Download IgG4-RD

IgG4-related disease
호흡기내과
R4 황인경 / pf.박명재
Introduction
• IgG4-related disease (IgG4-RD)
– A syndrome of unknown etiology comprised of a collection of di
sorders that share specific pathologic, serologic, and clinical feat
ures
• 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
Histopathological features
A. Dense lymphoplasmacytic
infiltrate and obliterative
phlebitis (arrow)
B. Storiform fibrosis
C-D. Nearly all plasma cells are
strongly positive for IgG4 on
immunoperoxidase staining
E. Obliterative phlebitis
F. Lymphocytes, plasma cells,
eosinophils, and fibroblast
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
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
Epidemiology
• 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, 59-68 years
– All the groups, except for head and neck involvement, were pre
dominantly men (75-86%)
– the group with only head and neck disease was nearly equally di
vided (48% men)
Am J Surg Pathol. 2010 Dec;34(12):1812-9
Pathophysiological mechanisms
• Multiple immune-mediated
mechanisms contribute to
fibroinflammatory process
of IgG4-RD
1.
2.
3.
4.
Potential triggers
Immune reaction
Cellular infiltrate within
affected organ
Clinical results
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
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
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
IgG4-RD associated disorders
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•
•
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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 inflammato
ry pseudotumor)
Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-related dacryoadenitis)
A subset of patients with “idiopathic” retroperitoneal fibrosis (Ormond’s disease) and relate
d 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-r
elated lung disease)
IgG4-related kidney disease (including tubulointerstitial nephritis and membranous glomeru
lonephritis secondary to IgG4-RD)
IgG4-related hypophysitis
IgG4-related pachymeningitis
IgG4-related lung disease (IgG4RLD)
• IgG4-related interstitial pneumonitis and pulmonary inflam
matory pseudotumors
• Fibroinflammatory entity that has diverse clinical manifestatio
ns
• 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
IgG4-related lung disease
• Four patterns of lung involvement on chest CT appearance
1.
2.
3.
4.
Solid nodular
Bronchovascular : thickening of bronchovascular bundle, interlobular
septum
Alveolar interstitial (with honeycombing, bronchiectasis, and diffuse
ground-glass opacities)
Round-shaped ground-glass opacities
• M/65; dyspnea, LUQ pain
• Lung biopsy on suspicious malignancy
– Infiltration of plasma cell with immunore
active for IgG4, fibrosis
• Elevated serum IgG4 level (341mg/dl)
• Diffuse, low attenuated enlarged pancre
as in abdominal CT
• Oral prednisolone 40mg/day
 pulmonary lesion, lymphadenopathy and
Sx were markedly improved; IgG4 71.4mg/dl
Diagnosis
• Biopsy findings (histopathologic + immunohistochemical staining)
– lymphoplasmacytic tissue infiltration of mainly IgG4-positi
ve plasma cells and small lymphocytes
– accompanied by storiform fibrosis and by obliterative phle
bitis
– modest tissue eosinophilia is often present
• Serum IgG4 levels are a significant aid in diagnosis
• Additional organ involvement 여부 확인
Diagnosis
• Indications for diagnostic evaluation
– 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 n
ot 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 acti
vity and the number of involved organs
Diagnosis
• Postdiagnostic evaluation (for the extent of disease)
– Imaging studies
• CT scan of the chest, abdomen, and pelvis in patients diagno
sed with IgG4-RD
• PET scan can also be highly effective in determining the exte
nt of disease in selected patients require additional imaging,
particularly if orbit is suspected
– Urinalysis
• asymptomatic proteinuria may be an indication of subclinica
l IgG4-related tubulointerstitial nephritis
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 si
ze of masses, improvement in organ function, and often a dec
rease in serum IgG4
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
Prognosis
• The natural course of IgG4-RD has not been well-defined
• Spontaneous improvement can be seen, but disease often rec
ur 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. 2009 Jul;38(5):523-6
Am J Gastroenterol. 2013 Apr;108(4):610-7