A Spotlight on
Prof. Dr/ AbdelAzeim M ElhefnyProf. of Internal Medicine, Rheumatology & Immunology
Ain Shams University
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
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
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
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
IgG4-positive plasma cells
stain brown.Lymphoplasmacytic infiltrate
with germinal center.
Summary of the pt. data
Our patient had a multiorgan system disease of at least
two years duration characterized by:-
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)
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
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).
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
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
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.
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.
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
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
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
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
features of IgG4-related disease.
of IgG4-Related Disease
Histopathological analysis of biopsy specimens remains the
cornerstone in the diagnosis.
Elevated concentrations of IgG4 in tissue and serum are