Ophthalmic manifestations of IgG4-related disease: Single-center experience and literature review

https://doi.org/10.1016/j.semarthrit.2013.11.008Get rights and content

Abstract

Objectives

IgG4-related disease (IgG4-RD) is an inflammatory disorder responsible for fibrosing, tumefactive lesions that can involve the lacrimal gland as well as the extraocular muscles, orbital soft tissues, sclera, and local nerves. We reviewed IgG4-related ophthalmic disease (IgG4-ROD), including the natural history, pathology, and treatment, based on our center's experience and that reported in the literature.

Methods

We identified 27 patients with orbital manifestations from our IgG4-RD registry; six were excluded because no pathology was available for review. All 21 cases included had histopathologically confirmed diagnoses of IgG4-RD, 11 of which were of the orbital tissue. Other data were obtained by a retrospective medical records review. MEDLINE and PubMed literature searches in English were conducted to identify articles for a literature review on the topic.

Results

Patients with IgG4-ROD were predominantly male (57%) and had an average age at symptom onset of 50 years (range: 21–79 years). The lacrimal gland was the most commonly involved structure (62%). Most patients (71%) had bilateral disease and extra-orbital involvement (71%); these patients also had elevated serum IgG4 concentrations compared to those with unilateral disease and no extra-orbital disease. Ten patients improved following rituximab treatment.

Conclusions

Ophthalmic involvement is a common manifestation of IgG4-RD and can affect nearly every orbital structure. Consideration of IgG4-RD and accurate diagnosis by biopsy have important implications for prognosis and treatment following the distinction of this condition from the Sjögren syndrome (SjS), granulomatosis with polyangiitis (GPA, formerly Wegener's), sarcoidosis, lymphoma, infection, and other disorders. Rituximab holds promise as an effective steroid-sparing agent or therapy for steroid-resistant cases.

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.

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  • Cited by (0)

    Dr. Stone has received funding from Genentech for an investigator-initiated study evaluating the use of rituximab in IgG4-RD.

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