- Email: [email protected]
IgG4-Related Systemic Disease as a Cause of “Idiopathic” Orbital Inflammation, Including Orbital Myositis, and Trigeminal Nerve Involvement
SURVEY OF OPHTHALMOLOGY
VOLUME 57 NUMBER 1 JANUARY–FEBRUARY 2012
CLINICAL PATHOLOGIC REVIEWS STEFAN SEREGARD AND MILTON BONIUK, EDITORS
IgG4-Related Systemic Disease as a Cause of ‘‘Idiopathic’’ Orbital Inflammation, Including Orbital Myositis, and Trigeminal Nerve Involvement Zachary S. Wallace, MD,1 Arezou Khosroshahi, MD,1,4 Frederick A. Jakobiec, MD,2,5 Vikram Deshpande, MD,2 Mark P. Hatton, MD,3 Jill Ritter, MD,6 Judith A. Ferry, MD,2 and John H. Stone, MD, MPH1,4 1
Department of Medicine; 2Department of Pathology; 3Department of Ophthalmology, Harvard Medical School, Cambridge, Massachusetts, and the Massachusetts General Hospital, Boston, Massachusetts; 4Division of Rheumatology, Allergy, & Immunology; 5The Cogan Eye Pathology Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA; and 6Private practice, New Jersey, USA
Abstract. IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been identified as the cause of tumefactive lesions in a number of tissues and organs. The role of the IgG4 remains to be clarified fully, but the histopathologic diagnosis hinges upon the finding of IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated seum IgG4. We present a 56-year-old man with orbital pseudotumor in whom, after 30 years of intractable disease, biopsy showed IgG4-RD involving the lacrimal gland, extraocular muscles, intraconal fat, and trigeminal nerve. Six months after initiating treatment with rituximab, his disease remained dormant, with improvement in his proptosis and normalization of serum IgG4 levels. We review the differential of idiopathic orbital inflammatory disease, including IgG4-RD, and emphasize the need for biopsy for accurate diagnosis and to guide appropriate treatment. (Surv Ophthalmol 57:26--33, 2012. Ó 2012 Elsevier Inc. All rights reserved.) Key words. dacryoadenitis Idiopathic Inflammation myositis orbital pseudotumor rituximab
IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been implicated in pathology affecting the pancreas, salivary glands, gallbladder, thyroid, aorta, and multiple other tissues and organs.10 We describe a patient with a 30-year history of proptosis who had been considered to have idiopathic orbital inflammation (IOI). His condition was refractory to glucocorticoid tapers and other immunosuppressive
IgG4-related
systemic
disease
agents, but responded to peripheral B-cell depletion with rituximab, a therapy initiated after diagnostic tissue had been obtained from lacrimal gland biopsies. Earlier treatment with prednisone appears to have delayed diagnosis by causing temporary normalization of the serum IgG4 concentration. Recent reports propose that a substantial proportion of IOI cases are associated with IgG4-RD.6 Accurate diagnosis and the administration of 26
Ó 2012 by Elsevier Inc. All rights reserved.
0039-6257/$ - see front matter doi:10.1016/j.survophthal.2011.07.004
IgG4-RELATED SYSTEMIC DISEASE
27
effective therapy often depend on obtaining adequate tissue samples. We discuss the differential diagnosis of IOI, with an emphasis on systemic conditions associated with orbital inflammation and the emerging condition of IgG4-RD.
Case Presentation A 56-year-old man with a history of gout, asthma, and infertility secondary to diethylstilbestrol exposure in utero presented with a 30-year history of recurrent, non-painful proptosis and chemosis of his orbits, left greater than right (Fig. 1A). The initial episode, which occurred in 1981, was acute and severe. Over a period of days, the patient was unable to open his left eye. Since that time, he had experienced recurrences approximately three to four times per year, usually in the left eye, but occasionally in the right. These were not associated with any changes in visual acuity or ocular motility. The patient had no fever, fatigue, rash, photosensitivity, adenopathy, alopecia, oral or nasal ulcers, salivary gland swelling, Raynaud’s phenomenon, abdominal pain, or jaundice. The patient’s ocular disease was attributed to environmental allergies for many years, but his symptoms had never responded to antihistamines or immunotherapy. Approximately 10 years before we saw him, magnetic resonance imaging (MRI) of the head demonstrated enlarged extraocular muscles, particularly those of the left orbit, with associated edema of the intraconal fat. It is unclear if biopsy of this orbital pseudotumor was ever considered and, if so, why it was not done. The patient was treated with 80 mg prednisone daily for 2 weeks, with dramatic clinical resolution of his ocular manifestations. Over the next several years, he was maintained on varying doses of prednisone. Any attempt to discontinue glucocorticoids precipitated a recrudescence of his symptoms. He experienced a number of corticosteroid complications , including herpes zoster and necrosis of the humeral head. Because of these complications, he was treated with methotrexate (25 mg/ week), and his prednisone was tapered to 7.5 mg daily. This regimen appeared to work well for 2 years, but ultimately his ocular disease proved refractory to methotrexate and then to mycophenolate mofetil. Only high doses of prednisone controlled his ocular swelling. Twice, serum IgG subclass quantifications were performed after courses of prednisone because of concern about a potential immunoglobulin immunodeficiency. On both occasions, these analyses revealed elevations of
Fig. 1. A: A 56-year-old man had experienced several exacerbations annually over a 30-year period of left eyelid swelling, shown here as a festoon of edema collecting in the left lower eyelid (arrow). B: At the time of his last presentation there was the fullness of the left lower eyelid without a conspicuous collection of edema. C: On everting the eyelid, multi-nodular erythematous lobules of the palpebral lobe of the lacrimal gland (arrow) can be observed.
the serum IgG2 concentration, but normal concentrations of the other subclasses, including IgG4. His medications were allopurinol, colchicine, a fluticasone/salmeterol inhaler, and montelukast. He had no drug allergies or family history of a similar disorder. He was a retired police officer, married without children, did not use tobacco, and
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Surv Ophthalmol 57 (1) January--February 2012
drank alcohol occasionally. Physical examination was remarkable for bilateral conjunctival injection, proptosis of the left eye (Fig. 1B), bilateral periorbital edema more prominent in the left lower eyelid, and left greater than right lacrimal gland enlargement (Fig. 1C). The extraocular movements were full and visual acuity was normal. There was no submandibular or parotid gland swelling and no rash, joint deformities, or tophi. Laboratory findings were significant for a serum IgG4 concentration that was elevated to nearly four times the upper limit of normal at 670 mg/dl (normal, 8--140 mg/dl). The total IgG was also elevated at 2,108 mg/dl (normal, 614--1,295 mg/dl), but the concentrations of IgG1, IgG2, and IgG3 and a serum protein electrophoresis were normal. The serum IgE concentration was 800 IU/ml (normal, 0--100 IU/ml). An antinuclear antibody assay was positive at a titer of 1:640 (homogenous), but assays for antineutrophil cytoplasmic antibodies, rheumatoid factor assay, antibodies to cyclic citrullinated peptides, doublestranded DNA, and the Ro and La antigens were all negative. A serum thyroid stimulating hormone assay was normal. Computed tomography (Fig. 2A--C) and MRI of the orbits demonstrated a bilateral expansion of the extraocular muscles, left greater than right, with mild enlargement of the left superior rectus--levator muscle complex. There was also bilateral lacrimal gland enlargement. The maxillary division of the left trigeminal nerve and its branches were notable for smoothly marginated, enhancing and enlarged tissue outlines (Fig. 2C and 2E). Histopathologic examination of bilateral lacrimal gland biopsies demonstrated dense lymphoplasmacytic infiltrates that effaced many lobules of the lacrimal acinar tissue entirely. Early periductular and periacinar fibrosis was present (Fig. 3A--D). In contrast to the involved areas, other regions had moderately well-preserved parenchyma (Fig. 3A and 3B). The lymphocytes were small, and there were scattered germinal centers (Figures 3C and 3D). Immunohistochemical evaluation disclosed roughly equal numbers of CD20-positive B-lymphocytes organized into aggregates (Fig. 4A) and CD35positive T-lymphocytes predominantly surrounding these structures in tracts (Fig. 4B). Bcl-2 (Fig. 4C) highlighted the negatively staining follicular center cells, which were Bcl-6 positive. Within the follicles were well-formed networks of CD-23 positive dendritic cells creating a tight scaffolding (Fig. 4C, insert). There were 150 IgG4-positive plasma cells (Fig. 4D) per high-power field (HPF, where HPF 5 0.0588 mm2), and the IgG4:IgG ratio was 0.93 (Fig. 4D). In situ hybridization for kappa and lambda light chains (Fig. 4E and 4F) revealed
WALLACE ET AL
a polyclonal plasma cell population without light chain restriction (Fig. 4E and 4F). The lesion was interpreted as lymphoid hyperplasia with secondary fibrosis. IgG4-RD was diagnosed based upon the patient’s dacryoadenitis, elevated serum IgG4 concentrations, and the histopathologic findings. His orbital myositis was also attributed to IgG4-RD because of its consistent association for years with the other ocular findings. Because of the inability of prednisone to induce durable disease remissions, rituximab was recommended.11,17,24 Before this treatment could be arranged, however, his ocular disease flared producing proptosis that required treatment again with a 1-month prednisone taper. Laboratory studies performed 10 days after completing a 4-week prednisone course revealed normalization of IgG4 to 17.8 mg/dL (normal, 8--140 mg/dL) and elevation of IgG2 to 944 mg/dL (normal, 171--632 mg/dL), the pattern of IgG subclass concentrations previously observed following courses of prednisone. The patient was treated with rituximab 1000 mg intravenously, two doses 15 days apart. His peripheral B cells became depleted within 2 weeks of the first dose of rituximab. His left eye and lacrimal gland involvement had resolved 3 months after this treatment. At that time, his total serum IgG had normalized (from 2108 mg/dL to 1,123 mg/dL), his serum IgG4 concentration remained normal (26.2 mg/dL), his IgG2 had nearly normalized (641 mg/dL), and his IgE remained elevated at 443 IU/ mL, albeit decreased substantially from the baseline value of 800 IU/mL. He remained off of glucocorticoids.
Case Discussion IgG4-RD is an inflammatory process of unclear etiology that is increasingly recognized as a cause of tumefactive lesions in multiple tissues and organs, including pancreas, submandibular and parotid glands, biliary tree, thyroid, retroperitoneum, kidneys, and lungs.8,10 This diversity of organ system involvement is unified by a consistent histopathology characterized by lymphoplasmacytic inflammation, phlebitis, and varying degrees of fibrosis that stains for a disproportionate number of plasma cells bearing IgG4 on their surfaces.2,13,18,21 The presence of elevated numbers of IgG4-bearing plasma cells in tissue in the absence of other characteristic histopathologic findings of IgG4-RD is nonspecific.2,21 A majority of patients have modestly elevated serum IgG4 concentrations, as our patient did, but some are up to 25 times greater than normal.12 The role of IgG4 in the disease process,
IgG4-RELATED SYSTEMIC DISEASE
29
Fig. 2. A: A computed axial tomogram discloses enlargement of the lateral rectus muscle (LR) and the lacrimal gland (LG). B: A coronal section shows thickening with irregular edges of the inferior rectus and oblique muscles (arrow). There is mucosal thickening of the left antrum. C: The left superior rectus and levator complex is swollen (crossed arrow). The small arrows indicate the optic nerves. The large uncrossed arrow below highlights an enlarged infraorbital nerve. D: A coronal section proceeding toward the orbital apex displays crowding of the optic nerves (arrows) simulating the myositis of Graves’ disease. Thyroid studies were normal. E: On the left side there is widening of the pterygopalatine canal (uncrossed arrow) compared with that on the right (crossed arrow). There is also an increased soft tissue density in the left pterygopalatine fossa (double crossed arrow) signifying involvement of the trigeminal nerve.
other than as a diagnostic marker, has yet to be elucidated, and the degree of serum IgG4 elevation is of unclear significance.
Our patient had a 30-year history of IgG4-RD affecting the lacrimal glands as well as the orbital muscles and the V2 branch of the seventh cranial
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Surv Ophthalmol 57 (1) January--February 2012
WALLACE ET AL
Fig. 3. A: A lymphoid infiltrate with associated eosinophilic fibrosis spills over into the adjacent orbital fat and effaces the lobules of the lacrimal gland (arrows). B: There are surviving acini of the lacrimal gland (LG) shown above, as well as interlobular ducts in the center of the field (arrows). C: The lymphocytes are small and there is periductal fibrosis (arrow). D: A germinal center (GC) composed of small germinal center cells is present toward the right, and a single duct with surrounding fibrosis is evident on the left (arrow). (Hematoxylin and eosin, A 25, B 100, C 200, D 200.)
nerve. Biopsies of both lacrimal glands and images of the orbit that demonstrated orbital myositis and inflammation of the intraconal fat confirmed the diagnosis. In a series of 21 patients with IgG4-RD involving the ocular adnexa, Sato et al found that approximately 80% had lacrimal gland involvement.18 Patients with IgG4-RD frequently require repeated courses of high-dose glucocorticoids that often become less effective over time.2,4,13,18 In our patient, tapering of the glucocorticoids inevitably led to rapid disease recrudescence, and he failed treatment with methotrexate and mycophenolate mofetil. The most effective therapy of IgG4-RD has yet to be defined, but rituximab appears to be a promising alternative to glucocorticoids.11,17,24 Our patient also demonstrates that treatment with prednisone may confound the diagnosis by causing a temporary normalization of the serum IgG4 concentration while failing to suppress inflammation within the target organ completely. The syndrome of orbital pseudotumor presents major challenges in diagnosis and treatment. Tumefactive orbital lesions invoke a lengthy differential diagnosis that includes infectious, neoplastic, and inflammatory conditions. A major objective of the histopathological examination is to distinguish
inflammation from a lymphoid neoplasm, the most common being an extranodal marginal zone lesion in the ocular adnexa. The patient’s prolonged course made neoplasm unlikely, but to be certain, we used immunohistochemical studies to demonstrate that the follicular center cells were Bcl-2-negative and that small T- and B-cells were both well represented in the infiltrate.22 Kappa and lambda light chains, identified with in situ hybridization, confirmed a polyclonal population. By definition, IOI has no associated systemic diagnosis.14 IOI can affect either the entire orbit or selected anatomic components such as the extraocular muscles, lacrimal system, optic nerve, or sclera. Proptosis is a presenting feature in up to 82% of cases.3 The inflammation in IOI may be unilateral or bilateral with an acute or insidious onset. Histopathology demonstrates a benign, nonspecific, polymorphic inflammatory infiltrate, sometimes accompanied by sclerosis. Many patients with presumed IOI, however, do not undergo biopsies and, even if a biopsy is obtained, IgG4 stains are not performed routinely. IOI sometimes causes sclerosis of involved tissues and can lead to bone destruction and intracranial infiltration.7 IOI is often responsive to high doses of glucocorticoids, but treatment
IgG4-RELATED SYSTEMIC DISEASE
31
Fig. 4. A: CD20 immunostaining demonstrates multiple B-cell aggregates (arrows). B: Interconnecting tracts of CD3positive T-lymphocytes are also present within the lesion. C: Bcl-2 fails to stain follicular center cells, whereas cells of the mantle zone are positively stained. The inset reveals a tight network of CD23-positive dendritic cells within the follicular centers. D: Myriad IgG4-positive plasma cells are present throughout the lacrimal infiltrate. Polyclonality is established by the presence of both kappa (E ) and lamda (F ) light chain staining. The arrows point out surviving elements of the lacrimal gland. (Immunoperoxidase staining, diaminobenzidine chromogen, A 100, B 100, C 100, Inset 200, D 100; in situ hybridization, E 100, F 100.)
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Surv Ophthalmol 57 (1) January--February 2012
failures are not rare, as in IgG4-RD.7 Without specific IgG4 staining, it is impossible to differentiate IOI from IgG4-RD. We believe it likely that a substantial proportion of cases of presumed idiopathic orbital pseudotumor in fact represent an ocular manifestation of IgG4-RD.6 Idiopathic orbital myositis is an obscure entity, largely because of the difficulty in accessing diseased tissue. Biopsy of the extraocular muscles is more challenging than a lacrimal gland biopsy, and surgeons are often reluctant to perform this procedure because of the risk of postoperative diplopia. This is probably why a muscle biopsy was deferred in our patient. Idiopathic orbital myositis must be distinguished from Graves orbitopathy, which also involves the extraocular muscles and is the most common cause of orbital inflammation.3,4,14 Imaging shows that idiopathic orbital myositis tends to affect one or more of the extraocular muscles in their entirety, from origin to insertion. In contrast, Graves orbitopathy has a predilection for the muscle’s belly. Orbital myositis, as with IOI, can be related to systemic or local inflammatory diseases and infections. Its presentation is variable (unilateral or bilateral and acute or insidious), but diplopia is a common symptom, as is pain with eye movements.3,14,19 Muscle biopsies have revealed infiltrates of plasma cells, lymphocytes, macrophages, and polymorphonuclear cells.19 We are not aware of any case of orbital myositis in which staining for IgG4 has been performed. Our patient highlights the importance of biopsy when evaluating orbital inflammatory disease. Some clinical or radiological features may suggest a diagnosis, but without histology it is impossible to differentiate among the multiple conditions that cause IOI. Emerging therapeutic approaches, such as using rituximab in IgG4-RD, make accurate histopathological diagnosis essential. Our patient’s orbital myositis was probably a manifestation of IgG4-RD, which appears to be a distinct clinical entity with its own natural history, potential for involvement of other organs, and response to treatment. Besides IOI and orbital myositis, other considerations in the differential for orbital pseudotumor and lacrimal gland enlargement include granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis) and sarcoidosis. More than half of GPA patients in some series have either secondary orbital invasion from the nearby ethmoid or maxillary sinuses or de novo involvement of the orbital soft tissue.1,3,7,14,23 Granulomatous inflammation with vasculitis and necrosis are key histologic features that distinguish GPA from IgG4-RD.
WALLACE ET AL
Sarcoidosis, also a disease of unknown etiology, is characterized by non-caseating granulomas. In one case series of 20 patients with orbital sarcoidosis, 55% presented with a palpable lacrimal mass.15 Sarcoidosis may present as orbital pseudotumor, and up to 90% of these patients have concurrent evidence of sarcoidosis in other organs.5,15 Clinical findings that distinguish sarcoidosis include typical skin involvement (e.g., erythema nodosum, lupus pernio) or pulmonary abnormalities (e.g., hilar lymphadenopathy). The presence of granulomas would exclude IgG4-RD. Lymphoproliferative diseases are another common cause of orbital tumefaction. In a review of 268 orbital lesions that presented to an eye oncology service, 25% were found to be lymphoproliferative tumors, most commonly lymphoma.16,20 Substantial fractions of these orbital lesions also resulted from either local (sinus carcinomas or brain tumors) or distant metastases. Imaging of our patient was also noteworthy for the smooth enhancement of the trigeminal nerve which, without knowledge of the patient’s preceding 30-year history, would have been highly concerning for lymphoma. Katsura et al described similar findings in a patient who was ultimately found to have IgG4-RD isolated to the trigeminal nerve.9 Orbital lymphoma usually presents as a palpable mass and may or may not be associated with systemic lymphoma. These facts underscore further the importance of obtaining adequate biopsies and performing the careful evaluations required to distinguish IgG4-RD from lymphomas. Of note, a few case reports suggest there may be an increased incidence of lymphoproliferative disease in the setting of IgG4-RD.2
Conclusion In our case the decision to pursue a tissue diagnosis after 30 years of empiric therapy led to a specific diagnosis and a targeted treatment. IgG4RD can cause IOI, including orbital myositis, that may be exquisitely sensitive to rituximab, offering an important new therapeutic option. The availability of such new treatments underscores the importance of histological diagnosis obtained from biopsy. Also, treatment with prednisone may confound the diagnosis by temporarily normalizing the serum IgG4 concentration.
Method of Literature Search The authors conducted Medline and PubMed literature searches in English. Search words included IgG4-related systemic disease, IgG4, idiopathic
IgG4-RELATED SYSTEMIC DISEASE
orbital inflammatory disease, orbital pseudotumor, rituximab, lacrimal gland, dacryoadenitis, orbital myositis, wegener’s granulomatosis, sarcoidosis, orbital lymphoma, grave’s disease, trigeminal nerve, and thyroid orbitopathy, in various combinations. Articles were reviewed critically and we included those that helped us better understand and characterize the unique findings in our patient, as well as in IgG4-RD.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
References 1. Ahmed M, Niffenegger JH, Jakobiec FA, et al. Diagnosis of limited ophthalmic Wegener granulomatosis: distinctive pathologic features with ANCA test confirmation. Int Ophthalmol. 2008;28:35--46 2. Cheuk W, Chan JK. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 2010;17:303--32 3. Costa RM, Dumitrascu OM, Gordon LK. Orbital myositis: diagnosis and management. Curr Allergy Asthma Rep. 2009; 9:316--23 4. Espinoza GM. Orbital inflammatory pseudotumors: etiology, differential diagnosis, and management. Curr Rheumatol Rep. 2010;12:443--7 5. Faller M, Purohit A, Kennel N, et al. Systemic sarcoidosis initially presenting as an orbital tumour. Eur Respir J. 1995; 8:474--6 6. Geyer JT, Deshpande V. IgG4-associated sialadenitis. Curr Opin Rheumatol. 2011;23:95--101 7. Golnik KC. Neuro-ophthalmologic manifestations of systemic disease: rheumatologic/Inflammatory. Ophthalmol Clin North Am. 2004;17:389--96, vi. 8. Jakobiec FA, Stacy RC, Mehta M, et al. IgG4-positive dacryoadenitis and Kuttner submandibular sclerosing inflammatory tumor. Arch Ophthalmol. 2010;128:942--4 9. Katsura M, Morita A, Horiuchi H, et al. IgG4-Related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease? AJNR Am J Neuroradiol. 2010; Epub ahead of print
33 10. Khosroshahi A, Stone JH. IgG4-related systemic disease: the age of discovery. Curr Opin Rheumatol. 2011;23: 72--3 11. Khosroshahi A, Bloch DB, Deshpande V, et al. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755--62 12. Khosroshahi A, Stone JR, Pratt DS, et al. Painless jaundice with serial multi-organ dysfunction. Lancet. 2009;373:1494 13. Kubota T, Moritani S, Katayama M, et al. Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder. Arch Ophthalmol. 2010;128:577--84 14. Lutt JR, Lim LL, Phal PM, et al. Orbital inflammatory disease. Semin Arthritis Rheum. 2008;37:207--22 15. Mavrikakis I, Rootman J. Diverse clinical presentations of orbital sarcoid. Am J Ophthalmol. 2007;144:769--75 16. McKelvie PA. Ocular adnexal lymphomas: a review. Adv Anat Pathol. 2010;17:251--61 17. Rueda JC, Duarte-Rey C, Casas N. Successful treatment of relapsing autoimmune pancreatitis in primary Sjogren’s syndrome with rituximab: report of a case and review of the literature. Rheumatol Int. 2009;29:1481--5 18. Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4related disease has uniform clinicopathology. Pathol Int. 2008;58:465--70 19. Schoser BG. Ocular myositis: diagnostic assessment, differential diagnoses, and therapy of a rare muscle disease—five new cases and review. Clin Ophthalmol. 2007;1:37--42 20. Shinder R, Al-Zubidi N, Esmaeli B. Survey of orbital tumors at a comprehensive cancer center in the United States. Head Neck. 2011;33(5):610--4 21. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 2011;23:74--9 22. Stacy RC, Jakobiec FA, Schoenfield L, et al. Unifocal and multifocal reactive lymphoid hyperplasia vs follicular lymphoma of the ocular adnexa. Am J Ophthalmol. 2010;150: 412--26.e1 23. Tarabishy AB, Schulte M, Papaliodis GN, et al. Wegener’s granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthalmol. 2010;55:429--44 24. Topazian M, Witzig TE, Smyrk TC, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4associated cholangitis. Clin Gastroenterol Hepatol. 2008;6: 364--6 Reprint address: Dr. John H. Stone, Rheumatology Unit / Yawkey 2, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. e-mail: [email protected].
VOLUME 57 NUMBER 1 JANUARY–FEBRUARY 2012
CLINICAL PATHOLOGIC REVIEWS STEFAN SEREGARD AND MILTON BONIUK, EDITORS
IgG4-Related Systemic Disease as a Cause of ‘‘Idiopathic’’ Orbital Inflammation, Including Orbital Myositis, and Trigeminal Nerve Involvement Zachary S. Wallace, MD,1 Arezou Khosroshahi, MD,1,4 Frederick A. Jakobiec, MD,2,5 Vikram Deshpande, MD,2 Mark P. Hatton, MD,3 Jill Ritter, MD,6 Judith A. Ferry, MD,2 and John H. Stone, MD, MPH1,4 1
Department of Medicine; 2Department of Pathology; 3Department of Ophthalmology, Harvard Medical School, Cambridge, Massachusetts, and the Massachusetts General Hospital, Boston, Massachusetts; 4Division of Rheumatology, Allergy, & Immunology; 5The Cogan Eye Pathology Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA; and 6Private practice, New Jersey, USA
Abstract. IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been identified as the cause of tumefactive lesions in a number of tissues and organs. The role of the IgG4 remains to be clarified fully, but the histopathologic diagnosis hinges upon the finding of IgG4-bearing plasma cells in addition to characteristic morphologic features, with or without elevated seum IgG4. We present a 56-year-old man with orbital pseudotumor in whom, after 30 years of intractable disease, biopsy showed IgG4-RD involving the lacrimal gland, extraocular muscles, intraconal fat, and trigeminal nerve. Six months after initiating treatment with rituximab, his disease remained dormant, with improvement in his proptosis and normalization of serum IgG4 levels. We review the differential of idiopathic orbital inflammatory disease, including IgG4-RD, and emphasize the need for biopsy for accurate diagnosis and to guide appropriate treatment. (Surv Ophthalmol 57:26--33, 2012. Ó 2012 Elsevier Inc. All rights reserved.) Key words. dacryoadenitis Idiopathic Inflammation myositis orbital pseudotumor rituximab
IgG4-related systemic disease (IgG4-RD) is an inflammatory condition of unknown etiology that has been implicated in pathology affecting the pancreas, salivary glands, gallbladder, thyroid, aorta, and multiple other tissues and organs.10 We describe a patient with a 30-year history of proptosis who had been considered to have idiopathic orbital inflammation (IOI). His condition was refractory to glucocorticoid tapers and other immunosuppressive
IgG4-related
systemic
disease
agents, but responded to peripheral B-cell depletion with rituximab, a therapy initiated after diagnostic tissue had been obtained from lacrimal gland biopsies. Earlier treatment with prednisone appears to have delayed diagnosis by causing temporary normalization of the serum IgG4 concentration. Recent reports propose that a substantial proportion of IOI cases are associated with IgG4-RD.6 Accurate diagnosis and the administration of 26
Ó 2012 by Elsevier Inc. All rights reserved.
0039-6257/$ - see front matter doi:10.1016/j.survophthal.2011.07.004
IgG4-RELATED SYSTEMIC DISEASE
27
effective therapy often depend on obtaining adequate tissue samples. We discuss the differential diagnosis of IOI, with an emphasis on systemic conditions associated with orbital inflammation and the emerging condition of IgG4-RD.
Case Presentation A 56-year-old man with a history of gout, asthma, and infertility secondary to diethylstilbestrol exposure in utero presented with a 30-year history of recurrent, non-painful proptosis and chemosis of his orbits, left greater than right (Fig. 1A). The initial episode, which occurred in 1981, was acute and severe. Over a period of days, the patient was unable to open his left eye. Since that time, he had experienced recurrences approximately three to four times per year, usually in the left eye, but occasionally in the right. These were not associated with any changes in visual acuity or ocular motility. The patient had no fever, fatigue, rash, photosensitivity, adenopathy, alopecia, oral or nasal ulcers, salivary gland swelling, Raynaud’s phenomenon, abdominal pain, or jaundice. The patient’s ocular disease was attributed to environmental allergies for many years, but his symptoms had never responded to antihistamines or immunotherapy. Approximately 10 years before we saw him, magnetic resonance imaging (MRI) of the head demonstrated enlarged extraocular muscles, particularly those of the left orbit, with associated edema of the intraconal fat. It is unclear if biopsy of this orbital pseudotumor was ever considered and, if so, why it was not done. The patient was treated with 80 mg prednisone daily for 2 weeks, with dramatic clinical resolution of his ocular manifestations. Over the next several years, he was maintained on varying doses of prednisone. Any attempt to discontinue glucocorticoids precipitated a recrudescence of his symptoms. He experienced a number of corticosteroid complications , including herpes zoster and necrosis of the humeral head. Because of these complications, he was treated with methotrexate (25 mg/ week), and his prednisone was tapered to 7.5 mg daily. This regimen appeared to work well for 2 years, but ultimately his ocular disease proved refractory to methotrexate and then to mycophenolate mofetil. Only high doses of prednisone controlled his ocular swelling. Twice, serum IgG subclass quantifications were performed after courses of prednisone because of concern about a potential immunoglobulin immunodeficiency. On both occasions, these analyses revealed elevations of
Fig. 1. A: A 56-year-old man had experienced several exacerbations annually over a 30-year period of left eyelid swelling, shown here as a festoon of edema collecting in the left lower eyelid (arrow). B: At the time of his last presentation there was the fullness of the left lower eyelid without a conspicuous collection of edema. C: On everting the eyelid, multi-nodular erythematous lobules of the palpebral lobe of the lacrimal gland (arrow) can be observed.
the serum IgG2 concentration, but normal concentrations of the other subclasses, including IgG4. His medications were allopurinol, colchicine, a fluticasone/salmeterol inhaler, and montelukast. He had no drug allergies or family history of a similar disorder. He was a retired police officer, married without children, did not use tobacco, and
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drank alcohol occasionally. Physical examination was remarkable for bilateral conjunctival injection, proptosis of the left eye (Fig. 1B), bilateral periorbital edema more prominent in the left lower eyelid, and left greater than right lacrimal gland enlargement (Fig. 1C). The extraocular movements were full and visual acuity was normal. There was no submandibular or parotid gland swelling and no rash, joint deformities, or tophi. Laboratory findings were significant for a serum IgG4 concentration that was elevated to nearly four times the upper limit of normal at 670 mg/dl (normal, 8--140 mg/dl). The total IgG was also elevated at 2,108 mg/dl (normal, 614--1,295 mg/dl), but the concentrations of IgG1, IgG2, and IgG3 and a serum protein electrophoresis were normal. The serum IgE concentration was 800 IU/ml (normal, 0--100 IU/ml). An antinuclear antibody assay was positive at a titer of 1:640 (homogenous), but assays for antineutrophil cytoplasmic antibodies, rheumatoid factor assay, antibodies to cyclic citrullinated peptides, doublestranded DNA, and the Ro and La antigens were all negative. A serum thyroid stimulating hormone assay was normal. Computed tomography (Fig. 2A--C) and MRI of the orbits demonstrated a bilateral expansion of the extraocular muscles, left greater than right, with mild enlargement of the left superior rectus--levator muscle complex. There was also bilateral lacrimal gland enlargement. The maxillary division of the left trigeminal nerve and its branches were notable for smoothly marginated, enhancing and enlarged tissue outlines (Fig. 2C and 2E). Histopathologic examination of bilateral lacrimal gland biopsies demonstrated dense lymphoplasmacytic infiltrates that effaced many lobules of the lacrimal acinar tissue entirely. Early periductular and periacinar fibrosis was present (Fig. 3A--D). In contrast to the involved areas, other regions had moderately well-preserved parenchyma (Fig. 3A and 3B). The lymphocytes were small, and there were scattered germinal centers (Figures 3C and 3D). Immunohistochemical evaluation disclosed roughly equal numbers of CD20-positive B-lymphocytes organized into aggregates (Fig. 4A) and CD35positive T-lymphocytes predominantly surrounding these structures in tracts (Fig. 4B). Bcl-2 (Fig. 4C) highlighted the negatively staining follicular center cells, which were Bcl-6 positive. Within the follicles were well-formed networks of CD-23 positive dendritic cells creating a tight scaffolding (Fig. 4C, insert). There were 150 IgG4-positive plasma cells (Fig. 4D) per high-power field (HPF, where HPF 5 0.0588 mm2), and the IgG4:IgG ratio was 0.93 (Fig. 4D). In situ hybridization for kappa and lambda light chains (Fig. 4E and 4F) revealed
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a polyclonal plasma cell population without light chain restriction (Fig. 4E and 4F). The lesion was interpreted as lymphoid hyperplasia with secondary fibrosis. IgG4-RD was diagnosed based upon the patient’s dacryoadenitis, elevated serum IgG4 concentrations, and the histopathologic findings. His orbital myositis was also attributed to IgG4-RD because of its consistent association for years with the other ocular findings. Because of the inability of prednisone to induce durable disease remissions, rituximab was recommended.11,17,24 Before this treatment could be arranged, however, his ocular disease flared producing proptosis that required treatment again with a 1-month prednisone taper. Laboratory studies performed 10 days after completing a 4-week prednisone course revealed normalization of IgG4 to 17.8 mg/dL (normal, 8--140 mg/dL) and elevation of IgG2 to 944 mg/dL (normal, 171--632 mg/dL), the pattern of IgG subclass concentrations previously observed following courses of prednisone. The patient was treated with rituximab 1000 mg intravenously, two doses 15 days apart. His peripheral B cells became depleted within 2 weeks of the first dose of rituximab. His left eye and lacrimal gland involvement had resolved 3 months after this treatment. At that time, his total serum IgG had normalized (from 2108 mg/dL to 1,123 mg/dL), his serum IgG4 concentration remained normal (26.2 mg/dL), his IgG2 had nearly normalized (641 mg/dL), and his IgE remained elevated at 443 IU/ mL, albeit decreased substantially from the baseline value of 800 IU/mL. He remained off of glucocorticoids.
Case Discussion IgG4-RD is an inflammatory process of unclear etiology that is increasingly recognized as a cause of tumefactive lesions in multiple tissues and organs, including pancreas, submandibular and parotid glands, biliary tree, thyroid, retroperitoneum, kidneys, and lungs.8,10 This diversity of organ system involvement is unified by a consistent histopathology characterized by lymphoplasmacytic inflammation, phlebitis, and varying degrees of fibrosis that stains for a disproportionate number of plasma cells bearing IgG4 on their surfaces.2,13,18,21 The presence of elevated numbers of IgG4-bearing plasma cells in tissue in the absence of other characteristic histopathologic findings of IgG4-RD is nonspecific.2,21 A majority of patients have modestly elevated serum IgG4 concentrations, as our patient did, but some are up to 25 times greater than normal.12 The role of IgG4 in the disease process,
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Fig. 2. A: A computed axial tomogram discloses enlargement of the lateral rectus muscle (LR) and the lacrimal gland (LG). B: A coronal section shows thickening with irregular edges of the inferior rectus and oblique muscles (arrow). There is mucosal thickening of the left antrum. C: The left superior rectus and levator complex is swollen (crossed arrow). The small arrows indicate the optic nerves. The large uncrossed arrow below highlights an enlarged infraorbital nerve. D: A coronal section proceeding toward the orbital apex displays crowding of the optic nerves (arrows) simulating the myositis of Graves’ disease. Thyroid studies were normal. E: On the left side there is widening of the pterygopalatine canal (uncrossed arrow) compared with that on the right (crossed arrow). There is also an increased soft tissue density in the left pterygopalatine fossa (double crossed arrow) signifying involvement of the trigeminal nerve.
other than as a diagnostic marker, has yet to be elucidated, and the degree of serum IgG4 elevation is of unclear significance.
Our patient had a 30-year history of IgG4-RD affecting the lacrimal glands as well as the orbital muscles and the V2 branch of the seventh cranial
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Fig. 3. A: A lymphoid infiltrate with associated eosinophilic fibrosis spills over into the adjacent orbital fat and effaces the lobules of the lacrimal gland (arrows). B: There are surviving acini of the lacrimal gland (LG) shown above, as well as interlobular ducts in the center of the field (arrows). C: The lymphocytes are small and there is periductal fibrosis (arrow). D: A germinal center (GC) composed of small germinal center cells is present toward the right, and a single duct with surrounding fibrosis is evident on the left (arrow). (Hematoxylin and eosin, A 25, B 100, C 200, D 200.)
nerve. Biopsies of both lacrimal glands and images of the orbit that demonstrated orbital myositis and inflammation of the intraconal fat confirmed the diagnosis. In a series of 21 patients with IgG4-RD involving the ocular adnexa, Sato et al found that approximately 80% had lacrimal gland involvement.18 Patients with IgG4-RD frequently require repeated courses of high-dose glucocorticoids that often become less effective over time.2,4,13,18 In our patient, tapering of the glucocorticoids inevitably led to rapid disease recrudescence, and he failed treatment with methotrexate and mycophenolate mofetil. The most effective therapy of IgG4-RD has yet to be defined, but rituximab appears to be a promising alternative to glucocorticoids.11,17,24 Our patient also demonstrates that treatment with prednisone may confound the diagnosis by causing a temporary normalization of the serum IgG4 concentration while failing to suppress inflammation within the target organ completely. The syndrome of orbital pseudotumor presents major challenges in diagnosis and treatment. Tumefactive orbital lesions invoke a lengthy differential diagnosis that includes infectious, neoplastic, and inflammatory conditions. A major objective of the histopathological examination is to distinguish
inflammation from a lymphoid neoplasm, the most common being an extranodal marginal zone lesion in the ocular adnexa. The patient’s prolonged course made neoplasm unlikely, but to be certain, we used immunohistochemical studies to demonstrate that the follicular center cells were Bcl-2-negative and that small T- and B-cells were both well represented in the infiltrate.22 Kappa and lambda light chains, identified with in situ hybridization, confirmed a polyclonal population. By definition, IOI has no associated systemic diagnosis.14 IOI can affect either the entire orbit or selected anatomic components such as the extraocular muscles, lacrimal system, optic nerve, or sclera. Proptosis is a presenting feature in up to 82% of cases.3 The inflammation in IOI may be unilateral or bilateral with an acute or insidious onset. Histopathology demonstrates a benign, nonspecific, polymorphic inflammatory infiltrate, sometimes accompanied by sclerosis. Many patients with presumed IOI, however, do not undergo biopsies and, even if a biopsy is obtained, IgG4 stains are not performed routinely. IOI sometimes causes sclerosis of involved tissues and can lead to bone destruction and intracranial infiltration.7 IOI is often responsive to high doses of glucocorticoids, but treatment
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31
Fig. 4. A: CD20 immunostaining demonstrates multiple B-cell aggregates (arrows). B: Interconnecting tracts of CD3positive T-lymphocytes are also present within the lesion. C: Bcl-2 fails to stain follicular center cells, whereas cells of the mantle zone are positively stained. The inset reveals a tight network of CD23-positive dendritic cells within the follicular centers. D: Myriad IgG4-positive plasma cells are present throughout the lacrimal infiltrate. Polyclonality is established by the presence of both kappa (E ) and lamda (F ) light chain staining. The arrows point out surviving elements of the lacrimal gland. (Immunoperoxidase staining, diaminobenzidine chromogen, A 100, B 100, C 100, Inset 200, D 100; in situ hybridization, E 100, F 100.)
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failures are not rare, as in IgG4-RD.7 Without specific IgG4 staining, it is impossible to differentiate IOI from IgG4-RD. We believe it likely that a substantial proportion of cases of presumed idiopathic orbital pseudotumor in fact represent an ocular manifestation of IgG4-RD.6 Idiopathic orbital myositis is an obscure entity, largely because of the difficulty in accessing diseased tissue. Biopsy of the extraocular muscles is more challenging than a lacrimal gland biopsy, and surgeons are often reluctant to perform this procedure because of the risk of postoperative diplopia. This is probably why a muscle biopsy was deferred in our patient. Idiopathic orbital myositis must be distinguished from Graves orbitopathy, which also involves the extraocular muscles and is the most common cause of orbital inflammation.3,4,14 Imaging shows that idiopathic orbital myositis tends to affect one or more of the extraocular muscles in their entirety, from origin to insertion. In contrast, Graves orbitopathy has a predilection for the muscle’s belly. Orbital myositis, as with IOI, can be related to systemic or local inflammatory diseases and infections. Its presentation is variable (unilateral or bilateral and acute or insidious), but diplopia is a common symptom, as is pain with eye movements.3,14,19 Muscle biopsies have revealed infiltrates of plasma cells, lymphocytes, macrophages, and polymorphonuclear cells.19 We are not aware of any case of orbital myositis in which staining for IgG4 has been performed. Our patient highlights the importance of biopsy when evaluating orbital inflammatory disease. Some clinical or radiological features may suggest a diagnosis, but without histology it is impossible to differentiate among the multiple conditions that cause IOI. Emerging therapeutic approaches, such as using rituximab in IgG4-RD, make accurate histopathological diagnosis essential. Our patient’s orbital myositis was probably a manifestation of IgG4-RD, which appears to be a distinct clinical entity with its own natural history, potential for involvement of other organs, and response to treatment. Besides IOI and orbital myositis, other considerations in the differential for orbital pseudotumor and lacrimal gland enlargement include granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis) and sarcoidosis. More than half of GPA patients in some series have either secondary orbital invasion from the nearby ethmoid or maxillary sinuses or de novo involvement of the orbital soft tissue.1,3,7,14,23 Granulomatous inflammation with vasculitis and necrosis are key histologic features that distinguish GPA from IgG4-RD.
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Sarcoidosis, also a disease of unknown etiology, is characterized by non-caseating granulomas. In one case series of 20 patients with orbital sarcoidosis, 55% presented with a palpable lacrimal mass.15 Sarcoidosis may present as orbital pseudotumor, and up to 90% of these patients have concurrent evidence of sarcoidosis in other organs.5,15 Clinical findings that distinguish sarcoidosis include typical skin involvement (e.g., erythema nodosum, lupus pernio) or pulmonary abnormalities (e.g., hilar lymphadenopathy). The presence of granulomas would exclude IgG4-RD. Lymphoproliferative diseases are another common cause of orbital tumefaction. In a review of 268 orbital lesions that presented to an eye oncology service, 25% were found to be lymphoproliferative tumors, most commonly lymphoma.16,20 Substantial fractions of these orbital lesions also resulted from either local (sinus carcinomas or brain tumors) or distant metastases. Imaging of our patient was also noteworthy for the smooth enhancement of the trigeminal nerve which, without knowledge of the patient’s preceding 30-year history, would have been highly concerning for lymphoma. Katsura et al described similar findings in a patient who was ultimately found to have IgG4-RD isolated to the trigeminal nerve.9 Orbital lymphoma usually presents as a palpable mass and may or may not be associated with systemic lymphoma. These facts underscore further the importance of obtaining adequate biopsies and performing the careful evaluations required to distinguish IgG4-RD from lymphomas. Of note, a few case reports suggest there may be an increased incidence of lymphoproliferative disease in the setting of IgG4-RD.2
Conclusion In our case the decision to pursue a tissue diagnosis after 30 years of empiric therapy led to a specific diagnosis and a targeted treatment. IgG4RD can cause IOI, including orbital myositis, that may be exquisitely sensitive to rituximab, offering an important new therapeutic option. The availability of such new treatments underscores the importance of histological diagnosis obtained from biopsy. Also, treatment with prednisone may confound the diagnosis by temporarily normalizing the serum IgG4 concentration.
Method of Literature Search The authors conducted Medline and PubMed literature searches in English. Search words included IgG4-related systemic disease, IgG4, idiopathic
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orbital inflammatory disease, orbital pseudotumor, rituximab, lacrimal gland, dacryoadenitis, orbital myositis, wegener’s granulomatosis, sarcoidosis, orbital lymphoma, grave’s disease, trigeminal nerve, and thyroid orbitopathy, in various combinations. Articles were reviewed critically and we included those that helped us better understand and characterize the unique findings in our patient, as well as in IgG4-RD.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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33 10. Khosroshahi A, Stone JH. IgG4-related systemic disease: the age of discovery. Curr Opin Rheumatol. 2011;23: 72--3 11. Khosroshahi A, Bloch DB, Deshpande V, et al. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755--62 12. Khosroshahi A, Stone JR, Pratt DS, et al. Painless jaundice with serial multi-organ dysfunction. Lancet. 2009;373:1494 13. Kubota T, Moritani S, Katayama M, et al. Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder. Arch Ophthalmol. 2010;128:577--84 14. Lutt JR, Lim LL, Phal PM, et al. Orbital inflammatory disease. Semin Arthritis Rheum. 2008;37:207--22 15. Mavrikakis I, Rootman J. Diverse clinical presentations of orbital sarcoid. Am J Ophthalmol. 2007;144:769--75 16. McKelvie PA. Ocular adnexal lymphomas: a review. Adv Anat Pathol. 2010;17:251--61 17. Rueda JC, Duarte-Rey C, Casas N. Successful treatment of relapsing autoimmune pancreatitis in primary Sjogren’s syndrome with rituximab: report of a case and review of the literature. Rheumatol Int. 2009;29:1481--5 18. Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4related disease has uniform clinicopathology. Pathol Int. 2008;58:465--70 19. Schoser BG. Ocular myositis: diagnostic assessment, differential diagnoses, and therapy of a rare muscle disease—five new cases and review. Clin Ophthalmol. 2007;1:37--42 20. Shinder R, Al-Zubidi N, Esmaeli B. Survey of orbital tumors at a comprehensive cancer center in the United States. Head Neck. 2011;33(5):610--4 21. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 2011;23:74--9 22. Stacy RC, Jakobiec FA, Schoenfield L, et al. Unifocal and multifocal reactive lymphoid hyperplasia vs follicular lymphoma of the ocular adnexa. Am J Ophthalmol. 2010;150: 412--26.e1 23. Tarabishy AB, Schulte M, Papaliodis GN, et al. Wegener’s granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthalmol. 2010;55:429--44 24. Topazian M, Witzig TE, Smyrk TC, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4associated cholangitis. Clin Gastroenterol Hepatol. 2008;6: 364--6 Reprint address: Dr. John H. Stone, Rheumatology Unit / Yawkey 2, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114. e-mail: [email protected].