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Neuro-ophthalmic complications of IgG4-related disease

Chwalisz, Bart K.a; Stone, John H.b

Current Opinion in Ophthalmology: November 2018 - Volume 29 - Issue 6 - p 485–494
doi: 10.1097/ICU.0000000000000523
NEURO-OPHTHALMOLOGY: Edited by Dean M. Cestari

Purpose of review IgG4-related disease (IgG4-RD) is increasingly recognized as a fibroinflammatory disease with a plethora of organ-specific manifestations but a particular predilection for head and neck tissues, including the nervous system. This review discusses general features and organ-specific presentations of IgG4-RD as well as treatment considerations, particularly emphasizing features of neuro-ophthalmic interest.

Recent findings IgG4-RD is emerging as a common cause of several fibroinflammatory disorders in the head and neck that were previously considered idiopathic, such as sclerosing orbital pseudotumor, orbital myositis, hypophysitis, and hypertrophic pachymeningitis. New and unusual presentations continue to be described, including a number of vascular manifestations. Substantial progress has been made in elucidating the cell types involved in IgG4-RD, and new pathogenic models are being proposed. Although clinicopathologic correlation remains the cornerstone of diagnosis, ancillary tests such as flow cytometry for circulating plasmablasts and PET–computed tomography have high sensitivity, and certain radiologic features are recognized to be particularly suggestive, such as infraorbital nerve enlargement in IgG4-RD orbitopathy. IgG4-RD often responds to steroids but incomplete responses and relapses are common. Rituximab is emerging as a promising new therapy.

Summary The current review summarizes manifestations of IgG4RD that are of particular relevance to neuro-ophthalmic practice.

aDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School

bDepartment of Neuro-Ophthalmology, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts, USA

Correspondence to Bart K. Chwalisz, MD, Instructor in Neurology, Department of Neurology, Massachusetts General Hospital/Harvard Medical School, 15 Parkman Street, Suite 835, Boston, MA 02114, USA. Tel: +1 617 643 5533; e-mail: bchwalisz@mgh.harvard.edu

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INTRODUCTION

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory systemic disease that is increasingly recognized as a unifying diagnosis for several conditions once considered unrelated but now recognized to be linked by consistent clinical and serological findings as well as histopathological features. IgG4-RD often presents with disease features confined primarily or exclusively to the head and neck region or nervous system. Manifestations in the orbits, meninges, pituitary, and peripheral nerves are of special neuro-ophthalmic interest. IgG4-RD can also more rarely affect the brain parenchyma and vasculature. Prompt recognition of IgG4-RD is important not only because it is generally highly treatable, but also because its treatment frequently differs substantially from that of other conditions that present in a similar fashion.

The name of the disease notwithstanding, IgG4 antibodies themselves are unlikely to be the prime movers of this condition. Compared with antibodies of the other IgG subclasses, IgG4 demonstrates poor cross-linking activity owing to a unique posttranslational modification. In this modification, known as ‘Fab arm exchange’, the two halves of an individual IgG4 antibody can dissociate from each other at the hinge region and recombine with another half-antibody. The result is an ‘asymmetric’ IgG4 antibody in which the two Fab portions have specificity for two unrelated antigens [1]. The resulting bispecific antibodies are believed to bind complement poorly.

Because of this characteristic of IgG4, this antibody may serve an immune-dampening function [2]. In fact, IgG4 in IgG4-RD may actually serve as an ‘antigen sink’ at sites of inflammation. One compelling pathophysiologic model for the disease involves continuous presentation of antigen or antigens by B cells and plasmablasts to CD4+ cytotoxic lymphocytes, which in turn elaborate fibrogenic, tissue-injuring products, leading to organ dysfunction [3▪▪]. The striking serum elevations of IgG4-RD observed in many patients with active, multiorgan inflammation suggests that this IgG4 response is largely ineffectual in those with clinically evident disease.

Box 1

Box 1

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EPIDEMIOLOGY AND GENERAL CLINICAL FEATURES

IgG4-RD in general most commonly affects middle-aged to elderly men. However, disease involving the head and neck area appears to affect women and men in an equal distribution [4] and ocular manifestations may be particularly common in the pediatric population [5,6]. The most common types of organ involvement are autoimmune pancreatitis, sclerosing cholangitis, chronic sclerosing sialadenitis (especially of the submandibular glands), dacryoadenitis, and retroperitoneal fibrosis [7]. Disease manifestations are also well described in the lymph nodes, kidneys, lungs, pleuropericardium, prostate gland, meninges, and essentially every other organ in the body.

IgG4-RD usually presents in a subacute fashion. In many cases, symptoms and evidence of organ dysfunction may be present for months or years before the diagnosis is established [7]. There can be periods of stability and (rarely) spontaneous improvement in one organ before re-emergence in another. Certain systemic symptoms are common, for example, gradual but substantial weight loss, fatigue, malaise, arthralgias, and enthesopathy (inflammation at sites of tendon insertion) [7]. In addition, many patients have allergic features such as rhinitis, nasal polyps, chronic sinusitis, nasal obstruction, and a history of asthma or atopic dermatitis [7]. Sicca symptoms are common but generally milder than in Sjögren's syndrome. Diabetes mellitus and diabetes insipidus can result from involvement of the pancreas and pituitary gland, respectively. Fevers and fulminant clinical presentations are unusual.

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ASSESSMENT

The physical examination should be aimed at the detection of common sites of IgG4-RD involvement. Periorbital swelling, proptosis, ptosis, and lacrimal gland enlargement should be noted (Fig. 1). The neck should be examined for lymphadenopathy and enlargement of the major salivary and thyroid glands. Affected lymph nodes are generally moderate in size (1–3 cm), mobile, and nontender. Submandibular gland involvement is particularly characteristic [8] (Fig. 2). The general physical examination should also search for evidence of lung or pleural disease, icterus, and hepatosplenomegaly. IgG4-RD may involve the skin, leading to erythematous nodules and papules occurring most commonly in the head and neck regions [9].

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

High IgG4 serum concentrations in isolation are neither sufficiently sensitive nor specific to make the diagnosis of IgG4-RD but are useful in screening, correlate with number of organs involved and are moderately reliable as a biomarker following the initiation of treatment [7,10,11▪▪,12]. Diagnostic specificity is increased by a serum ratio of IgG4 to IgG1 more than 0.24 [13], and an even lower cutoff of 0.114 has been suggested in patients not exposed to corticosteroids [14]. The sensitivity of nephelometry assays for serum IgG4 concentrations may be affected adversely in a high percentage of patients by the occurrence of the prozone phenomenon in the setting of an extremely high serum IgG4 concentration [15]; this can be prevented by adequate dilution of the sample. Among patients who have not been treated, flow cytometry to detect circulating plasmablasts (CD19+CD20CD27+CD38+) has a high sensitivity for IgG4-RD but is not specific for the diagnosis, and not yet widely available [16].

Common nonspecific laboratory abnormalities include mild to moderate eosinophilia (up to 20%), high concentrations of IgE [7], IgG1 [17], IgG2 [18], and hypocomplementemia of C3 and C4. No specific autoantibodies are known to be associated with IgG4-RD. Erythrocyte sedimentation rate (ESR) elevations often result from the associated hypergammaglobulinemia. C-reactive protein concentrations are uncommonly elevated and usually disproportionately low compared with the ESR.

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RADIOLOGY

Imaging findings can be supportive of an IgG4-RD diagnosis. As an example, the constellation of lacrimal, parotid, and submandibular gland enlargement (often accompanied by lymphadenopathy) is consistent with IgG4-RD, albeit a biopsy would generally be necessary to exclude lymphoma. Further radiologic evidence of the disease might be found in computed tomographic scanning of the chest and abdomen. PET imaging is helpful in defining the extent of organ involvement [19].

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HISTOPATHOLOGY

IgG4-RD is a clinicopathologic diagnosis, with key pathologic features of lymphoplasmacytic infiltration (sometimes associated with eosinophilia), ‘storiform’ fibrosis, and obliterative phlebitis [7]. The ‘storiform’ pattern fibrosis (derived from ‘storea’, the Latin word for woven mat) is due to the orientation of collagen fibers in affected tissues in a radial, basket-weave arrangement (Fig. 3) [7,20]. Notably, fibrosis may be absent in lymph nodes, and obliterative phlebitis is usually not present in hypertrophic pachymeningitis or ocular adnexal disease [16,21]. The extent of fibrosis determines the extent to which the disease responds to immunosuppressive treatment. Immunohistochemistry typically shows a large percentage of IgG4-positive cells, but the reported cutoffs for IgG-positive cells per high-power field and IgG4 : IgG ratio have differed among studies [8,22].

FIGURE 3

FIGURE 3

Biopsy is critical not only to help confirm the diagnosis but also to exclude IgG4-RD mimickers. Of note, substantial presence of IgG4-positive plasma cells has been documented in multiple other inflammatory or neoplastic disorders. The presence of necrosis, granulomatous inflammation, and monoclonality of cell types within an affected organ all implicate other diagnoses, as do findings of a histiocytic predominance or xanthogranulomatous changes [4,7]. Infection should be excluded with AFB and fungal stains in addition to routine stains and cultures. Lymphoma must be excluded by assessments for light chain restriction or heavy chain rearrangement and by flow cytometry studies.

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IGG4-RELATED ORBITOPATHY

IgG4-RD orbitopathy is one of the more common manifestations of IgG4-RD, affecting approximately a quarter of the IgG4-RD patients [4]. The most typical presentation involves chronic, progressive, painless periorbital, lacrimal gland, or lid swelling, which can be unilateral or bilateral (Fig. 4) [8,23▪]. This may progress to frank ptosis or proptosis, which results from infiltration of inflammation into the extraocular muscles (EOMs), orbital fat, or connective tissue (Fig. 5a and b) [7]. The EOMs can be enlarged and their function impaired, causing diplopia. In contrast to thyroid eye disease, which favors the inferior and medial recti, the lateral rectus is the most commonly involved muscle [24]. Vision loss can occur secondary to optic neuropathy [21], and orbital mass lesions can mimic an optic nerve sheath meningioma [25]. Visual distortion can also occur from mass effect on the globe, leading to chorioretinal folds [26]. Facial paresthesiae may occur secondary to involvement of branches of the trigeminal nerve (Fig. 6), but permanent sensory loss seldom occurs. Scleritis [27] and nasolacrimal duct involvement [23▪] have also been reported in a small number of cases.

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

FIGURE 6

FIGURE 6

The duration of symptoms may be remarkably long, extending over months and even years. Many patients with IgG4-RD of the orbit have been previously misdiagnosed with ‘idiopathic orbital inflammation’ (particularly the sclerosing subtype) or ‘orbital myositis’. Extraophthalmic manifestations are more likely in patients with bilateral involvement, longer symptom duration and higher serum IgG4 level [12,23▪,28].

The differential diagnosis of IgG4-RD-related ophthalmic disease includes idiopathic orbital inflammation, lymphoma, metastatic disease, infection, sarcoidosis, granulomatosis with polyangiitis, thyroid eye disease, Erdheim–Chester disease, and other histiocytoses such as the adult-onset asthma and periocular xanthogranuloma syndrome [4]. Compared with IgG4-RD, idiopathic orbital inflammation typically has an acute onset with pain, proptosis, injection, and restricted eye movement.

An increased risk of lymphoproliferative disorders, particularly mucosa-associated lymphoid tissue lymphoma, has been suggested in IgG4-RD [8,29,30,31▪]. Although it is conceivable that transformation to lymphoma may occur following disease affecting the ocular adnexa, it is clear that malignant transformation occurs in only a small minority of patients with IgG4-RD.

Radiology may show enlargement of the lacrimal, salivary or pituitary glands or localized nodules or masses [32,33]. The lesions are generally well defined and visible on computed tomography (CT), but the sensitivity of MRI is greater. On MRI, lesions are isointense on T1, isointense or hypointense on T2/fluid-attenuated inversion recovery, and demonstrate homogeneous enhancement [32,34]. Bone remodeling and rarely destruction can be seen. Concomitant lymphadenopathy may suggest lymphoma, but vascular occlusion or compression is atypical. IgG4-RD cervical lymphadenopathy is frequently unilateral, 2–3 cm in size, without central necrosis or perinodal infiltration, and most commonly affects the submandibular region [35].

The orbital myositis associated with IgG4-RD causes a smooth swelling of the muscles and tendons, unlike thyroid eye disease, which primarily affects the muscle bellies (Fig. 7) [4]. In some cases, there is radiologic involvement of the optic nerve sheath or intracranial extension involving the dura, pituitary, cavernous sinus, pterygopalatine fossa, and masticator space (Fig. 8) [8,32].

FIGURE 7

FIGURE 7

FIGURE 8

FIGURE 8

A characteristic feature is radiologic involvement of branches of the trigeminal nerve. In particular, enlargement of the infraorbital nerve and expansion of its canal correlates well with IgG4-RD, and can be diagnosed whenever the coronal section of the infraorbital nerve is larger than that of the optic nerve [36,37]. Some patients with trigeminal nerve involvement report facial paresthesiae, but many are asymptomatic.

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HYPERTROPHIC PACHYMENINGITIS AND CENTRAL NERVOUS SYSTEM PARENCHYMAL DISEASE

IgG4-RD is a common cause of hypertrophic pachymeningitis [38]. Men are affected more commonly than women, and peak incidence is in the sixth and seventh decades of life. Typical symptoms include headache and neurologic deficits dictated by the site of involvement. In one series, neurological issues included cranial nerve palsies (33%), vision problems (21%), motor weakness (15%), limb numbness (12%), seizures (6%), cognitive decline (3%), and gait instability [39]. Such deficits are likely to arise from compression of vascular or neural structures.

Serological investigations are often unremarkable if only the meninges are involved. Cerebrospinal fluid (CSF) studies typically demonstrate a lymphocytic pleocytosis (total nucleated cell count range 6–378), often accompanied by an elevated CSF protein [38]. These findings lack specificity and fail to distinguish IgG4-RD-associated hypertrophic pachymeningitis from other causes of this presentation. Patients with IgG4-RD-associated hypertrophic pachymeningitis may have elevations of CSF IgG4 level and IgG4 serum : CSF index, indicating intrathecal production of IgG4 [39,40]. Contrast-enhanced MRI is the study of choice for demonstrating pachymeningeal thickening and enhancement. The dura may be smooth with homogeneous linear enhancement (Fig. 9), or nodular with mass effect (Fig. 10). The latter type can mimic a meningioma. CT scans are useful for delineating associated bone involvement.

FIGURE 9

FIGURE 9

FIGURE 10

FIGURE 10

IgG4-RD-associated hypertrophic pachymeningitis may be contiguous with disease in the orbit, sinuses or pituitary gland. Cerebral involvement by IgG4-RD (‘pachymeningoencephalitis’) is exceptional but has been reported, characterized by prominent motor weakness and radiologic lesions that are T2 hyperintense and T1 hypointense with contrast enhancement [41–43].

Hypertrophic pachymeningitis has a broad differential that includes infections such as tuberculosis, lymphoma and other malignancies, and immune-mediated conditions such as sarcoidosis, rheumatoid arthritis, Behçet's disease, granulomatosis with polyangiitis, and giant cell arteritis. Pathological confirmation of IgG4-RD is therefore required.

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LESIONS OF THE PITUITARY GLAND AND STALK (INFUNDIBULO-HYPOPHYSITIS)

Patients with IgG4-related infundibulo-hypophysitis present with visual symptoms or endocrine dysfunction in the setting of a pituitary mass or a thickened pituitary stalk [44]. Symptoms may include general malaise, headache, visual impairment, diplopia, fever, appetite loss, weight loss, polyuria, and decreased libido [45]. Neurologic symptoms may arise from compression of the optic pathways or other cranial nerves by an enlarged pituitary gland. Decreased visual acuity and color vision and visual field defects, classically bitemporal hemianopia, may result from compression of the optic nerve or chiasm, and direct intrachiasmatic involvement is also possible [46]. In some cases, symptoms may be rapidly progressive, warranting initial surgical decompression [47].

The evaluation should include serum assays for hormones stimulating end organs in the hypothalamus–pituitary axis: luteinizing hormone and follicle stimulating hormone, adrenocorticotrophic hormone, thyroid stimulating hormone, growth hormone, prolactin, and electrolytes. Diabetes insipidus is common but may be masked. Abnormalities include isolated hypogonadism, central hypothyroidism or adrenocorticotropic hormone deficiency, or combined anterior pituitary hormone deficiencies [44]. Hyperprolactinemia may occur due to the stalk defect.

Radiologic studies demonstrate a symmetrically enlarged pituitary gland with thickened stalk (Fig. 11). There may be absence of the normal precontrast T1 hyperintensity of the posterior pituitary gland, which can be associated with central diabetes insipidus [32]. There is often involvement of the adjacent sphenoid sinus, meninges, or trigeminal nerve branches, which may extend into the orbit.

FIGURE 11

FIGURE 11

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CAROTID AND INTRACEREBRAL VASCULAR DISEASE

Although aortic disease with inflammation of the arterial wall is a well known complication IgG4-RD, involvement of the cervical and cerebral vessels is probably rare or at least usually subclinical. One patient had carotid and intracerebral inflammatory aneurysms in addition to retroperitoneal fibrosis, aortitis, and involvement of the iliac vessels [48]. Another patient has been reported with carotid aneurysm evolving into an acute dissection [49]. Vertebral dolichoectasia [50] and diffuse intracranial dilating vasculopathy with recurrent subarachnoid hemorrhage have been reported [51]. We have seen one patient whose clinical picture closely mimicked giant cell arteritis, whose temporal artery biopsy revealed inflammation of the vessel wall with IgG4-RD pathology [52].

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TREATMENT

IgG4-RD generally responds well to treatment, but chronic or recurrent courses of therapy are required for many patients. It is desirable to initiate immunosuppression at a stage when the dominant histopathology is a lymphoplasmacytic infiltrate rather than an acellular fibrosis, as the latter is often treatment-refractory.

Most manifestations of IgG4-RD can be treated successfully with glucocorticoids, which are currently the first-line standard of care for this condition. On the contrary, responses to treatment with glucocorticoids are often incomplete, relapses are common, and substantial treatment-related morbidity may occur [23▪,53]. B-cell depletion with rituximab has good efficacy in IgG4-RD [54], and sheds light onto the role of plasma cells and their B-cell precursors in the pathogenesis of IgG4-RD [20]. Radiotherapy may exceptionally be employed in refractory cases [23▪].

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CONCLUSION

IgG4-RD is a complex and fascinating disorder that unifies diverse manifestations in multiple organ system with a shared histopathology. A variety of neuro-ophthalmic manifestations have been recognized. The diagnosis can be suspected based on a combination of a full clinical history, physical examination, and appropriate laboratory and radiologic tests, but pathologic confirmation of the diagnosis is desirable. When recognized and treated appropriately, the prognosis is usually good. Early institution of treatment to prevent chronic fibrosis or other irreversible tissue injury is important.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

1. van der Neut Kolfschoten M, Schuurman J, Losen M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 2007; 317:1554–1557.
2. Xiao X, Lian M, Zhang W, et al. The immunologic paradoxes of IgG4-related disease. Clin Rev Allergy Immunol 2018; 54:344–351.
3▪▪. Perugino CA, Mattoo H, Mahajan VS, et al. Emerging treatment models in rheumatology: IgG4-related disease: insights into human immunology and targeted therapies. Arthritis Rheumatol 2017; 69:1722–1732.

Authoritative review of the historical development of treatment of IgG4-related disease (IgG4-RD), and its rationale.

4. Wallace ZS, Deshpande V, Stone JH. Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review. Semin Arthritis Rheum 2014; 43:806–817.
5. Karim F, Loeffen J, Bramer W, et al. IgG4-related disease: a systematic review of this unrecognized disease in pediatrics. Pediatr Rheumatol Online J 2016; 14:18.
6. Smerla RG, Rontogianni D, Fragoulis GE. Ocular manifestations of IgG4-related disease in children. More common than anticipated? Review of the literature and case report. Clin Rheumatol 2018; 37:1721–1727.
7. Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015; 385:1460–1471.
8. Ferry JA, Deshpande V. IgG4-related disease in the head and neck. Semin Diagn Pathol 2012; 29:235–244.
9. Ikeda T, Oka M, Shimizu H, et al. IgG4-related skin manifestations in patients with IgG4-related disease. Eur J Dermatol 2013; 23:241–245.
10. Carruthers MN, Khosroshahi A, Augustin T, et al. The diagnostic utility of serum IgG4 concentrations in IgG4-related disease. Ann Rheum Dis 2015; 74:14–18.
11▪▪. Martinez-Valle F, Fernandez-Codina A, Pinal-Fernandez I, et al. IgG4-related disease: evidence from six recent cohorts. Autoimmun Rev 2017; 16:168–172.

Summary of evidence from recent cohort studies.

12. Hong JW, Kang S, Song MK, et al. Clinicoserological factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease. British J Ophthalmol 2018; Feb 2. DOI: 10.1136/bjophthalmol-2017-311519.
13. Boonstra K, Culver EL, de Buy Wenniger LM, et al. Serum IgG4 and IgG1 for distinguishing IgG4-associated cholangitis from primary sclerosing cholangitis. Hepatology 2014; 59:1954–1963.
14. Xia CS, Fan CH, Liu YY. Diagnostic performance of serum IgG4 concentration and IgG4/IgG ratio in IgG4-related disease. Clin Rheumatol 2017; 36:2769–2774.
15. Khosroshahi A, Cheryk LA, Carruthers MN, et al. Brief report: spuriously low IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease. Arthritis Rheumatol 2014; 66:213–217.
16. Wallace ZS, Mattoo H, Carruthers MN, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis 2014; 74:190–195.
17. Sato Y, Notohara K, Kojima M, et al. IgG4-related disease: historical overview and pathology of hematological disorders. Pathol Int 2010; 60:247–258.
18. Chan ASY, Mudhar H, Shen SY, et al. Serum IgG2 and tissue IgG2 plasma cell elevation in orbital IgG4-related disease (IgG4-RD): potential use in IgG4-RD assessment. Br J Ophthalmol 2017; 101:1576–1582.
19. Nakatani K, Nakamoto Y, Togashi K. Utility of FDG PET/CT in IgG4-related systemic disease. Clin Radiol 2012; 67:297–305.
20. Lighaam LC, Aalberse RC, Rispens T. IgG4-related fibrotic diseases from an immunological perspective: regulators out of control? Int J Rheumatol 2012; 2012:789164.
21. Ebbo M, Patient M, Grados A, et al. Ophthalmic manifestations in IgG4-related disease: clinical presentation and response to treatment in a French case-series. Medicine (Baltimore) 2017; 96:e6205.
22. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012; 25:1181–1192.
23▪. Park J, Lee MJ, Kim N, et al. Risk factors for extraophthalmic involvement and treatment outcomes in patients with IgG4-related ophthalmic disease. British J Ophthalmol 2018; 102:736–741.

Retrospective study of risk factors that predict extraophthalmic involvement in patients presenting with IgG4-related ophthalmic disease in a Korean cohort.

24. Tiegs-Heiden CA, Eckel LJ, Hunt CH, et al. Immunoglobulin G4-related disease of the orbit: imaging features in 27 patient. AJNR Am J Neuroradiol 2014; 35:1393–1397.
25. Noshiro S, Wanibuchi M, Akiyama Y, et al. IgG4-related disease initially presented as an orbital mass lesion mimicking optic nerve sheath meningioma. Brain Tumor Pathol 2015; 32:286–290.
26. Kurokawa T, Hamano H, Muraki T, et al. Immunoglobulin G4-related dacryoadenitis presenting as bilateral chorioretinal folds from severely enlarged lacrimal glands. Am J Ophthalmol Case Rep 2018; 9:88–92.
27. Karim F, De Hoog J, Paridaens D, et al. IgG4-related disease as an emerging cause of scleritis. Acta Ophthalmol 2017; 95:e795–e796.
28. Wu A, Andrew NH, McNab AA, et al. Bilateral IgG4-related ophthalmic disease: a strong indication for systemic imaging. Br J Ophthalmol 2016; 100:1409–1411.
29. Cheuk W, Yuen HKL, Chan CL, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am J Surg Pathol 2008; 32:1159–1167.
30. Wallace ZS, Wallace CJ, Lu N, et al. Association of IgG4-related disease with history of malignancy. Arthritis Rheumatol 2016; 68:2283–2289.
31▪. Bledsoe JR, Wallace ZS, Stone JH, et al. Lymphomas in IgG4-related disease: clinicopathologic features in a Western population. Virchows Arch 2018; 472:839–852.

Retrospective pathologic case series that suggests that IgG4-RD and lymphoma can co-occur, but that lymphomas in IgG4-RD are more varied in location and type than previously suggested in Asian cohorts

32. Katsura M, Mori H, Kunimatsu A, et al. Radiological features of IgG4-related disease in the head, neck and brain. Neuroradiology 2012; 54:873–882.
33. Thompson A, Whyte A. Imaging of IgG4-related disease of the head and neck. Clin Radiol 2018; 73:106–120.
34. Song YS, Choung HK, Park SW, et al. Ocular adnexal IgG4-related disease: CT and MRI findings. Br J Ophthalmol 2013; 97:412–418.
35. Kawaguchi M, Kato H, Kito Y, et al. Imaging findings of primary immunoglobulin G4-related cervical lymphadenopathy. Neuroradiology 2017; 59:1111–1119.
36. Ohshima K, Sogabe Y, Sato Y. The usefulness of infraorbital nerve enlargement on MRI imaging in clinical diagnosis of IgG4-related orbital disease. Jpn J Ophthalmol 2012; 56:380–382.
37. Ben Soussan J, Deschamps R, Sadik JC, et al. Infraorbital nerve involvement on magnetic resonance imaging in European patients with IgG4-related ophthalmic disease: a specific sign. Eur Radiol 2017; 27:1335–1343.
38. Wallace ZS, Carruthers MN, Khosroshahi A, et al. IgG4-related disease and hypertrophic pachymeningitis. Medicine 2013; 92:206–216.
39. Lu LX, Della-Torre E, Stone JH, Clark SW. IgG4-related hypertrophic pachymeningitis. Clinical features, diagnostic criteria, and treatment. JAMA Neurol 2014; 71:785–793.
40. Fernandez-Codina A, Hernandez-Gonzalez M, Solans-Laque R, et al. Alteration of IgG4 levels in cerebrospinal fluid in IgG4-related disease. Int J Rheum Dis 2017; 20:1865–1867.
41. Kim EH, Kim SH, Cho JM, et al. Immunoglobulin G4-related hypertrophic pachymeningitis involving cerebral parenchyma. J Neurosurg 2011; 115:1242–1247.
42. Regev K, Nusbaum T, Cagnano E, et al. Central nervous system manifestation of IgG4-related disease. JAMA Neurol 2014; 71:767–770.
43. Li L, Tse PH, Tsang FC, et al. IgG4-related hypertrophic pachymeningitis at the falx cerebri with brain parenchymal invasion: a case report. World Neurosurg 2015; 84:591.e7–591.e10.
44. Shimatsu A, Oki Y, Fujisawa I, Sano T. Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocrine J 2009; 56:1033–1041.
45. Decker L, Crawford AM, Lorenzo G, et al. IgG4-related hypophysitis: case report and literature review. Cureus 2016; 8:e907.
46. Hadjigeorgiou GF, Lund EL, Poulsgaard L, et al. Intrachiasmatic abscess caused by IgG4-related hypophysitis. Acta Neurochir 2014; 159:2229–2233.
47. Yuen KCJ, Moloney KJ, Mercado JU, et al. A case series of atypical features of patients with biopsy-proven isolated IgG4-related hypophysitis and normal serum IgG4 levels. Pituitary 2018; 21:238–246.
48. Ebbo M, Daniel L, Pavic M, et al. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine 2012; 91:49–56.
49. Barp A, Fedrigo M, Farino FM, et al. Carotid aneurism with acute dissection: an unusual case of IgG4-related diseases. Cardiovasc Pathol 2016; 25:59–62.
50. Toyoshima Y, Emura I, Umeda Y, et al. Vertebral basilar system dolichoectasia with marked infiltration of IgG4-containing plasma cells: a manifestation of IgG4-related disease? Neuropathology 2012; 32:100–104.
51. Marlin ES, Dornbos D III, Ikeda DS, et al. IgG4-related disease: a new etiology underlying diffuse intracranial dilating vasculopathy. World Neurosurg 2017; 107:1048.e15–1048.e20.
52. Monach P, Nazarian R, Stone JH. Case 6-2017. A 57-year-old woman with fatigue, sweats, weight loss, headache, and skin lesions. N Engl J Med 2017; 376:775–786.
53. Perugino CA, Stone JH. Treatment of IgG4-related disease: current and future approaches. Z Rheumatol 2016; 75:681–686.
54. Carruthers M, Topazian M, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis 2015; 74:1171–1177.
Keywords:

hypertrophic pachymeningitis; hypophysitis; IgG4-related disease; orbital myositis; orbital pseudotumor

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