REVIEW ARTICLE

Ferrata Storti Foundation IgG4-related disease: what a hematologist

needs to know
Luke Y.C. Chen,1 Andre Mattman,2 Michael A. Seidman2,3
and Mollie N. Carruthers3
Division of Hematology, Department of Medicine, University of British Columbia;
1

Department of Pathology and Laboratory Medicine, St. Paul’s Hospital and 3Division of
2

Rheumatology, Department of Medicine, University of British Columbia, Vancouver, BC,

Canada
Haematologica 2019
Volume 104(3):444-455
ABSTRACT

I
gG4-related disease is a fibro-inflammatory condition that can affect
nearly any organ system. Common presentations include major sali-
vary and lacrimal gland enlargement, orbital disease, autoimmune
pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This
review focuses on the hematologic manifestations of IgG4-related dis-
ease, including lymphadenopathy, eosinophilia, and polyclonal hyper-
gammaglobulinemia. The disease can easily be missed by unsuspecting
hematologists, as patients may present with clinical problems that mimic
disorders such as multicentric Castleman disease, lymphoma, plasma cell
neoplasms and hypereosinophilic syndromes. When IgG4-related disease
is suspected, serum protein electrophoresis and IgG subclasses are helpful
as initial tests but a firm histological diagnosis is essential both to confirm
the diagnosis and to rule out mimickers. The central histopathological
features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched
with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), stori-
form fibrosis, and obliterative phlebitis. Importantly for hematologists,
Correspondence: the latter two features are seen in all tissues except bone marrow and
LUKE Y.C. CHEN lymph nodes, making these two sites suboptimal for histological confir-
[email protected] mation. Many patients follow an indolent course and respond well to
treatment, but a significant proportion may have highly morbid or fatal
Received: October 23, 2018. complications such as peri-aortitis, severe retroperitoneal fibrosis or
pachymeningitis. Corticosteroids are effective but cause new or worsen-
Accepted: January 7, 2019.
ing diabetes in about 40% of patients. Initial response rates to rituximab
Pre-published: January 31, 2019.
are high but durable remissions are rare. More intensive lymphoma
chemotherapy regimens may be required in rare cases of severe, refrac-
tory disease, and targeted therapy against plasmablasts, IgE and other dis-
doi:10.3324/haematol.2018.205526
ease biomarkers warrant further exploration.
Check the online version for the most updated
information on this article, online supplements,
and information on authorship & disclosures:
www.haematologica.org/content/104/3/444

Example case
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. An 80-year old Korean man was referred for evaluation of chronic lymphadenopathy,
All rights are reserved to the Ferrata Storti Foundation. Use of eosinophilia and polyclonal hypergammaglobulinemia. He had had abdominal pain since
published material is allowed under the following terms and
conditions:
the 1970s and was initially thought to have Crohn disease, subsequently complicated by
https://creativecommons.org/licenses/by-nc/4.0/legalcode. idiopathic common bile duct narrowing. In the 1990s, he was found to have a kidney mass
Copies of published material are allowed for personal or inter- on computed tomography which was suspected to be lymphoma, but after the mass was
nal use. Sharing published material for non-commercial pur- resected, the histology was in keeping with multifocal fibrosclerosis. At the time of referral, his
poses is subject to the following conditions:
physical examination revealed a low, firm, slightly enlarged, left submandibular gland, no
https://creativecommons.org/licenses/by-nc/4.0/legalcode,
sect. 3. Reproducing and sharing published material for com- lacrimal gland swelling, and multiple 2 cm or smaller soft inguinal lymph nodes bilaterally.
mercial purposes is not allowed without permission in writing His white blood cell count was 8.3x109/L, eosinophil count 2.0x109/L (normal values
from the publisher. <0.7x109/L), creatinine concentration 140 µmol/L, total protein 87 g/L (normal values <82
g/L), with a polyclonal increase in gamma globulins on serum protein electrophoresis of 20.5
g/L (normal values <14 g/L), and total IgG of 28.9 g/L (normal values <18.5 g/dL).

444 haematologica | 2019; 104(3)

 IgG4-related disease for hematologists

Introduction involvement is present in about 20-25% of IgG4-RD

cases, the true prevalence of the disease is likely much
Immunoglobulin G4-related disease (IgG4-RD) is a higher. There is a 2:1 male preponderance and the median
chronic immune-mediated disease that may present with age of affected patients at diagnosis is in the sixth to sev-
tumefactive lesions, fibrosis, and a polyclonal IgG4-posi- enth decade of life. Aside from one case report of identical
tive (IgG4+) plasma cell-enriched infiltrate in nearly any twins with IgG4-RD,6 evidence of genetic susceptibility is
anatomic site. In many centers, systemic therapy is guided sparse. Pediatric cases are rare, but a recent review identi-
by rheumatologists, yet nearly every medical, surgical and fied 25 cases in children, of whom 11 had orbital disease
pathology specialty must be aware of this entity and its and three had autoimmune pancreatitis.7
protean manifestations. Involvement of blood-forming At first glance, the presence of IgG4 in serum and IgG4+
and lymphoid organs, manifesting as lymphadenopathy, plasma cells in tissues, increased IgG4+ plasmablasts in
eosinophilia, and polyclonal hypergammaglobulinemia, is serum, and responsiveness to rituximab suggest that B-cell
common and IgG4-RD often mimics other hematologic activation drives the disease.8 However, the IgG4 antibody
conditions such as multicentric Castleman disease, lym- itself is not thought to be pathogenic since it does not bind
phoma, plasma cell neoplasms, and hypereosinophilic complement, does not traditionally form immune com-
syndromes (HES). This review provides an overview of plexes, and patients with other conditions with markedly
IgG4-RD with a focus on aspects most relevant to clinical elevated serum IgG4, such as IgG4 myeloma, do not
hematology practice. develop features of IgG4-RD.9,10 Recent studies have
In the early 2000s, while searching for non-invasive bio- demonstrated that an unconventional population of
markers to distinguish sclerosing (autoimmune) pancreati- CD4+SLAMF7+ cytotoxic T lymphocytes is central to the
tis from pancreatic cancer, Japanese investigators noticed a pathogenesis of the disease.11 Histopathologically, poly-
fast-moving band in the beta-gamma region of the serum clonal B cells are found in clusters near these CD4+ T cells,
protein electrophoresis of patients with sclerosing pancre- the latter of which are among the most abundant cells
atitis. This band represented markedly elevated serum within affected tissues. Oligoclonal expansion of these
IgG4.1 Subsequently, abundant polyclonal IgG4+ plasma CD4+ cytotoxic T lymphocytes in peripheral blood may
cells were found within a lymphoplasmacytic infiltrate in explain the high rates of T-cell clonality positivity deter-
tissue samples from patients with autoimmune pancreati- mined by polymerase chain reaction analysis.12 These
tis and in surrounding tissues including the liver and gall- CD4+ T cells produce profibrotic cytokines such as inter-
bladder.2 Once this entity was recognized as a distinct dis- leukin-1, transforming growth factor-beta and interferon-
ease with characteristic histological features, many histor- gamma, as well as cytolytic molecules such as granzyme
ically “idiopathic” and eponymous disorders such as mul- A and B and perforin.13 These cytotoxic T lymphocytes are
tifocal fibrosclerosis (mediastinal and retroperitoneal likely sustained by continuous antigen presentation by B
fibrosis), Kuttner tumor (chronic sclerosing sialadenitis) cells and plasmablasts. The responsible autoantigen(s)
and Reidel thyroiditis (woody infiltration of the thyroid) have not been definitively identified, but annexin A11 and
were found to be part of the IgG4-RD spectrum.3 galactin-3 have both recently been implicated in IgG4-
Numerous names were proposed in the early days of its RD.14,15 The autoantibody response to galactin-3 is prima-
discovery, including “IgG4-related sclerosing disease”, rily of the IgG4 and IgE isotypes, which correlates with
“IgG4-related systemic disease”, “IgG4-related multi- the typical immunoglobulin responses seen in IgG4-RD.
organ lymphoproliferative syndrome” and “systemic
IgG4-related plasmacytic syndrome”. An international
group of investigators, primarily from Japan, the USA and Clinical presentation
Europe met in Boston in 2011 and agreed upon uniform
nomenclature and diagnostic criteria.3 The accepted name IgG4-RD can affect nearly any organ except synovial tis-
“IgG4-related disease” reflects the universality of the sue. This “fibro-inflammatory” disease presents with
IgG4+ plasma cell infiltration in involved organs as well as tumefactive (puffy) inflammatory infiltrates and fibrosis
the frequency of elevation in serum IgG4 rather than a with a predilection for glandular tissue. Figure 1 illustrates
pathogenic role for IgG4 per se.4 The wide variety of dis- the manifestations of IgG4-RD by organ system. The
ease manifestations stems not only from multi-organ most common organ manifestations from two large
involvement, but also from the fact that different organs cohorts, one Japanese and one American, are shown in
may be involved in a metachronous fashion. Common Table 1.16,17 In patients presenting with the better-known
presentations are major salivary (parotid and submandibu- features of IgG4-RD, such as autoimmune pancreatitis,
lar) and lacrimal gland enlargement (Mickulicz disease), orbital disease and major salivary gland involvement, the
lymphadenopathy, orbital pseudotumor, pancreatitis, scle- disease tends to be recognized and histologically con-
rosing cholangitis, retroperitoneal fibrosis and tubulointer- firmed earlier, but patients referred to hematologists may
stitial nephritis.5 present with less obvious features of IgG4-RD, and a high
index of suspicion is needed to arrive at an accurate diag-
nosis. Common reasons for referral to a hematologist
Epidemiology and pathophysiology include lymphadenopathy, eosinophilia, and polyclonal
hypergammaglobulinemia.
Underrecognition has hindered accurate estimates of
the epidemiological burden of this disease, but a starting Lymphadenopathy
point is the prevalence of autoimmune pancreatitis in IgG4-related lymphadenopathy is one of the three most
Japan, which increased from 2.2/100 000 in 2007 to common manifestations of IgG4-RD, affecting 30-60% of
4.6/100 000 in 2011. The increase is almost certainly due patients with IgG4-RD in most large cohorts (Table 1).5,16,17
to increased recognition, and given that pancreatic IgG4-lymphadenompathy may be generalized or local-

haematologica | 2019; 104(3) 445

 L.Y.C. Chen et al.

Figure 1. Manifestations of IgG4-related disease by organ system. The most common primary disease features are indicated in bold.

Table 1. Clinical characteristics of patients from two large published

ized (the latter typically contiguous with involved organs cohorts.
such as pancreas and lungs). Parallel enlargement of sali-
vary, lacrimal and parotid glands is common. Five mor- Japan (n=334)17 Boston (125)16
phological subtypes, all of which display increased IgG4+ Mean age at diagnosis 63.8 years 55.2 years
plasma cells, have been described (see Figure 2 for exam- Male sex 61.4% 60.8%
ples):18-20
Ethnicity 100% Japanese 76% White
(i) Multi-centric Castleman disease-like: preserved nodal
architecture with patent sinusoids and hyperplastic folli- Elevated serum IgG4 >95% 51%
cles; abundant mature plasma cells in interfollicular areas Mean number of organs 3.2 (1-11) 2.3 (1-7)
with some eosinophils, similar to lymphadenopathy in involved (range)
multicentric Castleman disease or autoimmune disease. Affected organs
(ii) Reactive follicular hyperplasia: increased IgG4+ plas- Salivary glands 72.3% 28% (submandibular)
ma cells in germinal centers and often in the interfollicular + 16.8% (parotid)
zones with some eosinophils present. Lacrimal glands/orbit 57.1% 22.4%
(iii) Interfollicular expansion pattern: expanded interfol- Lymph nodes 56.5% 27.2%
licular zones with small lymphocytes, plasmablasts and Pancreas 25.5 19.2%
mature plasma cells and eosinophils which may resemble Retroperitoneal/ aorta 24.9 18.4% (retroperitoneal)
lymphoma (e.g. angioimmunoblastic lymphoma). + 11.2% (aorta)
Examples are given in Figure 2A-C. Kidney 23.7% 12%
(iv) Progressive transformation of germinal center-like: Lung 23.4% 17.6%

446 haematologica | 2019; 104(3)

 IgG4-related disease for hematologists

scattered larger or transformed follicles containing plasma trointestinal tract, and lymph nodes.12 Idiopathic HES and
cells. An example is given in Figure 2D,E. hypereosinophilia of unknown significance are diagnoses
(v) Inflammatory pseudotumor-like: lymph node partial- of exclusion, and account for a substantial proportion (30-
ly effaced by a fibro-inflammatory infiltrate and storiform 50%) of diagnoses of patients evaluated for eosinophilia.24-
26
fibrosis; this subtype is considered most specific for IgG4- Evaluating these patients for IgG4-RD is an important
RD in lymph nodes. An example is given in Figure 2F. and underappreciated aspect of their care. In fact, we pre-
viously published a case report with a diagnostic label of
IgG4-related lymphadenopathy has aptly been called idiopathic HES, reviewed by several world experts in
both “an underdiagnosed and overdiagnosed entity”:19 eosinophilia who concurred with the diagnosis, which
underdiagnosed because if it is not included in the differ- was subsequently found to be IgG4-RD.27,28 Findings of a
ential diagnosis, IgG4 and IgG stains may not be done and myeloid clonal disorder such as increased blast cells,
the disease may be missed, and overdiagnosed because abnormal karyotype, mutations in PDGFR-alpha/beta,
increased IgG4+ plasma cells may be seen in conditions FGFR-1 and PCM1-JAK2 are not seen in IgG4-RD.
ranging from Rosai-Dorfman-Destombes disease to However, differentiating lymphocytic-variant HES from
inflammatory vasculitis.21,22 Although not the optimal tis- IgG4-RD can be more challenging. The aberrant T-cell
sue for making the histological diagnosis of IgG4-RD, in a phenotypes found in lymphocytic-variant HES, including
patient with typical clinical features such as autoimmune increased CD4+CD3–, CD3+/CD4–/CD8– and CD4+/CD7– T
pancreatitis or retroperitoneal fibrosis, a lymph node biop- cells, with or without T-cell clonality as determined by
sy may be sufficient for diagnosis if biopsy of other affect- polymerase chain reaction analysis, have all been reported
ed organs is not feasible. Given the low specificity of in IgG4-RD.12,29 Increased IgG4 deposits have been found
increased IgG4+ plasma cells in lymph node and the vari- in tissue samples from adult and pediatric patients with
able histological patterns, the greatest utility of lymph eosinophilic esophagitis.30-33 In contrast to HES and chron-
node biopsy is perhaps excluding other diagnoses, such as ic eosinophilic leukemia, the eosinophilia secondary to
lymphoma and HHV8-associated Castleman disease. The IgG4-RD is typically mild to moderate, rarely exceeding
role of lymph node biopsy is further discussed in the sec- 5x109/L and typically quite evanescent, being ablated by
tion on “Diagnosis and staging”. steroids or rituximab therapy.

Eosinophilia Polyclonal hypergammaglobulinemia

Approximately 40% of patients with IgG4-RD have As for eosinophilia, IgG4-RD represents an important
peripheral blood eosinophilia, often accompanied by asth- new diagnostic consideration in patients with hypergam-
ma and atopy.23 Thus, IgG4-RD is an important and under- maglobulinemia. An elevated serum IgG4 level, often
appreciated cause of reactive or secondary eosinophilia.12 accompanied by an increase in IgG1, causes polyclonal
HES and IgG4-RD commonly involve the skin, lungs, gas- hypergammaglobulinemia. Rarely, this elevation can be

A B C

D E F

Figure 2. Lymph nodes in IgG4-related disease. (A,B) An example of the interfollicular pattern of IgG4-related lymphadenopathy, with mature plasma cells, many
expressing IgG4, distributed between benign follicles. (A) Hematoxylin and eosin stain. (B) IgG4 immunohistochemistry. (C) A needle core lymph node biopsy from a
different case with the interfollicular pattern (hematoxylin and eosin stain). (D,E) A case of IgG4-lymphadenoapthy with a progressive transformation of the follicular
center pattern, with the plasma cells within the follicle proper. (D) Hematoxylin and eosin stain. (E) IgG4 immunohistochemistry. (F) An example of a mass-like lesion
(inflammatory pseudotumor) with dense fibrosis and associated follicular hyperplasia in a case of IgG4-lymphadenoapthy (hematoxylin and eosin).

haematologica | 2019; 104(3) 447

 L.Y.C. Chen et al.

sufficient to result in polyclonal hyperviscosity clonal gammopathy of undetermined significance with

syndrome.27,28,34 It is not known what causes the exuberant IgG1, hypothyroidism and irritable bowel syndrome with
production of IgG4 immunoglobulins, currently consid- IgG2, rheumatoid arthritis with increased IgG3 and IgG1,
ered an epiphenomenon rather than a contributor to the and celiac disease with IgG4.43
pathogenesis of the disease.8 Not surprisingly, the serum IgG4 myeloma has been described but is rare; one large
free light chains tend to be abnormally elevated.35 IgE is case series found that 6/158 bone marrow biopsies in
often markedly increased, particularly in patients with myeloma patients expressed IgG4, in keeping with the rel-
eosinophilia and atopy, whereas IgA and IgM levels are atively small fraction of overall circulating gamma globu-
normal or modestly elevated. Serum IgG4 typically runs in lins normally made up by the IgG4 subtype.10 One case
the fast gamma or beta-gamma region on the serum pro- report of IgG4 subtype POEMS has been reported.44 The
tein electrophoresis, and thus the typical electrophoretic bone marrow morphology may mimic myeloma with
profile of a patient with IgG4-RD demonstrates polyclonal florid plasmacytosis,9,45 although in our experience, bone
hypergammaglobulinemia with beta-gamma bridging. marrow examination is very insensitive for the diagnosis
This sometimes prominent pattern is dependent on IgG4 of IgG4-RD, with many cases showing no increase in plas-
concentration and is highlighted in Figure 3. The hyper- ma cells or lymphocytes despite florid hypergammaglob-
gammaglobulinemia can be mistaken for a polyclonal ulinemia.
increase in IgA, monoclonal gammopathy of undeter-
mined significance or “biclonal” IgG kappa and lambda Important mimickers of IgG4-related disease
gammopathy, as laboratory physicians may not be famil- The diagnostic challenge of IgG4-RD for hematologists
iar with the dense bands of IgG-lambda and kappa which is heightened by overlap of clinical and laboratory features
in fact represent polyclonal IgG4.36,37 Some patients have with those of a number of other hematologic diseases
even been treated for myeloma before subsequently being including lymphoma, plasma cell neoplasms, and histio-
found to have IgG4-RD as the cause of their protein cyte disorders (Table 2). In addition to the diseases dis-
abnormalities, plasmacytosis and renal disease.9,38 cussed in this section and presented in Table 2, there are
Laboratory physicians must, therefore, consider the differ- numerous non-hematologic mimickers reviewed in detail
ential diagnosis of beta-gamma bridging and order or sug- elsewhere.46 Careful review of histological specimens and
gest additional investigations to clarify clonality and correlation with clinical, laboratory and radiological find-
heavy chain composition where necessary.39,40 ings are crucial for solidifying the correct diagnosis.
Prior to the recognition of IgG4-RD, a large case series Multicentric Castleman disease and IgG4-RD show con-
of 130 patients with polyclonal hypergammaglobulinemia siderable overlap given the high frequency of lym-
>30 g/L on serum protein electrophoresis showed that the phadenopathy, IgG4+ plasma cell-enriched tissue infil-
most common single diagnoses were liver disease (79/130, trates and elevated serum IgG4 levels seen in both dis-
66%), connective tissue disease (28/130, 22%), chronic eases.18 However, IgG4-RD typically affects older patients,
infection (8/130, 6%) and hematologic disorders (7/130, rarely exhibits the “hyper-interleukin-6” systemic inflam-
5%).41 In a recent, single-center study of 70 patients with matory features of multicentric Castleman disease such as
polyclonal increases in IgG ≥20 g/L it was found that 14 fever and elevated C-reactive protein, and the histological
(20%) had IgG4-RD as the cause of their hypergamma- features are distinct. The histiocytic disorders Rosai-
globulinemia, indicating that a substantial proportion of Dorfman-Destombes disease and Erdheim-Chester dis-
patients with hypergammaglobulinemia have IgG4-RD as ease both cause inflammatory mass lesions that can mimic
the underlying cause.42 The discovery of IgG4-RD has also IgG4-RD. Histopathological evaluation of Rosai-
led to increased recognition of other IgG subclass eleva- Dorfman-Destombes disease can show enrichment of
tions with specific diseases, such as hepatitis C and mono- IgG4+ plasma cells,22,47 but typically in the context of

Figure 3. Serum protein electrophoresis showing elec-

trophoretic patterns for four patients with mild to gross
elevations in IgG4 concentration in between two for
patients with low IgG4 concentration. The physicochemi-
cal properties of the IgG4 heavy chain result in a relative
anodal position (shift toward albumin) of the gamma glob-
ulins when the IgG4 becomes the predominant gamma
globulin. Apart from IgG4, IgA immunoglobulins are fre-
quently observed in the boundary between the beta and
gamma regions. Monoclonal bands may also migrate in
this region as shown in the gel (the monoclonal gammopa-
thy in this case is an IgG1 monoclonal band that has
physicochemical properties that are atypical for IgG1
immunoglobulins, which are normally found in a more
cathodal position). NC: normal control, MG: monoclonal
gammopathy.

448 haematologica | 2019; 104(3)

 IgG4-related disease for hematologists

CD68+ S100+ histiocytes, often associated with plasma cells,48 but in the absence of other evidence for a
emperipolesis. The most recent classification of the histio- common pathophysiological link, Rosai-Dorfman-
cyte disorders recommends evaluating suspected cases of Destombes disease is not considered part of the spectrum
Rosai-Dorfman-Destombes disease for increased IgG4+ of IgG4-RD or vice versa.49 One third of patients with

Table 2. Diseases that mimic hematologic manifestations of IgG4-RD (lymphadenopathy, eosinophilia and polyclonal hypergammaglobulinemia).
Mimicker of IgG4-related disease Areas of overlap Distinguishing features of the mimicker not typically
seen in IgG4-related disease
Multicentric Castleman disease (MCD) • Lymphadenopathy (particularly the MCD-like • MCD is a “hyper-IL-6” syndrome associated with
variant of IgG4-LAD) B symptoms and highly elevated CRP and IL-6 not seen in
• High serum IgG4 IgG4-RD
• IgG4+ plasma cells in tissue*
• Polyclonal hypergammaglobulinemia
Cutaneous and systemic plasmacytosis (CSP) • Lymphadenopathy • IgG4-RD rarely involves skin whereas cutaneous lesions
• Polyclonal hypergammaglobulinemia (round/oval, red/brown poorly circumscribed macules,
• Polyclonal plasmacytosis, including IgG4+ papules and plaques) are an obligatory feature of CSP;
plasma cells in bone marrow and skin* serum IgG4 in CSP is normal or mildly elevated
Rosai-Dorfman-Destombes disease (RDD, • Lymphadenopathy • Massive cervical lymphadenopathy is atypical for IgG4-RD
a.k.a “Sinus Histiocytosis with Massive • Extranodal RDD can involve the nasal cavity, • RDD may present with B symptoms
Lymphadenopathy; “R” group histiocytosis) and retro-orbital tissue • Large histiocytic cells with hypochromatic nuclei and
• Meningeal involvement of RDD may mimic pale cytoplasm; emperipolesis; positive for S100, CD68,
IgG4-pachymeningitis CD14 and CD163
• Salivary gland involvement
• CNS involvement including pachymeningitis
• Increased IgG4+ plasma cells in tissue*
Erdheim Chester disease • Retroperitoneal fibrosis • >95% of ECD patients have bone involvement, which is
(ECD; “L” group histiocytosis) • Central nervous system/hypophysitis rare in IgG4-RD (apart from rare IgG4+ angiocentric
• Pulmonary involvement eosinophilic fibrosis of the head and neck)
• Yellow peri-orbital xanthelasmas common in ECD
(skin involvement in IgG4-RD is rare, and when present
tends to be erythematous or flesh-colored papules)
• Foamy multi-nucleated histiocytes, few Touton cells,
fibrosis; CD68+, CD163+, CD1a–
• 50% of ECD patients are BRAF V600E-positive
Malignant lymphoma • Lymphadenopathy • B symptoms, bone involvement, brain parenchymal
• Extranodal mass lesions involvement and hypercalcemia are rare in IgG4-RD
• Blood and tissue eosinophilia
Sarcoidosis • Lymphadenopathy • Non-caseating granulomas
• Pulmonary nodules • Hypercalcemia and elevated ACE levels
• Pachymeningitis and/or hypophysitis
• Polyclonal hypergammaglobulinemia
• Multi-organ involvement
Hypereosinophilic syndrome (HES)/chronic • T-cell clonality by PCR • Increased blasts or myeloid clone in CEL
eosinophilic leukemia (CEL) • Atopy/asthma/elevated IgE • PDGFR-alpha/PDGFR-beta/FGFR1/PCM1-JAK2 positivity
• Lymphadenopathy are not seen in IgG4-RD
[particularly lymphocyte-variant HES] • Eosinophilia • More marked and persistent eosinophilia in HES
• Elevated serum IgG4
• Aberrant T cell phenotype in peripheral
blood (CD4+/3-, CD4+/7–, CD3+/4–/8–)
Plasma cell myeloma/monoclonal gammopathy • Plasma cell infiltrate • Plasma cell clonality
of undetermined significance • Hypergammaglobulinemia • Monoclonal paraprotein ± suppression of polyclonal
• Renal failure immunoglobulins
• Proteinuria • Lytic boney disease/hypercalcemia
• Light chains in urine rather than albuminuria
Vasculitis, particularly eosinophilic • Eosinophilia in blood and tissue • Highly elevated CRP in vasculitis
granulomatosis with polyangiitis • Polyclonal hypergammaglobulinemia with • Extravascular granulomas, small-medium vessel vasculitis
and granulomatosis with polyangiitis elevated serum IgG4 • Mononeuritis multiplex not a feature of IgG4-RD
• Peri-aortitis and rarely, Kawasaki-like coronary
arteritis are seen in IgG4-RD
• Multi-organ involvement, including respiratory,
gastrointestinal and renal structures
*Although increased IgG4+ plasma cells have been described in these diseases, the absolute counts and IgG4/IgG ratio are typically well below the thresholds for the diagnosis of IgG4-
RD and the other key features of IgG4-RD (storiform fibrosis and obliterative phlebitis) are not seen.3 IgG4-LAD: IgG4-lymphadenopathy; IL-6: interleukin-6; CRP: C-reactive protein; IgG4-
RD: IgG4-related disease; CNS: central nervous system; ACE: angiotensin-converting enzyme; PCR: polymerase chain reaction.

haematologica | 2019; 104(3) 449

 L.Y.C. Chen et al.

Erdheim-Chester disease have retroperitoneal fibrosis, common commercial method but not another) without
which may raise the suspicion of IgG4-RD; however, specifying the methodology. While mildly elevated serum
more than 95% of patients with Erdheim-Chester disease IgG4 can be seen in many conditions, markedly elevated
have skeletal involvement, which, aside from rare cases of serum IgG4 (>5 g/L) is approximately 90% specific for
IgG4-related angiocentric eosinophilic fibrosis (midline IgG4-RD. Aside from methodological differences, serum
destructive lesions of the head and neck), is generally not IgG4 levels in IgG4-RD can vary greatly depending on eth-
seen in IgG4-RD.50 The histology of Erdheim-Chester dis- nicity and degree of organ involvement. In the Boston
ease shows a CD68+S100–CD1a– histiocyte infiltration cohort of patients (76% White), only 53 of 103 patients
often with “foamy histiocytes”.51 Extra-pulmonary sar- had elevated serum IgG4 levels.16 In contrast, in a cohort
coidosis may share clinical features similar to those of of 334 Japanese patients, more than 95% had elevated
IgG4-RD, including polyclonal hypergammaglobulinemia, serum IgG4.17 In our multi-ethnic cohort, we found that
lymphadenopathy, pulmonary nodules, sclerosing mesen- Asians have a higher serum IgG4 than non-Asians (medi-
teritis and pachymeningitis. The association between an 11.2 g/L versus 2.9 g/L, P=0.0094), and elevated serum
IgG4-RD and malignant lymphoma has been studied IgG4 had a sensitivity of 96% in Asians compared to 67%
extensively. In Asian patients, mucosal-associated lym- in non-Asians.61 Patients with multi-organ involvement or
phoid tissue (MALT) lymphoma, particularly of ophthal- of Asian ethnicity typically have elevated serum IgG4,
mological tissues has been described, whereas in western sometimes markedly so, such as the patient in this illustra-
populations a variety of histologies (diffuse large B-cell, tive case. The serum IgG4/IgG ratio is typically >0.2 in
follicular, lymphoplasmacytic, and MALT) have been patients with IgG4-RD, although the ratio does not
reported.52,53 There are also case reports of IgG4-RD con- increase the diagnostic specificity of serum IgG4 alone.
comitant with autoimmune lymphoproliferative syn- Flow cytometric detection of plasmablasts may offer a
drome.54,55 more sensitive modality for diagnosing IgG4-RD, with a
reported sensitivity of 95% and specificity of 82% using a
Case continued cut-off of 900/mL.62 However, the flow cytometry method
The patient was suspected to have IgG4-RD, so serum IgG used to detect plasmablasts is not widely available.
subclasses were analyzed. His serum IgG4 level was markedly Most centers use immunonephelometry to measure IgG
elevated at 11.6 g/L (normal values <1.35). The tissue blocks subclasses, which can cause some challenges with inter-
from his previous nephrectomy were retrieved and pathology pretation. The two most common immunonephelometric
review showed a lymphoplasmacytic infiltrate, moderate tissue methods (Siemens and Binding Site) correlate well with
eosinophilia and interstitial fibrosis and atrophy. Staining for regard to IgG4, but the absolute IgG4 values differ by
IgG4 and IgG revealed abundant IgG4+ plasma cells with >40 approximately 50% at the upper limit of normal.63 IgG4
IgG4+ plasma cells per high power field and an IgG4/IgG ratio levels may also be markedly under-reported in cases of
>40%. Computed tomography scans of the neck, chest, abdomen extreme IgG4 elevations due to the hook effect. The hook
and pelvis revealed multiple pulmonary nodules, carinal lym- effect, or prozone phenomenon, occurs when an excessive
phadenopathy and a soft tissue density encasing the main coro- amount of analyte prevents binding of the capture anti-
nary arteries, previous right nephrectomy and pancreatic atrophy. body in a sandwich assay, yielding a falsely low or normal
His IgG4-RD Responder Index activity score was 12. result. Erroneously low measurements of serum IgG4
reported in the literature reflect this error.64 Furthermore,
IgG4 itself interferes with the nephelometric measure-
Diagnosis and staging ment of IgG1 and IgG2, in particular, which can obscure
the immunoglobulin profile that would otherwise high-
A careful history and thorough physical examination, light the disproportionate elevation of serum IgG4.65
attending to clues such as a history of waxing and waning Because of the traditional errors in immunonephelometry,
glandular swelling, sicca symptoms and unexplained pan- some have mistakenly reported increased serum IgG2 lev-
creatitis or jaundice must be accompanied by serum pro- els as a marker of IgG4-RD.66-68 Our group has recently
tein studies. Histological confirmation of the disease is demonstrated that mass spectrometry is an alternative
essential, and once a diagnosis has been established, inves- that eliminates these analytical errors and is more cost-
tigations to assess for symptomatic and subclinical organ effective than immunonephelometry.65
involvement, such as early retroperitoneal fibrosis and
albuminuria, are important for management planning. Histopathology
The IgG4-RD Responder Index is a standardized, validat- A firm diagnosis of IgG4-related disease requires
ed tool for the evaluation of disease activity at initial eval- histopathological confirmation, except in the case of
uation and subsequent follow up.56,57 Suggested laboratory autoimmune pancreatitis, in which radiological features
and imaging tests are summarized in Table 3. (diffuse “sausage-like” enlargement of the pancreas with
featureless borders and delayed enhancement with or
Serum protein studies without a capsule-like rim or “halo”) may be sufficiently
Approximately 70% of patients with IgG4-RD have an specific to exclude requirement for tissue biopsy.3,69 As in
elevated serum IgG4 level. Serum IgG subclasses should sarcoidosis, in which non-caseating granulomas may be
be investigated in conjunction with serum protein elec- seen in any of the organs affected by the disease, IgG4-RD
trophoresis to exclude a monoclonal paraprotein (Figure demonstrates common histology in most of the multitude
3). Serum IgG4 level has a diagnostic sensitivity ranging of organs that may be affected.
from 83-97% and specificity from 60-85% with a general The three major histological features of IgG4-RD in tis-
cut-off of “above the upper limit of normal”.58-60 Typically, sue are: (i) a dense, polyclonal lymphoplasmacytic infil-
1.35 g/L is used as the biomarker cut-off for IgG4-RD trate enriched with IgG4+ plasma cells; (ii) fibrosis; and (iii)
(which corresponds to the upper limit of normal for one obliterative phlebitis. With regards to the lymphoplasma-

450 haematologica | 2019; 104(3)

 IgG4-related disease for hematologists

Table 3. Diagnostic and staging tests in IgG4-RD.

Test(s) Typical findings
Complete blood count/differential/blood film Eosinophilia (~40% of patients, typically mild);
rouleaux formation due to polyclonal
hypergammaglobulinemia
C-reactive protein (CRP); interleukin-6 and other Normal or moderately elevated (CRP typically
markers of systemic inflammation <20 mg/L) in the absence of peri-aortitis or active
infection
Serum IgG subclasses Mildly elevated IgG4 <1.5-5 g/L is nonspecific, and 30%
of IgG4-RD patients have normal serum IgG4 levels.
Serum IgG4 >5 g/L is helpful both for diagnosis and
as a disease marker. Other IgG subclasses may be
moderately elevated (IgG4/IgG ratio is typically >0.2)*
Blood and urine tests Immunoglobulins (IgG, IgA, IgM, IgE); serum and urine IgA and IgM may be normal or mildly increased; IgE
protein electrophoresis (SPEP, UPEP) may be markedly increased. Immunoglobulin
suppression is atypical. SPEP and UPEP are important
to rule out monoclonal proteins
Autoantibodies (e.g. antinuclear antibody, May be weakly positive
rheumatoid factor)

Complements (C3/C4) Often low, especially with tubulointerstitial nephritis

Urinalysis, random albumin/creatinine ratio Albuminuria is common; nephrotic range proteinuria

can be seen with membranoproliferative
glomerulonephritis

Other markers of end organ damage: lipase, glucose Subclinical pancreatitis with elevated lipase, glucose
and hemoglobin A1c, liver enzymes, thyroid-stimulating intolerance, hepatitis and albuminuria are common
hormone, creatinine, urinalysis, urine
albumin/creatinine ratio

Computed tomography (CT) of the neck, chest, Diffuse “sausage-like” or segmental enlargement of
abdomen, pelvis pancreas, often with a “halo”; wedge-shaped hypodensities
in kidneys; ductal organs, such as bile duct and bronchus,
Imaging
show diffuse “pipe-stem” wall thickening; thickened aortic
wall; hepatic mass lesions; retroperitoneal fibrosis or
peri-aortic cuffing
If lacrimal enlargement ⇒CT to head (rule out Patients with orbital disease typically have lacrimal
orbital involvement) gland swelling

Archived specimens As long as tissue blocks are still available, the pathologist
should be able to examine the histology and then order
immunostaining for IgG4 and IgG if typical features are present
New biopsy Excisional is preferable to core biopsy when possible to look
for the central pathological features:
• Storiform fibrosis
• Obliterative phlebitis
• Polyclonal lymphoplasmacytic infiltrate with increased
IgG4+ plasma cells and IgG4+/IgG+ plasma cell
Pathology ratio > 40%**

Consider minor salivary gland (lip) biopsy if affected organs

are high risk for biopsy
Lymph node and bone marrow These tissues are unusual in that fibrosis and obliterative
phlebitis are typically not seen, and thus biopsy of other
tissues may be required for a definitive diagnosis. Involved
lymph nodes typically have >100 IgG4+ plasma cells/hpf
with an IgG4/IgG ratio >40%. Bone marrow involvement with
eosinophilia and increased IgG4+ plasma cells is rare and
may be absent even in patients with marked serum
hypergammaglobulinemia
*IgG2 may be spuriously elevated when nephelometric measurement is used.65 **The number of IgG4+ cells/hpf required varies, depending on the tissue, from >10/hpf in
meningeal tissue to >200/hpf in skin. In all tissues, the ratio of IgG4+ to IgG+ plasma cells should be ≥40%.3 Hpf: high-power field.

haematologica | 2019; 104(3) 451

 L.Y.C. Chen et al.

cytic infiltrate, the number of IgG4+ plasma cells per high- sis (not to be confused with myelofibrosis) are not typical-
power field (hpf) considered diagnostic varies according to ly seen in bone marrow and lymph nodes.70 Furthermore,
tissue site, from >10/hpf in meninges to >100/hpf in skin. even when involved, lymph nodes and bone marrow may
Regardless of the site, the ratio of IgG4+/IgG+ plasma cells not show robust elevation in IgG4-expressing plasma cells
is >40% in IgG4-RD. Fibrosis is a histological requirement as compared to the total IgG population, or the findings
for the diagnosis of IgG4-RD and should be arranged at may be only focal. Patterns of IgG4-RD have not been
least focally in a storiform pattern. Storiform fibrosis is a well established in the bone marrow, but the presence of
swirling, “cartwheel” pattern of fibrosis which may have a mature plasma cells would be supportive of marrow
patchy distribution and can, therefore, be missed with involvement, once plasma cell neoplasms are excluded.
small biopsies. In the obliterative phlebitis of IgG4-RD, Some examples of marrow involvement in IgG4-RD are
venous channels are obliterated by an inflammatory lym- shown in Figure 4.
phoplasmacytic infiltrate. Expert pathologists recommend In general, only organs with clinical or radiological evi-
looking for arteries/arterioles where the accompanying dence of involvement are likely to show diagnostic fea-
venous vessel is not readily apparent and may in fact have tures on biopsy, and thus biopsy should be directed at
been replaced by an inflammatory infiltrate; elastin stains affected organ(s). Patients with proteinuria or renal lesions
may be helpful in identifying completely obliterated ves- on imaging may require kidney biopsy, and renal involve-
sels. ment may demonstrate two distinct histological patterns:
Other histopathological features include phlebitis with- hypocomplementic tubulointerstitial nephritis in 80% of
out obliteration of the lumen and increased number of cases, and membranoproliferative glomerulonephritis in
eosinophils. As in the illustrative case, archival specimens 20% of cases.70 In patients in whom affected organs are
may be used to confirm a diagnosis, and many patients not amenable to biopsy, minor salivary gland (lip) biopsy
will have previous biopsies available due to their chronic should be considered. Even without clinical evidence of
disease course. As long as a tissue block is still available, major salivary gland swelling or sicca symptoms, minor
IgG4 and IgG stains can be done. When a new biopsy is salivary gland biopsy can be a minimally invasive way to
required, excisional specimens are preferred over core nee- reach a histological diagnosis in some patients. One study
dle biopsies to allow for proper assessment. There are cur- of 66 patients with suspected IgG4-RD reported a sensitiv-
rently no established criteria for the cytological diagnosis ity of 55% and specificity of 100% for labial salivary gland
of IgG4-RD from a fine needle aspirate. biopsy.71 From a pragmatic perspective, patients who have
Increased numbers of IgG4+ plasma cells are seen in all classic clinical, laboratory and radiological manifestations
tissues affected by IgG4-RD, but this is not, in itself, a spe- of IgG4-RD but are too frail to undergo an attempted
cific finding. Many chronic inflammatory conditions such biopsy attempt, or in whom small biopsies yield insuffi-
as vasculitis, inflammatory bowel disease and lymphoma cient diagnostic material,72 can be given a working diagno-
may exhibit increased numbers of IgG4+ plasma cells but sis of “suspected IgG4-RD” and treated as such provided
do not share the other histological features of storiform reasonable efforts have been made to exclude mimickers
fibrosis, obliterative phlebitis and absence of granuloma- of IgG4-RD.
tous inflammation.19,21 Unfortunately, for the purposes of Splenic involvement in IgG4-RD remains an enigma.
hematologists, bone marrow involvement is uncommon Overt splenomegaly and splenic lesions are rare in con-
in IgG4-RD and obliterative phlebitis and storiform fibro- firmed cases of IgG4-RD. A rare entity known as scleros-

A B

Figure 4. Bone marrow specimens

involved by IgG4-related disease. Both
cases show mature plasma cells distrib-
uted throughout the marrow. Ancillary
studies established that these plasma
cells were polyclonal, excluding a plasma
cell neoplasm. (A,C) Hematoxylin and
eosin stains. (B,D) IgG4 immunohisto-
C D chemistry.

452 haematologica | 2019; 104(3)

 IgG4-related disease for hematologists

ing angiomatoid transformation of the spleen (SANT) is sion for some patients.80-82 In the absence of prospective
known to be enriched with IgG4+ plasma cells, but clinical trials, an international consensus guideline on
whether this condition is part of the spectrum of IgG4-RD IgG4-RD treatment had only a 46% expert agreement on
remains unclear, as many patients with sclerosing whether disease-modifying anti-rheumatic drugs should
angiomatoid transformation of the spleen do not exhibit be started from the outset of treatment or not.83
other features of IgG4-RD.73 The inability to biopsy Rituximab has been shown to be highly effective for
splenic tissue short of full splenectomy hinders the histo- IgG4-RD, with a response rate of 97% (29 out of 30
logical characterization of IgG4-RD in this organ. patients) in one prospective trial.74 The majority of
patients did not require concomitant corticosteroids from
Imaging and staging the time of enrollment. However, rituximab is difficult to
Once histopathological confirmation of the diagnosis has access due to cost, particularly outside of the USA, and
been obtained, the disease can be staged by computed remissions are often short-lived. In a French database
tomography of the chest, abdomen and pelvis.74 Although study of 33 patients who received rituximab, a clinical
the orbit is a commonly involved organ in IgG4-RD, the response was seen in 29/31 (93.5%) patients, but 13/31
absence of dacryoadenitis is suggestive that there is no (41.9%) responders relapsed during a mean follow up of
underlying orbital pseudotumor and therefore dedicated 24.8 months (with the relapses occurring at a mean of 19
head or orbital computed tomography is not always neces- months after rituximab therapy).84 The severe infection
sary.75 Positron emission tomography/computed tomogra- rate was estimated to be 12.1/100 patient years and three
phy showed greater sensitivity for the detection of disease patients had hypogammaglobulinemia <5 g/L. In our prac-
in arteries, salivary glands and lymph nodes in a study of 21 tice, we often keep patients on a low dose of maintenance
patients but further evaluation is needed to clarify which prednisone to maintain remission after rituximab treat-
patients benefit from the combined tomographic method ment.
over conventional imaging.76 It is important to check the uri- A number of emerging therapeutic options show prom-
nary albumin/creatinine ratio and serum C3/C4 levels to ise. An open label, phase 2 clinical trial of a humanized
assess for renal involvement. IgG4-RD often behaves indo- anti-CD19 antibody (Xmab®5871) showed that this treat-
lently, but accurate diagnosis and staging are crucial because ment decreased the IgG-RD Responder Index score by ≥2
some patients have asymptomatic but potentially organ- or points in 12/12 patients who completed the study.85
life-threatening disease such as retroperitoneal fibrosis, Successful use of lymphoma chemoimmunotherapy regi-
peri-aortitis or coronary arteritis, the last of which may mens such as fludarabine and rituximab and bendamus-
develop suddenly. Moreover, fibrotic disease is typically tine and rituximab have been reported for two steroid-
irreversible, so early treatment is important. and rituximab-refractory cases.28 Whether these patients
needed T-cell directed therapy or simply more potent
Case continued immunosuppression than can be achieved by steroids or
Given the patient’s multi-organ involvement, particularly of the rituximab alone requires further exploration. Elotuzumab
coronary arteries, he was treated with two doses of rituximab 1 g is an enticing agent because of the expression of SLAMF7
administered intravenously 2 weeks apart. His IgG4 level both on circulating plasmablasts and on the CD4+ cyto-
improved from 11.6 g/L to 5.84 g/L after 6 months. A repeat toxic T lymphocytes thought to drive the disease process.
computed tomography scan of the chest and abdomen showed Anti-IgE therapy with omalizumab is also a potential tar-
improvement of his coronary artery vasculitis, pulmonary nodules get for those with severe atopic disease or asthma and ele-
and lymphadenopathy and his post-treatment IgG4-RD vated IgE levels.
Responder Index activity score was 3.

Conclusions
Treatment
IgG4-RD is an important condition for hematologists to
Steroids are the first-line therapy for most patients, with recognize, both because of its common hematologic man-
an overall response rate of 93% and complete response ifestations of lymphadenopathy, eosinophilia and poly-
rate of 66% in a phase 2 trial of 44 patients with IgG4-RD clonal hypergammaglobulinemia, as well as its overlap
from Japan.77 The regimen used in this trial was pred- with other hematologic inflammatory and neoplastic dis-
nisone 0.6 mg/kg/day initially with a gradual decrease of eases. When IgG4-RD is suspected, measurement of
5 mg every 2 weeks.77 Patients with higher eosinophil serum IgG subclasses is a simple, non-invasive screening
count, lacrimal gland involvement, five or more organs test; levels >5 g/L (normal <1.35 g/L) are highly suspicious
involved, and higher IgG4-RD Responder Index scores for IgG4-RD. Regardless of serum IgG4 level, the defini-
were at higher risk of glucocorticoid failure in a Chinese tive diagnosis requires histology, preferably in an affected
cohort of 215 patients.78 Some suggest a maintenance organ other than lymph node or bone marrow, to confirm
dosage of prednisone 5 mg daily for autoimmune pancre- IgG4-RD and to exclude its many mimics. Early recogni-
atitis specifically, which, as one would expect, decreases tion and treatment with steroids, rituximab, or other
relapse rates compared to placebo.79 However, the toxicity immunosuppressive therapies, is essential to prevent com-
associated with steroids is well known, with 40% of plications such as fibrosis, peri-aortitis, and renal failure.
patients experiencing new or worsening diabetes. Blood
glucose levels should be checked regularly in all patients
receiving steroid therapy and many of our patients are Key points
also followed by a diabetes specialist. Disease-modifying
anti-rheumatic drugs are not very effective for induction • IgG4-RD is an important cause of eosinophilia, lym-
of remission but may have a role in maintenance of remis- phadenopathy and polyclonal hypergammaglobulinemia.

haematologica | 2019; 104(3) 453

 L.Y.C. Chen et al.

Hematologists should include IgG4-RD in the differential include a dense lymphoplasmacytic infiltrate, storiform
diagnosis of these abnormalities. fibrosis and obliterative phlebitis. There must be an
• Other common manifestations of IgG4-RD include increased number of IgG4+ plasma cells with an IgG4:IgG
autoimmune pancreatitis, obstructive jaundice, orbital plasma cell ratio >40%.
pseudotumor, lacrimal and salivary gland swelling, • Early recognition and diagnosis are essential because
retroperitoneal fibrosis, and tubulointerstitial nephritis. patients typically respond well to steroids or rituximab in the
• Serum protein electrophoresis and IgG subclass evalu- early stages of the disease, but fibrotic disease and late com-
ation should be performed in patients with suspected plications such as chronic pancreatitis are often irreversible.
IgG4-RD. Serum IgG4 levels are elevated in approximate-
ly 70% of cases. Mildly increased serum IgG4 (1.5-5 g/L) Acknowledgments
is a non-specific finding, but a markedly elevated level (>5 The authors thank the clinicians and pathologists of the IgG4
g/L) is 90% specific for IgG4-RD. West working group in Vancouver for their invaluable collabora-
• A firm diagnosis requires histological confirmation tion, and Dr. Erica Peterson for providing critical comments on the
based on the International Consensus Criteria which draft of this manuscript.

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