Patients

We designed a retrospective cohort study to evaluate the relationship between the serum characteristics of patients with IgG4-related orbital inflammation with or without early relapse. All patients were examined between February 1, 2005 and May 31, 2011. We excluded patients with distinct autoimmune diseases including Sjögren syndrome, lymphoma (especially on marginal zone B-cell lymphoma with IgG4-positive plasma cells), thyroid orbitopathy, vasculitis (eg, Wegener granulomatosis), and granulomatous lesions (eg, xanthogranuloma and sarcoidosis).

Patients were diagnosed with IgG4-related orbital inflammation if the ocular adnexal lesion had dense lymphoplasmacytic infiltrations, an IgG4-to-IgG plasma cell ratio >40%, and >100 IgG4-positive plasma cells in a single high-power field. In addition, a serum IgG4 level of ≥135 mg/dL was used for the diagnosis. Of the 31 patients who met the criteria for IgG4-related orbital inflammation, 1 patient with concurrent autoimmune pancreatitis was excluded because the patient was undergoing treatment for pancreatitis. The study thus included 30 patients.

Clinical Data

We recorded each patient’s age, sex, laterality, duration of symptoms, illnesses (including allergic diseases), and the anatomic location of the lesion. To determine that there was systemic involvement, 23 patients (77%) underwent screening at their initial examinations by whole-body CT scans, gallium-67 imaging, or ¹⁸ F- fluorodeoxyglucose positron emission tomography. The remaining 7 patients refused to undergo screening for systemic involvement.

Laboratory Data

Hematologic examinations were performed on peripheral blood collected from all patients at the time of diagnosis and at each of the follow-up visits, with an emphasis on the serum levels of IgG, IgG4, and IgE. To analyze patients with high serum level of IgG4, we divided patients into 2 groups according to serum level: Group 1 included those with IgG4 levels ≥900 mg/dL and Group 2 included those with IgG4 levels ≥135 mg/dL but <900 mg/dL. Blood eosinophilia was diagnosed when the number of eosinophils was ≥600 cells/mm ³ . Patients with serum levels of soluble IL-2 receptor were examined in more detail to determine whether an in vivo activation of the immune system had occurred. We determined the serum levels of antinuclear antibody, anti-SS-A/Ro, and rheumatoid factor (a latex turbidimetric immunoassay) at the time of diagnosis in all patients. When the antibody titer was ≥1:160, the patient was classified as being positive for antinuclear antibody. We also compared the rheumatoid factor levels in patients with IgG4-related orbital inflammation with the levels in age- and sex-matched controls.

Treatments and Outcomes

Corticosteroid treatment was initiated only after informed consent was obtained from the patient. An alternative treatment for patients who were unwilling to receive corticosteroid treatment was 30 Gy radiotherapy. Four patients refused any treatment because of mild signs and symptoms. Two patients refused corticosteroid treatment but received 30 Gy radiotherapy because of diabetes mellitus. Of the remaining 24 patients, 23 patients received corticosteroid treatment and 1 patient received corticosteroid treatment following 30 Gy radiotherapy. Corticosteroid treatment began with oral administration of 30 mg/day prednisolone for 1 or 2 weeks, and this dose was reduced by 5 mg/day at 2-week intervals. Of the 24 patients receiving corticosteroid treatment, 12 patients received a maintenance dose of 5 mg/day for at least 3 months following the tapering of prednisolone.

A regression and a recurrence of IgG4-related orbital inflammation was determined radiologically. We evaluated the response of orbital lesions to medical treatment by comparing axial and coronal CT scans before and after treatment and at 6 months after discontinuation of corticosteroid treatment. To determine the degree of regression of the orbital lesion after corticosteroid treatment, we assumed that the shape of the lesion was an ellipsoid to calculate its approximate volume. We determined the regression factor for the semi-major axis (X), the semi-minor axis (Y), and the major axis (Z) before and after corticosteroid treatment. We defined the regression rate as the XYZ value after corticosteroid treatment divided by the XYZ value before corticosteroid treatment. We also defined the relapse ratio as the XYZ value at 6 months after discontinuation of corticosteroid treatment divided by the XYZ value before corticosteroid treatment. When the regression rate was <40%, it was considered regression ( Figure 1 ); when the rate was ≥40% but <80%, it was considered partial regression; and when the ratio was ≥80%, it was considered poor regression. When the relapse rate was ≥80%, it was considered complete relapse ( Figure 1 ); and when the relapse rate was ≥40% but <80%, it was considered partial relapse. Finally, when the relapse rate was <40%, it was considered minor relapse ( Figure 1 ).

IgG4-related orbital inflammation. Orbital computed tomographic (CT) scans before corticosteroid treatment (left), after corticosteroid treatment (middle), and 6 months after discontinuation of corticosteroid treatment (right). (Top row) A 78-year-old man with IgG4-related orbital inflammation with early relapse. The orbital lesions showed regression (middle), but relapsed (right). Laboratory data showed that his serum IgG4 level was 653 mg/dL before corticosteroid treatment, 332 mg/dL after corticosteroid treatment, and 477 mg/dL 6 months after discontinuation of corticosteroid treatment (normal range, 5-105 mg/dL). The rheumatoid factor level was 118 IU/mL before corticosteroid treatment, 20 IU/mL after corticosteroid treatment, and 37 IU/mL 6 months after the discontinuation of corticosteroid treatment (normal level, <20 IU/mL). (Bottom row) A 75-year-old woman with IgG4-related orbital inflammation without early relapse. The lesions showed regression (middle) and only minor relapse (right). Laboratory data showed that her serum IgG4 level was 642 mg/dL before corticosteroid treatment, 225 mg/dL after corticosteroid treatment, and 377 mg/dL 6 months after discontinuation of corticosteroid treatment. The rheumatoid factor level was 5 IU/mL at all determinations.

For patients without corticosteroid treatment, we defined the regression as a rate of the XYZ value at the 6-month follow-up divided by the XYZ value before the corticosteroid treatment. When the rate was ≥100%, it was considered proliferation; and when the rate was ≥80% but <100%, it was considered poor regression. When the rate was ≥40% but <80%, it was considered partial regression ( Figure 2 ).

A 44-year-old woman with IgG4-related orbital inflammation who did not undergo corticosteroid treatment. Orbital CT scans showed an enlargement of both lacrimal glands at the initial examination (Left) and partial regression at the 6-month follow-up examination (Right). Laboratory data showed that her serum IgG4 level was 834 mg/dL at the initial examination and 667 mg/dL at the 6-month follow-up examination. The rheumatoid factor level was 10 IU/mL at all determinations.

Histopathology, Immunohistochemistry, and Flow Cytometric Analysis

Biopsy specimens of the ocular adnexal mass–forming lesions including orbital soft tissues were collected from all patients. Part of the biopsy specimen was embedded in paraffin for conventional histologic and immunohistochemical analyses, and the remainder was used immediately for flow cytometry analysis. The histopathology and immunohistochemistry methods and procedures were described previously. Four fresh samples from the lesions were analyzed by flow cytometry (FACSCalibur direct dual-parameter flow cytometer; Becton Dickinson and Company, San Jose, California, USA) using fluorescein isothiocyanate– or phycoerythrin-conjugated monoclonal antibodies to CD4, CD5, CD20, and HLA-DR. Biopsy specimens from other organs were collected from 4 patients with systemic involvement.

Statistical Analyses

To determine the characteristics of patients with high serum IgG4 levels, we compared the sex, laterality distribution, duration of symptoms, association of allergic disease, and incidence of blood eosinophilia between the high IgG4 group (serum IgG4 level ≥900 mg/dL) and low IgG4 group (serum IgG4 level <900 mg/dL) using the χ ² test or Fisher exact test ( Table 1 ). Patient age, laboratory data, and duration of symptoms were compared using the Mann-Whitney U test ( Table 1 ). We also compared the incidence of systemic involvement of IgG4-related lesions between the 2 groups by the Mann-Whitney U test (eg, salivary gland involvement, 1; and salivary gland and lymph nodes involvement, 2).

To determine the characteristics of patients with early relapse of the lesions, we compared the sex, laterality distribution, duration of symptoms, association of allergic disease, incidence of rheumatoid factor, and maintenance corticosteroid treatment between the relapsed and nonrelapsed groups using the χ ² test or Fisher exact test ( Table 2 ). Patient age, duration of symptoms, and serum levels of IgG, IgG4, IgE, and soluble IL-2 receptor were compared between the 2 groups using the Mann-Whitney U test ( Table 2 ).

Table 2

Comparisons of the Clinical Characteristics and Serum Data of 24 Patients With Relapsed and Nonrelapsed IgG4-Related Orbital Inflammation Before and After Corticosteroid Treatment

	Relapse		P Value
	(Relapsed: n = 8)	(Nonrelapsed: n = 16)
Age, mean (SD)	54 (18)	59 (15)	.4
Sex, male (n)	4	10	.7
Laterality, bilateral (n)	7	10	.4
Duration of symptoms (mo), mean (SD)	17 (19)	23 (26)	1.0
Association of allergic diseases, n	5	6	.7
IgG level before CST, mg/dL, a mean (SD)	2554 (1015)	2644 (1713)	.2
IgG level after CST, mg/dL, a mean (SD)	1407 (424)	1370 (571)	.7
IgG4 level before CST, mg/dL, a mean (SD)	789 (356)	849 (770)	.5
IgG4 level after CST, mg/dL, a mean (SD)	376 (200)	295 (221)	.2
IgE level before CST, IU/mL, a mean (SD)	1269 (1516)	1442 (1962)	.7
IgE level after CST, IU/mL a mean (SD)	512 (601)	795 (1009)	.5
Rheumatoid factor before CST (>30 IU/mL), n	5	2	.02
Soluble IL-2 receptor, U/mL a	733 (350)	752 (446)	.8
Maintenance CST, n	5	7	.7

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