Journal of the Neurological Sciences 424 (2021) 117420

Contents lists available at ScienceDirect

Journal of the Neurological Sciences

journal homepage: www.elsevier.com/locate/jns

Review Article

The neurology of IGG4-related disease

G. Saitakis a, B.K. Chwalisz a, b, *
a
Division of Neuro-Ophthalmology, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary/Harvard Medical School, Boston, MA, USA
b
Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose of review: IgG4-related disease (IgG4-RD) is emerging as a fibro-inflammatory entity affecting multiple
Orbital inflammation organs, including manifold neurologic manifestations. This review discusses general characteristics of IgG4-RD
Hypertrophic pachymeningitis neurologic disease including epidemiology, histology, clinical picture and treatment approaches.
Hypophysitis
Recent findings: IgG4-RD is increasingly recognized as an important underlying pathophysiology in multiple
IgG4-related disease
disorders of neurologic interest, including orbital inflammation, infundibulo-hypophysitis, hypertrophic
pachymeningitis, and even in rare cases CNS parenchymal disease and cranial vascular involvement. These were
previously considered idiopathic and unrelated to any systemic disease but now known to share a common
histopathology. New knowledge regarding the pathogenesis, clinical features and epidemiology of IgG4 is
emerging, and new neurological manifestations continue to be described. Diagnostic progress includes CT-PET
imaging, the use of flow cytometry for plasmablast quantification, and the use of reverse passive latex agglu­
tination aiming to overcome the prozone phenomenon. Histopathologic confirmation of IgG4-RD remains the
gold standard method of diagnosis but new diagnostic criteria for systemic and organ-specific disease are being
proposed. Though glucorticoids remain the mainstay of therapy, relapses and incomplete recovery are frequent.
Rituximab is a promising treatment in IgG4-RD that is severe, refractory or glucocorticoid dependent. Initiation
of immunosuppression at an early stage of disease should be considered in order to avoid development of re­
fractory fibrosis.
Summary: The current review emphasizes the neurologic manifestations of IgG4-RD.

1. Introduction recently proposed by the American College of Rheumatology/European

IgG4-related disease (IgG4-RD) is an immune-mediated, chronic,
multi-organ fibro-inflammatory condition that causes tumefactive le­
sions with characteristic histopathological features (a lymphoplasma­
cytic infiltrate with a predominance of IgG4-positive plasma cells,
obliterative phlebitis, and storiform fibrosis). It has emerged as an entity
that integrates a spectrum of conditions that were not previously
recognized to be related to each other or to any systemic disease.
The potential importance of IgG4 to disease was first reported in
1961 in a case of pancreatitis with hypergammaglobulinemia [1].
However, IgG4 as a diagnostic marker was not proposed until 2003
when researchers reported increased serum levels of IgG4 in patients
with autoimmune pancreatitis [2,3]. The contemporary nomenclature
was introduced at the 2011 International IgG4-related Diseases Sym­
posium in Boston to unify these apparently heterogeneous conditions
into a definite clinical spectrum. New classification criteria have been
League Against Rheumatism.
IgG4-RD is of significant neurologic importance, as involvement of
the orbits, pituitary, peripheral nerves, meninges, central nervous sys­
tem (CNS) and blood vessels can occur. Of importance, IgG4-RD may
manifest primarily or exclusively in the head and neck region or nervous
system Although the disease is often indolent, subacute or even acute
presentations may occur, especially with vascular involvement [4]. It is
important to recognize as it is in most cases easily treatable, although
fibrotic changes in late stages of disease may be irreversible. In addition,
IgG4-RD treatment can differ substantially from that of other entities in
its differential diagnosis, which include malignancies, infections and
other inflammatory disorders such as sarcoidosis and granulomatosis
with polyangiitis.

* Corresponding author at: Department of Neurology, Massachusetts General Hospital/Harvard Medical School, 15 Parkman Street, Suite 835, Boston, MA 02114,
USA.
E-mail address: bchwalisz@mgh.harvard.edu (B.K. Chwalisz).

https://doi.org/10.1016/j.jns.2021.117420
Received 11 August 2020; Received in revised form 29 October 2020; Accepted 24 March 2021
Available online 27 March 2021
0022-510X/© 2021 Elsevier B.V. All rights reserved.
G. Saitakis and B.K. Chwalisz
2. Pathogenesis
The nomenclature of IgG4-RD notwithstanding, IgG4 subclass anti­
bodies seem to play a less important role in the pathogenesis. In fact,
IgG4 antibodies may even have anti-inflammatory properties. More
specifically, a process termed “Fab-arm exchange” results from the un­
stable disulfide bonds between the heavy chains of the IgG4 molecule,
leading to dissociation of the two halves of an IgG4 antibody from each
other, and recombination to form novel IgG4 molecules where the two
Fab arms have specificity for two unrelated antigens, and consequently
bind complement poorly [5]. This suggests that IgG4 antibodies may
actually have an immune-dampening function, and function as an “an­
tigen sink” in states of chronic inflammation [6]. For instance, high
levels of IgG4 are seen in beekeepers, successfully desensitized atopic
patients, parasitic disease, and other situations where as a rule IgG4-RD
does not develop.
In this context, it is important to highlight the difference between
IgG4-RD (a fibro-inflammatory condition without defined antigen or
antibody) and IgG4-antibody-mediated disorders. Examples of the latter
include neurologic conditions such as myasthenia associated with MuSK
(muscle specific kinase) antibodies, chronic inflammatory demyelin­
ating polyneuropathy associated NF155 antibodies, autoimmune en­
cephalitis associated with LGI1 (leucine-rich glioma-inactivated 1)
antibodies, and non-neurologic diseases such as certain forms of
pemphigus and glomerulonephritis, among others, where antibodies of
the IgG4 subclass are believed to play a pathogenic role [Koneczny I. A
New Classification System for IgG4 Autoantibodies. Front Immunol.
2018 Feb 12;9:97. doi: https://doi.org/10.3389/fimmu.2018.00097.
PMID: 29483905; PMCID: PMC5816565.].
Recently, CD4+SLAMF7+ cytotoxic T lymphocytes are emerging as
playing a central role into the pathogenesis of IgG4RD disease. These
CD4+ T cells are capable of producing profibrotic cytokines such as
interleukin-1, transforming growth factor-beta and interferon-gamma,
as well as cytolytic molecules such as granzyme A and B and perforin
[7]. These cytotoxic T lymphocytes are likely sustained by continuous
antigen presentation by B cells and plasmablasts. The role of B cells is
supported by the high efficacy of treatment with the monoclonal anti­
body rituximab, as discussed further below Potential autoantigens
involving in the pathogenesis of IgG4 include the annexin A11 and
galactin [4,8,9]. In a compelling model of the pathophysiology,
continuous antigen presentation by B cells and plasmablasts to CD4+
cytotoxic lymphocytes leads to elaboration of tissue-injuring and fibro­
genic products, which then cause tumefactive lesions and organ
dysfunction [10].
3. Epidemiology and general clinical features
IgG4-related disease (IgG4-RD) has an estimated prevalence of 4,6
/100.000 but this is a likely underestimate given the recent description
of this multi-organ immune-mediated condition [11]. IgG4-RD has a
worldwide distribution, affecting patients of all racial backgrounds,
though historically a large majority of reported patients are Japanese
[12]. The disease mainly affects middle-aged to elderly males, different
to the well-established female predominance of most other autoimmune
diseases, and typically manifests in the fifth, sixth, and seventh decades
of life [11,13]. The male preponderance is estimated to be 3:1 [13] and
is more pronounced in older patients [13], and in fact, a review of 25
pediatric cases demonstrated a mild female preponderance [14]. In
addition, female and male patients differ regarding their demographic
and clinical characteristics. Women manifest the disease earlier, and are
being diagnosed at a younger age with a longer interval between onset
and diagnosis compared to male patients. Moreover, female patients are
more likely to present with superficial organ involvement in contrast to
males who tend to present with internal organ involvement [14]. A
number of studies had suggested that female patients have a predispo­
sition for head and neck involvement, and more recent studies report
2
Journal of the Neurological Sciences 424 (2021) 117420
that females tend to have disease exclusively in the head and neck rather
than systemic disease with head and neck manifestations. Overall,
however, both IgG4-RD orbitopathy and IgG4-RD involving the head
and neck area appear to affect women and men in an equal distribution
[15]. A similar predilection for disease limited to the aforementioned
regions has been shown in patients of Asian descent [16]. In children,
IgG4-RD most commonly involves the orbit, followed by the salivary
gland, the pancreas, and the lymph nodes [14].
Major presentations of IgG4-RD include type 1 autoimmune
pancreatitis, sclerosing cholangitis, chronic sclerosing sialadenitis (fa­
voring the submandibular over the parotid glands), dacryoadenitis,
orbital disease, lymphadenopathy, kidney disease and retroperitoneal
fibrosis [17,18]. It has a predilection for glandular tissue [19]. However,
the disease can affect nearly any organ (with the notable exception of
synovial tissue), including meninges, aorta, prostate, breast, thyroid
gland, pleuropericardium, and skin tissue. At least half of IgG4-RD pa­
tients present with simultaneous disease of multiple organs. A meta­
chronous pattern may occur, with sequential involvement of different
organs and accumulating burden of disease in untreated patients.
Symptoms result either from the mass effect of the enlarged organs (e.g.
tumefactive lesions of the lacrimal and salivary glands, pancreas, kid­
ney, pituitary gland or meninges), or from inflammation-induced organ
injury. IgG4-RD may also be diagnosed incidentally during imaging
[12,20].
The disease typically presents in a subacute and indolent fashion.
Symptoms and signs may precede the diagnosis for months or even
years, and intervals of relapse and (rarely) spontaneous remission can
occur. The severity of the clinical symptoms varies among individuals.
Typical constitutional manifestations include weight loss (approxi­
mately 9–23 kg) over months (likely secondary to exocrine pancreatic
failure and a chronic inflammatory state), fatigue, arthralgia (typically
subtle and insidious without prominent inflammatory arthritis), and
enthesopathy (inflammation at the site of tendon insertion into a bone).
Fever is uncommon, except for cases with thoracic involvement and in
general fulminant inflammatory courses are atypical [12]. Patients with
hypertrophic meningitis are less likely to have generalized systemic
features, but those with orbital disease often have multi-organ
involvement [21].
Exocrine gland failure with sicca symptomatology is common (but
milder than in Sjögren’s syndrome), as are endocrine defects such as
diabetes mellitus or insipidus in the case of pancreas or pituitary gland
involvement, respectively, and hypothyroidism from Riedel’s thyroid­
itis. Moreover, an allergic and atopic history is very common in IgG4-RD
patients: allergic rhinitis, nasal polyps, chronic sinusitis, nasal obstruc­
tion, rhinorrhea, and bronchial asthma are present in about 40% of
patients [20,21]. In addition, given the capacity of IgG4-RD to affect
nearly every part of the body, an array of symptoms is possible,
including abdominal pain (due to intestinal obstruction, mass effect, or
even aortic dissection), or lower back and groin pain (suggestive of
retroperitoneal fibrosis), diarrhea, pruritus, dysphagia, thirst, cough,
shortness of breath, dyspnea, proptosis, vision changes, diplopia,
headaches, neurologic deficits, otalgia and progressive hearing loss
[18,19,22,23].
Recently, a multispecialty group of 86 physicians developed and
validated an international set of classification criteria for IgG4-RD, the
2019 American College of Rheumatology/ European League Against
Rheumatism classification criteria for IgG4 -related disease [24,25].
This involves a three-step classification process. First, it must be
demonstrated that a potential IgG4 -RD case has involvement of at least
one of 11 possible organs in a manner consistent with IgG4-RD. Second,
exclusion criteria consisting of a total of 32 clinical, serological, radio­
logical and pathological items must be applied; the presence of any of
these criteria eliminates the patient from IgG4 -RD classification. If a
case meets entry criteria and does not meet any exclusion criteria, in a
third step eight weighted inclusion criteria domains are assessed, con­
sisting of clinical findings, serological results, radiological assessments
G. Saitakis and B.K. Chwalisz
and pathological interpretations, and a scoring system is used. This
scoring system was validated and reported to have a sensitivity of 82%
and specificity of 97.8% [24,25]. However, it needs to be emphasized
that these are essentially research criteria, and cannot be relied on
exclusively for clinical purposes.
4. Assessment
Diagnosis of IgG4-RD requires high clinical suspicion, and an un­
derstanding of the whole spectrum of potential organ involvement.
Given the potential multiorgan involvement, a thorough review of sys­
tems should be performed. History of atopy should be inquired about. A
physical examination targeted at common sites of manifestations is
important. In the ocular examination, proptosis, ptosis, periorbital
swelling, and especially lacrimal gland enlargement [Fig. 1] may be key
clinical findings; the size of the lacrimal gland is best assessed by
elevation of the lid. Careful examination of the neck is important to
search for the presence of a painless lump or mass at the major salivary
glands and thyroid glands. Submandibular gland involvement in
particular is a signature sign, typically presenting as a firm painless
mass. Lymphadenopathy is present in about 25% of cases, and the nodes
tend to be mobile, nontender and vary in size from 1 to 3 cm [19].
Moreover, the physician should search for organomegaly, icterus, signs
of lung or pleural involvement, and changes in the hue or texture of the
stool as clues to pancreatic or biliary disease [26]. IgG4-RD skin mani­
festations include ulcers [27], alopecia [28], and erythematous nodules
and papules, commonly in the head and the neck. Importantly, skin
involvement may be a clue to underlying internal disease.
5. Laboratory evaluation
IgG4 is a subclass of IgG representing less than 5% of the total IgG in
healthy adults. In general, 70% of IgG4-RD patients demonstrate an
increased serum lgG4 level. Serum lgG4 concentrations are considered a
useful biomarker in screening, and demonstrate a correlation with the
number of affected organs. Although mildly elevated IgG4 levels are
insufficient for diagnosing IgG4-related disease, markedly elevated
serum IgG4 (>5 g/L) is considered 90% specific for the disease [29].
More specifically, a serum ratio of IgG4 to IgG1 higher than 0.24, and an
even a lower threshold of 0.114 in patients not exposed to glucocorti­
coids, enhances diagnostic specificity [30,31]. However, levels of IgG4
are unreliable for evaluating efficacy of the treatment as increased levels
can be seen in up to 70% of patients after withdrawal of glucocorticoids
[4,29]. In addition, serum levels can differ widely based on ethnicity and
degree of involvement of organs. According to the recent 2019 classi­
fication IgG4-RD criteria, serum IgG4 concentrations can provide an
important clue to the diagnosis and some guidance in the longitudinal
assessment of disease activity; however, the presence of an elevated
serum IgG4 level is no longer considered essential to the diagnosis of
IgG4 -RD. Notably, certain organ systems and anatomic regions (e.g., the
retroperitoneum or meninges) are less likely to be associated with a
serum IgG4 elevation than others [24,25].
The traditional use of immunonephelometry for detection of serum
Fig. 1. Lacrimal gland involvement (A: patient photo, B: MRI coronal T1 post contrast with fat suppression).
3
Journal of the Neurological Sciences 424 (2021) 117420
IgG4 levels has the drawback of underestimating the levels in patients
with extremely high lgG4 concentrations due to the prozone phenome­
non [32]. In addition, IgG4 can interfere with the nephelometric mea­
surements of IgG1 and IgG2 [4]. In an effort to overcome these
limitations, serial dilution of the samples may need to be done. In
addition, a novel IgG4 assay has been developed, which is based on the
principle of reverse passive latex agglutination that can mitigate
occurrence of the prozone phenomenon [34]. Mass spectrometry is an
alternative to traditional nephelometry [35]. Recently, flow cytometric
detection of plasmablasts (CD19 + CD20-CD27 + CD38+) has been
validated as a more sensitive tool for diagnosing IgG4-RD in untreated
patients with a sensitivity of 95% and specificity of 82% [33] but is
unfortunately not yet widely available.
A wide array of additional laboratory tests might be abnormal. A
mild to moderate eosinophilia is present in up to 40% of IgG4-RD pa­
tients [4]. Increased serum levels of IgE, IgG1, IgG2, lgA, and IgM may
be seen. Low complement factors levels (C3/C4, CH50) suggest IgG4-
related tubulointerstitial nephritis. Nonspecific autoantibodies
including antinuclear antibody and rheumatoid factor can be weakly
increased [4] but more specific markers of connective tissue disease such
as Ro/La antibodies of Sjögren’s syndrome should be absent. C-reactive
protein (CRP) can be moderately increased in up to 25% of patients
(<20 mg/dl). In contrast, Erythrocyte Sedimentation Rate (ESR) in­
creases are common, secondary to hypergammaglobulinemia in un­
treated cases, and a pattern of acute phase reactants demonstrating high
ESR and low CRP has been described [12]. Other laboratory tests that
may be abnormal include lipase, amylase, glucose, hemoglobin A1c,
thyroid functions, pituitary hormones, electrolytes, liver enzymes,
creatinine, glomerular filtration rate, urine albumin/creatinine ratio,
blood counts bilirubin, stool elastase. Other biological markers include
interleukin 6, serum soluble IL-2 receptor, CC-chemokine ligand 18,
circulating activated follicular helper T cells [12,36,37].
6. Radiology
Computed tomography (CT) and Magnetic resonance imaging (MRI)
findings can support the diagnosis of IgG4-RD. Both modalities can
identify the tumor-like enlargement of the affected tissue. Characteris­
tically, a sausage-shaped pancreas with delayed enhancement and a
capsule-like low density rim suggests the diagnosis. Furthermore, a
constellation of lacrimal, submandibular and parotid gland enlarge­
ment, frequently accompanied by lymphadenopathy, implies IgG4-RD
provided that lymphoma can be excluded. Infraorbital nerve enlarge­
ment on MRI is highly indicative of ocular IgG4-RD [38,39]. In addition,
imaging of the chest, pelvis and abdomen can be useful either for further
assessment of the extent of disease. 18F-fluorodeoxyglucose-positron
emission tomography/computed tomography can also be used to
assess disease activity and extent [40,41].
7. Histopathology
IgG4-RD is generally a clinico-pathologic diagnosis. Although in
some cases the diagnosis can be strongly suggested and even presumed
G. Saitakis and B.K. Chwalisz
based on clinical and radiologic data, histopathological confirmation is
considered the gold standard for establishing a diagnosis of IgG4-RD.
Grossly, organs are enlarged and hardened. The disease has three
major histological features: 1) a dense, polyclonal lymphoplasmacytic
infiltrate enriched with IgG4+ plasma cells (as demonstrated by immu­
nohistochemistry); 2) fibrosis, which at least focally should be arranged
in a “storiform” pattern (a term derived from the Latin “storea”, meaning
a woven mat), i.e., a radial, basket-weave arrangement of collagen fibers
in the involved tissues; 3) obliterative phlebitis, i.e., destruction of
venous channels by an inflammatory lymphoplasmacytic infiltrate.
Elastin stains can be helpful in recognizing completely obliterated ves­
sels [4].
Some important details must be recognized. Firstly, the number of
IgG4+ plasma cells per high-power field (hpf) considered diagnostic
varies according to tissue site, from >10/hpf in meninges to >100/hpf
in skin. However, in any affected site the ratio of IgG4+/IgG+ plasma
cells should be >40%. Secondly, it should be noted that the aforemen­
tioned pattern of fibrosis might have a patchy distribution, a diagnostic
pitfall with small biopsies. Nevertheless, the extent of fibrosis may
predict the extent of IgG4-RD response to immunosuppressive treatment
[4].
Additional less specific histopathological features include phlebitis
without obliteration of the lumen, non-storiform fibrosis, and increased
number of eosinophils. In general, the disease features common histo­
logical characteristics in the majority of the multitude of organs that
may be involved, however, storiform fibrosis and obliterative phlebitis
may be absent in bone marrow and lymph nodes; it also not typically
seen in ocular adnexal disease or hypertrophic pachymeningitis [33,42].
Organs with clinical or radiological proof of involvement are most likely
to yield a histological diagnosis. In case of affected organs that are not
accessible for biopsy, minor salivary gland biopsy can be considered
even without clinical evidence of involvement. Since there is frequently
a long delay to diagnosis, patients may have undergone previous bi­
opsies, and a review of archival specimens from previous biopsies can be
very helpful for arriving at the correct diagnosis [4].
An equally important role of biopsy is in differentiating IgG4-RD
from other entities with similar manifestations. Notably, although
increased numbers of IgG4+ plasma cells are seen in all tissues affected
by IgG4-RD, this by itself is not considered a specific finding as many
chronic inflammatory conditions (vasculitis, lymphoma, inflammatory
bowel disease) may demonstrate a similar increase in IgG4 plasma cells;
thus the IgG4-RD diagnosis still rests on the presence of the combination
of histopathologic features of storiform fibrosis, obliterative phlebitis,
and the absence of incompatible features [43,44]. The histopathology
needs to be specifically surveyed for features that would be incompatible
with IgG4-RD and might suggest an alternative diagnosis. The 2019
American College of Rheumatology/European League Against Rheu­
matism Classification Criteria for IgG4-Related Disease defined the
following pathological exclusion criteria: cellular infiltrates suggesting
malignancy, markers consistent with inflammatory myofibroblastic
tumor, prominent neutrophilic inflammation, necrotizing vasculitis,
prominent necrosis, primarily granulomatous inflammation, xanthog­
ranulomatous changes, and pathologic features of macrophage/histio­
cytic disorder [24,25]. Infection and malignancy always need to be
excluded, and besides the routine stains and cultures, stains for acid fast
bacteria and fungi are necessary. Flow cytometry studies and assess­
ments for light chain restriction or heavy chain rearrangement should be
employed to rule out lymphoma [4,45].
8. IgG4-related orbitopathy
IgG4-RD orbitopathy is a recurrent, progressive and fairly common
manifestation of IgG4-RD (23% in one American series) [15,46]. It
represents the most common site of head and neck region involvement
[47]. Most frequently affected is the lacrimal gland (up to 90%) [46],
with potential for involvement of the periorbital soft tissue, extraocular
4
Journal of the Neurological Sciences 424 (2021) 117420
muscles, eyelids, orbital fat, trigeminal nerve branches such as espe­
cially the infraorbital nerve [38,48], sclera, uvea, tarsus [49], con­
junctiva [47], and nasolacrimal duct [50]. Bilateral involvement can be
seen in 70% to 90% of IgG4-RD cases and might be asymmetric [46].
Notably, Mikulicz disease, a historical term referring to the combination
of lacrimal and salivary gland fibrosis that was previously attributed to
Sjögren’s syndrome is now recognized to be a manifestation of IgG4-RD.
Common clinical manifestations of IgG4-RD orbitopathy include a
chronic, progressive, painless swelling of the affected structures with
subsequent exophthalmos or ptosis, and eye movement deficits [40]
secondary to infiltration and inflammation of the extraocular muscles
(EOM) [Fig. 2], fat and connective tissue. Isolated involvement of the
EOMs is unusual and muscles are affected more commonly in the setting
of lacrimal gland disease [50]. Although there is a predilection for
lateral rectus involvement (contrasting with preferential involvement of
inferior and medial recti in thyroid eye disease), any of the extraocular
muscles can be affected with potential for muscle enlargement and re­
striction of motility resulting in diplopia.
Optic neuropathy is a potential risk in IgG4-RD orbitopathy, and can
be caused by involvement of the optic nerve and optic nerve sheath
directly, or by compression by the enlarged EOMs, infraorbital nerve or
orbital soft tissue fibrosis [46,47] [Fig. 3]. Clinical findings include
decreased visual acuity, visual field defects, dyschromatopsia and a
relative afferent pupillary defect. Cases of optic nerve compression
causing blindness have been reported [51]. The optic disc may appear
edematous or normal initially, and disc pallor can ensue if untreated.
The presentation may mimic an optic nerve sheath meningioma [52]. In
addition, vision may be affected by mass effect distorting the globe
resulting in chorioretinal folds [38,46,51].
The course of lgG4-RD orbitopathy may be prolonged, in some cases
with symptomatology for years. Bilateral involvement, longer duration
of symptoms and higher IgG4 and sIL-2R levels constitute risk factors for
extraophthalmic involvement in patients with IgG4-RD orbitopathy
[47,53]. In addition, optic neuropathy is more commonly accompanied
by extraophthalmic disease.
The diagnosis of IgG4-RD orbitopathy can be challenging given that
the clinical course and symptoms of the disease can mimic those of
lymphoma and other immune-mediated diseases such as thyroid eye
disease, sarcoidosis, granulomatosis with polyangiitis, and idiopathic
inflammatory syndromes such as orbital pseudotumor, orbital myositis,
and optic neuritis and perineuritis. Compared to IgG4-RD orbitopathy,
idiopathic orbital inflammation more frequently presents acutely with
pain, exophthalmos, eye motility restrictions, injection and a longer
recurrence-free interval [46].
Fig. 2. Massive Enlargement of lateral rectus (1), medial rectus (2), inferior
rectus (3), MRI orbit T1 post contrast coronal with fat suppression.
G. Saitakis and B.K. Chwalisz
Fig. 3. IgG4RD involving left posterior orbit and optic nerve (1), cavernous sinus (2) and adjacent meninges (3) (MRI T1 post contrast with fat suppression; A: axial,
B: coronal).
The differential diagnosis of lgG4-RD orbitopathy also includes
infection, primary orbital tumors, lymphoma, metastases, Langerhans
cell histiocytosis, Erdheim-Chester disease and the adult onset asthma
and periocular xanthogranuloma (AAPOX) [46].
A positive association between IgG4-RD and lymphoproliferative
malignancies has been suggested and a case of bilateral IgG4-RD orbit­
opathy evolving into mucosa associated lymphoid tissue (MALT) lym­
phoma has been reported [53], potentially resulting from the
background of IgG4-related chronic inflammation. In addition, a
remarkable overlap between ocular IgG4 MALT lymphoma and IgG4-
related ophthalmic disease in serology and histology has been demon­
strated [53,54]. However, malignant transformation to MALT lym­
phoma is probably extremely rare.
Radiological findings of lgG4-RD orbitopathy may show enlargement
of the orbital contents, extraocular muscles, cranial nerves, and lacrimal
glands (as well as salivary glands, pituitary, and lymph nodes). Localized
nodules or masses can be seen, characterized by homogenous internal
architecture, well-defined margins, and contrast enhancement. It is
uncommon to see destruction of adjacent orbital bone, but bony
involvement has been seen particularly in patients with sinus involve­
ment [47,57]. In addition, adjacent compartments must be surveyed
systematically, as IgG4-RD orbitopathy may be accompanied by
cavernous sinus or pituitary involvement, pachymeningitis, or mass le­
sions of the pterygopalatine fossa infiltrating along the trigeminal nerve
[55,56] [FIG. 3]. CT and MR imaging findings of IgG4-related disease
are usually nonspecific. Regarding CT, affected structures demonstrate
enlargement or decreased attenuation and a homogeneous post-contrast
enhancement. MR typically shows T1 isointensity, and T2 low signal
owing to the increased cellularity and amount of fibrosis, while contrast
enhances the lesions homogeneously [58,59].
In IgG4-RD orbital myositis there is typically concomitant swelling
both of the muscle bellies and tendons, in contrast to thyroid eye disease
that affects mainly the muscle bellies. Another characteristic radiologic
finding is the enhancement of optic nerve sheath which commonly co­
exists with dacryoadenitis and infraorbital nerve enlargement [47]. The
significance of infraorbital nerve enlargement has been pointed out. This
is best appreciated in coronal view when the infraorbital nerve is thicker
than the optic nerve [Fig. 4]. Patients with infraorbital nerve involve­
ment often have few or no sensory symptoms, probably because the
involvement is primarily of the epineurium [60,61].
9. Hypertrophic pachymeningitis and central nervous system
parenchymal disease
Meningeal involvement of IgG4-RD was first reported in 2009, and
although it is not a common presentation of IgG4-RD overall, with a
prevalence slightly above 2% of overall clinical manifestations in IgG4-
RD [62,63], it accounts for a significant portion of the cases previously
described as idiopathic hypertrophic cranial pachymeningitis. IgG4-RD
Hypertrophic Pachymeningitis (HP) is infrequently associated with
systemic disease, being isolated in more than half of the cases [64–66].
5
Journal of the Neurological Sciences 424 (2021) 117420
Fig. 4. Massive enlargement of inferior rectus (1) and adjacent orbit, infraor­
bital nerve (2), superior maxillary sinus (3); MRI T1 coronal post contrast
without fat suppression.
Regarding the pathogenesis of IgG4-RD HP, it has been suggested that a
specific response against an unknown antigen may play an important
role [65,66].
IgG4-RD HP disproportionately affects men during the fifth and sixth
decades. Clinical symptoms may include headache, seizures or focal
deficits, compression or involvement of cranial nerves resulting in
neuropathies, dural venous sinus and vessel occlusions [63]. Neuro­
logical involvement in one series occurred with the following fre­
quencies: cranial nerve palsies (33%), vision problems (21%), motor
weakness (15%), limb numbness (12%), seizures (6%), cognitive decline
(3%) and gait instability [67]. Synchronous pachymeningitis of the
brain and spinal cord occurs but is uncommon. Cord compression is
possible. IgG4-RD HP manifestations are not specific, and are generally
indistinguishable from other potential causes of HP. Consequently,
clinical presentations beyond the meninges may be helpful in suggesting
the diagnosis.
MRI is the preferred imaging modality for assessing HP, although CT
scan can complement MRI by demonstrating bony involvement. MRI
may show mass-like thickening or diffuse and smooth, homogenous,
linear involvement of the dura over the cerebral hemispheres and/or the
spinal cord [Fig. 5]. On T1- and T2-weighted sequences the signal is low
to intermediate and the lesions show enhancement after the adminis­
tration of gadolinium [68]. When bulging masses connected to the dura
are present, a meningioma should be considered in the differential [67].
A high-quality MRI of the skull base also allows delineation of the
involvement of contiguous areas, including the paranasal sinuses, pitu­
itary gland, cavernous sinus or orbit.
True CNS involvement, i.e., pachymeningoencephalitis is rare in
IgG4-RD, but has been described with a presentation with motor
weakness and radiological features of T2 hyperintensity, T1 hypo­
intensity and contrast enhancement [69,70]. In addition, exceptional
cases of inflammatory pseudotumor-like presentation with direct brain
involvement have been reported [71].
G. Saitakis and B.K. Chwalisz
Fig. 5. IgG4RD Hypertrophic pachymeningitis (1) with involvement of
ethmoid air cells (2) (MRI T1 post contrast).
Cerebrospinal fluid (CSF) analysis shows normal glucose levels,
protein levels that are normal or slightly elevated in 50% of cases, and
commonly pleocytosis (lymphocytic, monocytic) with a total nucleated
cell count in the range of 6–378 [72]. The CSF profile is not specific in
IgG4-RD HP but CSF studies may help exclude other possible pathologies
including central nervous system (CNS) infections and malignancy.
There can be intrathecal synthesis of IgG with oligoclonal bands. In
addition, patients with IgG4-RD HP may have increased CSF IgG4 levels
and IgG4 serum:CSF index that may reflect disease activity [73]. IgG4-
RD HP is often unassociated with elevated IgG4 plasma levels, inflam­
matory markers, complement consumption and eosinophilia. Conse­
quently, when these serologic markers are significantly abnormal in
patients with IgG4-RD HP, involvement of organs beyond the CNS
should be suspected [74,75].
Hypertrophic meningeal involvement can occur in a wide array of
diseases including lymphoma, other malignant conditions, infectious
diseases (such as syphilis, tuberculosis, Lyme disease), immune-
mediated and vasculitic conditions, histiocytoses, and might be also
idiopathic. Immunologic diseases to consider in the differential include
sarcoidosis, rheumatoid arthritis, giant cell arteritis, Behcet’s disease
and granulomatosis with polyangiitis (GPA) [75]. GPA notably can also
have increased plasma IgG4 levels, potentially confounding the diag­
nosis [77]. In addition, intracranial hypotension and reactive change to
tumor in surrounding bone may have a similar radiologic appearance.
Meningeal biopsy is considered the gold standard for establishing the
diagnosis of IgG4-RD-HP disease, which has signature histological
findings of lymphoplasmacytic infiltration with a large percentage of
IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis
A threshold of 10 IgG4 + plasma cells/ high-power field, and an IgG4+/
IgG+ plasma cell ratio > 40%, are recognized as sufficient for the
diagnosis of IgG4-RD of the meninges [71]. Just as importantly,
meningeal biopsy can rule out alternative diagnoses. In particular, the
presence of necrosis, granulomas, infectious elements, histiocytic pre­
dominance or clonal proliferation of lymphocytes are features that are
not seen in IgG4-RD HP, and would point to an alternative diagnosis.
10. Lesions of the pituitary gland and stalk (infundibulo-
hypophysitis)
IgG4-related Indundibulo-hypophysitis (IHP) was first reported in
2004 in a 66-year-old woman with multiple pseudotumors in the sali­
vary glands, pancreas, and retroperitoneum. Multiple other reports have
since emerged of pituitary involvement in multisystemic disease
[78,79]. Isolated cases of IgG4-related hypophysitis on biopsy with no
other systemic lesions have also been reported [79,80]. Although it was
6
Journal of the Neurological Sciences 424 (2021) 117420
initially considered a rare entity, studies have demonstrated that its
prevalence could be as high as 41% in histologically confirmed hypo­
physitis cases [81]. IgG4-RD IHP shows a male predominance of 2:1 with
a mean age of onset at 64 years. However, another peak in young women
has also been demonstrated [78,81]. More than half of the reported
cases come from Japan, suggesting that ethnic origin is a potential
contributing factor [82]. The pathogenesis of IgG4-RD IHP has not yet
been clarified and potential interpretations include autoimmunity and/
or an abnormal tolerance to unspecified allergens and infectious agents
[83].
Patients with IgG-IHP usually manifest symptoms from headache,
mass effect on surrounding structures, hyperprolactinemia from a stalk
effect and/or hypopituitarism [81]. A thickened pituitary stalk and
gland can affect the optic pathways (optic nerve or chiasm) leading to
decreased visual acuity, diminished color resolution and visual field
defects, most frequently bitemporal hemianopia [80]. In addition, visual
disfunction can also be caused by direct intrachiasmatic involvement.
Other manifestations include vomiting, nausea, weight loss, fever,
appetite loss, polyuria, decreased libido, diplopia and general malaise.
In terms of pituitary function, the disease may be characterized by
various degrees of anterior pituitary hormone deficiencies with or
without posterior involvement (diabetes insipidus), with potential for
temporary or permanent disfunction [81]. Hormonal aberrations can
include any combination of isolated hypogonadism, individual or com­
bined anterior pituitary hormone deficiency, and hyperprolactinemia.
Diabetes insipidus is common and may be overt or masked. Regarding
the sequence of pituitary deficiencies in IgG4-IHP patients, a recent
study suggested that the most common endocrine manifestation was
antidiuretic hormone deficiency (80%), followed by follicle stimulating
hormone/luteinizing hormone (50%), adrenocorticotropic hormone
(30%), thyroid-stimulating hormone (20%), and growth hormone/
insulin-like growth factor1 (10%) axis deficiency [84]. Symptoms of
hypopituitarism can be nonspecific but are important to identify, as the
endocrine disturbances can lead to major morbidity, and in the case of
adrenal insufficiency, even mortality [85]. The workup should thus
include serological evaluation for electrolytes and hormones in the
hypothalamus-pituitary axis.
MRI shows diffuse thickening of the pituitary stalk with symmetri­
cally enlarged pituitary and homogeneous contrast enhancement of the
gland with gadolinium. Loss of the normal bright spot of the neurohy­
pophysis in pre-contrast T1-weighted images can be seen, and this
finding may be correlated with central diabetes insipidus [86].
Furthermore, imaging can demonstrate additional involvement of the
adjacent cavernous sinus, sphenoid sinus, trigeminal nerve branches,
orbit and meninges.
An IgG4-RD IHP diagnosis can be suggested based on a combination
of clinical, radiological, and serological evidence. Where necessary, pi­
tuitary biopsy may provide a definitive histological diagnosis. Leporati
in 2011 introduced the following criteria, which potentially enable
diagnosis without pituitary biopsy: 1) the presence of a mononuclear cell
infiltration of the pituitary gland that is rich in lymphocytes and plasma
cells, with more than ten IgG4-positive cells per high-power field or
IgG4-positive/IgG-positive cells > 40% on pituitary histopathology, 2)
the presence of a sellar mass and/or thickened pituitary stalk on MRI, 3)
a biopsy proving the involvement in other organs, 4) an increased serum
IgG4 level (>140 mg/dl), 5) a prompt shrinkage of the pituitary mass
and symptom improvement with steroids; diagnosis can be made when
criteria (1), or (2) and (3), or (1), (4), and (5) are fulfilled [87]. Another
research group suggested similar criteria including a lower cut-off level
for serum IgG4 (135 mg/dL) and also immunohistochemistry evidence
(IgG4+/IgG+ plasma cell ratio of more than 40%) [80].
Typically, pituitary masses in the disease are characterized by a
dense lymphoplasmacytic infiltrate among residual nests of adenohy­
pophyseal cells and fibrosis in histopathological analysis. Histologically,
IgG4-RD IHP is remarkably similar to lymphocytic hypophysitis (lym­
phocytic infiltrations of varying density, predominantly of the T cell
G. Saitakis and B.K. Chwalisz Journal of the Neurological Sciences 424 (2021) 117420

type), with the additional feature of a massive IgG4-positive plasmacyte stenosis or aneurysm rupture. In general, IgG4-related vasculitis most
infiltration, polymorphs and eosinophils and areas of fibrosis (“stori­ frequently presents as aortitis with aneurysm formation, followed by
form” pattern) [87,89]. It is worth noting that the diagnostic signifi­ periaortitis with relative sparing of the aortic wall [93,94]. The affected
cance of the number of IgG4-positive infiltrating cells remain vessels show involvement of the adventitia, in the form of notable
controversial, with 50 or more IgG4-positive plasma cells in diffuse in­ adventitial fibrous thickening with infiltration of inflammatory cells.
filtrates being considered highly specific [86]. In regard to serum IgG4, Cervical and cerebral vessels involvement is either infrequent or
as is the case in the diagnosis of IgG4-RD generally, changes of the levels possibly subclinical. A case of diffuse intracranial dilating vasculopathy
are not a prerequisite for the diagnosis of IgG4-RD IHP. A particular with secondary subarachnoid hemorrhage has been described [95]. In
challenge arises in patients already on treatment with glucocorticoids, addition, in one patient with symptomatology compatible with a tem­
which may mask the manifestation of central adrenal insufficiency poral arteritis syndrome, biopsy of the affected vessel revealed IgG4-RD
associated with hypophysitis and normalize serum IgG4 levels, making [96]. Moreover, vertebral basilar system dolichoectasia with features of
clinical diagnosis of hypophysitis difficult [90]. marked infiltration of IgG4-containing plasma cells has been reported
IgG4-RD IHP must be differentiated from a spectrum of diseases that [97]. A patient with IG4-RD manifestations of retroperitoneal fibrosis,
can manifest as tumorous pituitary lesions including inflammatory en­ iliac vessel disease and aortitis, also developed carotid and intracerebral
tities, granulomatous processes infections, adenomas, metastases, and inflammatory aneurysms [34]. Another patient, a 67-year-old man with
Rathke’s cleft cysts. a history of IgG4-RD manifested as autoimmune pancreatitis, pericar­
In patients with IgG4-RD IHP, treatment with glucocorticoids should ditis, asthma, peripheral eosinophilia and bilateral dacryoadenitis pre­
be initiated promptly to reverse symptoms and minimize the risk of sented with recurrent episodes of right-sided amaurosis fugax; imaging
fibrosis, which can compromise return of pituitary function. In case of revealed severe stenosis of the right common carotid artery and the
rapidly progressive symptoms initial surgical decompression may be pathologic specimen obtained after endarterectomy was indicative of
needed [91,92]. focal involvement by IgG4-RD [93]. Furthermore, in a 67-year-old man
Differential diagnosis of IgG4-RD in the head and neck with speech impairment and right-hand clumsiness, imaging demon­
Focal disorders Systemic diseases
strated acute ischemia in the left frontal lobe and a tight stenosis of left
internal carotid artery from carotid artery dissection and pseudoaneur­
Orbital Orbital pseudotumor IgG4-related disease
ysm; histology was compatible with IgG4-RD [98].
Inflammation Orbital myositis Sarcoidosis
Posterior scleritis ANCA-associated
Dacryoadenitis vasculitis 12. Peripheral nerve disease: radiculopathy and perineuritis
Optic perineuritis Thyroid eye disease
Periocular Xanthogranuloma Langerhans cell
IgG4-RD perineural disease refers to a tumefactive inflammation of
Primary orbital tumors Histiocytosis
Erdheim-Chester peripheral nerves or nerve roots, with a predilection for the epineurium,
disease in some cases with a massive lymphoplasmacytic infiltrate [99]. Peri­
Infection neural disease affects mainly the orbital or paravertebral regions [99],
Lymphoma and is often recognized incidentally during radiographic evaluation of
Metastases
Cavernous sinus Tolosa-Hunt syndrome IgG4-related disease
IgG4 involvement in other organs. Frequently affected nerves include
Isolated cranial neuritis Sarcoidosis the infra- or supraorbital branches of the trigeminal nerve or the cervical
ANCA-associated and lumbosacral spinal nerves. Peripheral nerve lesions in the peri­
vasculitis orbital area are generally associated with dacryoadenitis or other fea­
Infection
tures of IgG4-RD orbitopathy. The finding of infraorbital nerve
Malignancy
Sellar area Primary hypophysitis IgG4-related disease enlargement in particular serves as a particularly valuable clue to this
Iatrogenic hypophysitis Sarcoidosis diagnosis [38]; the nerve can be considered definitely enlarged when its
Adenoma Langerhans cell diameter is greater than that of the optic nerve in a coronal image of the
Rathke’s cleft cysts histiocytosis orbit [FIG. 4]. Of particular importance, an enlarged infraorbital nerve
Erdheim-Chester
has the potential to compress optic nerve leading to optic neuropathy.
disease
Infection Sensory nerves appear to be involved preferentially and are often
Malignancy associated with little symptomatology, however, cases with facial par­
Inflammation esthesiae have been described [38]. IgG4-related perineural disease
Pachymeninges Idiopathic hypertrophic IgG4-related disease
probably almost never occurs as an isolated phenomenon unassociated
pachymeningitis Sarcoidosis
Giant cell arteritis
with other organ lesions, although we recently observed a case of
ANCA-associated apparently isolated tumorous enlargement of a hypoglossal nerve
vasculitis associated with raised IgG4 levels that resolved with steroids and rit­
Rheumatoid arthritis uximab but could not be biopsied without risking permanent morbidity.
Sjögren’s syndrome
Imaging of IgG4-related perineural disease demonstrates circumscribed,
Behcet’s disease
Infection nerve-centered masses of round or lobular shape, with homogeneous
Malignancy contrast enhancement, and no calcification or necrosis. In addition,
Histiocytoses some lesions can show PET avidity. Other entities in the differential
Intracranial
diagnosis that have similar radiological features include schwannoma,
Hypotension
neurofibroma, inflammatory myofibroblastic tumor, and perineural
spread of malignancy.

11. Carotid and intracerebral vascular disease
Inflammation within the arterial wall (aortitis and arteritis) and
surrounding vessels (periaortitis or periarteritis) can manifest in 10%–
30% of patients with IgG4-RD either as an isolated finding or in the
setting of multi-organ involvement. It can cause life-threatening arterial
13. Treatment
Glucocorticoids currently constitute the first-line therapy for most
patients with IgG4-RD, with an overall response rate of 93% and com­
plete response rate of 66% [100]. Within weeks, most patients treated
with glucocorticoids demonstrate improvement in symptoms, reduction
in mass effect, and commonly a remarkable decrease in serum IgG4

7
G. Saitakis and B.K. Chwalisz
[101]. Unfortunately, the majority of patients with IgG4-RD experience
disease relapse during follow-up [102]. Features such as higher eosin­
ophil levels, involvement of five or more organs and specifically lacrimal
gland involvement are correlated with higher rate of glucocorticoid
failure [103]. In addition, poor response to steroids appears to be more
likely in patients with more fibrotic changes, chronic stage of the disease
and low serum IgG4 level [104]. Specifically, in IgG4-RD orbitopathy,
the relapse rate ranges from 17% to 50%, necessitating retreatment with
steroids and introduction of a maintenance therapy [2]. In this specific
situation, intraorbital injection of glucocorticoids has been suggested as
an alternative when the anterior orbit is predominantly affected, in
order to avoid systemic immunosuppression [105].
The monoclonal anti-CD20 antibody rituximab is a promising
treatment in patients with disease refractory to glucocorticoids, or un­
able to have their dose reduced sufficiently to avoid adverse effects of
the long-term use [101]. Rituximab efficiently depletes B-cells in
steroid-dependent or steroid-resistant patients with IgG4-RD, with a
satisfactory relapse-free interval [106], highlighting the role of plasma
cells and their B-cell precursors in the pathogenesis of IgG4-RD. In
addition, a retrospective trial showed a response rate of 97%, and the
majority of patients did not require concomitant corticosteroids after the
initiation of rituximab [107]. In clinical practice, rituximab remains
mostly a second-line therapy because of high cost and the potential for
side-effects, but it should be considered up front in life-threatening or
organ-threatening disease.
We emphasize that initiation of immunosuppression is more likely to
be beneficial when introduced at a stage characterized histologically
mainly by a lymphoplasmacytic infiltrate compared to an acellular one
which commonly implies refractory disease [101]. A similar consider­
ation leads to treatment of asymptomatic IgG4-RD patients in order to
avoid fibrosis that can render recovery impossible in case of delayed
intervention [108].
A number of emerging therapeutic options include a humanized anti-
CD19 antibody (Xmab®5871) [109], the SLAMF7-directed antibody
elotuzumab (an enticing agent given the expression of SLAMF7 both on
circulating plasmablasts and on the CD4+ cytotoxic T lymphocytes in
IgG4-RD), and anti-IgE therapy with omalizumab in patients with severe
atopic disease or asthma and elevated IgE levels [4]. Radiation therapy
in IgG4-RD is mainly adjunctive to systemic medical treatment in pa­
tients with refractory disease or intolerance to corticosteroids
[110–112].
14. Conclusion
IgG4-RD unifies a wide spectrum of clinical manifestations in mul­
tiple different organs, with common histopathologic features in the
affected regions. Neurological involvement is being increasingly recog­
nized. IgG4-RD is of major etiologic importance in the syndromes of
orbital inflammation, infundibulo-hypophysitis and hypertrophic men­
ingitis. In addition, new and atypical presentations continue to be
described. Although clinical history, physical examination, serological
tests and imaging can strongly suggest it, biopsy remains confirmatory
for the clinicopathologic diagnosis of IgG4-RD. Though the disease often
responds well to steroids, in severe, refractory and steroid-dependent
cases addition of rituximab is a promising adjunct treatment strategy.
Early immune suppression should be considered to prevent refractory
fibrosis.
References
[1] H. Sarles, J.C. Sarles, R. Muratore, C. Guien, Chronic inflammatory sclerosis of
the pancreas – An autonomous pancreatic disease? Am J Dig Dis 6 (1961)
688–698.
[2] T. Kamisawa, N. Egawa, H. Nakajima, Autoimmune pancreatitis is a systemic
autoimmune disease, Am. J. Gastroenterol. 98 (2003) 2811–2812.
[3] T. Kamisawa, N. Funata, Y. Hayashi, et al., A new clinicopathological entity of
IgG4-related autoimmune disease, J. Gastroenterol. 38 (2003) 982–984.
8
Journal of the Neurological Sciences 424 (2021) 117420
[4] Luke Y.C. Chen, Andre Mattman, Michael A. Seidman, Mollie N. Carruthers, IgG4-
related disease: what a hematologist needs to know, Haematologica 104 (3)
(2019) 444–455, https://doi.org/10.3324/haematol.2018.205526 (Epub 2019
Jan 31).
[5] M. van der Neut Kolfschoten, J. Schuurman, M. Losen, W.K. Bleeker, P. Martínez-
Martínez, E. Vermeulen, T.H. den Bleker, L. Wiegman, T. Vink, L.A. Aarden, M.
H. De Baets, J.G. van de Winkel, R.C. Aalberse, P.W. Parren, Anti-inflammatory
activity of human IgG4 antibodies by dynamic Fab arm exchange, Science 317
(5844) (2007) 1554–1557.
[6] X. Xiao, M. Lian, W. Zhang, M. Eric Gershwin, X. Ma, The immunologic paradoxes
of IgG4-related disease, Clin. Rev. Allergy Immunol. 54 (2) (2018 Apr) 344–351,
https://doi.org/10.1007/s12016-018-8679-y.
[7] H. Mattoo, V.S. Mahajan, T. Maehara, et al., Clonal expansion of CD4(+)
cytotoxic T lymphocytes in patients with IgG4-related disease, J. Allergy Clin.
Immunol. 138 (3) (2016) 825–838, https://doi.org/10.1016/j.jaci.2015.12.1330.
[8] L.M. Hubers, H. Vos, A.R. Schuurman, et al., Annexin A11 is targeted by IgG4 and
IgG1 autoantibodies in IgG4-related disease, Gut. 67 (4) (2018) 728–735.
[9] C.A. Perugino, S.B. AlSalem, H. Mattoo, E. Della-Torre, V. Mahajan, G. Ganesh,
H. Allard-Chamard, Z. Wallace, S.B. Montesi, J. Kreuzer, W. Haas, J.H. Stone,
S. Pillai, Identification of galectin-3 as an autoantigen in patients with IgG4-
related disease, J. Allergy Clin. Immunol. 143 (2) (2019) 736–745, e6.
[10] C.A. Perugino, H. Mattoo, V.S. Mahajan, et al., Emerging treatment models in
rheumatology: IgG4-related disease: insights into human immunology and
targeted therapies, Arthritis Rheum. 69 (2017) 1722–1732.
[11] A. Kanno, A. Masamune, K. Okazaki, T. Kamisawa, S. Kawa, I. Nishimori, et al.,
Nationwide epidemiological survey of autoimmune pancreatitis in Japan in 2011,
Pancreas. 44 (2015) 535–539, https://doi.org/10.1097/
MPA.0000000000000325.
[12] Z.S. Wallace, C. Perugino, M. Matza, V. Deshpande, A. Sharma, J.H. Stone,
Immunoglobulin G4-related disease, Clin. Chest Med. 40 (3) (2019 Sep) 583–597,
https://doi.org/10.1016/j.ccm.2019.05.005.
[13] K. Miyabe, Y. Zen, L.D. Cornell, G. Rajagopalan, V.R. Chowdhary, L.R. Roberts, S.
T. Chari, Gastrointestinal and extra-intestinal manifestations of IgG4 related
disease, Gastroenterology. 155 (4) (2018 Oct) 990–1003, https://doi.org/
10.1053/j.gastro.2018.06.082.
[14] L. Wang, P. Zhang, X. Zhang, W. Lin, H. Tang, J. Li, M. Wang, X. Liu, Y. Fei,
H. Chen, L. Peng, L. Zhang, Y. Lai, X. Zeng, X. Li, H. Xue, Y. Zhao, F. Zhang,
W. Zhang, Sex disparities in clinical characteristics and prognosis of
immunoglobulin G4-related disease: a prospective study of 403 patients,
Rheumatology (Oxford) 58 (5) (2019 May 1) 820–830, https://doi.org/10.1093/
rheumatology/key397.
[15] Z.S. Wallace, V. Deshpande, J.H. Stone, Ophthalmic manifestations of IgG4-
related disease: single-center experience and literature review, Semin. Arthritis
Rheum. 43 (2014) 806–817.
[16] Z.S. Wallace, Y. Zhang, C.A. Perugino, R. Naden, H.K. Choi, J.H. Stone, ACR/
EULAR IgG4-RD Classification Criteria Committee, Clinical phenotypes of IgG4-
related disease: an analysis of two international cross-sectional cohorts, Ann.
Rheum. Dis. 78 (3) (2019 Mar) 406–412, https://doi.org/10.1136/annrheumdis-
2018-214603.
[17] L. Iaccarino, R. Talarico, C.A. Scirè, Z. Amoura, G. Burmester, A. Doria, K. Faiz,
C. Frank, E. Hachulla, M. Hie, D. Launay, C. Montecucco, S. Monti, L. Mouthon,
A. Tincani, P. Toniati, P.M. Van Hagen, R.F. Van Vollenhoven, S. Bombardieri,
U. Mueller-Ladner, M. Schneider, V. Smith, M. Cutolo, M. Mosca, T. Alexander,
IgG4-related diseases: state of the art on clinical practice guidelines, RMD Open 4
(Suppl. 1) (2019 Jan 19), e000787, https://doi.org/10.1136/rmdopen-2018-
000787 (eCollection 2018).
[18] X. Cheng, Y. Shu, B. Chen, A solely ear-involved IgG4-related sclerosing disease
with two-years following-up, Eur. Ann. Otorhinolaryngol. Head Neck Dis. 136 (5)
(2019 Oct) 401–403, https://doi.org/10.1016/j.anorl.2018.02.002.
[19] S. Naramala, S. Biswas, S. Adapa, V. Gayam, V.M. Konala, S. Bose, An overlapping
case of IgG4-related disease and systemic lupus erythematosus, J. Investig. Med.
High Impact Case Rep. 7 (2019 Jan-Dec), https://doi.org/10.1177/
2324709619862297, 2324709619862297.
[20] S. Nambiar, T.I. Oliver, IgG4 Related Disease (IgG4-RD). StatPearls [Internet],
StatPearls Publishing, Treasure Island (FL), 2019.
[21] Y. Gao, M. Zheng, L. Cui, N. Chen, Y.N. Wang, Y.T. Zhan, Z.G. Wang, IgG4-related
disease: association between chronic rhino-sinusitis and systemic symptoms, Eur.
Arch. Otorhinolaryngol. 275 (8) (2018 Aug) 2013–2019, https://doi.org/
10.1007/s00405-018-5013-5.
[22] K. Hasegawa, Y. Hanayama, M. Obika, T. Miyoshi, H. Ogawa, E. Kondo,
H. Kataoka, Y. Sato, F. Otsuka, Clinical and biochemical characteristics of patients
having general symptoms with increased serum IgG4, Mod. Rheumatol. 1 (2019
Aug) 1–8, https://doi.org/10.1080/14397595.2019.1642291.
[23] S.Y. Lim, M. McInnis, Z. Wallace, et al., Intrathoracic manifestations of IgG4-
related disease: findings in a cohort study from North America, Arthritis Rheum.
68 (2016).
[24] Z.S. Wallace, R.P. Naden, S. Chari, H.K. Choi, E. Della-Torre, J.F. Dicaire, P.
A. Hart, D. Inoue, M. Kawano, A. Khosroshahi, M. Lanzillotta, K. Okazaki, C.
A. Perugino, A. Sharma, T. Saeki, N. Schleinitz, N. Takahashi, H. Umehara,
Y. Zen, J.H. Stone, Members of the ACR/EULAR IgG4-RD Classification Criteria
Working Group, The 2019 American College of Rheumatology/European League
Against Rheumatism classification criteria for IgG4-related disease, Ann. Rheum.
Dis. 79 (1) (2020 Jan) 77–87, https://doi.org/10.1136/annrheumdis-2019-
216561. Epub 2019 Dec 3. Review.
[25] Z.S. Wallace, R.P. Naden, S. Chari, H. Choi, E. Della-Torre, J.F. Dicaire, P.A. Hart,
D. Inoue, M. Kawano, A. Khosroshahi, K. Kubota, M. Lanzillotta, K. Okazaki, C.
G. Saitakis and B.K. Chwalisz
A. Perugino, A. Sharma, T. Saeki, H. Sekiguchi, N. Schleinitz, J.R. Stone,
N. Takahashi, H. Umehara, G. Webster, Y. Zen, J.H. Stone, The 2019 American
College of Rheumatology/European League Against Rheumatism Classification
Criteria for IgG4-Related Disease.American College of Rheumatology/European
League Against Rheumatism IgG4-Related Disease Classification Criteria Working
Group, Arthritis Rheum. 72 (1) (2020 Jan) 7–19, https://doi.org/10.1002/
art.41120 (Epub 2019 Dec 2).
[26] S. Kasashima, A. Kawashima, S. Ozaki, T. Kita, T. Araya, Y. Ohta, M. Suzuki,
Clinicopathological features of immunoglobulin G4-related pleural lesions and
diagnostic utility of pleural effusion cytology, Cytopathology. 30 (3) (2019 May)
285–294, https://doi.org/10.1111/cyt.12641.
[27] V. Ashoka Menon, E. Tong, D.R.L. Slape, T.A. Phan, R.C. Chan, Cutaneous
manifestation of IgG4-related disease mimicking dermatitis artefacta, Australas.
J. Dermatol. (2019 Sep 11), https://doi.org/10.1111/ajd.13162.
[28] T. Ikeda, C. Kaminaka, F. Furukawa, A case of alopecia as IgG4-related skin
disease, Mod. Rheumatol. 29 (3) (2019 May) 538–541, https://doi.org/10.1080/
14397595.2016.1233929.
[29] S.J.S. Nagpal, S.T. Chari, Immunoglobulin G4 Levels, JAMA. 321 (2) (2019 Jan
15) 202–203, https://doi.org/10.1001/jama.2018.16665.
[30] K. Boonstra, E.L. Culver, L.M. de Buy Wenniger, et al., Serum IgG4 and IgG1 for
distinguishing IgG4-associated cholangitis from primary sclerosing cholangitis,
Hepatology 59 (2014) 1954–1963.
[31] C.S. Xia, C.H. Fan, Y.Y. Liu, Diagnostic performance of serum IgG4 concentration
and IgG4/IgG ratio in IgG4-related disease, Clin. Rheumatol. 36 (2017)
2769–2774.
[32] A. Khosroshahi, L.A. Cheryk, M.N. Carruthers, J.A. Edwards, et al., Brief report:
spuriously low IgG4 concentrations caused by the prozone phenomenon in
patients with IgG4-related disease, Arthritis Rheum. 66 (1) (2014) 213–217.
[33] Z.S. Wallace, H. Mattoo, M. Carruthers, V.S. Mahajan, E. Della Torre, H. Lee,
M. Kulikova, V. Deshpande, S. Pillai, J.H. Stone, Plasmablasts as a biomarker for
IgG4-related disease, independent of serum IgG4 concentrations, Ann. Rheum.
Dis. 74 (1) (2015 Jan) 190–195, https://doi.org/10.1136/annrheumdis-2014-
205233.
[34] Y. Usami, K. Ichihara, T. Uehara, M. Sugano, N. Ishimine, K. Kawasaki,
K. Yamauchi, H. Hamano, T. Honda, Evaluation of a novel serum IgG4 assay and
determination of reference interval for the Japanese population, Clin. Chim. Acta
(2019), https://doi.org/10.1016/j.cca.2019.10.032 pii: S0009–8981(19)
32097–2.
[35] G. van der Gugten, M.L. DeMarco, L.Y.C. Chen, A. Chin, M. Carruthers, D.
T. Holmes, A. Mattman, Resolution of spurious immunonephelometric IgG
subclass measurement discrepancies by LC-MS/MS, Clin. Chem. 64 (4) (2018
Apr) 735–742, https://doi.org/10.1373/clinchem.2017.282319.
[36] M. Akiyama, T. Sasaki, Y. Kaneko, H. Yasuoka, K. Suzuki, K. Yamaoka,
T. Takeuchi, Serum soluble interleukin-2 receptor is a useful biomarker for
disease activity but not for differential diagnosis in IgG4-related disease and
primary Sjögren’s syndrome adults from a defined population, Clin. Exp.
Rheumatol. 112 (3) (2018) 157–164.
[37] M. Akiyama, H. Yasuoka, K. Yoshimoto, T. Takeuchi, CC-chemokine ligand 18 is a
useful biomarker associated with disease activity in IgG4-related disease, Ann.
Rheum. Dis. 77 (9) (2018 Sep) 1386–1387, https://doi.org/10.1136/
annrheumdis-2017-212110.
[38] K. Ohshima, Y. Sogabe, Y. Sato, The usefulness of infraorbital nerve enlargement
on MRI imaging in clinical diagnosis of IgG4-related orbital disease, Jpn. J.
Ophthalmol. 56 (2012) 380–382, https://doi.org/10.1007/s10384-012-0151-6.
[39] J. Ben Soussan, R. Deschamps, J.C. Sadik, et al., Infraorbital nerve involvement
on magnetic resonance imaging in European patients with IgG4-related
ophthalmic disease: a specific sign, Eur. Radiol. 19 (2016 Jul).
[40] K. Nakatani, Y. Nakamoto, K. Togashi, Utility of FDG PET/CT in IgG4-related
systemic diseas, Clin. Radiol. 67 (2012) 297–305.
[41] M. Ebbo, A. Grados, E. Guedj, D. Gobert, C. Colavolpe, M. Zaidan, et al.,
Usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/
computed tomography for staging and evaluation of treatment response in IgG4-
related disease: a retrospective multicenter study, Arthritis Care Res. 66 (2014)
86–96, https://doi.org/10.1002/acr.22058.
[42] M. Ebbo, M. Patient, A. Grados, M. Groh, J. Desblaches, E. Hachulla, D. Saadoun,
S. Audia, A. Rigolet, B. Terrier, A. Perlat, C. Guillaud, F. Renou, E. Bernit,
N. Costedoat-Chalumeau, J.R. Harlé, N. Schleinitz, Ophthalmic manifestations in
IgG4-related disease: clinical presentation and response to treatment in a French
case-series, Medicine (Baltimore) 96 (10) (2017 Mar), e6205, https://doi.org/
10.1097/MD.0000000000006205.
[43] W. Cheuk, J.K. Chan, Lymphadenopathy of IgG4-related disease: an
underdiagnosed and overdiagnosed entity, Semin. Diagn. Pathol. 29 (4) (2012)
226–234, https://doi.org/10.1053/j.semdp.2012.07.001.
[44] S.Y. Chang, K.A. Keogh, J.E. Lewis, et al., IgG4-positive plasma cells in
granulomatosis with polyangiitis (Wegener’s): a clinicopathologic and
immunohistochemical study on 43 granulomatosis with polyangiitis and 20
control cases, Hum. Pathol. 44 (11) (2013) 2432–2437, https://doi.org/10.1016/
j.humpath.2013.05.023.
[45] K. Arora, M. Rivera, D.T. Ting, V. Deshpande, The histological diagnosis of IgG4-
related disease on small biopsies: challenges and pitfalls, Histopathology. 74 (5)
(2019 Apr) 688–698, https://doi.org/10.1111/his.13787.
[46] H.K. Min, Y.S. Lee, S.W. Yang, J. Lee, S.K. Kwok, J.H. Ju, W.U. Kim, S.H. Park,
Clinical outcomes and pathological characteristics of immunoglobulin G4-related
ophthalmic disease versus orbital inflammatory pseudotumor, Korean J. Int. Med.
34 (1) (2019 Jan) 220–226, https://doi.org/10.3904/kjim.2016.304.
9
Journal of the Neurological Sciences 424 (2021) 117420
[47] J. Li, Y. Zhang, H. Zhou, L. Wang, Z. Wang, H. Li, Magnetic resonance imaging
indicator of the causes of optic neuropathy in IgG4-related ophthalmic disease,
BMC Med. Imaging 19 (1) (2019 Jun 18) 49, https://doi.org/10.1186/s12880-
019-0347-z.
[48] N. Wu, F.Y. Sun, Clinical observation of orbital IgG4-related diseases, Exp. Ther.
Med. 17 (1) (2019 Jan) 883–887, https://doi.org/10.3892/etm.2018.7002.
[49] J.S.N. Verhoekx, A.F. Karim, J.A.M. van Laar, R.M. Verdijk, D. Paridaens, The
tarsal plate manifestation of IgG4-related disease, Int. Ophthalmol. 39 (7) (2019
Jul) 1613–1615, https://doi.org/10.1007/s10792-018-0974-3.
[50] J. Ominato, T. Oyama, H. Cho, N. Shiozaki, H. Umezu, J. Takizawa, T. Fukuchi,
The natural course of IgG4-related ophthalmic disease after debulking surgery: a
single-centre retrospective study, BMJ Open Ophthalmol. 4 (1) (2019 Aug 9),
e000295, https://doi.org/10.1136/bmjophth-2019-000295 (eCollection 2019).
[51] W. Cheuk, H.K. Yuen, J.K. Chan, Chronic sclerosing dacryoadenitis: part of the
spectrum of IgG4-related sclerosing disease? Am. J. Surg. Pathol. 31 (2007)
643–645.
[52] S. Noshiro, M. Wanibuchi, Y. Akiyama, et al., IgG4-related disease initially
presented as an orbital mass lesion mimicking optic nerve sheath meningioma,
Brain Tumor Pathol. 32 (2015) 286–290.
[53] K. Mulay, E. Aggarwal, IgG4-related dacryoadenitis evolving into an extra-nodal,
marginal zone B-cell lymphoma (EMZL): a tale of two lacrimal glands, Pathology.
46 (2014) 464–466, https://doi.org/10.1097/PAT.0000000000000132.
[54] M. Yamamoto, H. Takahashi, T. Tabeya, C. Suzuki, Y. Naishiro, K. Ishigami, et al.,
Risk of malignancies in IgG4-related disease, Mod. Rheumatol. 22 (2012)
414–418, https://doi.org/10.1007/s10165-011-0520-x.
[55] D. Queen, A.A. Hedayat, C. Magro, L.J. Geskin, An unusual cause of bilateral
orbital swelling: immunoglobulin G4-related orbital disease arising in a patient
with ulcerative colitis, JAAD Case Rep. 5 (7) (2019 Jul 13) 634–638, https://doi.
org/10.1016/j.jdcr.2019.05.018. eCollection 2019 Jul.
[56] K. Toyoda, H. Oba, K. Kutomi, S. Furui, A. Oohara, H. Mori, K. Sakurai,
K. Tsuchiya, S. Kan, Y. Numaguchi, MR imaging of IgG4-related disease in the
head and neck and brain, AJNR Am. J. Neuroradiol. 33 (11) (2012 Dec)
2136–2139, https://doi.org/10.3174/ajnr.A3147.
[57] J.A. Alt, G.T. Whitaker, R.W. Allan, M. Vaysberg, Locally destructive skull base
lesion: IgG4-related sclerosing disease, Allergy Rhinol. (Providence) 3 (1) (2012),
https://doi.org/10.2500/ar.2012.3.0026 e41-5.
[58] A. Fujita, O. Sakai, M.N. Chapman, H. Sugimoto, IgG4-related disease of the head
and neck: CT and MR imaging manifestations, Radiographics 32 (7) (2012 Nov-
Dec) 1945–1958, https://doi.org/10.1148/rg.327125032.
[59] J.B. Soussan, R. Deschamps, J.C. Sadik, J. Savatovsky, L. Deschamps,
M. Puttermann, M. Zmuda, F. Heran, O. Galatoire, H. Picard, A. Lecler,
Infraorbital nerve involvement on magnetic resonance imaging in European
patients with IgG4-related ophthalmic disease: a specific sign, Eur. Radiol. 27 (4)
(2017 Apr) 1335–1343, https://doi.org/10.1007/s00330-016-4481-5.
[60] Y. Sogabe, K. Miyatani, R. Goto, G. Ishii, K. Ohshima, Y. Sato, Pathological
findings of infraorbital nerve enlargement in IgG4-related ophthalmic disease,
Jpn. J. Ophthalmol. 56 (2012) 511–514, https://doi.org/10.1007/s10384-012-
0170-3.
[61] Y. Sogabe, K. Ohshima, A. Azumi, M. Takahira, S. Kase, H. Tsuji, et al., Location
and frequency of lesions in patients with IgG4-related ophthalmic diseases,
Graefes Arch. Clin. Exp. Ophthalmol. 252 (2014) 531–538, https://doi.org/
10.1007/s00417-013-2548-4.
[62] S.-K. Chan, W. Cheuk, K.-T. Chan, J.K.C. Chan, IgG4-related sclerosing
pachymeningitis, Am. J. Surg. Pathol. 33 (2009) 1249–1252, https://doi.org/
10.1097/PAS.0b013e3181abdfc2.
[63] Z.S. Wallace, V. Deshpande, H. Mattoo, et al., IgG4-related disease: clinical and
laboratory features in one hundred twenty-five patients, Arthritis Rheum. 67
(2015) 2466–2475, https://doi.org/10.1002/art.39205.
[64] H. Umehara, K. Okazaki, T. Nakamura, et al., Current approach to the diagnosis
of IgG4-related disease–combination of comprehensive diagnostic and organ-
specific criteria, Mod. Rheumatol. 27 (2017) 381–391, https://doi.org/10.1080/
14397595.2017.1290911.
[65] H. Sekiguchi, R. Horie, M. Kanai, R. Suzuki, E.S. Yi, J.H. Ryu, IgG4-related
disease: retrospective analysis of one hundred sixty-six patients, Arthritis Rheum.
68 (2016) 2290–2299, https://doi.org/10.1002/art.39686.
[66] D. Inoue, K. Yoshida, N. Yoneda, et al., IgG4-related disease: dataset of 235
consecutive patients, Medicine (Baltimore) 94 (2015), e680, https://doi.org/
10.1097/MD.0000000000000680.
[67] S.H. Mehta, J. Switzer, P. Biddinger, A.M. Rojiani, IgG4-related leptomeningitis: a
reversible cause of rapidly progressive cognitive decline, Neurology. 82 (6)
(2014) 540–542, https://doi.org/10.1212/WNL.0000000000000100.
[68] S.H. Choi, S.H. Lee, S.K. Khang, S.R. Jeon, IgG4-related sclerosing
pachymeningitis causing spinal cord compression, Neurology. 75 (2010)
1388–1390, https://doi.org/10.1212/WNL.0b013e3181f73614.
[69] E.H. Kim, S.H. Kim, J.M. Cho, et al., Immunoglobulin G4-related hypertrophic
pachymeningitis involving cerebral parenchyma, J. Neurosurg. 115 (2011)
1242–1247, https://doi.org/10.3171/2011.7.JNS1166.
[70] K. Regev, T. Nusbaum, E. Cagnano, et al., Central nervous system manifestation of
IgG4-related disease, JAMA Neurol. 71 (2014) 767–770, https://doi.org/
10.1001/jamaneurol.2014.40.
[71] Y. Sireesha, M.S. Uppin, S. Ganti, R. Alugolu, V.S. Mudumba, S. Bhattacharjee, M.
L. Neeharika, J. Bastia, M.A. Kanikannan, A series of biopsy-proven patients with
immunoglobulin G4-related neurological disease, Ann. Indian Acad. Neurol. 22
(1) (2019 Jan-Mar) 73–78, https://doi.org/10.4103/aian.AIAN_283_18.
G. Saitakis and B.K. Chwalisz
[72] W. Lin, S. Lu, H. Chen, et al., Clinical characteristics of immunoglobulin G4-
related disease: a prospective study of 118 Chinese patients, Rheumatology
(Oxford) 54 (2015) 1982–1990, https://doi.org/10.1093/rheumatology/kev203.
[73] E. Della-Torre, G. Passerini, R. Furlan, et al., Cerebrospinal fluid analysis in IgG4-
related hypertrophic pachymeningitis, J. Rheumatol. 40 (11) (2013) 1927–1929,
https://doi.org/10.1016/j.jneuroim.2013.10.008.
[74] H. Takahashi, H. Yamashita, M. Morooka, et al., The utility of FDG-PET/CT and
other imaging techniques in the evaluation of IgG4-related disease, Joint Bone
Spine 81 (2014) 331–336, https://doi.org/10.1016/j.jbspin.2014.01.010.
[75] J. Lee, S.H. Hyun, S. Kim, et al., Utility of FDG PET/CT for differential diagnosis
of patients clinically suspected of IgG4-related disease, Clin. Nucl. Med. 41 (2016)
e237–e243, https://doi.org/10.1097/RLU.0000000000001153.
[77] F.-X. Danlos, G.M. Rossi, D. Blockmans, et al., Antineutrophil cytoplasmic
antibody-associated vasculitides and IgG4-related disease: a new overlap
syndrome, Autoimmun. Rev. 16 (2017) 1036–1043, https://doi.org/10.1016/j.
autrev.2017.07.020.
[78] H.J. van der Vliet, R.M. Perenboom, Multiple pseudotumors in IgG4-associated
multifocal systemic fibrosis, Ann. Intern. Med. 141 (2004) 896–897, https://doi.
org/10.7326/0003-4819-141-11-200412070-00033.
[79] Keitaro Kanie, Hironori Bando, Genzo Iguchi, Hideyuki Shiomi, Atsuhiro Masuda,
Hidenori Fukuoka, Hitoshi Nishizawa, Yasunori Fujita, Arata Sakai,
Takashi Kobayashi, Yuuki Shiomi, Kenichi Yoshida, Ryusaku Matsumoto,
Kentaro Suda, Yuzo Kodama, Wataru Ogawa, Yutaka Takahashi, IgG4-related
hypophysitis in patients with autoimmune pancreatitis, Pituitary 22 (2019)
54–61, https://doi.org/10.1007/s11102-018-00930-y.
[80] P. Leporati, M.A. Landek-Salagado, I. Lupi, L. Chiovato, P. Caturegli, IgG4-related
hypophysitis: a new addition to the hypophysitis spectrum, J. Clin. Endocrinol.
Metab. 96 (2011) 1971–1980, https://doi.org/10.1210/jc.2010-2970.
[81] H. Joshi, M. Hikmat, A.P. Devadass, S.O. Oyibo, S.V. Sagi, Anterior
hypopituitarism secondary to biopsy-proven IgG4-related hypophysitis in a young
man, Endocrinol. Diabetes Metab. Case Rep. (2019 Apr 3), https://doi.org/
10.1530/EDM-18-0137, 2019. pii: EDM180137.
[82] C. Patrizio, Shintaro I from Japan with love: another tessera in the hypophysitis
mosaic, J. Clin. Endocrinol. Metab. 98 (2013) 1865–1868, https://doi.org/
10.1210/jc.2013-1912.
[83] Y. Zen, Y. Nakanuma, Pathogenesis of IgG4-related disease, Curr. Opin.
Rheumatol. 23 (2011) 114–118, https://doi.org/10.1097/
BOR.0b013e3283412f4a.
[84] Y. Liu, L. Wang, W. Zhang, H. Pan, H. Yang, K. Deng, L. Lu, Y. Yao, S. Chen,
X. Chai, F. Feng, H. You, Z. Jin, H. Zhu, Hypophyseal involvement in
immunoglobulin G4-related disease: a retrospective study from a Single Tertiary
Center, Int. J. Endocrinol. (2018 Mar 20), 7637435, https://doi.org/10.1155/
2018/7637435 (eCollection 2018).
[85] H.J. Schneider, G. Aimaretti, I. Kreitschmann-Andermahr, G.K. Stalla, E. Ghigo,
Hypopituitarism, Lancet 369 (9571) (2007) 1461–1470, https://doi.org/
10.1016/S0140-6736(07)60673-4.
[86] Hisashi Koide, Akina Shiga, Eri Komai, Azusa Yamato, Masanori Fujimoto,
Ai Tamura, Takashi Kono, Akitoshi Nakayama, Tomoko Takiguchi,
Seiichiro Higuchi, Ikki Sakuma, Hidekazu Nagano, Naoko Hashimoto,
Sawako Suzuki, Yasuaki Takeda, Makoto Shibuya, Hiroshi Nishioka,
Shozo Yamada, Naoko Inoshita, Norio Ishiwatari, Kentaro Horiguchi,
Koutaro Yokote, Tomoaki Tanaka, Prednisolone-responsive postpartum IgG4-
related hypophysitis, Intern. Med. 57 (3) (2018 Feb 1) 367–375, https://doi.org/
10.2169/internalmedicine.8446-16.
[87] W. Saeger, Hypophysitis: formen und differenzial diagnose, Pathologe 37 (3)
(2016) 230–237.
[89] H. Nishioka, M. Shibuya, J. Haraoka, Immunohistochemical study for IgG4-
positive plasmacytes in pituitary inflammatory lesions, Endocr. Pathol. 21 (4)
(2010) 236–241, https://doi.org/10.1007/s12022-010-9128-5.
[90] S. Lee, J.H. Choi, C.J. Kim, et al., Clinical interrogation for unveiling an isolated
hypophysitis mimicking pituitary adenoma, World Neurosurg. 99 (2017)
735–744, https://doi.org/10.1016/j.wneu.2016.07.071.
[91] I. Iseda, K. Hida, A. Tone, et al., Prednisolone markedly reduced serum IgG4
levels along with the improvement of pituitary mass and anterior pituitary
function in a patient with IgG4-related infundibulo-hypophysitis, Endocr. J. 61
(2014) 195–203.
[92] H. Koide, A. Shiga, E. Komai, et al., Prednisolone-responsive postpartum IgG4-
related hypophysitis, Intern. Med. 57 (2018) 367–375, https://doi.org/10.2169/
internalmedicine.8446-16.
[93] C.A. Perugino, Z.S. Wallace, N. Meyersohn, G. Oliveira, J.R. Stone, J.H. Stone,
Large vessel involvement by IgG4-related disease, Medicine (Baltimore) 95 (28)
(2016 Jul), e3344, https://doi.org/10.1097/MD.0000000000003344.
10
Journal of the Neurological Sciences 424 (2021) 117420
[94] I. Mizushima, S. Kasashima, Y. Fujinaga, M. Kawano, N. Ishizaka, IgG4-related
periaortitis/periarteritis: an under-recognized condition that is potentially life-
threatening, Mod. Rheumatol. 29 (2019) 240–250, https://doi.org/10.1080/
14397595.2018.1546367.
[95] E.S. Marlin, D. Dornbos III, D.S. Ikeda, et al., IgG4-related: a new etiology
underlying diffuse intracranial dilating vasculopathy, Word Neurosurg. 107
(2017), https://doi.org/10.1016/j.wneu.2017.08.012, 1048.e15–1048.e20.
[96] P.A. Monach, J.H. Stone, A. Sharma, R.M. Nazarian, Case 6-2017. A 57-year-old
woman with fatigue, sweats, weight loss, headache, and skin lesions, N. Engl. J.
Med. 376 (8) (2017 Feb 23) 775–786, https://doi.org/10.1056/
NEJMcpc1613461.
[97] Y. Toyoshima, I. Emura, Y. Umeda, N. Fujita, A. Kakita, H. Takahashi, Vertebral
basilar system dolichoectasia with marked infiltration of IgG4-containing plasma
cells: a manifestation of IgG4-related disease? Neuropathology. 32 (1) (2012 Feb)
100–104, https://doi.org/10.1111/j.1440-1789.2011.01227.x.
[98] A. Barp, M. Fedrigo, F.M. Farina, S. Lepidi, F. Causin, C. Castellani, G. Cester,
G. Thiene, M. Valente, C. Baracchini, A. Angelini, Carotid aneurism with acute
dissection: an unusual case of IgG4-related diseases, Cardiovasc. Pathol. 25 (1)
(2016 Jan-Feb) 59–62, https://doi.org/10.1016/j.carpath.2015.08.006.
[99] D. Inoue, Y. Zen, Y. Sato, H. Abo, H. Demachi, A. Uchiyama, T. Gabata, O. Matsui,
IgG4-related perineural disease, Int. J. Rheumatol. 2012 (2012) 401890, https://
doi.org/10.1155/2012/401890.
[100] Y. Masaki, S. Matsui, T. Saeki, et al., A multi-center phase II prospective clinical
trial of glucocorticoid for patients with untreated IgG4-related disease, Mod.
Rheumatol. 27 (5) (2017) 849–854, https://doi.org/10.1080/
14397595.2016.1259602.
[101] Wei-Kuang Yu, Chieh-Chih Tsai, Shu-Ching Kao, Catherine Jui-Ling Liu,
Immunoglobulin G4-related ophthalmic disease, Taiwan J. Ophthalmol. 8 (1)
(2018 Jan-Mar) 9–14.
[102] M. Yamamoto, H. Yajima, H. Takahashi, Y. Yokoyama, K. Ishigami, Y. Shimizu, et
al., Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis:
results from the SMART database, Mod. Rheumatol. 25 (2015) 199–204, https://
doi.org/10.3109/14397595.2014.950036.
[103] L. Wang, P. Zhang, M. Wang, et al., Failure of remission induction by
glucocorticoids alone or in combination with immunosuppressive agents in IgG4-
related disease: a prospective study of 215 patients, Arthritis Res. Ther. 20 (1)
(2018) 65, https://doi.org/10.1186/s13075-018-1567-2.
[104] W.K. Yu, S.C. Kao, C.F. Yang, F.L. Lee, C.C. Tsai, Ocular adnexal IgG4-related
disease: clinical features, outcome, and factors associated with response to
systemic steroids, Jpn. J. Ophthalmol. 59 (2015) 8–13, https://doi.org/10.1007/
s10384-014-0353-1.
[105] N.H. Andrew, A. Gajdatsy, D. Selva, Intraorbital corticosteroid injection for the
treatment of IgG4-related ophthalmic disease, Br. J. Ophthalmol. 100 (2016)
644–647, https://doi.org/10.1136/bjophthalmol-2015-307164.
[106] A. Wu, N.H. Andrew, A. Tsirbas, P. Tan, A. Gajdatsy, D. Selva, Rituximab for the
treatment of IgG4-related orbital disease: experience from five cases, Eye (Lond)
29 (2015) 122–128, https://doi.org/10.1038/eye.2014.251.
[107] M. Ebbo, A. Grados, M. Samson, M. Groh, A. Loundou, A. Rigolet, et al., Long-
term efficacy and safety of rituximab in IgG4-related disease: data from a French
nationwide study of thirty-three patients, PLoS One 12 (2017), e0183844,
https://doi.org/10.1371/journal.pone.0183844 (eCollection 2017).
[108] Y. Shimizu, M. Yamamoto, Y. Naishiro, G. Sudoh, K. Ishigami, H. Yajima, et al.,
Necessity of early intervention for IgG4-related disease–delayed treatment
induces fibrosis progression, Rheumatology (Oxford) 52 (2013) 679–683, https://
doi.org/10.1093/rheumatology/kes358.
[109] J.H. Stone, Z.S. Wallace, C.A. Perugino, et al., A Trial of XmAb (R) 5871, a
reversible inhibitor of CD19+ cells, in IgG4-related disease, Arthritis Rheum. 68
(Suppl. 10) (2016).
[110] Y. Sato, M. Kojima, K. Takata, T. Morito, H. Asaoku, T. Takeuchi, et al., Systemic
IgG4-related lymphadenopathy: a clinical and pathologic comparison to
multicentric Castleman’s disease, Mod. Pathol. 22 (2009) 589–599, https://doi.
org/10.1038/modpathol.2009.17.
[111] T.S. Chen, E. Figueira, O.C. Lau, P.A. McKelvie, R.I. Smee, L.C. Dawes, et al.,
Successful “medical” orbital decompression with adjunctive rituximab for severe
visual loss in IgG4-related orbital inflammatory disease with orbital myositis,
Ophthal. Plast. Reconstr. Surg. 30 (2014), https://doi.org/10.1097/
IOP.0b013e3182a64fa4 e122-5.
[112] Y.H. Lin, S.H. Yen, C.C. Tsai, S.C. Kao, F.L. Lee, Adjunctive orbital radiotherapy
for ocular adnexal IgG4-related disease: preliminary experience in patients
refractory or intolerant to corticosteroid therapy, Ocul. Immunol. Inflamm. 23
(2015) 162–167, https://doi.org/10.3109/09273948.2014.928735.