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A Spotlight on

IgG4-related disease

BY

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 Sjögren`s syndrome (SS)

complicated by interstitial nephritis was rendered.

Following a short course of prednisone, the patient’s renal

function returned to normal.

Emine Atac et al., The Rheumatologist, January 2013

http://www.the-rheumatologist.org/details/print/4214391/January_2013.html

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

removed.

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 Küttner’s 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,

jaundice,

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

eosinophils.

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

patient’s multisystem condition?

Immunoglobulin G4–related 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

occasions.

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?

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

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 represents—in most cases—IgG4-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.

BRIEF OVERVIEW OF IgG4-RD

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

1

The

2

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, <121).

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

deciliter.

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

helpful in diagnosing IgG4-RD, but neither one is a specific

diagnostic marker.

Correlation with specific histopathological findings is

essential, regardless of the serum IgG4 concentration, the

number of IgG4-positive plasma cells in tissue, or the ratio

of IgG4 to IgG in tissue.

J Clin Pathol 2011;64:237-43.

Curr Opin Rheumatol 2011;23:108-13.

The key morphologic features of IgG4-related disease are:

a dense lymphoplasmacytic infiltrate that is organized in a

storiform (i.e., matted and irregularly whorled) pattern,

obliterative phlebitis,

a mild-to-moderate eosinophil infiltrate.

The inflammatory lesion frequently forms a tumefactive

mass that may destroy the involved organ.

Pathological Features

of IgG4-Related Disease

Zen Y, Nakanuma Y. Am J Surg Pathol 2010;34:1812-9.

brisk intra-

pancreatic periductal

inflammation associated

with fibrosis &

thickening of the wall.

The pattern is often

likened to a

cartwheel,

The bands of fibrosis

(arrowheads)

emanating from the

center (asterisk)

representing the

spokes of the wheel.

Obliterative

phlebitis

(arrows).

a dense

lymphoplasmacytic

infiltrate

lymphocytes,

plasma cells (long

arrow),

eosinophils

(arrowhead)

fibroblasts (short

arrow).

IgG4-positive

plasma cells

(arrows)

Is Elevated Serum IgG4 Concentration

Diagnostic of IgG4-RD?

No, many other conditions can be associated with

elevations in the serum IgG4 concentration.

However, the higher the concentration of IgG4 in the

blood, the greater the suspicion for IgG4-RD,

particularly if the patient’s clinical manifestations are

consistent with this disorder.

Our patient’s serum IgG4 concentration was 2,020

mg/dL (normal<121 mg/dL).

<20% of those who have not been treated—have normal

serum IgG4 concentrations in the setting of diagnostic

histopathology and immunostaining findings .

Are Radiologic Examinations Specific for

IgG4-RD?

Radiologic findings in IgG4-RD may mimic malignancies

in their presentation as pseudotumors.

This fact usually makes histopathological confirmation

of the diagnosis essential.

In the proper clinical setting, the finding of a diffusely

enlarged, “sausage-shaped” pancreas with

peripancreatic stranding is sometimes sufficient for the

diagnosis of type 1 autoimmune (IgG4-related)

pancreatitis.

DIAGNOSIS

A typical case with IgG4-related disease exemplifying key

diagnostic features




Diagnostic algorithm for comprehensive diagnostic criteria for IgG4-RD




Deferential Diagnosis

The disease tends to cause mass-forming lesions that can

mimic cancer, infections, and rheumatic conditions such

as granulomatosis with polyangiitis (Wegener’s) and SS.

Malignant tumors

Granulomatous vasculitis

Sarcoidisis

Sjogren

Thyroid diseases

Pancreatic disorders

Other causes of retroperitoneal fibrosis

What Is the Treatment for IgG4-RD?

Glucocorticoids are the first-line treatment for IgG4-RD.

Many cases require aggressive and immediate treatment to

prevent organ dysfunction and failure.

IgG4-related lymphadenopathy may remain indolent and

relatively asymptomatic for years.

Therefore, the treatment regimens must be individualized for

each patient.

Initially prednisolone dose of 0.6 mg/kgm /day for 2-4 weeks

and then to taper the steroids over 3-6 months.

Agents such as AZA, MMF, and MTX have been employed as

potential glucocorticoid-sparing agents or remission–

maintenance drugs, but their true efficacy in these roles is

unclear. Cheuk W, Yuen HK, Chu SY, et al. Am J Surg Pathol. 2008;32:671-68

Rituximab may represent a promising

approach to treatmen

B-cell depletion with rituximab may represent a promising

approach to treatment.

For patients with IgG4-RD that is refractory to

glucocorticoids,

Patients that are unable to taper below a desired dose,

Patients with recurrent IgG4-RD,

Patients demonstrated prompt clinical and serological

responses, with the ability to taper glucocorticoids rapidly

and a swift decline in serum IgG4 concentrations.

Leaving the concentrations of IgG1, IgG2, and IgG3

(stable). through interference with the repletion of short-

lived plasma cells that are producing IgG4 .

Khosroshahi A, Carruthers MN, et al. Medicine (Baltimore).2012;

Algorithm informing treatment decisions in patients

with IgG4-related disease




A

Diagnostic guidelines for IgG4-related disease in Japanese populations




References

Deshpande, V. et al. Subclassification of Autoimmune pancreatitis: a

histologic classification with clinical significance. Am. J. Surg. Pathol. 35, 26–

35 (2011).

Zen, Y. & Nakanuma, Y. IgG4-related disease: a cross-sectional study of 114

cases. Am. J. Surg. Pathol. 34, 1812–1819 (2010).

Chiba, K. et al. Clinical features of 10 patients with IgG4-related

retroperitoneal fibrosis.Intern. Med. 52, 1545–1551 (2013).

Matsui, S. et al. Immunoglogulin G4-related lung disease: clinicoradiological

and pathological features. Respirology 18, 480–487 (2013).

Watanabe, T. et al. Clinical features of a new disease concept, IgG4-related

thyroiditis.Scand. J. Rheumatol. 42, 325–330 (2013).

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systemic disease. Arch Ophthalmol 2011;129:421-8.

2. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg

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3. Geyer JT, Deshpande V. IgG4-associated sialadenitis. Curr Opin Rheumatol 2011;23:95-101.

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2010;120:765-76.

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8. Inoue D, Zen Y, Abo H, et al. Immunoglobulin G4-related lung disease: CT findings with pathologic correlations. Radiology 2009;251:260-70.

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