764793

case-report2018
JSO0010.1177/2397198318764793Journal of Scleroderma and Related DisordersSimopoulou et al.

JSRD Journal of
Scleroderma and
Related
Case Report Disorders

Journal of Scleroderma and

Inferior vena cava thrombosis as the

Related Disorders
2018, Vol. 3(3) NP1­–NP6
© The Author(s) 2018
initial presentation of IgG4-related Article reuse guidelines:
sagepub.com/journals-permissions

retroperitoneal fibrosis: Case report https://doi.org/10.1177/2397198318764793

DOI: 10.1177/2397198318764793
journals.sagepub.com/home/jso

and literature review

Theodora Simopoulou1, Serafim Klimopoulos2,

Dimitrios Sampaziotis3, Apostolos Tzortziotis1,
Dimitrios Bogdanos1 and Lazaros I Sakkas1

Abstract
IgG4-related disease is an immune-mediated deposition of fibro-inflammatory tissue with IgG4-positive plasma cells
and dense fibrosis in a single or multiple organs. It often raises concern for malignancy requiring biopsy for diagnosis.
Presentation may vary according to organ involved. IgG4-related retroperitoneal fibrosis accounts for two-thirds of
the previously considered idiopathic retroperitoneal fibrosis cases. In IgG4-related retroperitoneal fibrosis, computed
tomography scan or magnetic resonance imaging shows periaortic soft tissue that extends from below the kidneys
to iliac arteries and entrap ureters causing hydronephrosis and renal failure. We present a rare case of IgG4-related
retroperitoneal fibrosis presenting with leg swelling and pain due to inferior vena cava compression and thrombosis, and
we review current concepts on disease pathogenesis, diagnosis and treatment.

Keywords
IgG4-related disease, intermittent claudication, inferior vena cava thrombosis, retroperitoneal fibrosis

Date received: 11 December 2017; accepted: 21 February 2018.

Introduction
IgG4-related disease is a recently characterized
immune-mediated entity characterized by deposition of
fibro-inflammatory tissue with IgG4-positive plasma
cells in a single or multiple organs.1 Presentation varies
substantially according to the affected organ. Its clinical
spectrum comprises many previously considered as sep-
arated disorders, like autoimmune pancreatitis and idi-
opathic retroperitoneal fibrosis (IRF).2,3 IgG4-related
retroperitoneal fibrosis (IgG4-RF) accounts for two-
thirds of the previously considered IRF cases.3
Computed tomography (CT) scan or magnetic reso-
nance imaging (MRI) shows soft tissue around abdomi-
nal aorta that usually entraps ureters and causes
hydronephrosis and renal failure. Involvement of infe-
rior vena cava (IVC) is rare. Therefore, we present a
case with IgG4-RF causing thrombosis and compres-
sion of IVC.
Case report
A 45-year-old male presented to our clinic with a 4-day
history of severe lower extremity pain evoked after a few
walking steps, which forced patient to stop. The patient
1Department of Rheumatology and Clinical Immunology, Faculty of
Medicine, School of Health Sciences, University of Thessaly, Larissa,
Greece
22nd Department of Surgery, Evangelismos General Hospital, Athens,
Greece
3Department of Pathology, Evangelismos General Hospital, Athens,
Greece
Corresponding author:
Lazaros I Sakkas, Department of Rheumatology and Clinical
Immunology, Faculty of Medicine, School of Health Sciences, University
of Thessaly, Larissa 41110, Greece.
Email: lsakkas@med.uth.gr
NP2 Journal of Scleroderma and Related Disorders 3(3)
Figure 1.  Magnetic resonance imaging shows periarticular soft tissue: (a) stenosis and (b) thrombosis of inferior vena cava (IVC).
also reported 2-week history of mild lower back pain. He
consulted an orthopaedic surgeon, and a CT scan of the
lumbar spine was interpreted as soft mass around abdomi-
nal aorta, compressing IVC and extending up to the level
of the second lumbar vertebra.
On examination, the patient was afebrile, with regular
pulse and normal blood pressure. Constitutional symptoms
– weight loss, fevers, night sweat, fatigue – were not
reported. There were bilateral lower extremity swelling,
mostly in the right leg, with 7 cm difference in mid-thigh
circumference. No varicosities in legs, lymphadenopathy,
hepatomegaly or splenomegaly were detected. Laboratory
tests were unremarkable, except elevated serum inflamma-
tion markers (C-reactive protein (CRP): 8.2 mg/dL, nor-
mal, <0.7 mg/dL) and D-dimers (963 mg/dL; normal
range: 180–440 mg/dL). Serum IgG4 was elevated (152
mg/dL; normal range: 8–140 mg/dL). The lower extremity
swelling was attributed to IVC compression or
thrombosis.
Lower limb venous ultrasonography was consistent
with deep and superficial venous thrombosis of the right
leg. The patient was started on low-molecular-weight hep-
arin. MRI and CT venography were performed to better
define the soft tissue mass, the extent of the IVC thrombo-
sis and to possibly estimate the age of the IVC thrombus.
There was IVC compression and extended thrombosis
(Figure 1). The thrombus was estimated to be more than 10
days old. Since thrombosis of IVC is not common in RF
(either IgG4-related or not) and malignancies were
included in the differential diagnosis, it was suggested that
a biopsy be done, and patient was referred to another hos-
pital to undergo laparoscopic biopsy. A retrievable IVC
filter was placed and then a laparoscopic tissue biopsy was
performed.
Histopathological examination showed fibrosis
arranged in a storiform pattern, dense lymphoplasmacytic
infiltrates and the presence of eosinophils (Figure 2(a) and
(b)). Immunostaining revealed IgG4+ plasma cells, with
IgG4+/IgG+ plasma cell ratio above 40% (Figure 2(c) and
(d)). The diagnosis of IgG4-RF with secondary IVC
thrombosis was made and the patient was arranged for
high-dose corticosteroid treatment.
The patient received methylprednisolone Intravenous
pulses (500 mg/day for three consecutive days) and then
60 mg prednisolone/day with gradual tapering. His symp-
toms gradually improved. A CT venography performed 2
months later showed a thin blood flow in the IVC with
filling defect in the common femoral vein. There was a
small reduction of the retroperitoneal mass. The IVC filter
was removed.
Discussion
IgG4-related disease, now considered to be a separate
entity, unifies many conditions once regarded as isolated
single-organ diseases, such as those affecting pancreas,
liver, thyroid, lacrimal glands, salivary glands, retroperito-
neum and brain, and many more, outlined in detail else-
where.1–3 True prevalence remains unknown, as recognition
of the disease is relatively low,4 but it appears that the dis-
ease affects middle-aged individuals and more frequently
men than women.5 Histology of tissue biopsy shows high
numbers of IgG4-positive plasma cells and dense fibrosis
in a typical storiform pattern. Obliterative phlebitis is also
present. Eosinophils are commonly present, while neutro-
phils are generally absent.6
The pathogenesis of IgG4-related disease (IgG4-RD) is
not clear. Also, it is not clear whether or not IgG4 itself is
Simopoulou et al. NP3

Figure 2.  Histology and immunohistology of biopsy. (a) Irregular fibrosis is seen in low magnification (40×) and (b) dense infiltrates
with lymphocytes, plasma cells and eosinophils (200×). (c) IgG-positive plasma cells and (d) IgG4-positive plasma cells.

pathogenic. The IgG4 isotype accounts for less than 5% of
the total IgG in healthy individuals. It undergoes a process
known as fragment antigen-binding (Fab)-arm exchange,
which leads to heavy chain dissociation and random
recombination. As a result, IgG4 antibodies do not directly
fix complement and are unable to cross-link antigen, play-
ing an anti-inflammatory rather than a pro-inflammatory
role.3,7 Moreover, in allergic disorders, IgG4 levels
increase after IgE decline, giving rise to a theory propos-
ing that IgG4 has evolved to an antigen-clearing mecha-
nism attenuating inflammation.3 Biopsy samples have
shown that CD4+ T cells are also present in affected tis-
sues, and a role for interleukin (IL)-4 and IL-10 in disease
pathogenesis has been suggested.3 Effective treatment
with B-cell depletion agent (rituximab) has provided fur-
ther insight into disease pathogenesis.8 It has been sug-
gested that B-cells generating IgG4 in IgG4-RD are mainly
of the short-lived type, which normally undergo apoptosis
within weeks. Circulating IgG4+ plasmablasts are oligo-
clonal, which indicates that these cells have undergone
antigen-specific proliferation and clonal expansion.9
Diagnostic criteria for IgG-RD have been published10
and definite diagnosis requires all three criteria: (1) diffuse
or localized swelling or mass in one or more organs, (2)
elevated serum IgG4 levels (>135 mg/dL) and (3)
histology showing marked lymphoplasmacytic infiltrates
with IgG4+/IgG+ plasma cells >40% and >10 IgG4+
plasma cells/high power field.10 Elevated serum IgG4 con-
centrations should not be used as a sole diagnostic marker
because they lack adequative specificity and sensitivity
and are subject to measurement errors due to a type of
‘prozone’ effect.3,10,11 Furthermore, elevated serum IgG4
levels may be found in multicentric Castleman’s disease
and malignancy. Quantitation of circulating plasmablasts
emerges as a good test for the diagnosis and monitoring of
IgG4-related disease, but it is still a research tool.12 Also,
CD19+CD24-CD38hi plasmablasts/plasma cells secrete
more IgG4 compared to other B-cell populations.13 IgG4/
IgG RNA ratio also emerges as a novel marker for
IgG4-RD.14 Elevation of serum inflammation markers
(erythrocyte sedimentation rate (ESR) and CRP) and
eosinophilia may also be observed, but are non-specific.
Imaging is required for diagnosis and follow-up. CT
scan with contrast enhancement and, still better, MRI can
assess the extension of the mass and the degree of inflam-
mation. Positron emission tomography (PET)/CT scan
with the glucose analogue 2-[(18)F]-fluoro-2-deoxy-d-
glucose better defines the activity of the disease and
assesses multi-organ involvement.15 Ultrasonography is
used to evaluate ureter dilatation and hydronephrosis.
NP4 Journal of Scleroderma and Related Disorders 3(3)

Table 1.  IVC-related manifestations in patients with IRF.

Patient population IVC-related manifestations Ref.

IRF, 346 patients Symptomatic iliocaval obstruction: 7 patients (6 with chronic obstruction and 1 with 18
acute obstruction)
IRF, 24 patients Hydrocele and/or varicocoele: 11/16 patients 21
Deep vein thrombosis in lower extremities: 8%
IRF, 48 patients Hydrocele: 7/26 (27%) patients 22
Oedema of lower extremities: 11/48 (23%) patients
Pulmonary embolism: 3/48 (6%) patients
IRF, 53 patients Testicular pain: 46% 23
Hydrocele: 29%
Oedema of lower extremities: 8%
RF, registry: 204 patients Compression of IVC with oedema of lower extremities: 16.6% 24
Thrombosis: 4.9%
IRF, 185 patients Testicular pain: 14/108 (13%) of men 20
New oedema of lower extremities: 23/183(13%) patients
Prominent venous collaterals: 4/183 patients
Hydrocele: 3/183 patients
IRF, 61 patients Oedema of lower extremities: 0.6% 25
IgG4-related RF, 10 patients Oedema of lower extremities: 2/10 patients 26
IRF, 23 patients Pericaval mass: 2/12 patients with IgG4-related RF and 0/10 patients with non-IgG4- 17
related RF

IRF: idiopathic retroperitoneal fibrosis; RF: retroperitoneal fibrosis; IVC: inferior vena cava.
It should be mentioned that previously characterized IRF includes IgG4-related RF.

The manifestations of IgG4-RD include constitutional
symptoms, such as fatigue and weight loss, and manifesta-
tions related to affected organ. Multiple organ involve-
ment, either synchronously or in succession, is not rare.10,16
About two-thirds of the previously considered IRF is
caused by IgG4-RD.3 Patients with IgG4 RF usually pre-
sent with a subacute poorly localized pain, in the back,
flanks and lower abdomen, which may be accompanied by
leg swelling. The location of the fibro-inflammatory mass
is mainly around the aorta, which frequently encases ure-
ters causing hydronephrosis and less frequently IVC.17,18
This explains the low frequency of IVC thrombosis. Ureter
entrapment leads to hydronephrosis and renal failure.
We systematically reviewed the English literature on
IVC occlusion/thrombosis in RF. Search of IgG4-related
disease and IVC thrombosis (and/or occlusion) resulted in
a single case report of a patient with deep vein thrombo-
sis.19 A summary of venous manifestations in IRF is shown
in Table 1.17,18,20–26 Sporadic cases of venous thrombosis in
patients with RF also have been reported.27,28 As in our
patient, where the fibro-inflammatory mass compressed
IVC and caused extended thrombus formation, thigh pain
on walking plus thigh swelling should prompt a test for
IVC obstruction/thrombosis. In chronic IVC obstruction/
thrombosis, collateral pathways must be formed to main-
tain venous circulation, such as large left gonadal vein
with scrotal swelling or varicocele.29 Ascending lumbar
veins arising from common iliac veins drain into azygos
vein on the right and hemi-azygos vein on the left. The lat-
ter collaterals cause enlargement of anterior epidural veins
presenting with radicular symptoms.30 Superficial collater-
als in the anterior abdominal wall are formed from inferior
epigastric vein which through superior epigastric vein and
internal mammary vein drains into subclavian vein and
from circumflex iliac vein which arising from common
femoral vein through lateral thoracic vein drains into axil-
lary vein.31
Differential diagnosis of IgG4-RF is not broad but
includes malignancies, mainly lymphoma and sarcoma,
sarcoidosis, primary large-vessel vasculitis, drugs (methy-
sergide) and Erdheim–Chester disease. Erdheim–Chester
disease is a rare inflammatory disorder characterized by
infiltration with non-Langerhans cell histiocytes of many
organs, including retroperitoneal and perirenal mass and
sclerotic bone lesions.32,33 Biopsy is required in most cases,
although sometimes it is difficult to obtain. When mass
extends above kidneys, IgG4-RF is unlikely, alternative
etiologies should be sought and biopsy is mandatory.
Although there are no randomized controlled trials,
there is international consensus guide for the management
and treatment of IgG4-RD which includes induction and
maintenance treatment.34 Treatment of IgG4-RF includes
corticosteroids as the first-line agent with initial pred-
nisone dose of 0.6–1 mg/kg daily for 2–4 weeks. The use
of conventional steroid-sparing agents is highly encour-
aged.34 B-cell depletion therapy has provided encouraging
results in recent trials.35 Surgical intervention may be
needed to relieve obstructions. For IVC thrombosis,
anticoagulation is needed in addition to immunosuppres-
sion. Guidelines for IVC filter insertion vary among
Simopoulou et al. NP5
professional societies. Consensus is limited to acute
venous thromboembolism and inability to anticoagulated
as well as for anticoagulation failure. Removable IVC fil-
ter may be needed temporarily in case of IVC thrombosis,
especially when biopsy of retroperitoneal mass is
contemplated.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship and/or publication of this
article.
Funding
18. Rhee RY, Gloviczki P, Luthra HS, et al. Iliocaval complica-
The author(s) received no financial support for the research,
authorship and/or publication of this article.
19. Liu Y, Xue F, Yang J, et al. Immunoglobulin G4-related dis-
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