IgG4-related tubulointerstitial nephritis

18. Treatment
The optimal treatment has not been established, treatment is based on our clinical experience
Most patients respond to glucocorticoids within several weeks, typically with symptomatic improvement, reductions in the size of masses, improvement in organ function, and often a decrease in serum IgG4

19. Treatment
Initially oral prednisone, usually approximately 40 mg/day within 2-4 weeks
Once a significant response is clinically evident in the affected organ, gradually taper the dose over a two-month period, as tolerated, with the goal of discontinuing the medication
In patients who are resistant to glucocorticoids or who are unable to have their dose reduced sufficiently, we use azathioprine (2 mg/kg/day) or mycophenolate mofetil (up to 2.5 g/day as tolerated)
B cell depletion therapy with rituximab is an effective treatment in many of the patients with disease that is refractory to glucocorticoids and other medications

20. Prognosis The natural course of IgG4-RD has not been well-defined
Spontaneous improvement can be seen, but disease often recur without treatment
Most patients respond initially to glucocorticoids, but relapses are common following discontinuation of therapy
Significant organ dysfunction may arise from uncontrolled and progressive inflammatory and fibrotic changes
Risk of malignancy
Several types of lymphoma have been reported in patients with IgG4-RD, both in North America and Japan
Requires further study
Pancreas Jul;38(5):523-6
Am J Gastroenterol Apr;108(4):610-7