Clinical Manifestations of IgG4-related Disease (IgG4 RD) - PowerPoint PPT Presentation

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Clinical Manifestations of IgG4-related Disease (IgG4 RD)


Clinical Manifestations of IgG4-related Disease (IgG4 RD) – PowerPoint PPT presentation

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Why and how: Clinical Manifestations of IgG4-related Disease (IgG4 RD)


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Title: Clinical Manifestations of IgG4-related Disease (IgG4 RD)

Clinical Manifestations of IgG4-related
Disease (IgG4 RD)
  • IRAQ

IgG4-related disease (IgG4-RD) is a
fibro-inflammatory disorder that can affect
almost any organ. The main histopathological
features are a dense, polyclonal,
lymphoplasmacytic infiltrate rich in IgG4 plasma
cells, storiform fibrosis and obliterative
  • .

Common presentations include
  • major salivary and lacrimal gland enlargement,
  • orbital disease,
  • autoimmune pancreatitis,
  • retroperitoneal fibrosis
  • and tubulointerstitial nephritis.

  • The clinical manifestations of IgG4-RD are
    extremely variable .
  • In 6090 of the patients the disease involves
    multiple organs.

  • the clinical suspicion of IgG4-RD relies on the
    presence of tumefactive lesions involving one or
    more organs.

General symptoms are rare. Fever is usually
absent .
Lymphadenopathy is common
Weight loss is reported especially in cases with
exocrine pancreatic failure caused by
IgG4-related AIP, resulting in a malabsorption
The pancreas is the most frequently involved
organ (2060 in different series). The main
presenting symptoms of pancreatic involvement
include jaundice, pruritus, abdominal pain,
steatorrhea and new-onset diabetes mellitus.
Imaging of the pancreas typically shows diffuse
or segmental pancreatic enlargement, accompanied
by loss of normal lobularity and a diffuse
narrowing of the pancreatic duct.
Sclerosing cholangitis affects 20 of patients .
This condition responds well to steroid therapy
but, if left untreated, can progress to end-stage
liver disease. IgG4-related cholecystitis is
rarer and is often diagnosed accidentally.
The submandibular, parotid and sublingual glands
are often involved, with a frequency of 20-80.
The prominent, usually asymmetrical,
submandibular gland enlargement, formerly known
as K├╝ttners tumour, is a typical IgG4-related
manifestation. Orbital and lacrimal gland
involvement is often associated with the
involvement of salivary glands in the context of
Mikuliczs disease, and occurs in 1050 of
The typical IgG4-related ophthalmic disease
presents as painless enlarging masses over
lacrimal glands with or without proptosis.
Bilateral disease is common but not necessarily
symmetrical. Visual acuity is usually not
impaired, although optic nerve compression
causing blindness has been reported. The mass
may involve also orbit tissues, including muscles
and eyelid, and it may extend into the
pterygopalatine fossa and infiltrate the
trigeminal nerve, mimicking neoplastic lesions.
Such lesions can be similar to those encountered
in granulomatosis with polyangiitis (GPA,
Wegeners), although in the latter condition they
often coexist with aggressive sino-nasal disease.
Some cases of fibrosing thyroiditis, a subset of
Hashimotos thyroiditis, determining
hypothyroidism, appear to be part of the IgG4-RD
spectrum together with some cases of Riedels
Lung involvement has a frequency of 1030. Four
major clinical pulmonary syndromes have been
identified in the context of IgG4-RD
inflammatory pseudotumour, central airway
disease, localized or diffuse interstitial
pneumonia, and pleuritis. Clinical symptoms
include cough, haemoptysis, dyspnoea and pleural
effusion. The radiologic features of this
condition are often confused with other pulmonary
diseases and include solid nodular lesions,
ground-glass opacities, alveolar interstitial
disease, thickening of the bronchovascular bundle
and pleural nodular thickening.
Mediastinal involvement with fibrosing
mediastinitis is rare but sometimes severe. This
process can compress vital mediastinal
structures, culminating in organ dysfunction that
is difficult to treat.
A variety of macrovascular manifestations of
IgG4-RD have been described with a frequency of
1020, including vessel wall and perivascular
infiltration. IgG4-related large-vessel disease
has a predilection for the aortic adventitia and
the peri-adventitial tissues and may involve the
aorta, pulmonary arteries, iliac arteries or
iliac veins. Medium-vessel vasculitis may also
occur and the involvement of carotid branches and
coronary arteries has been described. The
vascular wall affected by IgG4-RD is susceptible
to aneurysm formation and occasionally to
dissection or perforation.
Retroperitoneal fibrosis (RPF) is one of the most
common manifestations of IgG4-RD, with a
frequency of 1027. Many RPF series suggest that
IgG4-RD is responsible for 40 of idiopathic RPF
cases. The main symptoms of RPF are abdominal,
flank or lumbar pain, lower extremity oedema,
lower urinary tract symptoms, fever lt38C and
weight loss. Chronic inflammatory and fibrotic
changes spread from the aorta and the iliac
artery walls to the regional structures, such as
the ureters, leading to obstructive uropathy and
acute kidney failure. The frequency of
hydronephrosis has been reported to be 4067,
with a prevalence of unilateral involvement.
Renal involvement has a variable frequency,
ranging from 7 to 24 of cases . The most common
manifestation is tubulointerstitial nephritis
(TIN), called IgG4-related TIN (IgG4-TIN). This
condition often leads to varying degrees of renal
failure with sub-nephrotic proteinuria. The
most important serological feature is elevated
serum IgG4 level, together with serum IgE
elevation, eosinophilia and hypergammaglobulinemia
. In addition, gt50 of patients with active
IgG4-TIN have low concentrations of complement
fractions. Recently, an association between very
low levels of C3 (lt50 mg/dl) and kidney
involvement in IgG4-RD has been demonstrated.
The most specific histopathological feature is
storiform fibrosis, which is rare in other forms
of TIN . Sometimes, instead of the typical
storiform fibrosis, irregular fibres surrounding
inflammatory cell clusters (defined as birds
eye fibrosis) can be found.
Glomerular lesions has been reported in the
context of IgG4-RD. Membranous nephropathy is
the most common, but IgA nephropathy,
endocapillary proliferative glomerulonephritis
and membranoproliferative glomerulonephritis have
also been described.
Besides these major organ involvements, several
reports have indicated that other tissues can be
affected by the characteristic pathological
changes of the disease, including skin
(erythematous papules with a predilection for the
head and cheeks), prostate, peripheral nerves and
intracranial structures (with pachymeningitis and
A recent study identified four subgroups of
IgG4-RD patients with distinct clinical
phenotypes, defined as pancreato-hepato-biliary
retroperitoneum and aorta head and
neck-limited Mikulicz and systemic
The diagnosis of IgG4-RD is currently based on
the Comprehensive Diagnostic Criteria proposed by
Umehara. They include (i) typical organ
involvement (dysfunction, diffuse or localized
swelling) (ii) serum IgG4 gt135 mg/dl and
(iii) histopathological findings characteristic
of IgG4-RD (e.g. lymphoplasmacytic infiltrates,
storiform fibrosis, obliterative phlebitis),
with the immunohistochemical evidence of a high
proportion of IgG4 plasma cells (gt40 of total
IgG plasma cells, gt10 IgG4 plasma
cells/high-power field). If all three criteria
are met, the diagnosis is considered to be
definite if (i) and (iii) are met, it is
probable finally, fulfilment of (i) and (ii)
makes the diagnosis of IgG4-RD possible
THANKSIgG4-related disease a clinical
perspective Federica Maritati, Francesco
Peyronel, Augusto VaglioRheumatology, Volume 59,
Issue Supplement_3, May 2020, Pages iii123iii131,
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