Ig g4 related disease

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  • A Spotlight on

    IgG4-related disease


    Prof. Dr/ AbdelAzeim M ElhefnyProf. of Internal Medicine, Rheumatology & Immunology

    Ain Shams University

  • Chief Complaint

    January 2010

    Mr. G H is a 55 year old male who presents with

    nonspecific complaints, particularly fatigue, led him to

    visit his primary care doctor.

    A serum creatinine of 3.5 mg/dL was identified by

    routine laboratory testing.

    This new-onset renal insufficiency was accompanied by

    severe proteinuria (urine protein:creatinine ratio of 9).

  • Past Medical History:

    The patient had a medical history of pancreatitis and

    type II diabetes mellitus but was otherwise well

  • Additional History

    A renal biopsy revealed interstitial nephritis (see Figure 1).

    It was observed simultaneously that the patient had

    symptoms of xerostomia, and physical examination then

    confirmed both parotid and submandibular gland

    enlargement (see Figure 2).

    The presumptive diagnosis of Sjgren`s syndrome (SS)

    complicated by interstitial nephritis was rendered.

    Following a short course of prednisone, the patients renal

    function returned to normal.

    Emine Atac et al., The Rheumatologist, January 2013


  • A: Kidney showing a lymphoplasmacytic

    infiltrate in the renal interstitium. There is

    also a moderate number of eosinophils

    B: Collagen stain (blue) demonstrating fibrosis

    within the renal interstitium.

    The fibrosis has a storiform pattern.

    Figure 1: Tubulointerstitial nephritis

  • Figure 2: Salivary gland enlargement.

    Enlargement in the tail of the left

    parotid glandEnlargement of the right

    submandibular gland.

  • The patient developed pruritus and jaundice.

    His serum bilirubin was 7.9 mg/dL (direct 5.1 mg/dL).

    Other liver function tests are shown in Table 1.

    An ERCP showed a mildly dilated distal common bile duct but

    otherwise normal intra- and extrahepatic biliary systems.

    A liver biopsy revealed only nonspecific findings.

    The cholestasis was attributed to severe papillary stenosis.

    His cholestasis resolved following papillary sphincterotomy

    and the placement of pancreatic stents, which were later


    Six months later, in (July 2010)

  • The patient was noted to have diffuse lymphadenopathy,

    anemia, and an elevated ESR, raising the possibility of a

    lymphproliferative disorder.

    However, a biopsy of an enlarged right axillary lymph node

    was interpreted as reactive hyperplasia, with follicular

    hyperplasia and reactive plasmacytosis.

    A bone marrow biopsy showed normal hematopoiesis, and

    there was no evidence of lymphomatous infiltration,

    myeloma, or intrinsic marrow pathology.

    Two months later, in (September 2010)

  • After two years, in January 2012

    The patient suffered from recurrent submandibular

    gland enlargement led to an excisional biopsy.

    This revealed a Kttners tumor (see Figure 3).

  • Figure 3: Histopathology of the

    submandibular gland.

    IgG4-positive plasma cells

    stain brown.Lymphoplasmacytic infiltrate

    with germinal center.

  • Laboratory Findings

  • Summary of the pt. data

    Our patient had a multiorgan system disease of at least

    two years duration characterized by:-

    tubulointerstitial nephritis,

    salivary gland enlargement,


    diffuse lymphadenopathy, and

    an elevated ESR.

    In addition, it is likely that his pancreatitis, which led to

    glucose intolerance, was in fact IgG4-related (type 1)

    autoimmune pancreatitis.

    He was misdiagnosed with a number of other conditions

    before the correct diagnosis of IgG4-RD was recognized.

  • The Diagnostic Test

    The diagnosis was made following a careful review of

    the submandibular gland biopsy.

    It revealed a gland largely replaced by a

    lymphoplasmacytic infiltrate: reactive lymphoid follicles

    surrounded by small lymphocytes and plasma cells (see

    Figure 3A).

    In addition, there was striking storiform fibrosis (see

    Figure 3B), obliterative phlebitis, and scattered


    Immunostaining of the tissue for IgG4 and IgG

    demonstrated more than 100 IgG4-positive plasma cells

    per high-power field and an IgG4:total IgG ratio of 0.92.

    This biopsy was diagnostic of the case.

  • Which diagnosis can explain this

    patients multisystem condition?

    Immunoglobulin G4related disease (IgG4-RD).

  • Follow-up

    Because of his glucose intolerance and the extensive

    nature of his disease, we treated our patient with

    rituximab 1 gram intravenously given on two separate


    Within one month of his first dose, his parotid gland

    swelling had resolved, and his serum IgG4 concentration

    had declined by more than 600 mg/dL.

  • IgG4-related disease (IgG4-RD) is an under recognized,

    multiorgan fibro-inflammatory condition of unknown

    aetiology that is defined by its unique histopathological

    features, that are fairly similar regardless of the

    affected organ.

    Patients with IgG4-RD also share certain clinical

    features: a tendency for formation of mass lesion(s),

    frequent elevations in their serum IgG4 concentration,

    as well as an excellent response to glucocorticoid

    treatment. http://dx.doi.org/10.1016/j.mpdhp.2013.01.004

    What Is IgG4-RD?


  • Is This a New Disease?

    No. Scrutiny and reinterpretation of the medical literature

    in light of the emerging knowledge of this newly

    recognized disorder indicates that IgG4-RD has been

    known by other names, generally while being regarded as

    an entity isolated to an individual organ system.

    A disorder termed multisystemic fibrosclerosis in the

    1960s probably representsin most casesIgG4-RD.

    The following Table displays a list of previously recognized

    conditions known by other names that comprise (or may

    comprise) parts of the IgG4-RD spectrum.


    First case described in 1961 Autoimmune pancreatitis (Sarles et al.)

    In 2001, Hamano et al demonstrated that the serum level of IgG4 was significantly elevated in patients with sclerosingpancreatitis (now called type 1 AIP).

    In 2003, (Kamisawa et al.) reported the presence of numerous IgG4-positive plasma cell infiltrates in both the pancreatic and extrapancreatic lesions of type 1 AIP and proposed a new clinicopathological entity: IgG4-related systemic disease.

  • The


  • The


  • Common Clinical Manifestations

    IgG4-RD has now been described in virtually every

    organ system: the biliary tree, salivary glands,

    periorbital tissues, kidneys, lungs, lymph nodes,

    meninges, aorta, breast, prostate, thyroid,

    pericardium, and skin.

    A list of the common clinical manifestations in a broad

    variety of organ systems is shown in Table 3.

    The histopathologic features of this disease bear

    striking similarities across organs, regardless of the site

    of involvement.1

    IgG4-RD is therefore analogous to sarcoidosis, another

    systemic disease in which diverse organ manifestations

    are linked by unique histopathology.

  • Systemic organ involvement in IgG4-related disease

    Yamamoto, M. et al. (2013) Mechanisms and assessment of IgG4-related disease:

    lessons for the rheumatologist

    Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.183

  • Panel A shows bilateral

    enlargement of the

    submandibular glands in a

    45-year-old woman. Her

    serum IgG4 concentration

    was 240 mg per deciliter

    (normal level,

  • Panel B shows bilateral

    enlargement of the parotid gland

    in a 54-year-old man, who also had

    asthma, marked enlargement of

    the extraocular muscles, swelling

    of the left fifth cranial nerve, and

    abnormal soft tissue extending

    from his left orbit through the left

    greater palatine foramen into the

    pterygomaxillary cistern, causing

    proptosis. His serum IgG4

    concentration was 1560 mg per


  • Panel C shows proptosis of the left

    eye, caused by enlargement of the

    lacrimal gland, in a 62-year-old

    man. His serum IgG4 concentration

    was 30 mg per deciliter, indicating

    that patients can have classic

    histopathological and

    immunohistochemical features of

    IgG4-related disease within tissue

    yet have normal serum IgG values.

  • Panel D shows a computed

    tomographic scan of a diffusely

    enlarged pancreas and an irregular,

    low-attenuation area (arrow) in

    the left kidney.

    These radiologic findings

    correspond to autoimmune

    pancreatitis and tubulointerstitial

    nephritis, with histopathological

    and immunohistochemical-staining

    features of IgG4-related disease.

  • Pathological Features

    of IgG4-Related Disease

    Histopathological analysis of biopsy specimens remains the

    cornerstone in the diagnosis.

    Elevated concentrations of IgG4 in tissue and serum are