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IgG4-Related Disease: A Neuro-Ophthalmological Perspective

Kashii, Satoshi MD, PhD

Section Editor(s): Biousse, Valérie MD; Galetta, Steven MD

doi: 10.1097/WNO.0000000000000193
State-of-the-Art Review

Abstract: Immunoglobulin G4–related disease (IgG4-RD) is a multifocal inflammatory disorder that causes tumefactive lesions with a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells and storiform-pattern fibrosis. The clinical symptoms are relatively mild, and the condition is usually recognized by organ swelling and damage. When referring to the ophthalmic manifestations of IgG4-RD, the term IgG4-related ophthalmic disease (IgG4-ROD) is used. IgG4-ROD is characterized by bilateral lacrimal gland enlargement accompanied by 3 distinctive features: infraorbital nerve enlargement, extraocular myositis, and compressive optic neuropathy. IgG4 implies an underlying systemic disease process requiring evaluation to detect other systemic involvement. This includes hypophysitis and hypertrophic pachymeningitis, entities of neuro-ophthalmic interest. IgG4-ROD usually responds favorably to systemic corticosteroids but may be complicated by relapse during steroid taper. Rituximab has been shown to be effective for controlling steroid-refractory IgG4-RD. In contrast to IgG4-RD, an increasing number of cases of extranodal marginal B-cell lymphoma (MALT type) associated with IgG4-ROD have been described. IgG4 may be a risk factor for later emergence of low-grade B-cell lymphoma.

Department of Visual Sciences and Ophthalmology, Faculty of Health and Medical Sciences, Aichi Shukutoku University, Aichi, Japan.

Address correspondence to Satoshi Kashii, MD, PhD, Department of Visual Sciences and Ophthalmology, Faculty of Health and Medical Sciences, Aichi Shukutoku University, Nagakute Campus, Aichi 480-1197, Japan.

The authors report no conflicts of interest.

A companion article by Yamamoto et al (1) presents an historical and general overview of IgG4-related disease (IgG4-RD). Neuro-ophthalmic manifestations of this disorder are the subject of this review.

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In 2011, the organizing committee of the International Symposium on IgG4-RD adopted the term IgG4-RD to describe a multifocal inflammatory disorder that causes tumefactive lesions with a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells and storiform-pattern fibrosis (2). The systemic disease affects almost all organs. Although there are some exceptions such as IgG4-related lymphadenopathy or the membranous glomerulonephritis secondary to IgG4-RD, the histopathologic findings generally show marked similarities across affected organs. The designation IgG4-related ophthalmic disease (IgG4-ROD) was proposed when referring to the ophthalmic manifestations of IgG4-RD, with more specific terms applied with involvement of the lacrimal glands, extraocular muscles, and other orbital structures (Table 1).

The diagnostic criteria for IgG4-RD are not yet firmly established nor are those for IgG4-ROD. The unifying features linking the disparate manifestations of IgG4-RD include characteristic histopathologic appearance and elevated number of IgG4+ plasma cells within organ tissue (3) (see table 1 in Ref. 1). Increased numbers of infiltrating IgG4-bearing plasma cells within involved organs are the sine qua non of the diagnosis. Although IgG4+/IgG+ plasma cell ratio in tissue >40% is generally accepted for diagnosis, there are some discordance in cutoff values of IgG4+ plasma cells. Comprehensive diagnostic criteria for IgG4-RD proposed by the Japanese IgG4-RD study groups set IgG4+ plasma cell counts >10 cells/high power field (HPF: magnification ×400) along with the IgG4+/IgG+ ratio >40% in the affected tissue (4). Both IgG4+ cell numbers and IgG4+/IgG+ cell ratio are required for diagnosis. Elevated serum IgG4 titers (>135 mg/dL) are not a diagnostic requirement as levels can be normal in 40% of patients with biopsy-proven IgG4-RD (5).

The Japanese study group on IgG4-ROD reported the prevalence of IgG4-ROD based on either the number of IgG4+ plasma cells >30/HPF or a ratio of IgG4+/IgG+ cells >40% (6). In contrast, the Massachusetts General Hospital Center for IgG4-RD applied a cutoff of >100 IgG4+ plasma cells/HPF for IgG4-ROD of the lacrimal glands (7). This seems based on a single study of 6 cases with chronic sclerosing dacryoadenitis (8). Deschamps et al (9) have questioned the validity of the >100 cells per HPF threshold, indicating that a significant number of previously reported cases of IgG4-related orbital inflammation fell short of this threshold and that the variability of the cutoff value reflected heterogeneity of immunostaining for IgG4, the variability of selected sites for counting and sizes of HPF. The Japanese study group on IgG4-ROD now advocates a ratio of IgG4+/IgG+ cells >40% and the number of IgG4+ cells >50 cells/HPF (10). To further complicate matters, typical histologic findings, such as storiform-type fibrosis and obliterative phlebitis may be absent in lacrimal gland involvement. Currently, it seems prudent when making the diagnosis of IgG4-ROD to use the proposed 3-tiered diagnostic terminology for IgG4-RD (3) (see table 1 in Ref. 1).

Table 2 summarizes the demographic data of 6 large case series of patients with IgG4-ROD. Although male predominance is characteristic of IgG4-RD, there is no gender predilection in IgG4-ROD (15). Bronchial asthma and allergic rhinitis are systemic conditions frequently associated with IgG4-ROD (16,17).

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The lacrimal gland is the most common site of IgG4-ROD and usually affected bilaterally. Yamamoto et al (18) first reported elevated serum IgG4 in patients with Mikulicz disease, characterized by symmetrical swelling of the lacrimal and/or major salivary glands. From studies conducted by the Japanese Society of Sjörgen syndrome (SjS) (19,20), it has become clear that SjS and Mikulicz disease are different clinical entities (see table 2 in Ref. 1). The most distinguishing feature lies in the pathological appearance of Mikulicz disease characterized by marked infiltration of IgG4+ plasma cells, with a ratio of IgG4+ of >40%. This is rarely seen in patients with SjS. In contrast to SjS, Mikulicz disease is not associated with antinuclear antibody or anti-Ro or anti-La antibodies (21). Mikulicz disease had not been regarded as a systemic disease until reports documented its association with extraglandular disorders, including allergic rhinitis, interstitial pneumonia, autoimmune pancreatitis, and interstitial nephritis (16). In a report of 44 patients with Mikulicz disease, approximately one-half had distant lesions consistent with IgG4-RD (22).

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Sato et al (23) conducted the first large review of 112 patients with ocular adnexal lymphoproliferative disorders diagnosed between 1990 and 2006 and identified 21 cases of IgG4-orbital disease using the stored tissue samples. The diagnostic criterion used was 10 IgG4+ plasma cells per HPF. Of the 21 patients, 17 had lacrimal gland involvement with bilateral involvement in 12. Obliterative phlebitis was detected in only 2 patients, possibly indicating that obliterative phlebitis was organ-specific and not a clinical feature of IgG4-RD. In another study of archived paraffin-embedded tissues of orbital biopsy specimens, 21 patients were diagnosed with idiopathic orbital inflammation or reactive lymphoid hyperplasia (RLH) of which 11 (54%) had increased IgG4 cells (>10/HPF) (24). Unique clinical features of the IgG4 patients included eyelid swelling, bilateral orbital involvement, other organ involvement (pancreas, biliary tract, and liver), and a prolonged clinical course. A history of asthma was noted in 5 patients. In another retrospective study using archived biopsied specimens, 10 of 25 (40%) patients with idiopathic orbital inflammation fulfilled both criteria >10 IgG4+ plasma cells per HPF and ratios of IgG4+/IgG plasma cells >40%. Only 2 of 10 patients with a positive biopsy for IgG4 had bilateral involvement, and no distinctive systemic features in the IgG4+ patients were detected compared with IgG4-negative patients.

Neuroimaging of IgG4-ROD reveals orbital lesions with soft tissue attenuation and well-defined margins on precontrast CT, isosignal intensity on T1-weighted magnetic resonance imaging (MRI), hypointensity of T2-weighted scans reflecting increased cellularity and fibrosis, and a homogenous enhancement pattern after intravenous contrast (25). Lesions usually are not destructive, and bone adjacent to the lesions demonstrates remodeling without destruction (26). However, there are case reports of destructive bone involvement in biopsy-proven IgG4-RD, especially in cases affecting the paranasal sinuses (7,27–29). IgG4-RD involving the nasal cavity and paranasal sinuses also may show perineural and bone marrow infiltration mimicking malignant lymphoma (30).

In an orbital imaging study of 65 patients with IgG4-related orbital disease by Sogabe et al (31), lacrimal gland involvement was present in 56 patients (88%) of these 56 patients, it was isolated in 31 and bilateral in 52. Isolated lacrimal gland enlargement and trigeminal nerve enlargement were seen in 49% (31/65). After lacrimal gland enlargement, (40%, 25/65), extraocular myositis (25%, 16/65) and compressive optic neuropathy (9%, 6/65) were the most frequent imaging findings. There are some clinical features that distinguish IgG4-related orbital disease from idiopathic orbital inflammation (Table 3).

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Extraocular muscle involvement has not been reported in isolation but rather accompanied by involvement of the lacrimal gland, infra-orbital nerve, and/or surrounding orbital soft tissue. Sogabe et al (31) found no predilection for any particular extraocular muscle in 16 patients with IgG4-related orbital disease. Only 3 of the 16 patients had restricted eye movements. The disparity between the enlargement of extraocular muscles on CT and relatively spared eye movements seems suggestive of IgG4-related orbital myositis. In a case of biopsy-confirmed IgG4-related orbital myositis, the lateral rectus muscle was diffusely expanded with an inflammatory infiltrate composed of lymphoid follicles and abundant plasma cells of which >90% were IgG4+ (32). On occasion, it may be difficult to differentiate thyroid eye disease from IgG4-related orbital disease (33).

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In contrast to IgG4-ROD primarily affecting the lacrimal gland, Mehta et al (34) reported a unique case of IgG4-related orbital sclerosing pseudotumor involving the orbital periosteum preferentially and sparing the lacrimal glands. Biopsy of the orbital mass revealed a classic histopathologic picture of idiopathic sclerosing inflammation with scattered lymphoid aggregates without germinal center. IgG4-positive plasma cells (>35 per HPF) were identified in the lymphoid clusters. The authors proposed 2 types of IgG4-ROD (Table 4).

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The consensus statement on Pathology of IgG4-RD (3) listed a number of conditions that fall outside the IgG4-RD spectrum, which may be associated with increased number of IgG4+ plasma cells. This includes anti-neutrophil cytoplasmic antibody (ANCA)–associated vasculitis, Rosai–Dorfman disease, and multicentric Castleman disease. It remains unsettled whether there is a xanthogranulomatous variant of IgG4-ROD. Orbital xanthogranulomas is a histiocytic disorder of non-Langerham cells (class II) and divided into 4 categories: adult-onset xanthogranuloma (AOX) typically not associated with systemic lesions, adult-onset asthma and periocular xanthogranulomatous (AAPOX), necrobiotic xanthogranuloma, and Erdheim–Chester disease. Sivak-Callcot et al (35) have shown that xanthogranulomatous lesions are localized to the anterior preseptal portion of the orbit. Some reports suggest that xanthogranulomatous cases are a variant of IgG4-ROD (36,37), whereas others contend that AOX and AAPOX may be manifestations of IgG4-ROD (7).

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Trigeminal nerve branch enlargement is a unique clinical feature of IgG4-related orbital disease. Ohshima et al (38) first called attention to infra-orbital nerve enlargement (see figure 2 in Ref. 1), as a useful clinical sign for IgG4-related orbital disease based on their case series study of 71 patients with orbital lymphoproliferative disorders. Subsequent reports have confirmed these findings (26,39). Sogabe et al (31) documented this in 25 of 65 (40%) of these patients, with bilateral involvement in 16 of 25 (40%). Interestingly, none of the patients with trigeminal nerve enlargement complained of sensory disturbances. Hardy et al (40) examined IgG4-positivity of stored orbital biopsy samples in 14 patients including 6 specimens with infra-orbital nerve lesions. Immunophenotypic compatibility was based on an absolute IgG4 cell count of >10 cells per HPF. Seven specimens fulfilled this criterion, whereas the rest were categorized as RLH. All cases of infra-orbital nerve enlargement also had extraocular muscle enlargement and sinus disease. Two-thirds also had lacrimal gland enlargement. Inflammatory infiltration of the trigeminal epineurium was present in all 6 biopsy specimens, whereas the endoneurium and perineurium were unaffected. The lack of involvement of the perineurium or nerve fibers of the trigeminal nerve may explain the lack of sensory symptoms.

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Sixteen patients with optic nerve involvement have been reported in the literature (age range, 28–73; male/female ratio: 13/3) (8,24,31,32,41) (Fig. 1). Presumed causes of the optic neuropathy include infra-orbital nerve enlargement compressing the optic nerve in the orbital apex in 5 patients, a localized orbital mass surrounding the optic nerve in 5 patients, extraocular muscle enlargement in the orbital apex in 3 patients, a diffuse orbital fat lesion surrounding the optic nerve in 2 patients, and localized orbital mass compressing the optic nerve in 1 patient. In 4 patients, Inoue et al (41) demonstrated that IgG4-related compressive optic neuropathy was steroid-responsive including 1 patient with recurrence during steroid taper that promptly responded to an increased dose of steroids. On MRI, the lesion was reduced in size but was still present. It is possible that the optic neuropathy may be due to an infiltrative or inflammatory process, given the observation of perineural spread of IgG4 plasma cells along the trigeminal nerve.

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According to the prevalence study of the Japanese multicenter study group (6), IgG4-ROD accounts for about a quarter of orbital lymphoproliferative disorders in Japan. In that report, 44 of 448 (9.8%) cases of extranodal marginal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type were found to have IgG4+ plasma cell infiltrates. In contrast to IgG4-RD in other organs, the extensive morphologic overlap with reactive lesions and low-grade B-cell lymphoma has been described in IgG4-related orbital disease (32). Cheuk et al (42) first reported 6 patients with ocular adnexal lymphoma associated with IgG4-related chronic dacryoadenitis. Monoclonal B-cell proliferation, as demonstrated by the presence of monoclonal immunoglobulin heavy chain gene rearrangement or light chain restriction, was documented in 2 of 17 (12%) patients (14) and 2 of 14 (14.3%) (23) patients with IgG4-related orbital disease. A number of case series have raised the issue whether MALT lymphomas develop from IgG4-related orbital inflammation or IgG4-producing cells are capable of transforming to de novo IgG4-orbital MALT lymphoma (12,43–45).

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ANCA-associated vasculitis may affect ocular adnexa and create a clinical appearance of idiopathic orbital inflammation accompanied by hyper-IgG4 gammaglobulinemia and increased number of IgG4 plasma cells. ANCA vasculidities include microscopic polyangiitis, granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), and eosinophilic granulomatosis with polyangitis (formerly known as Churg–Strauss Syndrome). These lesions are characterized by the presence of granulomatous inflammation with vasculitis and necrosis. Periocular pain can differentiate these patients from those with IgG4-related orbital disease who do not complain of pain.

Multicentric Castleman disease has been recognized to exhibit hyper-IgG4 gammaglobulinemia and IgG4+ plasma cell infiltration with fibrosclerosis of tissue. In such cases, measurement of the serum interleukin-6 has been recommended to differentiate Castleman disease from IgG4-ROD and to determine whether corticosteroids should be initiated (16).

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Central nervous system involvement of IgG4-RD has been described in the form of either hypophysitis (46) or hypertrophic cranial pachymeningitis (47).

The pituitary gland and stalk are known to be involved in IgG4-related systemic disease (48). The first pathologically proven case of IgG4-related hypophysitis was a 77-year-old man with a medical history of autoimmune pancreatitis and sclerosing cholangitis who reported visual failure over several months (49). He was found to have optic atrophy due to a suprasellar mass. Transsphenoidal resection revealed a histopathology compatible with IgG4-RD. Immunohistochemical study also showed IgG4+ plasma cell infiltration in the pancreatic biopsy and cholecystectomy specimen. Thirty-five cases of IgG4-related hypophysitis have been reported based on the presence of pituitary and stalk lesions associated with high serum IgG4 levels and/or histopathologic findings of pituitary biopsy (50,51). Pituitary biopsies were performed in 14 cases. Twelve biopsies showed IgG4+ plasma cell infiltration. Twenty-nine cases (83%) were men, and ages ranged from the third to ninth decade (mean: 65.7 years). In contrast to lymphocytic hypophysitis that primarily affects women, IgG4-related hypophysitis seems to develop in older men. Twenty-five patients presented with hypopituitarism and 21 with diabetes insipidus. In two-thirds of cases, both pituitary and stalk enlargement (infundibulo-hypophysitis) were observed on neuroimaging. Five patients (14%) had isolated hypophysitis without any other lesions. One of them presented bitemporal hemianopia that was the sole clinical manifestation of the biopsy-proven IgG4-related hypophysitis (52). Thirty patients had other IgG4-related systemic diseases, including pulmonary lesions, retroperitoneal fibrosis, autoimmune pancreatitis, lymph node swelling, salivary and/or lacrimal glands lesions, pachymeningitis, and kidney lesions. Of note, Shimatsu et al (53) found that in patients with IgG4-related hypophysitis there was an association with pachymeningitis, sinusitis, and/or orbital inflammation. Lymphocytic hypophysitis is considered to rarely spread to the surrounding structures in contrast to IgG4-related hypophysitis (54).

Hypertrophic pachymeningitis is a chronic fibrosing inflammatory disorder causing diffuse or localized thickening of the cranial and spinal cord dura mater. According to a recent nationwide survey of hypertrophic pachymeningitis (n = 159) in Japan (55), headache was the most common initial symptoms (56/159, 35%), followed by ophthalmological symptoms, such as visual loss (21/159, 14%), and diplopia (20/159, 13%). Known causes included ANCA-associated vasculitis (48/159, 30%) and IgG4-RD (14/159, 9%). Six additional patients with ANCA-associated vasculitis also showed either hyper-IgG4 gammaglobulinemia or increased number of IgG4+ plasma cells in the biopsied dura. IgG4-related hypertrophic pachymeningitis (IgG4-RHP, n = 14) affected predominantly men, whereas ANCA-RHP preferentially affected women. There was no difference in age at onset between IgG4-RHP (56.7 ± 12.5 years) and ANCA-RHP (62.5 ± 14.4 years). All IgG4-RHP patients had cranial pachymeningitis, and none presented with isolated hypertrophic spinal pachymeningitis. Otological symptoms and elevated systemic inflammatory markers (erythrocyte sedimentation rate, C-reactive protein, white blood cell count) were more frequently noted in patients with ANCA-RHP, whereas IgG4-RHP showed higher frequency of diplopia (P = 0.0149). It has been suggested that some patients diagnosed with Tolosa–Hunt syndrome on clinical grounds alone actually may have IgG4-RD (7,47).

When active lesions in patients with IgG4-RHP are in close proximity to the blood–brain barrier and cerebrospinal fluid (CSF) circulation, serum IgG4 levels may remain normal. Lu et al (56) proposed that elevated serum IgG4 levels in patients with IgG4-RHP indicate extrameningeal involvement. CSF examination in patients with IgG4-RHP generally shows a lymphocytic pleocytosis with a variable degree of protein elevation. Della-Torre et al (57) have evaluated the intrathecal production of total IgG and IgG subclasses using IgG index (CSF IgG/serum IgG ÷ serum albumin/CSF albumin) and IgGLOC values in patients with other causes of hypertrophic pachymeningitis. These investigators proposed that CSF IgG4 levels (>2.27 mg/dL) and IgG4Loc (>0.47) may be helpful for diagnosing IgG4-RHP. Radiologically, fibrotic hypertrophihc dura is iso- to hypo-intense on T1-weighted MRI and hypointense on T2-weighted images with occasional scattered foci of hyperintensity suggestive of inflammation (56). Gadolinium-enhanced MRI demonstrates intense dural enhancement in a linear or nodular pattern reflecting a linear dural thickening or a bulging mass. Wallace et al (47) noted that nonspecific scattered white matter T2 hyperintensities were observed in aged patients with ANCA-associated vasculitis, rheumatoid arthritis, neurosarcoidosis, and lymphoma but not in patients with IgG4-RD.

The standard first-line treatment for IgG4-RHP is systemic corticosteroids followed by the addition of other immunosuppressants such as methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide in the event of a recurrence (56). Rituximab is the most promising emerging steroid-sparing agent for IgG4-RD, but the published clinical experience of rituximab in patients with IgG4-RHP is limited (47) (56).

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At present, there are no evidence-based treatment guidelines for either IgG4-ROD or IgG4-RD. Rather, treatment should be individualized. Some cases of IgG4-ROD may show spontaneous remission (23). Generally, IgG4-ROD is characterized by a marked response to corticosteroid early in the disease course. However, IgG4 disease has been often known to recur during steroid taper and often requires long-term therapy. Using rituximab, anti-CD20+ monoclonal antibody, Khosroshahi et al (58) succeeded in discontinuing system steroids without relapse in 10 consecutive patients with steroid-refractory IgG4-RD. In a meta-analysis of definite and probable cases of IgG4-ROD (n = 59), men and women showed equal resistance to 1 or more treatment modalities (15). Further data on treatment of IgG4-ROD will become available with publication of ongoing clinical trials (7).

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