IgG4 related disease Clinical Manifestations of IgG4 related disease

1. Clinical manifestations of
IgG4-related Disease
(IgG4 RD)
ANWER GHANI
FIBMS
IRAQ

2. 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 phlebitis.
.

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

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 The clinical manifestations of IgG4-RD are extremely variable
.
 In 60–90% of the patients the disease involves multiple
organs.

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

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General symptoms are rare.
Fever is usually absent .

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Lymphadenopathy is common

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Weight loss is reported especially in cases with exocrine
pancreatic failure caused by IgG4-related AIP, resulting in a
malabsorption syndrome.

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The pancreas is the most frequently involved organ (20–60% 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.

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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.

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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 Küttner’s 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 Mikulicz’s
disease, and occurs in 10–50% of cases.

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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, Wegener’s), although in the latter condition they often coexist with aggressive sino-
nasal disease.

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Some cases of fibrosing thyroiditis, a subset of
Hashimoto’s thyroiditis, determining hypothyroidism,
appear to be part of the IgG4-RD spectrum together
with some cases of Riedel’s thyroiditis.

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Lung involvement has a frequency of 10–30%.
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.

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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.

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A variety of macrovascular manifestations of IgG4-RD have
been described with a frequency of 10–20%, 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.

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Retroperitoneal fibrosis (RPF) is one of the most common
manifestations of IgG4-RD, with a frequency of 10–27.
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 <38°C 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 40–67%, with a
prevalence of unilateral involvement.

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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, >50% of patients with active IgG4-TIN have low
concentrations of complement fractions. Recently, an association between very low levels of C3 (<50 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 ‘bird’s eye fibrosis’) can be found.

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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.

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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 hypophysitis).

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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’

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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 >135 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 (>40% of total IgG+
plasma cells, >10 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

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