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Abstract
Background/aim To analyse the clinical risk factors for extraophthalmic involvement and treatment outcomes in patients with IgG4-related ophthalmic disease (IgG4-ROD) in Korea.
Methods We retrospectively reviewed medical records of 42 patients diagnosed with IgG4-ROD confirmed by a surgical biopsy during the 7-year period, between January 2009 and March 2015, at three tertiary referral centres in Korea. Data regarding patients’ demographics, clinical characteristics and radiological findings were obtained. The relapse rate was compared between systemic steroids only and combined immunosuppressant therapy.
Results The mean patient age was 55.2 years (male:female ratio, 1:1). Based on the primary orbital structure affected, the IgG4-RODs were classified as dacryoadenitis (52.4%), orbital soft tissue inflammation (21.4%), trigeminal nerve involvement (11.9%) and myositis (9.5%). Extraophthalmic involvement (n=21) was associated with bilateral involvement (p=0.004), longer symptom duration (p=0.033) and a higher serum IgG4 level (p=0.034). Initial treatment regimens included attentive observation (n=7), prednisolone alone (n=22) and prednisolone plus immunosuppressive agent (n=13). During follow-up (mean, 24 months), 13 patients (37.1%) experienced relapse. In the extraophthalmic involvement group, steroid therapy alone resulted in a significantly higher relapse rate than combined immunosuppressant treatment (p=0.028).
Conclusion Bilateral involvement, longer symptom duration and higher IgG4 levels were significant risk factors for extraophthalmic involvement in Korean patients with IgG4-ROD. In patients with an extraophthalmic involvement, prednisolone combined with an immunosuppressive agent was more effective for preventing recurrence than prednisolone alone.
- orbit
- inflammation
- lacrimal gland
- pathology
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Introduction
IgG4-related disease (IgG4-RD) is an increasingly recognised immune-mediated condition characterised by enlargement of the affected organ, lymphoplasmacytic infiltration with a predominance of IgG4-positive plasma cells and elevated serum IgG4.1 Recently, manifestations of IgG4-RD have been described in nearly every organ system, including the pancreas, salivary glands, kidney and periorbital tissues.2 3 IgG4-related ophthalmic diseases (IgG4-ROD) is a disease entity that includes some portions of disorders that were previously known as Mikulicz’s disease, orbital benign lymphoid hyperplasia, idiopathic orbital inflammation and idiopathic sclerosing orbital inflammation before recognition of IgG4-RD.4–6 In recent years, much has been learnt about the clinical manifestations of IgG4-ROD; however, most studies have been small case series, and there has been little comprehensive or systematic research.
The first-line treatment for IgG4-ROD is usually a systemic steroid, which tends to elicit a satisfactory response; however, the rate of relapse can be as high as 70%, and prolonged treatment is often required, which leads to a high risk for steroid-related complications.7 8 Other immunomodulating agents are also effective, and are often used in recurrent or refractory cases; however, there have been insufficient prospective, randomised clinical trials to establish an optimal treatment strategy.
The purpose of this study was to investigate the clinical features, disease course and treatment outcomes of IgG4-ROD in Korean patients. Furthermore, we suggest a therapeutic strategy for IgG4-ROD.
Patients and methods
During the 7-year period from January 2009 to March 2015, the records of patients with a diagnosis of IgG4-ROD confirmed by surgical biopsy at the Department of Ophthalmology at Seoul National University Hospital, Seoul National University Boramae Hospital and Seoul National University Bundang Hospital were collected. This study adhered to the tenets of the Declaration of Helsinki, and the study protocol was approved by the institutional review board of each hospital. The requirement for informed written consent was waived due to the retrospective nature of the research. IgG4-ROD was diagnosed based on the diagnostic criteria for definite or probable IgG4-ROD proposed by Goto et al 9; histopathological diagnosis of IgG4-ROD was confirmed on the basis of pathognomonic features, which included a diffuse lymphoplasmacytic infiltrate with a preponderance of IgG4-positive plasma cells (>50 IgG4-positive cells per high-power field), and a positive IgG4:IgG plasma cell ratio (>40%), with either fibrosis or sclerosis.
Data collected from medical records included information regarding age, sex, duration of symptoms, laterality, location of lesions, serological findings including serum IgG4 levels, extraophthalmic manifestations, treatment modalities used, initial response and disease course focusing on relapse. The duration of symptom was defined as the total length of time before diagnosis, and carefully assessed on a monthly basis based on history taking. All radiological images were reviewed by one radiologist specialising in the head and neck, and two ophthalmologists.
In all cases, the extraophthalmic work-up included a physical examination with emphasis on the neck lymph nodes and salivary glands, blood testing (complete blood count with differential counts, serum electrolyte evaluations, and renal and liver function tests) and chest radiography. A rheumatologist was subsequently consulted to make a decision regarding systemic imaging if the patient exhibited systemic symptoms, a suspicious palpable mass on physical examination, or abnormalities on blood tests or chest radiographs. According to clinical suspicion, imaging work-up was selectively performed: CT of the neck (n=22); abdomen/pelvis (n=10); chest (n=6); MRI of the head (n=4); and whole-body fluorodeoxyglucose positron emission tomography (n=4). Biopsy of extraophthalmic lesions, an invasive procedure, was performed when it was considered necessary to confirm the diagnosis of extraophthalmic disease.
The Fisher’s exact test was used to compare possible associations between extraophthalmic involvement and the categorical variables, and the relapse rate according to the treatment regimen and the presence of extraophthalmic involvement. The Mann-Whitney U test was used to determine whether the continuous variables were associated with the extraophthalmic involvement. Survival curves for relapse were determined using the Kaplan-Meier method and compared with the results of log-rank tests. All the statistical analyses were performed using SPSS software (version 21.0; SPSS Inc., Chicago, IL, USA) and p<0.05 (two tailed) was considered to be statistically significant.
Results
Demographics and locational characteristics
The mean age of the 42 patients was 55.2 years, with a male-to-female ratio of 1:1. The most common presenting symptom was eyelid swelling, which occurred in 34 (80.9%) patients, followed by proptosis in 16 (38.1%) and diplopia in 5 (11.9%). The mean duration of symptoms was 21.5 months. The anatomical locations primarily affected were the lacrimal glands, the extraocular muscles (EOM), the orbital soft tissue and the trigeminal nerve. IgG4-ROD types classified according to mainly involved location were dacryoadenitis in 52.4%, followed by orbital soft tissue type (21.4%), trigeminal nerve involvement type (11.9%) and myositis type (9.5%) (figure 1).
Representative CT findings of four types of IgG4-related ophthalmic disease according to the anatomical location that is most involved. (A) Dacryoadenitis type. Diffuse enlargement of bilateral lacrimal glands (white arrows) is shown on an axial CT scan. (B) Orbital fat tissue type. A space-occupying fatty mass (white arrow) is detected in the left retrobulbar area on an axial fat-saturated T2-weighted image. (C) Orbital myositis type. Diffuse enlargement of the left medial and lateral rectus muscles (black arrows) is shown on an axial CT scan. (D) Trigeminal nerve enlargement type. Markedly enlarged supraorbital and infraorbital nerves on both sides (black arrows) are demonstrated on a coronal CT scan.
The clinical findings according to the type of IgG4-ROD are summarised in table 1. Regarding the extent of the disease, lacrimal gland enlargement was observed in 35 patients (83.3%), EOM enlargement in 13 (31.1%), trigeminal nerve involvement in 10 (23.8%), orbital fat infiltration in 14 (33.3%), nasolacrimal duct involvement in 1 (2.4%) and eyelid involvement in 1 (2.4%). A unifocal lesion was observed in 22 patients (55%) whereas the other 20 patients exhibited multifocal involvement.
Demographic and clinical features related to the locational type of IgG4-related ophthalmic disease
Extraophthalmic involvement was noted in 21 of 42 (50.0%) patients, and the salivary gland was the most commonly involved site (n=18), followed by the kidney (n=7), paranasal sinuses (n=6), lymph nodes (n=6), lung (n=3), peritoneum (n=2), pancreas (n=1) and aorta (n=1). Regarding renal involvement, three patients exhibited a retroperitoneal mass, which causes obstructive nephropathy, and four patients exhibited multiple cortical masses or diffuse enlargement of both kidneys on enhanced abdominal CT scan, with a clinical diagnosis of interstitial nephritis. In the case of aortitis, the patient complained of intermittent periumbilical pain, and the abdominopelvic CT scan revealed circumferential wall thickening of the abdominal aorta. During follow-up, the aortitis developed into an abdominal aortic rupture; consequently, the patient underwent aortofemoral bypass, and IgG4-RD was finally confirmed by surgical biopsy.
The clinical characteristics of patients with (n=21) and without extraophthalmic involvement (n=21) are summarised in table 2. In the 21 patients with extraophthalmic involvement, 18 (85.7%) exhibited bilateral ophthalmic involvement, whereas 8 of 21 (38.1%) without extraophthalmic involvement had bilateral disease (p=0.004). In addition, patients with extraophthalmic involvement tended to have had a longer duration of symptoms than those without extraophthalmic involvement (p=0.033). The initial mean (±SD) serum IgG4 levels were available for 38 patients (322.9±403.6 mg/dL), and 21 (55.3%) of these had an elevated serum IgG4 level (>135 mg/dL). The mean serum IgG4 concentration was significantly higher in patients with extraophthalmic involvement (483.2 mg/dL) than in those without extraophthalmic involvement (134.4 mg/dL) (p=0.034).
Comparison of clinical characteristics between patients with IgG4-ROD with and without extraophthalmic involvement
Treatment regimens and outcomes
The initial treatment regimens included prednisolone alone (n=22), and combined immunosuppressant treatment comprising prednisolone plus an immunosuppressive agent (n=13). The immunosuppressive agents used were azathioprine (n=4), methotrexate (n=6) and cyclosporine (n=3). Seven patients with mild symptoms were actively monitored without treatment. Oral prednisolone was administrated at an initial dose of 0.6–0.8 mg/kg/day and then tapered by 10 mg every 2–4 weeks. All patients responded well to their medication and reached a remission state in an average of 9.9 weeks (median 8 weeks).
During the follow-up period (23.7±17.4 months), 13 (37.1%) cases experienced a relapse. While relapse occurred in 11 of 22 patients in the group taking prednisolone alone, only 2 of 13 in the prednisolone plus immunosuppressant group relapsed. The relapse rate in the prednisolone alone group was significantly higher than that in the combined immunosuppressant group (p=0.022) (figure 2). In the group with extraophthalmic involvement, the recurrence rate was 50% (10/20), which was significantly higher than that in the group without extraophthalmic involvement (13.6%, 3/22) (p=0.011). When the subgroup of patients with extraophthalmic manifestations (n=20) was divided into those taking prednisolone only and those on combined immunosuppressant therapy, the prednisolone only group again demonstrated a higher rate of relapse (p=0.028). Furthermore, in this subgroup, patients on combined immunosuppressant treatment had a significantly prolonged relapse-free survival compared with those who took steroids only (p=0.04) (figure 3).
Treatment options and comparisons of relapse rate for 42 patients with IgG4-related ophthalmic disease. FU, follow-up; Pd, prednisolone.
Analyses of relapse-free survival in patients with IgG4-related ophthalmic disease. (A) Kaplan-Meier survival curves for comparing relapse rates between the prednisolone alone group and the prednisolone plus immunosuppressant (IS) group. Subgroup analyses for (B) patients without extraophthalmic involvement and (C) patients with extraophthalmic involvement.
Of the patients who relapsed, 3 were treated by increasing the prednisolone dosage incrementally, and 10 were treated with prednisolone plus an immunosuppressive agent (azathioprine in 8 cases, and methotrexate in 2). Two refractory cases required radiotherapy due to progressed proptosis, although they were treated with steroid and immunosuppressive agents; both had bilateral disease and multifocal involvement. Each patient received 20 and 24 Gy fractional orbital radiotherapy. One achieved partial remission with improved symptoms without additional medication over 2 years’ follow-up. The other patient achieved complete remission, but experienced recurrence 6 months later and required maintenance with immunosuppressive agent until the last follow-up with a quiescent state.
At the time of the last follow-up, all patients exhibited either no evidence of disease or stable disease, and no severe complications associated with treatment were observed.
Discussion
In this study, we investigated 42 Korean patients with IgG4-ROD and found that extraophthalmic manifestations of IgG4-RD were associated with bilateral disease, a high serum IgG4 level and longer duration of symptoms. In addition, we determined that combined immunosuppressant therapy is more effective than an oral steroid alone in terms of preventing relapse, especially in patients with extraophthalmic involvement.
Our study showed that IgG4-ROD primarily developed in a middle-aged population, with a peak incidence in the sixth decade of life, and that men and women appear to be affected equally, which is consistent with previous reports.10 11 We also demonstrated that the site most frequently involved is the lacrimal gland, with half of our patients having dacryoadenitis type IgG4-ROD, and the most common extraophthalmic manifestations occur in the salivary glands and lymph nodes, which are consistent with previous studies.12–17
In this study, half of patients with IgG4-ROD had extraophthalmic disease, and we analysed possible demographic and clinical risk factors for extraophthalmic involvement. Bilateral IgG4-ROD was the strongest risk factor for extraophthalmic involvement (p=0.004), which concurs with a report by Wu et al.14 Higher initial serum IgG4 level was also noted in patients with extraophthalmic disease (p=0.034). One study from a Japanese group reported that higher serum IgG4 level was associated with extraophthalmic involvement in patients with IgG4-related dacryoadenitis.18 In addition, our study was the first document that the duration of symptoms was also significantly longer in cases with extraophthalmic disease (p=0.033). Somewhat unsurprisingly, bilaterality, high IgG4 and long duration of disease may reflect a heavy burden of IgG4-positive cells, suggesting that these findings are indicative of greater disease severity, in which extraophthalmic manifestations of IgG4-RD are more likely and systemic evaluation is needed.
There are no evidence-based guidelines for the treatment of IgG4-ROD. Systemic corticosteroid treatment is well known as a first-line treatment modality, and there is generally a satisfactory response. However, relapse is common after cessation of steroids; consequently, patients may remain on long-term steroid therapy.19 Immunosuppressive agents were used in some previous case series; however, their efficacy compared with steroid treatment was not evaluated.11 16 20 21 In this study, the prednisolone alone group showed a significantly higher rate of relapse than the combined immunosuppressant group. This is the first report to document that combined immunosuppressant treatment is more effective than steroid therapy alone in preventing relapse of IgG4-ROD. This finding is especially notable because we applied prednisolone alone therapy in patients with relatively mild clinical manifestations. Notably, combined immunosuppressant treatment was highly effective for preventing relapse in patients with extraophthalmic involvement. In addition, no previous study had demonstrated that extraophthalmic involvement is a risk factor for frequent orbital relapse after corticosteroid treatment.
Limitations of this study included its retrospective design, and the non-controlled investigation and treatment protocol. The duration of symptoms completely depended on patient self-report; consequently, the possibility of memory bias exists, although we carefully verified symptom duration. All patients were not examined using the same imaging modalities in investigating extraophthalmic manifestation, which may have introduced bias. However, we had specific protocols for systemic evaluation of IgG4-ROD in clinical practice, and attempted to apply them equally to all patients. All patients underwent detailed history taking, physical examination, blood testing and chest radiography. Further imaging work-up was ordered if a patient exhibited specific signs or symptoms, or demonstrated laboratory test abnormalities. Furthermore, several recent retrospective studies reported the effectiveness of rituximab in relapsed or refractory IgG4-ROD.22–24 A large-scale prospective study to identify which immunosuppressant combination is most effective and to elucidate the role of monoclonal antibodies in IgG4-ROD treatment is warranted.
In conclusion, our study demonstrated that IgG4-ROD with extraophthalmic involvement has a high rate of bilaterality, a higher IgG4 level and longer symptom duration. Combination therapy with prednisolone and an immunosuppressant agent is recommended to prevent relapse in these patients.
References
Footnotes
Contributors Conceptualisation: HKC, JP, MJL, SIK. Methodology: JP, MJL, NK. Formal analysis: JP, MJL, SWP, JEK. Investigation: HKC, JP, MJL. Writing (original draft preparation): JP, MJL, NK. Writing (review and editing): HKC, SIK. Supervision: HKC. All authors have read and approved the final manuscript. MJL and JP contributed equally, and are the co-first authors for this paper.
Competing interests None declared.
Ethics approval The Institutional Review Board of Seoul National University Hospital, Seoul National University Boramae Hospital and Seoul National University Bundang Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
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