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Ig g4 related diseases
2. Immunoglobulin G4-related disease (IgG4-
RD) is an increasingly recognized immune-
mediated condition comprised of a collection
of disorders that share specific pathologic,
serologic, and clinical features.
AIP – Auto Immune Pancreatitis is considered
the prototype IgG4-RD.
3. The commonly shared features include
Tumor-like swelling of involved organs
A lymphoplasmacytic infiltrate enriched in
IgG4-positive plasma cells
A variable degree of fibrosis that has a
characteristic “storiform” pattern, and
obliterative phlebitis
Elevated serum concentrations of IgG4 ( in
60-70 % of the patients)
Response to glucocorticoids, particularly in
early stage of the disease.
4. The disease was not recognized as a systemic
condition till 2003, when extra pancreatic
manifestations were identified in patients of
AIP.
AIP had been linked to elevated serum IgG4
levels as early as in 2001.
AIP is now considered the prototype IgG4-RD,
and majority of the research regarding these
diseases has been done on AIP.
5. IgG4-RD has 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.
The histopathological features bear striking
similarities across organs, regardless of the site
of disease.
IgG4-RD is therefore analogous to sarcoidosis,
another systemic disease in which diverse organ
manifestations are linked by the same
histopathological characteristics.
6. The preferred name for the overall condition is IgG4-
related disease. However, multiple names have been
employed to describe this entity. These include:
●IgG4-related disease
●IgG4-related systemic disease
●IgG4-syndrome
●IgG4-associated disease
●IgG4-related sclerosing disease
●IgG4-related systemic sclerosing disease
●IgG4-related autoimmune disease
●IgG4-positive multiorgan lymphoproliferative
syndrome
●Hyper-IgG4 disease
●Systemic IgG4-related plasmacytic syndrome
●Systemic IgG4-related sclerosing syndrome
●Multifocal fibrosclerosis
●Multifocal idiopathic fibrosclerosis
7. The hallmarks of IgG4-RD are lymphoplasmacytic
tissue infiltration with a predominance of IgG4-
positive plasma cells, usually accompanied by
fibrosis, obliterative phlebitis, and elevated serum
levels of IgG4.
A sizeable minority of patients (less than 40 percent)
have normal serum IgG4 concentrations despite the
presence of the classic histopathological changes in
tissue.
The fibrosis associated with IgG4-RD has a
characteristic “storiform” pattern, typified by a
cartwheel appearance of the arranged fibroblasts and
inflammatory cells. Modest tissue eosinophilia is also
common.
11. IgG4-RD generally occurs most commonly in middle-aged
and older men. This is certainly true for conditions such as
AIP, retroperitoneal fibrosis, IgG4-related tubulointerstitial
nephritis (TIN), and many other organ manifestations.
However, the sex distribution differs somewhat with
regard to patients with involvement of organs of the head
and neck. As examples, in patients with IgG4-related
sialadenitis and IgG4-related ophthalmic disease, males
and females appear to be affected more equally.
Beyond these general statements, the epidemiology of
IgG4-RD requires further definition. Initially, study of the
condition suffered from a lack of definitions, incomplete
nomenclature, and underrecognition among clinicians and
pathologists. These deficits are gradually being overcome
and should facilitate more complete understanding of the
disease epidemiology.
12. The pathogenesis of IgG4-RD is poorly understood;
findings consistent with both an autoimmune disorder and
an allergic disorder are present. IgG4 has been postulated
to have a role in tolerance to allergens and in responses to
certain infectious agents, but its physiologic role is poorly
understood. A specific autoantigenic target has not been
identified, and it is not clear whether the IgG4 antibodies
are pathogenic.
An emerging consensus holds that the IgG4 antibodies in
this disease are not pathogenic, but rather represent a
down-regulatory response to another primary process(es).
Elevations in serum and tissue IgG4 concentrations are not
specific to IgG4-RD; they are also found in disorders such
as multicentric Castleman’s disease, allergic disorders, the
Churg-Strauss syndrome and sarcoidosis.
13. Findings in IgG4-RD suggesting
autoimmunity have been particularly evident
in patients with type 1 (IgG4-related) AIP, the
prototypic IgG4-related disorder.
Evidence for an allergic response includes
elevated levels of Th2 cytokines in affected
tissues and increased amounts of serum IgE.
In addition, patients with IgG4-RD have an
increased prevalence of allergic rhinitis and
bronchial asthma
14. Pathogenetic Mechanisms
in IgG4-Related Disease and Clinical
Implications.
Autoimmunity and infectious agents are
potential immunologic triggers in IgG4-
related disease (Panel A). Interleukins 4,
5, 10, and 13 and transforming growth
factor β (TGF-β) are overexpressed
through an immune reaction in which
type 2 helper T (Th2) cells predominate,
followed by activation of regulatory T
(Treg) cells (Panel B). These cytokines
contribute to the eosinophilia, elevated
serum IgG4 and IgE concentrations, and
progression of fibrosis that are
characteristic of IgG4-related disease.
Massive infiltration by inflammatory
cells results in organ damage (Panel C).
The inflammatory-cell infiltrate leads to
tumefactive enlargement of the affected
sites and organ dysfunction (Panel D).
16. IgG4-RD can involve one or multiple organs. Patients can
present with
1) Subacute development of a mass in the affected organ
(eg, an orbital pseudotumor, a renal mass resembling
renal cell carcinoma, nodular lesions in the lung) or
2) Diffuse enlargement of an organ (eg, the pancreas)
Multiple organs are affected in 60 to 90 percent of
patients with IgG4-RD. The affected tissues share specific
pathologic, serologic, and clinical features, regardless of
the organ involved, in a manner analogous to the systemic
involvement of sarcoidosis, another disorder with shared
histopathologic features in the different tissues that are
affected.
Lymphadenopathy is common, and symptoms of asthma
or allergy are present in approximately 40 percent of
patients.
IgG4-RD is often recognized incidentally based upon a
radiologic finding or histopathologic examination of a
tissue specimen.
17. The relatively commonly studied IgG4-RD include the following
Type 1 (IgG4-related) AIP
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
inflammatory pseudotumor)
Chronic sclerosing dacryoadenitis (lacrimal gland enlargement, IgG4-related
dacryoadenitis)
Idiopathic retroperitoneal fibrosis (Ormond’s disease)
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-
related lung disease)
IgG4-related kidney disease (including tubulointerstitial nephritis [TIN] and membranous
glomerulonephritis [GN] secondary to IgG4-RD)
IgG4-related hypophysitis
IgG4-related pachymeningitis
IgG4-related midline destructive disease
18. Type 1 (IgG4-related) AIP is the prototypical form of IgG4-RD.
The prevalence of this condition in Japan has been estimated to
be 0.82 per 100,000 persons, but this is likely to be an
underestimate as clinical recognition of this disorder is growing .
AIP has been estimated to account for 2–6 %percent of patients
with chronic pancreatitis. It often presents as a pancreatic mass
or as painless obstructive jaundice and can be mistaken for
pancreatic cancer.
Some patients with type 1 AIP exhibit acute, recurrent, or chronic
pancreatitis, and AIP is frequently associated with diabetes
mellitus.
Most patients have another concomitant IgG4-related condition,
such as IgG4-related sclerosing cholangitis, lymphadenopathy,
or salivary or lacrimal gland involvement
The differentiation of AIP from adenocarcinoma of the pancreas
is sometimes difficult on the basis of clinical presentations.
Painless jaundice, for example, is common to both. Many
patients have undergone Whipple procedures out of concern for
pancreatic cancer.
19. A form of sclerosing cholangitis that is clinically distinct
from primary sclerosing cholangitis may occur as part of
the IgG4-RD.
IgG4-related sclerosing cholangitis is the most frequent
extrapancreatic manifestation of type 1 AIP (IgG4-related),
present in over 70 percent of such patients. It very rarely
occurs in the absence of pancreatitis.
Distinctions between primary sclerosing cholangitis and
IgG4-related sclerosing cholangitis are crucial because of
the drastically different prognoses in these conditions.
Unfortunately, the clinical distinction between primary
sclerosing cholangitis and/or cholangiocarcinoma and
IgG4-related sclerosing cholangitis can be difficult
because biopsies performed via endoscopic retrograde
cholangiopancreatography (ERCP) are seldom deep enough
to define the histopathological features of IgG4-RD.
20. Although clearly defined diagnostic criteria
for IgG4 sclerosing cholangitis are lacking,
differentiation from primary sclerosing
cholangitis is based upon
1. Tissue biopsy with infiltrates of IgG4+
plasma cells and severe interstitial fibrosis
2. Increased IgG4 serum levels
3. Characteristic responsiveness to
glucocorticoids.
4. The presence of clinical manifestations of
IgG4-RD in extra-biliary organs can also be
an important clue to the presence of IgG4-
RD
21. Asymptomatic IgG4-related lymphadenopathy is
common, occurring in 80 percent of patients with
AIP; it is usually observed together with other
clinical or laboratory manifestations of the
syndrome, but may be the initial or only
manifestation.
Symptoms occasionally occur due to mass effect of
the enlarging nodes; individual nodes are typically
no more than 2 centimetres in diameter but may
range up to 5 centimetres.
Multiple groups of lymph nodes are usually
involved; the mediastinal, hilar, intraabdominal,
and axillary are most common.
The lymphadenopathy is generally non-tender and
the nodes themselves are rubbery rather than hard.
22. Patients with lymphadenopathy may exhibit elevated
serum IgG4, serum IgG and IgE, polyclonal
hypergammaglobulinemia, and elevations in the
erythrocyte sedimentation rate (ESR).
The differential diagnosis in patients with generalized
lymphadenopathy includes sarcoidosis, multicentric
Castleman disease, infection (eg, tuberculosis), and
lymphoma or other malignancy.
IgG4-related lymphadenopathy is distinguished from
these conditions by the modest lymph node
enlargement, histologic distinctions on biopsy, lack
of constitutional features, and the usually striking
clinical response to glucocorticoids
23. Salivary gland involvement is a common feature
of IgG4-RD. Patients may either present with
1. enlargement of lacrimal and salivary glands
(parotid and/or submandibular), previously
referred to as Mikulicz disease, or with
2. Chronic sclerosing sialadenitis and unilateral or
bilateral submandibular gland enlargement,
previously referred to as Küttner’s tumor.
These diseases were initially considered to be a
part of the spectrum of SS.
24. Nearly 40 percent of patients with IgG4-related
pancreatitis also have salivary or lacrimal gland
involvement, while AIP may be seen in only 17
percent of patients presenting with sialadenitis.
Patients with salivary and lacrimal involvement
include comparable numbers of both men and
women.
The pathologic findings are typical of those in other
patients with IgG4-RD, including the
lymphoplasmacytic infiltrate with IgG4-positive cells,
sometimes with obliterative phlebitis and fibrosis.
Increased IgG4 and IgE serum levels are also present.
These histopathologic and laboratory findings
distinguish IgG4-related sialadenitis from SS.
25. The clinical features that characterize IgG4-
related sialadenitis and also help to
distinguish it from SS include :
●Fewer patients with dry mouth, dry eyes, or
arthralgias .
●A higher frequency of allergic rhinitis and
bronchial asthma .
●A higher frequency of AIP and interstitial
nephritis.
●Low frequencies of autoantibodies.
27. Previously known as Ormond’s disease,
Retroperitoneal fibrosis is now considered a part
of the IgG4-RD spectrum.
A variable proportion of patients with idiopathic
retroperitoneal fibrosis exhibits histologic and
serologic changes consistent with IgG4-RD.
In some cases, the syndrome is responsive to
glucocorticoids.
All of the published cases of IgG4-related
retroperitoneal fibrosis exhibited involvement of
other organs, including the pancreas, salivary
glands, lymph nodes and the pituitary gland.
28. Aortitis and periaortitis — IgG4-RD has been
recognized as one of the causes of
noninfectious aortitis.
Thyroid disease — Two forms of thyroid
involvement in IgG4-RD have been described,
including Reidel’s thyroiditis (IgG4-related
thyroid disease) and the fibrous variant of
Hashimoto’s thyroiditis.
29. Multiple reports have documented IgG4-related
pulmonary disease, which may be asymptomatic
or present with cough, hemoptysis, dyspnea,
pleurisy, or chest pain.
Pseudotumors and interstitial pneumonia have
been associated with AIP.
The affected tissues exhibit characteristic
lymphoplasmacytic infiltrates enriched in IgG4-
positive plasma cells, interspersed with abundant
storiform fibrosis.
Obliterative arteritis is more common in the lung
than in other organs affected by IgG4-RD.
30. Renal involvement in patients with IgG4-RD; the
most common finding is tubulointerstitial nephritis
(TIN).
Affected patients are primarily middle-aged and
older men, and histopathology and other
laboratory characteristics are similar to those
observed in patients with AIP.
The histologic findings include lymphoplasmacytic
infiltration of the renal interstitium and the
presence of fibrosis.
Nodular lesions mimicking renal carcinoma may be
seen.
IgG4-related membranous nephropathy is much
less frequent than IgG4-related TIN, and these
sometimes occur together.
31. Other involved organs and tissues — Involvement
of other organs and tissues by IgG4-RD:
●Skin disease, including a subset of cutaneous
pseudolymphoma.
●IgG4-hepatopathy, resembling autoimmune
hepatitis.
●Lymphoplasmacytic gastritis.
●Sclerosing mastitis and inflammatory
pseudotumors of the breast
●Hypopituitarism with IgG4-related hypophysitis
●Pachymeningitis
●Prostatitis
●Constrictive pericarditis
●Nasopharyngeal disease
●Midline-destructive lesion
32. The diagnosis of IgG4-RD is based upon biopsy findings
demonstrating the characteristic histopathologic findings
and immunohistochemical staining.
These findings include lymphoplasmacytic tissue
infiltration of mainly IgG4-positive plasma cells and
lymphocytes, accompanied by fibrosis that has storiform
features and often by obliterative phlebitis.
Modest tissue eosinophilia.
Serum IgG4 levels should be measured, and isolated
elevated levels are a significant aid in diagnosis, although
they are not diagnostic.
The histopathological and immunohistochemical staining
features of IgG4-RD are strikingly similar in different
tissues, regardless of the organ or tissue involved
33. Indications for diagnostic evaluation
Patients at high risk for having IgG4-RD are
those with any of the following:
●Pancreatitis of unknown origin
●Sclerosing cholangitis
●Bilateral salivary and/or lacrimal gland
enlargement
●Retroperitoneal fibrosis
●Orbital pseudotumor or proptosis
The likelihood of IgG4-RD for patients presenting
with at least one of these conditions is
significantly increased if high serum levels of
IgG4, allergic symptoms, and/or other fibrotic
processes are also present.
34. 1.Tissue biopsy – A core needle biopsy is
often adequate, but fine-needle aspirates do
not provide adequate tissue. In the presence
of abnormal histopathology characteristic of
the syndrome, we generally do not perform
additional biopsies of other organs,
particularly if improvement in these other
areas has occurred with glucocorticoid
treatment.
35. The serum IgG4 level was elevated above the
upper limit of normal (>135 mg/dL) in 60-70
% of the patients. The degree of IgG4
elevation correlates imperfectly with the
degree of disease activity, but is often a
useful parameter to follow in individual
patients. The serum IgG4 concentration tends
to increase with the number of organs
involved and usually decreases after
treatment with glucocorticoid.
36. Blood plasmablast concentrations may be a
better biomarker than the serum IgG4
concentration, both for the purposes of diagnosis
and following disease activity. Plasmablasts were
identified through flow cytometry of peripheral
blood.
These studies of circulating plasmablasts confirm
that these cells are elevated to dramatically high
levels in patients with active IgG4-RD, even in
patients with normal serum IgG4 concentrations.
Plasmablast counts therefore are a potentially
useful biomarker for diagnosis, assessing
response to treatment, and determining the
appropriate time for retreatment.
37. Well-defined diagnostic criteria had previously
been proposed only for AIP. The
histopathological findings of a dense
lymphoplasmacytic infiltrate, storiform fibrosis,
and obliterative phlebitis are critical features for
establishing the diagnosis . The presence of
these findings, often together with mild tissue
eosinophilia, is strongly suggestive if
accompanied by increased numbers of IgG4-
positive plasma cells.
The number of IgG4-positive plasma cells per
high-power field (HPF) that is regarded as
consistent with or suggestive of IgG4-RD varies
somewhat from tissue to tissue.
38. The diagnosis cannot be predicted entirely upon
the number of IgG4-positive plasma cells.
Similarly, the diagnosis of IgG4-RD cannot be
based upon serum concentrations of IgG4 alone.
Thus, confirmation of the diagnosis by biopsy of
an involved organ whenever this is possible is
advised.
Blood plasmablast concentration measurements,
particularly those for IgG4+ plasmablasts, are
not widely available
39. Imaging studies – Computed tomography
(CT) scan of the chest, abdomen, and pelvis
in patients diagnosed with IgG4-RD, because
of the frequency of subclinical disease.
Markers of allergic disease – Markers of
allergic disease such as serum IgE
concentrations and the peripheral eosinophil
count, should be tested.
40. The optimal treatment for IgG4-RD has not
been established.
A growing number of reports support the
efficacy of B cell depletion with Rituximab in
this condition.
However, no randomized trials have evaluated
approaches to the treatment of IgG4-RD.
41. Most patients respond to glucocorticoids within
several weeks, typically with symptomatic
improvement, reductions in the size of masses or
organ enlargement, improvement in organ
function, and often a decrease in serum levels of
IgG4.
However, some require a few months to respond,
and there are some patients who relapse and
others who respond less well or not at all initially.
Those who respond poorly may include patients
with more advanced fibrotic changes.
42. Patients who are symptomatic from their
organ involvement at the time of the
diagnosis often benefit from treatment.
By contrast, for a subset of patients such as
those who have mild lymphadenopathy or
incidentally-detected lung nodules, watchful
waiting may be appropriate.
43. The currently recommend protocol suggests
beginning treatment with Prednisolone, usually at
a dose of approximately 40 mg/day.
A response is frequently seen within two to four
weeks and often sooner.
Once a significant response is clinically evident in
the affected organ system, it is recommended to
gradually taper the dose of glucocorticoids, with
a planned reduction over a two-month period, as
tolerated.
The tapering should be done with a goal of
discontinuing the medicine completely.
44. In patients who are resistant to
glucocorticoids or who are unable to have
their dose reduced sufficiently (usually to
below 10 mg/day) to avoid adverse effects of
the medication due to chronic use, the
preferred drug is Rituximab.
The recommended dosage is 1 gram IV every
fifteen days for a total of two doses.
45. B cell depletion leads to the targeted
reduction, often swiftly, of serum IgG4
concentrations, with relative preservation of
the concentrations of other immunoglobulins
and immunoglobulin subclasses.
Rituximab also leads even more swiftly to
steep declines in blood plasmablast
concentrations.
46. If Rituximab is not available,
either Azathioprine (2 mg/kg/day) or
Mycophenolate mofetil (up to 2.5 g/day as
tolerated) are reasonable choices for second-
line agents that have potential as
glucocorticoid-sparing therapies.
However, the effects of these glucocorticoid-
sparing medications in IgG4-RD have not
been evaluated adequately to clearly define
their role relative to other agents.
47. The natural history of IgG4-RD has not been
well-defined.
A minority of patients improve at least
temporarily without treatment, but the majority
of these relapse and most patients have chronic
disease that progresses at variable rates.
Causes of significant morbidity and mortality in
untreated patients include cirrhosis and portal
hypertension; retroperitoneal fibrosis;
complications from aortic aneurysms, including
dissection; biliary obstruction and diabetes
mellitus.
48. A subset of patients have subacute
constitutional symptoms marked by fatigue
and weight loss that may be substantial over
months, on the order of 20 or 30 pounds.
Sustained benefit may be observed in treated
patients, but relapses are common after
discontinuation of therapy.
Additional studies of long term prognosis are
needed.
49. Several types of cancers have been reported
in individual case studies, in relation to IgG4-
RD.
Non-Hodgkin’s Lymphoma, gastric
carcinoma, salivary duct carcinoma,
pancreatic carcinoma, pulmonary
adenocarcinoma, small cell carcinoma of the
lung, and prostate carcinoma have been
reported.
50. None of these documented patients
experienced relapse of their IgG4-related
disease after successful treatment of their
cancers, raising the question as to whether
IgG4-RD may occur as a paraneoplastic
syndrome in these patients.
Additional study is required to determine the
degree, if any, of increased risk for
malignancies in patients of IgG4-RD.
51. Immunoglobulin G4-related systemic disease
(IgG4-RD) is an increasingly recognized
syndrome of unknown etiology, most often
occurring in middle-aged and older men,
which is comprised of a collection of
disorders that share specific pathologic,
serologic, and clinical features.
Several of the manifestations typically occur
in the same patient.
52. The commonly studied IgG4-RD include the following.
1. Type 1 autoimmune pancreatitis (AIP) and IgG4-related
sclerosing cholangitis
2. Mikulicz’s disease and sclerosing sialadenitis (Küttner’s
tumor), inflammatory orbital pseudotumor, and chronic
sclerosing dacryoadenitis.
3. Idiopathic retroperitoneal fibrosis.
4. Chronic sclerosing aortitis and periaortitis.
5. Riedel’s thyroiditis and a subset of Hashimoto’s
thyroiditis.
6. IgG4-related interstitial pneumonitis and pulmonary
inflammatory pseudotumors.
7. IgG4-related renal disease, particularly tubulointerstitial
nephritis.
53. The hallmarks of IgG4-RD are lymphoplasmacytic
tissue infiltration of mainly IgG4-positive plasma
cells and small lymphocytes, which may be
accompanied by fibrosis, obliterative phlebitis,
and, in the majority of patients, elevated serum
levels of IgG4.
Patients often present with subacute
development of a mass in the affected organ or
diffuse enlargement of an organ.
Lymphadenopathy is common, and symptoms of
asthma or allergy may be present.
A good initial therapeutic response to
glucocorticoids is also characteristic
54. The diagnosis of IgG4-RD is based upon
biopsy findings demonstrating the
characteristic histopathology.
Serum IgG4 levels should be measured, and
isolated elevated levels are a significant aid in
diagnosis, although they are not diagnostic.
Additional organ involvement may be
identified.
55. It is currently recommended to begin treatment
with glucocorticoids. Therapy is usually initiated
with Prednisolone (40 mg/day), which is then
tapered as tolerated over a two-month period.
Responses are characterized by symptomatic
improvement, reductions in the size of masses or
organ enlargement, improvement in organ
function, and often a decrease in serum levels of
IgG4.
In patients who do not respond to up to
40 mg/day of prednisolone, or who cannot be
tapered to less than 10 mg daily, Rituximab can
be used.
56. The natural history and prognosis are not well-
described.
Spontaneous improvement can be seen, but
disease often recurs without treatment.
Most patients respond initially to therapy with
glucocorticoids, but relapses are common
following discontinuation of therapy.
Significant organ dysfunction may arise from
uncontrolled and progressive inflammatory and
fibrotic changes in affected tissues.
The possibility of increased risk of malignancy in
patients with IgG4-RD requires further study.