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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 • • • • • • • • • • • • • 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