Ophthalmic manifestations of IgG4-related disease: Single-center experience and literature review
Introduction
IgG4-related disease (IgG4-RD) is a systemic inflammatory disorder that typically causes tumefactive, fibrosing lesions [1]. Such lesions have been described in nearly every organ in the body, with some organs affected more commonly than others. IgG4-RD was first described in the pancreas as a cause of “lymphoplasmacytic sclerosing pancreatitis,” now known as type 1 (IgG4 related) autoimmune pancreatitis. Other frequent sites of involvement include the liver, thyroid gland, bile ducts, aorta, retroperitoneum, and lymph nodes (Table 1) [2], [3]. In the head and neck lesions have been identified in the meninges, pituitary gland, salivary glands, sinuses, and middle ear [4], [5], [6]. The ophthalmic manifestations of IgG4-RD are common and reported in the lacrimal gland and duct, extraocular muscles, orbital soft tissue, and sclera, as well as the cranial nerves and their branches (Table 1) [7], [8], [9], [10], [11]. We review the ophthalmic and orbital manifestations of IgG4-RD from a rheumatologist's perspective and describe the experience at our center with this condition, now known as IgG4-related ophthalmic disease (IgG4-ROD).
IgG4-RD has a strong overall tendency to affect men more often than women and to target middle-aged to elderly males [1], but the situation appears to be altered in IgG4-ROD. In IgG4-ROD as well as in other organ involvement of the head and neck, women and men appear to be affected equally by IgG4-ROD [11], [12], [13].
Because of the disease's relatively recent arrival in the diagnostic lexicon, the continued under-recognition of IgG4-RD by clinicians and pathologists, and challenges in diagnosis that stem from both of those factors, the epidemiology of IgG4-RD remains poorly described. No sufficiently thorough estimates of its incidence are available. Guma and Firestein [12] have estimated the incidence of IgG4-related pancreatitis to be 0.28–1.08/100,000. However, this figure fails to account for undiagnosed cases and involvement of the disease at multiple extra-pancreatic sites. Thus, the true incidence and prevalence are likely much higher.
The presentation of patients with IgG4-RD is variable and generally due to organ dysfunction, pain, or swelling. Some cases are asymptomatic and found incidentally on physical examinations or imaging studies performed for other reasons. Patients may present with single-organ involvement or have evidence of multiple organs involved simultaneously (synchronous organ involvement). Other patients evolve cumulative organ involvement over time (metachronous disease). IgG4-ROD typically presents with a mass lesion or lesions, such as lacrimal gland swelling or exophthalmos from orbital soft tissue swelling. Because of its tendency to cause tumefactive lesions, IgG4-ROD is frequently mistaken initially for cancer.
A number of important inflammatory conditions are known to involve structures housed within the orbit. These include sarcoidosis and granulomatosis with polyangiitis (GPA, formerly Wegener's). Moreover, many cases of inflammation involving the orbits have been previously regarded in the past as “idiopathic orbital inflammation” (IOI), often in the absence of biopsy or at least in the absence of knowledge about the recently described IgG4-RD (Table 2). As IgG4-RD has become recognized more widely, accumulating evidence supports the hypothesis that many cases of IOI are actually ophthalmic manifestations of IgG4-RD [8], [10]. As with IOI, IgG4-ROD may involve either a single anatomic structure or multiple structures within the orbit (e.g., both ocular muscles and lacrimal gland).
Section snippets
Methods
The Massachusetts General Hospital Center for IgG4-related disease, established within the Division of Rheumatology, Allergy, and Immunology, maintains a database of all patients diagnosed with IgG4-RD at our institution. As of January 1, 2013, the database included 115 patients, of whom 27 had histories of IgG4-ROD. Thus, patients with suspected IgG4-ROD comprised 23% of the total IgG4-RD database at our institution. We excluded six cases from this analysis (despite the strong clinical
Literature search
The authors conducted MEDLINE and PubMed literature searches in English. Search words included IgG4-related disease, IgG4, idiopathic 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
Results
Table 4 includes the clinical characteristics of the 21 cases. Of the 21 patients in our cohort, nine (43%) were women. The mean age of the cohort overall was 50 years (range: 24–79), with no difference in the mean ages of the male and female patients (mean age for men = 47.1 and for women = 53.6; p = 0.42). The cohort included patients of Caucasian (n = 13), Asian (n = 5), and African–American (n = 3) ancestry. The most common orbital structure involved was the lacrimal gland (13 patients),
Discussion
Our cases series of 21 patients represents the full, diverse spectrum of manifestations of IgG4-ROD known at this time (Table 4). The ophthalmic manifestations of IgG4-RD are protean and those of the orbit are among the most common features of this disease, in general. The series of patients from our center described in this manuscript represents the largest case series thus far of patients evaluated and managed at a single institution. Andrew et al. [11] published a “meta-analysis” that
Treatment
The optimal treatment strategy of IgG4-RD has yet to be elucidated but recent publications suggest two major strategies: glucocorticoids and rituximab. Other immunosuppressants such as azathioprine and mycophenolate mofetil have been tried with limited success [59]. Glucocorticoids are typically effective at controlling disease but tapering is often complicated by recurrence, and prolonged courses of treatment with these medications are fraught with complications [60]. Rituximab, an anti-CD20+
Limitations
Our study describes a retrospective series. One limitation, therefore, is that some patients may have had unrecognized orbital disease due to lack of symptoms, physical examination findings, or imaging of the region. The role of screening asymptomatic patients with IgG4-RD for ophthalmic involvement at baseline is unclear. We suspect that undiagnosed ophthalmic disease is likely to respond similarly to disease elsewhere. A second limitation is that patients were not followed prospectively and
Conclusion
Ophthalmic involvement of IgG4-RD is common and can affect nearly every anatomic structure of the orbit. The diagnosis of IgG4-RD in each case described in this series was reached using the recently defined consensus criteria based on biopsy of either orbital disease or extra-orbital disease. Recognition of IgG4-RD and accurate diagnosis by biopsy has important implications for prognosis and treatment, especially with the discovery of rituximab as an effective steroid-sparing agent.
References (62)
- et al.
IgG4-related disease in the head and neck
Semin Diagn Pathol
(2012) - et al.
IgG4-related diseases
Best Pract Res Clin Rheumatol
(2012) - et al.
Consensus statement on IgG4-RD diagnosis
Mod Rheumatol
(2012) - et al.
IgG4-related systemic disease as a cause of “idiopathic” orbital inflammation, including orbital myositis, and trigeminal nerve involvement
Surv Ophthalmol
(2012) - et al.
Clinicopathologic analysis of 166 patients with primary acquired nasolacrimal duct obstruction
Ophthalmology
(2001) - et al.
Scleritis and peripheral ulcerative keratitis
Rheum Dis Clin North Am
(2007) - et al.
Immunoglobulin G4-related sclerosing inflammatory pseudotumors presenting in the oral cavity
J Oral Maxillofac Surg
(2012) - et al.
Inflammatory pseudotumor of the skull base
Otolaryngol Head Neck Surg
(2010) - et al.
Orbital inflammatory disease
Semin Arthritis Rheum
(2008) - et al.
Utility of FDG PET/CT in IgG4-related systemic disease
Clin Radiol
(2012)
Wegener's granulomatosis: ophthalmic manifestations and management
Semin Arthritis Rheum
Diverse clinical presentations of orbital sarcoid
Am J Ophthalmol
Extranodal marginal zone lymphoma of the ocular adnexa
Blood
IgG4-related disease
N Engl J Med
The latest on IgG4-RD: a rapidly emerging disease
Curr Opin Rheumatol
IgG4-Related disease: recommendations for the nomenclature of this condition and its individual organ system manifestations
Arthritis Rheum
Radiological features of IgG4-related disease in the head, neck, and brain
Neuroradiology
IgG4-related disease and hypertrophic pachymeningitis
Medicine (Baltimore)
Orbital IgG4-related disease: clinical features and diagnosis
ISRN Rheumatol
Systemic immunoglobulin G4 (IgG4) disease and idiopathic orbital inflammation; removing ‘idiopathic’ from the nomenclature?
Eye
IgG4 orbital inflammation in a 5-year-old child presenting as an orbital mass
Orbit
Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4 systemic disease
Arch Ophthalmol
IgG4-related orbital disease: a meta-analysis and review
Acta Ophthalmol
Clinical aspects of IgG4-related orbital inflammation in a case series of ocular adnexal lymphoproliferative disorders
Int J Rheumatol
Commentary on IgG4-related sialadenitis: Mikulicz's disease, Kuttner's tumour, and eponymy
Histopathology
A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease
Mod Rheumatol
IgG4-related systemic sclerosing disease of the ocular adnexa: a potential mimic of ocular lymphoma
Am J Clin Pathol
A case of extraocular muscle swelling due to IgG4-related sclerosing disease
Jpn J Ophthalmol
Bilateral enlargement of the lacrimal glands from IgG4-related systemic disease
Ann Intern Med
Orbital myositis: diagnosis and management
Curr Allergy Asthma Rep
Orbital inflammatory pseudotumors: etiology, differential diagnosis, and management
Curr Rheumatol Rep
Cited by (171)
Ocular Surface Evaluation in Immunoglobulin G4–Related Ophthalmic Disease
2023, American Journal of OphthalmologyInfectious and Inflammatory Processes of the Orbits in Children
2023, Neuroimaging Clinics of North AmericaOphthalmoparesis and bilateral orbital mass in an HIV patient: A diagnostic dilemma
2023, Journal Francais d'OphtalmologieRadiological Determinants of Complicated Immunoglobulin G4-Related Ophthalmic Disease: A Territory-Wide Cohort Study
2022, Asia-Pacific Journal of OphthalmologyCases with IgG4-related ophthalmic disease with mass lesions surrounding the optic nerve
2022, American Journal of Ophthalmology Case ReportsNon-infectious Dacryoadenitis
2022, Survey of Ophthalmology
Dr. Stone has received funding from Genentech for an investigator-initiated study evaluating the use of rituximab in IgG4-RD.