Jpn J Ophthalmol (2015) 59:8–13 DOI 10.1007/s10384-014-0353-1
CLINICAL INVESTIGATION
Ocular adnexal IgG4-related disease: clinical features, outcome, and factors associated with response to systemic steroids Wei-Kuang Yu • Shu-Ching Kao • Ching-Fen Yang Fenq-Lih Lee • Chieh-Chih Tsai
•
Received: 17 February 2014 / Accepted: 5 September 2014 / Published online: 7 November 2014 Ó Japanese Ophthalmological Society 2014
Abstract Purpose The aim of this study was to investigate clinical characteristics, outcome, and factors associated with response to systemic administration of steroids in patients with ocular adnexal immunoglobulin G4 (IgG4)-related disease. Methods This was a retrospective evaluation of 11 patients with histopathologically verified ocular adnexal IgG4-related diseases at a medical center in Taiwan between January 2006 and December 2012. Clinical features and outcome, including serial change of serum IgG4 and clinical factors related to response to steroids systemically were evaluated. Results Seven men and four women, mean age 54.5 years and mean follow-up of 33.5 months, were evaluated. Elevated serum IgG4 levels ([135 mg/dl) were observed in ten patients (91 %). Lacrimal gland involvement was noted in eight (72.7 %), followed by orbit, extraocular muscles, and eyelids. Seven patients (63.6 %) had bilateral ocular lesions and eight (72.7 %) had extraorbital involvement. Eight of ten patients who underwent systemic steroid treatment responded well in the early phase. Recurrence developed in five patients (45 %), requiring repeat steroid W.-K. Yu S.-C. Kao F.-L. Lee C.-C. Tsai (&) Department of Ophthalmology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan e-mail: [email protected] S.-C. Kao F.-L. Lee C.-C. Tsai Faculty of Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan C.-F. Yang Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
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therapy and adjunctive treatment. Median serum levels of IgG4 reduced from 540 to 101 mg/dl in ten patients after systemic corticosteroid administration. Patients with lower serum IgG4 and IgG4:IgG ratio at diagnosis were associated with poor response (p = 0.037). Conclusions Ocular adnexal IgG4-related disease predominantly involved the lacrimal glands bilaterally and was usually associated with high serum IgG4 levels and multiple organ involvement. Most patients responded well to steroid therapy, which was accompanied by a marked decrease in serum IgG4. Keywords Ocular adnexal IgG4-related disease IgG4related disease Steroid Idiopathic orbital inflammation
Introduction Immunoglobulin G4-related disease (IgG4-RD), first recognized as a type of autoimmune pancreatitis, is increasingly considered to be an emerging idiopathic inflammatory disorder [1]. IgG4-RD often presents clinicians with a diagnostic challenge not only because of the limited understanding of the disease but because of the simultaneous or sequential involvement of multiple organs, including pancreas, hepatobiliary tract, lung, kidneys, retroperitoneum, lymph nodes, submandibular and parotid glands, thyroid gland, and ocular adnexa [2–6]. Emerging evidence suggests that some idiopathic orbital inflammations are linked to IgG4-RD [7–9]. A recent Japanese prevalence study of IgG4-related ophthalmic disease showed that approximately a quarter of orbital lymphoproliferative disorders are related to IgG4 [10]. Despite the fact that ocular adnexa, especially in the lacrimal gland, is a common site involved by IgG4-RD, its clinical features,
Clinical outcome of ocular IgG4-RD
therapy, and outcomes have not been well clarified. In this study, we investigated the clinical features, laboratory findings, treatment, and outcomes of biopsy-proven ocular adnexal IgG4-RD and determined the factors associated with response to systemic steroid administration in these patients.
Materials and methods We retrospectively reviewed the medical records of all patients with ocular adnexal IgG4-RD treated in Taipei Veterans General Hospital between January 2006 and December 2012. Inclusion criteria included a confirmed histopathological diagnosis of IgG4-RD and a minimum follow-up of 12 months to observe response to treatment. Biopsy specimens from ocular adnexal or systemic lesions were collected from all patients: ten (90.9 %) had ocular adnexal biopsies and six (54.5 %) had systemic biopsies. Histopathological diagnosis of IgG4-RD was confirmed by one experienced pathologist (YCF) on the basis of the pathological features reported to date [1, 8, 11, 12], which include diffuse lymphoplasmacytes and high IgG4-positive plasma-cell infiltration [[30 IgG4-positive cells per highpower field (HPF) and a positive IgG4:IgG cell ratio [40 %) with either fibrosis or sclerosis. The following data were obtained from patients’ charts: age, gender, systemic involvement, involved side and location, treatment, and outcome. Laboratory findings comprised serum change of IgG and IgG4 levels. All patients received systemic corticosteroid treatment, except one patient with an eyelid lesion who underwent surgical excision. Systemic corticosteroid treatment was initiated orally with prednisolone 0.6 mg/kg/day for 4 weeks and then tapered by 5 mg every 2–4 weeks. It generally took 4–6 months to discontinue steroid treatment. In patients refractory to prednisolone orally or unable to have their dose reduced sufficiently to avoid adverse effects of the medication due to chronic use, we used adjunctive radiotherapy and/or rituximab. Initial responses to systemic corticosteroid therapy were divided into three categories: (1) complete response (CR), defined as marked resolution of clinical symptoms and radiographic findings with eventual discontinuation of corticosteroids, (2) partial response (PR), defined as moderate resolution of clinical symptoms or radiographic findings and successful withdrawal of corticosteroids; (3) nonresponse (Non-R) was defined as no clinical improvement, even under high doses of steroids. Disease recurrence and adjuvant treatment were also reviewed. Overall treatment outcome measures were defined as no evidence of disease (NOD), stable disease (SD), and progressive disease (PD). The study was
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performed according to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Taipei Veterans General Hospital. Statistical analysis Difference between pretreatment and posttreatment serum IgG4 level was analyzed using the Wilcoxon signed-rank test. Possible factors associated with Non-R vs. GR or PR in patients who underwent systemic corticosteroid treatment were determined using Fisher’s exact test for category data and Wilcoxon rank-sum test for continuous data. P \ 0.05 was considered significant. All statistical analyses were performed using STATA computer statistical software (version 12; StataCorp., TX, USA).
Results Clinical features Eleven patients with ocular adnexal IgG4-RDs were reviewed, and their clinical features are summarized in Table 1. Seven men (63.6 %) and four women (36.4 %), mean age 54.5 years (range 21–75) and a mean follow-up 33.5 months (range 19–106) were assessed. Seven patients (63.6 %) had bilateral ocular involvement. Lacrimal gland was the most common location (eight patients), followed by orbital cavity (four patients), extraocular muscles (three patients), and eyelid (one patient). All had elevated serum IgG4 greater than normal range at the time of diagnosis, and ten patients (91 %) had serum IgG4 concentration C135 mg/ dl. Mean serum IgG4 concentration was 529.8 mg/dl, and the mean serum IgG4:IgG ratio was 29.1 %. Anti-SSA and Anti-SSB was checked in six patients, none of whom showed positive results. Systemic involvement at diagnosis was noted in eight patients (72.7 %), including neck lymphadenopathy (four patients), salivary gland inflammation (two patients), autoimmune pancreatitis (two patients), cheek mass (one patient), and retroperitoneal mass (one patient). Treatment outcomes Initial therapy included systemic corticosteroid administration in ten patients and eyelid lesion excision in one. Outcomes after treatment are shown in Table 2. Eight of ten patients (80 %) underwent systemic corticosteroid treatment, demonstrating significant improvement in clinical symptoms and on radiographic findings. Were able to discontinue corticosteroid treatment in these eight patients, with six showing good and two partial responses. Two (20 %) showed poor response, one of whom had bilateral vision loss due to recurrent and progressive compressive
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Table 1 Clinical features of ocular adnexal immunoglobulin-G4 (IgG4)-related disease Case
Sex
Age
Anatomic location
Side
Systemic involvement
Serum IgG4 (mg/dl)
Serum IgG (mg/dl)
Serum IgG4:IgG, ratio
1
M
72
LG, EOM
B
Not found
578
1,760
33 %
2
M
67
LG, Orbit
B
Autoimmune pancreatitis
149
1,170
13 %
3
M
60
LG
L
Retroperitoneal mass
924
3,120
30 %
4
F
53
LG
B
Autoimmune pancreatitis, Salivary gland
275
1,660
17 %
5
M
35
Orbit
R
Cheek mass
106
1,350
8%
6
F
67
Orbit
L
Not found
462
1,200
39 %
7 8
F M
66 75
LG LG, EOM
B B
Neck lymphadenopathy Salivary gland, Neck lymphadenopathy
501 941
1,530 1,960
33 % 48 %
9
M
42
Eyelid
L
Not found
135
1,560
9%
10
F
21
LG, EOM
B
Neck lymphadenopathy
988
1,800
55 %
11
M
42
LG, Orbit
B
Neck lymphadenopathy
769
2,040
38 %
LG lacrimal gland, EOM extraocular muscle, B bilateral, L left, R right
Table 2 Treatment outcome of ocular adnexal immunoglobulin 4 (IgG4)-related disease Case
Before treatment IgG4
a
IgG4/IgG
Treatment
Response
b
After treatment a
Recurrence
Adjunctive treatment
Outcome
b
IgG4
IgG4/IgG
Follow-up (months)
1
578
33 %
Steroid
GR
67
10 %
No
R/T
NED
23
2
149
13 %
Steroid
Non-R
61
5%
Yes
R/T, Rituximab
PD
23
3
924
30 %
Steroid
GR
135
11 %
No
NED
34
4
275
17 %
Steroid
GR
63
6%
No
NED
34
5
106
8%
Steroid
Non-R
61
6%
No
SD
37
6
462
39 %
Steroid
PR
413
32 %
Yes
NED
42
7 8
501 941
33 % 48 %
Steroid Steroid
GR GR
293 499
25 % 36 %
Yes No
SD NED
19 55
9
135
9%
Excision
GR
N/A
N/A
No
NED
46
10
988
55 %
Steroid
GR
58
13 %
Yes
11
769
38 %
Steroid
PR
169
17 %
Yes
R/T
R/T
SD
22
SD
106
GR Good response, PR partial response, Non-R Non response, R/T:radiotherapy, NED no evidence of disease, PD progressive disease, SD stable disease a
Serum IgG4 level (mg/dl)
b
Serum IgG4:IgG ratio (%)
optic neuropathy, even after adjunctive radiotherapy and rituximab. Median serum levels of igG4 of the ten patients administered systemic corticosteroids were reduced from 540 to 101 mg/dl (P = 0.022, Wilcoxon signed-rank test). Five patients (45 %) developed recurrent disease and received repeated steroid therapy, adjunctive radiotherapy, or rituximab. One patient (case 1) received adjunctive radiotherapy because he developed upper gastrointestinal bleeding and diabetes, requiring a rapid reduction in steroid therapy. Of the four patients treated with adjunctive orbital radiotherapy (2,000 cGy; 10 fractions), two achieved complete remission, one partial remission with improved control of quiescent state, and one showed poor response.
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Ten of 11 patients achieved stable disease or no evidence of disease at the end of follow-up. Factors associated with response to systemic corticosteroid Factors related to therapeutic response to corticosteroids are shown in Table 3. Non-R had a significant lower serum IgG4 (127.5 vs. 673.5 mg/dl, p = 0.037) and IgG4:IgG ratio (10 vs. 35 %, p = 0.037), compared with CR or PR. However, no other significant demographic (age and gender) or clinical (laterality and systemic involvement) factors were associated with PR.
Clinical outcome of ocular IgG4-RD
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Table 3 Factors associated with response to corticosteroid treatment Characteristic
Steroid treatment response Responsive (n = 8)
Poor (n = 2)
P value
Median agea (year)
63 (54)
51 (32)
0.694
Median serum IgG4 levela (mg/dl)
673.5 (713)
127.5 (43)
0.037
Median serum IgG levela (mg/dl)
1780 (1920)
1260 (180)
0.089
Median serum IgG4:IgG ratioa (%)
35.3 (38.3)
10.3 (4.9)
0.037
Male:female ratio
4:4
2:0
0.467
Unilateral:bilateral disease Involvement of other organs
2:6 6
1:1 2
1 1
a
Shown as median (range)
Discussion The results of this study demonstrate that ocular adnexal IgG4-RD is frequently related to lacrimal gland involvement, bilateral disease, elevation of serum IgG4 levels, systemic involvement, and high recurrent rates. Most patients showed initial good response to steroid therapy, accompanied by a decrease of serum IgG4 after treatment. Table 4 summarizes the clinical characteristics of ocular adnexal IgG4-RD from various case series in the published literature [13–18]. The mean age of ocular adnexal IgG4RD in this study was 55 years, concurrent with other studies within the range of 50–61 years. Based on these findings, no patients with ocular adnexal IgG4-RD are \20 years of age. The Japanese IgG4-related ophthalmic disease study group further revealed that the median age of patients with IgG4-related orbital inflammation is lower than that of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and higher than the non-IgG4 orbital inflammation [10]. IgG4-RD is known to be a predilection for middle-aged to elderly men [19]. Male predominance was also noted in our study, similar to the findings from some other categories of IgG4-RD [18, 20, 21]. However, some reports indicate no gender difference in patients with ocular adnexal IgG4-RD [14, 16, 17]. Based on findings from our current study and other case series on ocular adnexal IgG4-RD, lacrimal gland (84 %) is the most frequent site of involvement, followed by orbital soft tissues (19 %) and extraocular muscles (19 %) [13– 18]. Other periocular lesions include eyelid and infraorbital and supraorbital nerves. Conjunctival involvement is often not a feature. However, in some cases, clinical presentation seems to be more diffuse, bilateral, and commonly associated with involvement of multiple organs simultaneously. Most studies reveal a tendency toward bilateral
involvement of ocular adnexal IgG4-RD, ranging from 50 % to 85 %. Extraorbital involvement of ocular adnexal IgG4-RD at diagnosis was 73 % in this study and most commonly associated with neck lymphadenopathy (36 %), whereas systemic involvement rates vary from 29 % to 88 % in previous studies. With the understanding that IgG4-RD often affects more than one organ, additional sites of involvement could be observed following a detailed systemic workup or long-term follow-up. Based on our findings and previous observations, patients with ocular adnexal IgG4-RD have a higher incidence of elevated serum IgG4, bilateral disease, and systemic involvement, which can distinguish them from patients with non-IgG4 orbital inflammation [13–18]. IgG4 is a subtype of IgG, which accounts for 3–6 % of total IgG in normal serum. Elevated serum levels of IgG4 of C135 mg/dl are considered a diagnosis criteria for IgG4-RD [22]. However, other conditions have also been associated with high serum IgG4 levels, such as pemphigoid diseases, IgE-negative allergies, inflammatory disease, cancer, and infection [23–25]. So far, there is no evidence to show that IgG4 contributes directly to the pathogenesis of IgG4-RD, and the actual role of IgG4 in the disease process remains to be clarified. In 2001, Hamano et al. [26] reported elevated serum IgG4 levels in patients with sclerosing pancreatitis, and serum IgG4 titer correlated with disease activity. The proportion of elevated serum IgG4 in patients with ocular adnexal IgG4-RD ranges from 91 % to 100 % (Table 4). In particular, we are the first to show serial changes in elevated serum IgG4 levels in patients with ocular adnexal IgG4-RD after steroid therapy. Mean IgG4 levels and IgG4:IgG ratio decreased in all patients after steroid therapy and reduced by a mean value of 569–182 mg/dl (31.1–16.1 %). These changes were often accompanied by improvement in clinical symptoms and radiologic findings, especially for patients with higher serum IgG4 at diagnosis, suggesting that serum IgG4 and IgG4:IgG ratio may be useful indicators of disease activity for ocular adnexal IgG4-RD. IgG4-RD involving the lacrimal gland was previously referred to as Mikulicz syndrome, which was considered to be a subcategory of Sjo¨gren’s syndrome (SS). Recent studies show that the clinical features of IgG4-RD are different from SS, including low frequencies of presenting autoimmune antibodies, such as anti-SSA and anti-SSB [27]; and an increased prevalence of allergic rhinitis and bronchial asthma [28, 29]. In this study, anti-SSA and antiSSB had been checked in six patients, and none of them showed positive results. However, none of 11 patients in our study had a medical history of allergic rhinitis or bronchial asthma. The optimal therapeutic strategy for IgG4-RD is not well established. Steroid therapy remains the primary treatment but may fail to reverse the condition in severe
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Table 4 Clinical features of ocular adnexal immunoglobulin G4 (IgG4)-related disease in different studies Agea
Sex M:F
Bilateral
Ocular adnexal involvements LG
Orbit
EOM
Other
Serum IgG4 [ 135 mg/dl
Systemic involvement
Relapse
Sato et al., N = 21
60.4 (38–86)
10:11
12/21 (57 %)
16/21 (76 %)
7/21 (33 %)
None
None
N/Ab
6/21 (29 %)
5 (28 %)
Kubota et al., N = 10
57.6 (38–73)
5:5
8/10 (80 %)
5/10 (50 %)
2/10 (20 %)
1/10 (10 %)
4/10 (40 %)
10/10 (100 %)
7/10 (70 %)
2 (20 %)
Plaza et al., N = 11
50.4 (30–70)
6:5
6/11 (55 %)
10/11 (90 %)
2/11 (18 %)
4/11 (36 %)
None
N/Ab
5/11 (45 %)
2 (18 %)
Go et al., N = 14
51.2 (20–72)
7:7
10/14 (71 %)
13/14 (93 %)
None
None
1/14 (7 %)
13/14 (93 %)
6/14 (43 %)
7 (50 %)
Takahira et al., N = 16
56.4 (41–76)
8:8
N/Ab
16/16 (100 %)
None
4/16 (25 %)
5/16 (31 %)
15/16 (94 %)
14/16 (88 %)
5 (31 %)
Koizumi et al., N = 12
60.9 (25–74)
7:5
6/12 (50 %)
12/12 (100 %)
3/12 (25 %)
6/12 (50 %)
3/12 (25 %)
12/12 (100 %)
9/12 (75 %)
2 (17 %)
Current Study, N = 11
54.5 (21–75)
7:4
7/11 (64 %)
8/11 (73 %)
4/11 (36 %)
3/11 (27 %)
1/11 (9 %)
10/11 (91 %)
8/11 (73 %)
5 (45 %)
Overall, N = 95
56.3 (20–86)
50:45
49/79 (62 %)
80/95 (84 %)
18/95 (19 %)
18/95 (19 %)
14/95 (15 %)
60/63 (95 %)
55/95 (58 %)
28/95 (29 %)
LG lacrimal gland, EOM extraocular muscle a
Mean (min–max)
b
Data not available or incomplete
cases with advanced sclerosis and fibrosis of affected tissues. Our analysis reveals that pretreatment serum levels of IgG4 or the IgG4:IgG ratio in patients with ocular adnexal IgG4-RD at diagnosis were the only significant factors affecting their response to glucocorticoid therapy. Serial changes in serum IgG4 levels are reported to reflect the activity of IgG4-RD [26, 30]. Our findings further demonstrate that patients with lower serum IgG4 levels at diagnosis, reflecting lower disease activity, were correlated with poor response to steroid treatment. Recurrence rate was 45 % within a mean follow-up of 33.5 months, compared with a range of 18–50 % in prior studies. Recurrent disease often requires repeated steroid therapy, adjunctive radiotherapy, or rituximab administration. The use of radiotherapy in ocular adnexal IgG-RD is supported by its effectiveness in treating reactive lymphoid hyperplasia and orbital pseudotumors. Of the eight patients undergoing radiotherapy in the Sato study [13], five achieved complete remission, one partial remission, and two relapsed. In this study, adjunctive radiotherapy helped achieve complete remission or stabilization, allowing subsequent cessation of corticosteroids in patients who developed recurrent disease (cases 6 and 10) and intolerance to corticosteroid therapy (case 1). Specific immunomodulatory therapy, such as rituximab, is now being investigated as a treatment for IgG4-RD, and early data show promising results [5]. In our study, however, one patient (case 2) developed complete bilateral visual loss due to progressive fibrosclerotic orbital
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lesions, even after treatment with systemic steroids, adjunctive radiotherapy, and rituximab. Lower disease activity (relative to lower serum IgG4) and fibrosclerotic lesions in this case may explain why the patient showed poor response to steroids and other adjunctive therapy. In conclusion, our study shows ocular adnexal IgG4-RD has a high rate of systemic involvement, synchronous bilateral lacrimal gland involvement, and elevated serum IgG4 level at presentation. Most patients responded well to steroid therapy in accordance with serial changes of serum IgG4. However, continued surveillance and long-term follow-up are warranted because of the high recurrent rate. Conflicts of interest W.-K. Yu, None; S.-C. Kao, None; C.-F. Yang, None; F.-L. Lee, None; C.-C. Tsai, None.
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CLINICAL INVESTIGATION
Ocular adnexal IgG4-related disease: clinical features, outcome, and factors associated with response to systemic steroids Wei-Kuang Yu • Shu-Ching Kao • Ching-Fen Yang Fenq-Lih Lee • Chieh-Chih Tsai
•
Received: 17 February 2014 / Accepted: 5 September 2014 / Published online: 7 November 2014 Ó Japanese Ophthalmological Society 2014
Abstract Purpose The aim of this study was to investigate clinical characteristics, outcome, and factors associated with response to systemic administration of steroids in patients with ocular adnexal immunoglobulin G4 (IgG4)-related disease. Methods This was a retrospective evaluation of 11 patients with histopathologically verified ocular adnexal IgG4-related diseases at a medical center in Taiwan between January 2006 and December 2012. Clinical features and outcome, including serial change of serum IgG4 and clinical factors related to response to steroids systemically were evaluated. Results Seven men and four women, mean age 54.5 years and mean follow-up of 33.5 months, were evaluated. Elevated serum IgG4 levels ([135 mg/dl) were observed in ten patients (91 %). Lacrimal gland involvement was noted in eight (72.7 %), followed by orbit, extraocular muscles, and eyelids. Seven patients (63.6 %) had bilateral ocular lesions and eight (72.7 %) had extraorbital involvement. Eight of ten patients who underwent systemic steroid treatment responded well in the early phase. Recurrence developed in five patients (45 %), requiring repeat steroid W.-K. Yu S.-C. Kao F.-L. Lee C.-C. Tsai (&) Department of Ophthalmology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan e-mail: [email protected] S.-C. Kao F.-L. Lee C.-C. Tsai Faculty of Medicine, National Yang Ming University School of Medicine, Taipei, Taiwan C.-F. Yang Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
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therapy and adjunctive treatment. Median serum levels of IgG4 reduced from 540 to 101 mg/dl in ten patients after systemic corticosteroid administration. Patients with lower serum IgG4 and IgG4:IgG ratio at diagnosis were associated with poor response (p = 0.037). Conclusions Ocular adnexal IgG4-related disease predominantly involved the lacrimal glands bilaterally and was usually associated with high serum IgG4 levels and multiple organ involvement. Most patients responded well to steroid therapy, which was accompanied by a marked decrease in serum IgG4. Keywords Ocular adnexal IgG4-related disease IgG4related disease Steroid Idiopathic orbital inflammation
Introduction Immunoglobulin G4-related disease (IgG4-RD), first recognized as a type of autoimmune pancreatitis, is increasingly considered to be an emerging idiopathic inflammatory disorder [1]. IgG4-RD often presents clinicians with a diagnostic challenge not only because of the limited understanding of the disease but because of the simultaneous or sequential involvement of multiple organs, including pancreas, hepatobiliary tract, lung, kidneys, retroperitoneum, lymph nodes, submandibular and parotid glands, thyroid gland, and ocular adnexa [2–6]. Emerging evidence suggests that some idiopathic orbital inflammations are linked to IgG4-RD [7–9]. A recent Japanese prevalence study of IgG4-related ophthalmic disease showed that approximately a quarter of orbital lymphoproliferative disorders are related to IgG4 [10]. Despite the fact that ocular adnexa, especially in the lacrimal gland, is a common site involved by IgG4-RD, its clinical features,
Clinical outcome of ocular IgG4-RD
therapy, and outcomes have not been well clarified. In this study, we investigated the clinical features, laboratory findings, treatment, and outcomes of biopsy-proven ocular adnexal IgG4-RD and determined the factors associated with response to systemic steroid administration in these patients.
Materials and methods We retrospectively reviewed the medical records of all patients with ocular adnexal IgG4-RD treated in Taipei Veterans General Hospital between January 2006 and December 2012. Inclusion criteria included a confirmed histopathological diagnosis of IgG4-RD and a minimum follow-up of 12 months to observe response to treatment. Biopsy specimens from ocular adnexal or systemic lesions were collected from all patients: ten (90.9 %) had ocular adnexal biopsies and six (54.5 %) had systemic biopsies. Histopathological diagnosis of IgG4-RD was confirmed by one experienced pathologist (YCF) on the basis of the pathological features reported to date [1, 8, 11, 12], which include diffuse lymphoplasmacytes and high IgG4-positive plasma-cell infiltration [[30 IgG4-positive cells per highpower field (HPF) and a positive IgG4:IgG cell ratio [40 %) with either fibrosis or sclerosis. The following data were obtained from patients’ charts: age, gender, systemic involvement, involved side and location, treatment, and outcome. Laboratory findings comprised serum change of IgG and IgG4 levels. All patients received systemic corticosteroid treatment, except one patient with an eyelid lesion who underwent surgical excision. Systemic corticosteroid treatment was initiated orally with prednisolone 0.6 mg/kg/day for 4 weeks and then tapered by 5 mg every 2–4 weeks. It generally took 4–6 months to discontinue steroid treatment. In patients refractory to prednisolone orally or unable to have their dose reduced sufficiently to avoid adverse effects of the medication due to chronic use, we used adjunctive radiotherapy and/or rituximab. Initial responses to systemic corticosteroid therapy were divided into three categories: (1) complete response (CR), defined as marked resolution of clinical symptoms and radiographic findings with eventual discontinuation of corticosteroids, (2) partial response (PR), defined as moderate resolution of clinical symptoms or radiographic findings and successful withdrawal of corticosteroids; (3) nonresponse (Non-R) was defined as no clinical improvement, even under high doses of steroids. Disease recurrence and adjuvant treatment were also reviewed. Overall treatment outcome measures were defined as no evidence of disease (NOD), stable disease (SD), and progressive disease (PD). The study was
9
performed according to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Taipei Veterans General Hospital. Statistical analysis Difference between pretreatment and posttreatment serum IgG4 level was analyzed using the Wilcoxon signed-rank test. Possible factors associated with Non-R vs. GR or PR in patients who underwent systemic corticosteroid treatment were determined using Fisher’s exact test for category data and Wilcoxon rank-sum test for continuous data. P \ 0.05 was considered significant. All statistical analyses were performed using STATA computer statistical software (version 12; StataCorp., TX, USA).
Results Clinical features Eleven patients with ocular adnexal IgG4-RDs were reviewed, and their clinical features are summarized in Table 1. Seven men (63.6 %) and four women (36.4 %), mean age 54.5 years (range 21–75) and a mean follow-up 33.5 months (range 19–106) were assessed. Seven patients (63.6 %) had bilateral ocular involvement. Lacrimal gland was the most common location (eight patients), followed by orbital cavity (four patients), extraocular muscles (three patients), and eyelid (one patient). All had elevated serum IgG4 greater than normal range at the time of diagnosis, and ten patients (91 %) had serum IgG4 concentration C135 mg/ dl. Mean serum IgG4 concentration was 529.8 mg/dl, and the mean serum IgG4:IgG ratio was 29.1 %. Anti-SSA and Anti-SSB was checked in six patients, none of whom showed positive results. Systemic involvement at diagnosis was noted in eight patients (72.7 %), including neck lymphadenopathy (four patients), salivary gland inflammation (two patients), autoimmune pancreatitis (two patients), cheek mass (one patient), and retroperitoneal mass (one patient). Treatment outcomes Initial therapy included systemic corticosteroid administration in ten patients and eyelid lesion excision in one. Outcomes after treatment are shown in Table 2. Eight of ten patients (80 %) underwent systemic corticosteroid treatment, demonstrating significant improvement in clinical symptoms and on radiographic findings. Were able to discontinue corticosteroid treatment in these eight patients, with six showing good and two partial responses. Two (20 %) showed poor response, one of whom had bilateral vision loss due to recurrent and progressive compressive
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Table 1 Clinical features of ocular adnexal immunoglobulin-G4 (IgG4)-related disease Case
Sex
Age
Anatomic location
Side
Systemic involvement
Serum IgG4 (mg/dl)
Serum IgG (mg/dl)
Serum IgG4:IgG, ratio
1
M
72
LG, EOM
B
Not found
578
1,760
33 %
2
M
67
LG, Orbit
B
Autoimmune pancreatitis
149
1,170
13 %
3
M
60
LG
L
Retroperitoneal mass
924
3,120
30 %
4
F
53
LG
B
Autoimmune pancreatitis, Salivary gland
275
1,660
17 %
5
M
35
Orbit
R
Cheek mass
106
1,350
8%
6
F
67
Orbit
L
Not found
462
1,200
39 %
7 8
F M
66 75
LG LG, EOM
B B
Neck lymphadenopathy Salivary gland, Neck lymphadenopathy
501 941
1,530 1,960
33 % 48 %
9
M
42
Eyelid
L
Not found
135
1,560
9%
10
F
21
LG, EOM
B
Neck lymphadenopathy
988
1,800
55 %
11
M
42
LG, Orbit
B
Neck lymphadenopathy
769
2,040
38 %
LG lacrimal gland, EOM extraocular muscle, B bilateral, L left, R right
Table 2 Treatment outcome of ocular adnexal immunoglobulin 4 (IgG4)-related disease Case
Before treatment IgG4
a
IgG4/IgG
Treatment
Response
b
After treatment a
Recurrence
Adjunctive treatment
Outcome
b
IgG4
IgG4/IgG
Follow-up (months)
1
578
33 %
Steroid
GR
67
10 %
No
R/T
NED
23
2
149
13 %
Steroid
Non-R
61
5%
Yes
R/T, Rituximab
PD
23
3
924
30 %
Steroid
GR
135
11 %
No
NED
34
4
275
17 %
Steroid
GR
63
6%
No
NED
34
5
106
8%
Steroid
Non-R
61
6%
No
SD
37
6
462
39 %
Steroid
PR
413
32 %
Yes
NED
42
7 8
501 941
33 % 48 %
Steroid Steroid
GR GR
293 499
25 % 36 %
Yes No
SD NED
19 55
9
135
9%
Excision
GR
N/A
N/A
No
NED
46
10
988
55 %
Steroid
GR
58
13 %
Yes
11
769
38 %
Steroid
PR
169
17 %
Yes
R/T
R/T
SD
22
SD
106
GR Good response, PR partial response, Non-R Non response, R/T:radiotherapy, NED no evidence of disease, PD progressive disease, SD stable disease a
Serum IgG4 level (mg/dl)
b
Serum IgG4:IgG ratio (%)
optic neuropathy, even after adjunctive radiotherapy and rituximab. Median serum levels of igG4 of the ten patients administered systemic corticosteroids were reduced from 540 to 101 mg/dl (P = 0.022, Wilcoxon signed-rank test). Five patients (45 %) developed recurrent disease and received repeated steroid therapy, adjunctive radiotherapy, or rituximab. One patient (case 1) received adjunctive radiotherapy because he developed upper gastrointestinal bleeding and diabetes, requiring a rapid reduction in steroid therapy. Of the four patients treated with adjunctive orbital radiotherapy (2,000 cGy; 10 fractions), two achieved complete remission, one partial remission with improved control of quiescent state, and one showed poor response.
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Ten of 11 patients achieved stable disease or no evidence of disease at the end of follow-up. Factors associated with response to systemic corticosteroid Factors related to therapeutic response to corticosteroids are shown in Table 3. Non-R had a significant lower serum IgG4 (127.5 vs. 673.5 mg/dl, p = 0.037) and IgG4:IgG ratio (10 vs. 35 %, p = 0.037), compared with CR or PR. However, no other significant demographic (age and gender) or clinical (laterality and systemic involvement) factors were associated with PR.
Clinical outcome of ocular IgG4-RD
11
Table 3 Factors associated with response to corticosteroid treatment Characteristic
Steroid treatment response Responsive (n = 8)
Poor (n = 2)
P value
Median agea (year)
63 (54)
51 (32)
0.694
Median serum IgG4 levela (mg/dl)
673.5 (713)
127.5 (43)
0.037
Median serum IgG levela (mg/dl)
1780 (1920)
1260 (180)
0.089
Median serum IgG4:IgG ratioa (%)
35.3 (38.3)
10.3 (4.9)
0.037
Male:female ratio
4:4
2:0
0.467
Unilateral:bilateral disease Involvement of other organs
2:6 6
1:1 2
1 1
a
Shown as median (range)
Discussion The results of this study demonstrate that ocular adnexal IgG4-RD is frequently related to lacrimal gland involvement, bilateral disease, elevation of serum IgG4 levels, systemic involvement, and high recurrent rates. Most patients showed initial good response to steroid therapy, accompanied by a decrease of serum IgG4 after treatment. Table 4 summarizes the clinical characteristics of ocular adnexal IgG4-RD from various case series in the published literature [13–18]. The mean age of ocular adnexal IgG4RD in this study was 55 years, concurrent with other studies within the range of 50–61 years. Based on these findings, no patients with ocular adnexal IgG4-RD are \20 years of age. The Japanese IgG4-related ophthalmic disease study group further revealed that the median age of patients with IgG4-related orbital inflammation is lower than that of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and higher than the non-IgG4 orbital inflammation [10]. IgG4-RD is known to be a predilection for middle-aged to elderly men [19]. Male predominance was also noted in our study, similar to the findings from some other categories of IgG4-RD [18, 20, 21]. However, some reports indicate no gender difference in patients with ocular adnexal IgG4-RD [14, 16, 17]. Based on findings from our current study and other case series on ocular adnexal IgG4-RD, lacrimal gland (84 %) is the most frequent site of involvement, followed by orbital soft tissues (19 %) and extraocular muscles (19 %) [13– 18]. Other periocular lesions include eyelid and infraorbital and supraorbital nerves. Conjunctival involvement is often not a feature. However, in some cases, clinical presentation seems to be more diffuse, bilateral, and commonly associated with involvement of multiple organs simultaneously. Most studies reveal a tendency toward bilateral
involvement of ocular adnexal IgG4-RD, ranging from 50 % to 85 %. Extraorbital involvement of ocular adnexal IgG4-RD at diagnosis was 73 % in this study and most commonly associated with neck lymphadenopathy (36 %), whereas systemic involvement rates vary from 29 % to 88 % in previous studies. With the understanding that IgG4-RD often affects more than one organ, additional sites of involvement could be observed following a detailed systemic workup or long-term follow-up. Based on our findings and previous observations, patients with ocular adnexal IgG4-RD have a higher incidence of elevated serum IgG4, bilateral disease, and systemic involvement, which can distinguish them from patients with non-IgG4 orbital inflammation [13–18]. IgG4 is a subtype of IgG, which accounts for 3–6 % of total IgG in normal serum. Elevated serum levels of IgG4 of C135 mg/dl are considered a diagnosis criteria for IgG4-RD [22]. However, other conditions have also been associated with high serum IgG4 levels, such as pemphigoid diseases, IgE-negative allergies, inflammatory disease, cancer, and infection [23–25]. So far, there is no evidence to show that IgG4 contributes directly to the pathogenesis of IgG4-RD, and the actual role of IgG4 in the disease process remains to be clarified. In 2001, Hamano et al. [26] reported elevated serum IgG4 levels in patients with sclerosing pancreatitis, and serum IgG4 titer correlated with disease activity. The proportion of elevated serum IgG4 in patients with ocular adnexal IgG4-RD ranges from 91 % to 100 % (Table 4). In particular, we are the first to show serial changes in elevated serum IgG4 levels in patients with ocular adnexal IgG4-RD after steroid therapy. Mean IgG4 levels and IgG4:IgG ratio decreased in all patients after steroid therapy and reduced by a mean value of 569–182 mg/dl (31.1–16.1 %). These changes were often accompanied by improvement in clinical symptoms and radiologic findings, especially for patients with higher serum IgG4 at diagnosis, suggesting that serum IgG4 and IgG4:IgG ratio may be useful indicators of disease activity for ocular adnexal IgG4-RD. IgG4-RD involving the lacrimal gland was previously referred to as Mikulicz syndrome, which was considered to be a subcategory of Sjo¨gren’s syndrome (SS). Recent studies show that the clinical features of IgG4-RD are different from SS, including low frequencies of presenting autoimmune antibodies, such as anti-SSA and anti-SSB [27]; and an increased prevalence of allergic rhinitis and bronchial asthma [28, 29]. In this study, anti-SSA and antiSSB had been checked in six patients, and none of them showed positive results. However, none of 11 patients in our study had a medical history of allergic rhinitis or bronchial asthma. The optimal therapeutic strategy for IgG4-RD is not well established. Steroid therapy remains the primary treatment but may fail to reverse the condition in severe
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Table 4 Clinical features of ocular adnexal immunoglobulin G4 (IgG4)-related disease in different studies Agea
Sex M:F
Bilateral
Ocular adnexal involvements LG
Orbit
EOM
Other
Serum IgG4 [ 135 mg/dl
Systemic involvement
Relapse
Sato et al., N = 21
60.4 (38–86)
10:11
12/21 (57 %)
16/21 (76 %)
7/21 (33 %)
None
None
N/Ab
6/21 (29 %)
5 (28 %)
Kubota et al., N = 10
57.6 (38–73)
5:5
8/10 (80 %)
5/10 (50 %)
2/10 (20 %)
1/10 (10 %)
4/10 (40 %)
10/10 (100 %)
7/10 (70 %)
2 (20 %)
Plaza et al., N = 11
50.4 (30–70)
6:5
6/11 (55 %)
10/11 (90 %)
2/11 (18 %)
4/11 (36 %)
None
N/Ab
5/11 (45 %)
2 (18 %)
Go et al., N = 14
51.2 (20–72)
7:7
10/14 (71 %)
13/14 (93 %)
None
None
1/14 (7 %)
13/14 (93 %)
6/14 (43 %)
7 (50 %)
Takahira et al., N = 16
56.4 (41–76)
8:8
N/Ab
16/16 (100 %)
None
4/16 (25 %)
5/16 (31 %)
15/16 (94 %)
14/16 (88 %)
5 (31 %)
Koizumi et al., N = 12
60.9 (25–74)
7:5
6/12 (50 %)
12/12 (100 %)
3/12 (25 %)
6/12 (50 %)
3/12 (25 %)
12/12 (100 %)
9/12 (75 %)
2 (17 %)
Current Study, N = 11
54.5 (21–75)
7:4
7/11 (64 %)
8/11 (73 %)
4/11 (36 %)
3/11 (27 %)
1/11 (9 %)
10/11 (91 %)
8/11 (73 %)
5 (45 %)
Overall, N = 95
56.3 (20–86)
50:45
49/79 (62 %)
80/95 (84 %)
18/95 (19 %)
18/95 (19 %)
14/95 (15 %)
60/63 (95 %)
55/95 (58 %)
28/95 (29 %)
LG lacrimal gland, EOM extraocular muscle a
Mean (min–max)
b
Data not available or incomplete
cases with advanced sclerosis and fibrosis of affected tissues. Our analysis reveals that pretreatment serum levels of IgG4 or the IgG4:IgG ratio in patients with ocular adnexal IgG4-RD at diagnosis were the only significant factors affecting their response to glucocorticoid therapy. Serial changes in serum IgG4 levels are reported to reflect the activity of IgG4-RD [26, 30]. Our findings further demonstrate that patients with lower serum IgG4 levels at diagnosis, reflecting lower disease activity, were correlated with poor response to steroid treatment. Recurrence rate was 45 % within a mean follow-up of 33.5 months, compared with a range of 18–50 % in prior studies. Recurrent disease often requires repeated steroid therapy, adjunctive radiotherapy, or rituximab administration. The use of radiotherapy in ocular adnexal IgG-RD is supported by its effectiveness in treating reactive lymphoid hyperplasia and orbital pseudotumors. Of the eight patients undergoing radiotherapy in the Sato study [13], five achieved complete remission, one partial remission, and two relapsed. In this study, adjunctive radiotherapy helped achieve complete remission or stabilization, allowing subsequent cessation of corticosteroids in patients who developed recurrent disease (cases 6 and 10) and intolerance to corticosteroid therapy (case 1). Specific immunomodulatory therapy, such as rituximab, is now being investigated as a treatment for IgG4-RD, and early data show promising results [5]. In our study, however, one patient (case 2) developed complete bilateral visual loss due to progressive fibrosclerotic orbital
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lesions, even after treatment with systemic steroids, adjunctive radiotherapy, and rituximab. Lower disease activity (relative to lower serum IgG4) and fibrosclerotic lesions in this case may explain why the patient showed poor response to steroids and other adjunctive therapy. In conclusion, our study shows ocular adnexal IgG4-RD has a high rate of systemic involvement, synchronous bilateral lacrimal gland involvement, and elevated serum IgG4 level at presentation. Most patients responded well to steroid therapy in accordance with serial changes of serum IgG4. However, continued surveillance and long-term follow-up are warranted because of the high recurrent rate. Conflicts of interest W.-K. Yu, None; S.-C. Kao, None; C.-F. Yang, None; F.-L. Lee, None; C.-C. Tsai, None.
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