Article Text

Download PDFPDF

Clinicoserological factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease
  1. Ji Wook Hong,
  2. Sunah Kang,
  3. Min Kyung Song,
  4. Chan Joo Ahn,
  5. Ho-Seok Sa
  1. Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, Songpa-gu, Seoul, Korea
  1. Correspondence to Dr Ho-Seok Sa, Department of Ophthalmology, University of Ulsan, Songpa-gu, Seoul 05505, Korea; lineblue{at}hanmail.net

Abstract

Purpose To investigate the factors associated with response to steroid treatment and recurrence in patients with IgG4-related ophthalmic disease (ROD).

Methods Twenty-eight patients with biopsy-proven IgG4-ROD treated between March 2010 and January 2017 were included in this retrospective study. Clinical features, serum IgG4 levels, systemic involvement, treatments and treatment outcome, factors associated with response to treatment and recurrence were assessed.

Result Thirteen men and 15 women (mean age 50.8 years) were evaluated over mean follow-up period of 27.3 months. Elevated serum IgG4 levels (>1.35 g/L) and systemic disease were noted in 9 (32%) and 18 patients (64%), respectively. The lacrimal gland was involved in all patients, and 22 patients (78.6%) had bilateral involvement. Most patients (82%) responded well to systemic steroids, but 12 (43%) relapsed after the initial steroid treatment, requiring additional therapies to achieve remission. Complete response to initial steroid treatment was associated with elevated serum IgG4 levels before treatment (P=0.001) and bilateral orbital involvement (P=0.050). Recurrence was associated with elevated serum IgG4 levels before treatment (P=0.007), lower dose (P=0.057) and shorter duration of initial steroids (P=0.042). Patients with recurrence eventually required significantly more steroids than those without recurrence (P=0.011).

Conclusions Patients with IgG4-ROD responded well to systemic steroid treatment, but recurrence was common, particularly among those with elevated serum IgG4 levels and shorter duration of initial steroid treatment. Low-dose maintenance treatment with systemic steroids should be considered to avoid recurrence in patients with elevated serum IgG4 levels.

  • orbital IgG4-related disease
  • serum IgG4 level
  • systemic steroid treatment

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Introduction

IgG4-related disease (RD) was first described in 2001, in relation to autoimmune pancreatitis,1 and has since been reported to involve multiple organs, including the orbital tissues. The condition is characterised by inflammatory lesions with lymphoplasmacytic infiltration with significant numbers of IgG4-positive plasma cells and frequent elevation of serum IgG4 levels.2 In the field of ophthalmology, IgG4-related ophthalmic disease (ROD) may manifest in the lacrimal glands, and may extensively involve the orbital tissues, such as the extraocular muscles, orbital nerve, orbital fat and eyelid.3

Previous studies on IgG4-ROD reported that, empirically, the disease responds well to corticosteroids, but relapse occurs soon after steroid treatment is discontinued,4 5 in about 50% of patients.6 7 It is important to establish the standardised steroid regimen including the dose and duration of maintenance for IgG4-ROD as well as to investigate the factors associated with disease recurrence, and some studies on prognostic factors are currently underway.8 This study therefore investigated the clinical characteristics, treatment outcomes of biopsy-proven IgG4-ROD and clinicoserological factors associated with response to steroid treatment and with recurrence in patients with IgG4-ROD.

Materials and methods

We retrospectively reviewed the medical records of all patients with IgG4-ROD treated by one ophthalmologist (H-SS) at the Department of Ophthalmology, Asan Medical Center, Seoul, Korea, between March 2010 and January 2017. Only patients with biopsy-proven IgG4-ROD, who were followed up for >6 months after the initial treatment, were included in this study. Diagnosis of IgG4-ROD was based on the criteria by the Japanese Study Group for IgG4-ROD in 2014, and the patients were categorised as ‘probable’, ‘possible’ or ‘definitive’ according to the criteria9 (box 1). All patients underwent a baseline systemic evaluation; review of medical history, physical examination, laboratory tests (including serum IgG, IgG subclass, rheumatoid factor and IgE level) and imaging studies (neck, chest, abdominal and pelvic CT scans, and/or positron emission tomography).

Box 1

Diagnostic criteria for IgG4-related ophthalmic disease, 20149

(1) Imaging studies show enlargement of the lacrimal gland, trigeminal nerve or extraocular muscle as well as masses, enlargement or hypertrophic lesions in various ophthalmic tissues.

(2) Histopathological examination shows marked lymphocyte and plasmacyte infiltration, and sometimes fibrosis. A germinal centre is frequently observed. IgG4+plasmacytes are found and satisfy the following criteria: ratio of IgG4+cells to IgG+cells of 40% or above, or >50 IgG4+cells per high-power field (x400).

(3) Blood test shows elevated serum IgG4 (≥1.35 g/L).

  • Diagnosis is classified as ‘probable’ when (1) and (2) are satisfied; ‘possible’ when (1) and (3) are satisfied and ‘definitive’ when (1), (2) and (3) are satisfied.

All patients underwent systemic corticosteroid treatment, except for one patient diagnosed simultaneously with marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) type. Systemic corticosteroids were administered either orally or intravenously, depending on each patient’s clinical and social circumstances such as disease severity, liver and gastrointestinal condition, diabetes and access to hospital. Intravenous steroids were considered by an experienced physician (H-SS) when the patient had bilateral disease, large lesion, systemic disease in imaging studies and no contraindications to intravenous administration. Oral corticosteroids were given with an initial dose of 0.6 mg/kg/day for 4 weeks, and were then tapered by 5 mg every 2–4 weeks with adjusting the duration according to the patient’s response. In the case of intravenous steroid therapy, methylprednisolone was infused once a week for 12 weeks (500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks) with the allowances of subsequent oral taper using response-based dose titration. If attempts to discontinue corticosteroids were frequently accompanied by exacerbations of symptoms, low-dose oral corticosteroids (5–10 mg/day) as low as possible while keeping satisfactory response were maintained for a long period of time. The withdrawal of corticosteroids in initial treatment was determined by the remission of disease-related symptoms and signs for a reasonable period of time based on clinical and imaging assessments. In patient refractory to systemic corticosteroid treatment (ie, those requiring >12 weeks of consecutive corticosteroids with a dose of 20 mg/day or more to achieve clinical remission or lacking response to a marginal dose of >9 g of steroid), the patients were given adjuvant immunosuppressants, such as azathioprine or methotrexate.

Patients were followed up every 1–2 months for a minimum of 6 months, and then the interval was adjusted to 3–6 months according to the patient’s condition. Serum IgG and IgG4 concentrations were measured every 3–6 months, including before and after the initial treatment and after the recurrence. Follow-up imaging was performed according to clinical need including after the initial treatment and when a recurrence is suspected.

Responses to systemic corticosteroid treatment were divided into two categories: complete response (CR) and partial response (PR). CR was defined as complete clinical remission, in which corticosteroids were withdrawn without emergence of relapse symptoms and signs in the involved ophthalmic and extraorbital structures based on clinical and imaging assessments. PR was defined as requiring consecutive treatment with corticosteroids for >12 weeks to achieve remission, or requiring additional treatment modalities due to resistance to steroids.

Disease recurrence and adjunctive treatment were also reviewed. Recurrence was defined as a relapse of disease-related symptoms, increased lesion size on imaging follow-up or the requirement of additional treatment after >4 weeks of discontinuation of steroid therapy.

Statistical analysis

The normality of data distribution was confirmed using the Kolmogorov-Smirnov test. For comparisons of serum IgG4 levels before and after steroid treatment, the paired t-test was used. Based on CR and PR categorisation, factors associated with response to corticosteroid treatment were determined using Student’s t-test and Fisher’s exact test, for continuous and categorical variables, respectively. These tests were also used to compare the mean duration and total dose of corticosteroid therapy in the relapsed and non-relapsed group. P<0.05 was considered to be statistically significant. SPSS software, V.22.0 (SPSS, Chicago, Illinois, USA) was used for statistical analyses.

Results

Clinical characteristics

Twenty-eight patients with biopsy-proven IgG4-ROD were retrospectively assessed. According to the diagnostic criteria for IgG4-ROD,9 19 (68%) patients had ‘probable’ and 9 (32%) had ‘definitive’ diagnoses (figure 1). The clinical characteristics of patients are summarised in tables 1 and 2. The mean age of the patients was 50.8 years, and there was a slight female predominance (n=15, 53.6%). Patients were followed up for a mean period of 27.3 months (range: 6–79 months). Common symptoms and signs included periorbital swelling (n=17, 60.7%) and periorbital palpable mass (n=14, 50.0%). The mean duration of symptoms prior to diagnosis was 9.3 months (range: 1–36).

Figure 1

Classification of patients according to diagnostic criteria for IgG4-related ophthalmic disease (1) imaging study, (2) histopathological study and (3) serological study.  Diagnosis is classified as ‘probable’ when (1) and (2) are satisfied; ‘possible’ when (1) and (3) are satisfied and ‘definitive’ when (1), (2) and (3) are satisfied. Two patients with marginal zone lymphoma of mucosa-associated lymphoid tissue type in this study were classified as ’probable'.

Table 1

Baseline characteristics of patients with IgG4-related ophthalmic disease (n=28)

Table 2

Symptoms and signs in 28 patients at the time of diagnosis

The sites affected by IgG4-RD in this cohort are illustrated in figure 2. In terms of orbital lesions, all patients showed involvement of the lacrimal gland, and 22 patients (78.6%) had bilateral involvement. The other locations included the infraorbital nerve (n=3, 10.7%) and extraocular muscle (n=2, 7.1%).

Figure 2

Sites of IgG4-related disease involvement. pt, patient.

There were 18 cases (67.9%) with systemic involvement, other than the orbits. Sixteen of these patients showed head and neck involvement, including involvement of the submandibular gland (n=9, 32.1%), parotid gland (n=4, 14.3%), cervical lymph nodes (n=4, 14.3%), nasal cavity (n=2, 7.1%) and sublingual gland (n=1, 3.6%). Other systemic regions involved were the lungs (n=6, 21.4%), lymph nodes other than those in the head and neck (n=4, 14.3%), pancreas (n=3, 10.7%) and kidney (n=2, 7.1%). In cases with systemic involvement, multiple organs were invaded simultaneously. Two patients (7.1%) were also diagnosed with marginal zone lymphoma of MALT type associated with IgG4-ROD.

The mean serum IgG4 levels before treatment was 1.38±1.71 g/L, and only nine patients (32.1%) showed elevated serum IgG4 levels exceeding 1.35 g/L; the mean serum IgG4 level in those nine patients was 3.53±1.43 g/L, while that in the other patients was 0.32±0.19 g/L. There were no correlations between initial serum IgG4 levels in patients with and without systemic involvement, and in patients with bilateral and unilateral involvement (P=0.858 and P=0.718, respectively).

Factors associated with response to corticosteroid treatment

Initial therapy included oral corticosteroids alone (12 patients, 42.8%), intravenous methylprednisolone with/without oral taper of corticosteroids (8 patients, 28.7%), systemic corticosteroids with adjunctive immunosuppressants (7 patients, 25.0%) or chemotherapy alone (1 patient, 3.6%). There were 23 patients (82%) in the CR group and 5 patients (18%) in the PR group. Factors related to therapeutic response to corticosteroids are shown in table 3. There was no difference in the mean age, sex and extraorbital involvement between the CR and PR groups. Bilateral orbital lesions were significantly more frequent in the CR group (20/23, 87.0%) than in the PR group (2/5, 40.0%) (P=0.050). Serum IgG4 levels before treatment was significantly higher in the CR group (2.03±1.87 g/L) than in the PR group (0.31±0.16 g/L) (P=0.001). Serum IgG4 levels after treatment were 0.71±0.74 g/L in the CR group and 0.36±0.83 g/L in the PR group (P=0.096), and tended to decrease more in the CR group than in the PR group (P=0.032). There was no statistically significant difference in other serum markers, such as IgE and rheumatoid factor, between the CR and PR groups.

Table 3

Factors associated with response to corticosteroid treatment

Factors associated with recurrence

Twelve patients (42.9%) experienced relapse during follow-up. The mean time to recurrence after initial remission was 10.77±8.29 months. Sites of recurrence included the lacrimal gland (10/12, 83.3%), submandibular gland (1/12, 8.3%) and lung (1/12, 8.3%). Age, sex, bilaterality and systemic involvement were not associated with recurrence (P>0.05). High serum IgG4 levels before treatment were associated with relapse; the IgG4 levels in the relapse group (2.61±1.89 g/L) were significantly higher than those in the non-relapse group (1.06±1.27 g/L) (P=0.007). We also assessed whether patterns of initial steroid treatment determined by clinical remissions affected recurrence. The total dose of initial steroid treatment required to achieve remission was lower with a trend towards significance in the relapse group, and the duration of initial steroid treatment was also significantly shorter in the relapse group; the total dose of initial steroids was 2.75±1.99 g in the relapse group and 4.43±2.19 g in the non-relapse group (P=0.057), and the duration of initial treatment was 3.10±1.14 months in the relapse group and 8.28±9.23 months in the non-relapse group (P=0.042). However, the total amount of steroids used until the last follow-up was greater in the relapse group than in the non-relapse group (6.94±2.63 g vs 4.43±2.19 g, P=0.011). Thus, when patients had less dose and shorter period of initial steroid treatment they were more likely to experience recurrence, and more steroids were eventually required for further treatment. To estimate the appropriate period of initial treatment to reduce recurrence, we compared the recurrence rates according to initial treatment periods. There was a significant difference in the recurrence rates between the patients who used the initial steroids for <5 months (10/14, 71.4%) and the patients who had >5 months or more (2/14, 14.3%) (P=0.002) (table 4).

Table 4

Comparison of clinical manifestations between patients with relapsed and non-relapsed IgG4-related disease

Additionally, analysis of 10 patients with recurrence (2 patients were excluded because of the serum IgG and IgG4 levels after recurrence were not available) showed that the serum IgG levels after recurrence tended to be higher than those immediately before recurrence (14.75±7.54 vs 11.85±9.18, P=0.005). However, serum IgG4 levels after recurrence were not different from those before recurrence (1.53±0.56 vs 1.30±0.52, P=0.594). Age, sex ratio, bilateral involvement, systemic involvement and duration of steroid use required to achieve initial remission were not statistically significantly associated with recurrence.

Discussion

The incidence of IgG4-RD is estimated to be 0.28–1.08 per 100 000 people and the orbit is the fifth most commonly involved site.10 11 In IgG4-ROD, the lacrimal gland is most commonly affected,12 as it was in all patients in this study (all of whom presented for ophthalmic reasons). Additional intraorbital involvement was seen in 8 patients (28.6%), head and neck involvement in 16 patients (57.1%) and other systemic involvement in 9 patients (32.1%). The systemic involvement in our patients (approximately 67.9%) was therefore similar to that previously reported.6 7

The present finding of a high proportion (78%, 22) of patients with bilateral involvement contrasted with previous papers, which reported more monocular involvement.13–16 We performed a thorough systemic evaluation to determine whether bilaterality was associated with systemic involvement, but found no statistically significant association. IgG4-ROD is generally more prevalent in males (M:F ratio, 1.3:1),17 but there was a slight female predominance (M:F ratio, 0.87:1) in our study. Bilaterality and systemic involvement were not associated with recurrence in our study.

Only nine patients in our study met the serological criterion of elevated serum IgG4 (≥1.35 g/L). The proportion of patients with elevated serum IgG4 levels in our study (32.1%) was lower than those in previous studies (approximately 60%).18 The clinical interpretation of serum IgG4 levels in IgG4-ROD remains controversial, but low serum IgG4 levels might be caused by the prozone phenomenon.19 If sample dilution had been performed to calibrate the prozone effect, a more accurate mean serum IgG4 concentration may have been obtained.

Patients with elevated pretreatment levels of serum IgG4 were more likely to respond well to steroids (P=0.001). The serum IgG4 levels after treatment tended to decrease significantly in the CR group, but not in the PR group. Whether elevation of serum IgG4 directly mediates the disease process, and is a surrogate marker, or protects against the anti-inflammatory response, remains unclear. However, serum IgG4 levels may be useful in the management of IgG4-RD and represent an important biomarker for assessing disease activity.20 Previous reports have indicated that IgG4-positive plasma cell infiltration was more prevalent in various organs in patients with higher serum IgG4 levels.21–23 This suggests that serum IgG4 elevation reflects the active phase of the disease, causing active formation of mass lesions, due to IgG4-positive plasma cell infiltration. Steroid therapy may be able to reduce the lesion size during the active phase of IgG4-RD, suggesting that patients with elevated serum IgG4 levels in this study had a higher rate of CR after steroid treatment. Conversely, when fibrosclerotic masses have already formed, the possibility of mass size reduction by steroids might be relatively low, which may be the reason for the low CR in patients with low serum IgG4 levels. We did not perform a comparative analysis between serum IgG4 levels and pathological findings in this study. Nevertheless, the response to treatment between lymphoplasmacytic type and fibrosclerotic type is still expected to differ, and further research is needed.

Bilateral lacrimal gland involvement was also associated with a good response to corticosteroid treatment; bilateral lesions were significantly more frequent in the CR group (87.0%) than in the PR group (40.04%) (P=0.050). This could be explained by the association between the bilaterality and the disease activity, or the elevated serum IgG4 levels before treatment. In our study, there was a tendency for serum IgG4 levels to be higher in the group with bilateral involvement than in the group with unilateral involvement, although this was not statistically significant (1.55±1.83 vs 0.73±1.07, P=0.304). We assumed that the bilateral lesions may be more frequent in the active phase and that steroid therapy could reverse mass lesions more effectively. Care should be taken when interpreting these results, and further studies with a sufficient sample size are required.

Disease recurrence was experienced by 42.9% (12/28) of our patients, and the mean time to recurrence after initial remission was 10.77 months. Recurrent lesions mostly involved the lacrimal gland (10/12, 83.3%), followed by the submandibular gland (1/12, 8.3%) and lungs (1/12, 8.3%). Elevated serum IgG4 levels before initial steroid treatment correlated with disease relapse (2.61±1.89 vs 1.06±1.27 g/L, P=0.007). In addition, our results showed that the patterns of initial steroid treatment also affected recurrence. In our study, dose and duration of initial steroids for IgG4-ROD were determined by disease remission based on clinical and imaging assessments. The total dose of initial steroids tended to be lower in the relapse group, and the duration of initial steroids was also significantly shorter in the relapse group (P=0.057 and P=0.042, respectively). As already mentioned, steroid therapy may be able to effectively reduce inflammation and mass size in patients with active IgG4-RD, and initial remission could be achieved more easily with lower dose and shorter period of steroids. However, the risk of recurrence might be higher if initial treatment is not continued until the disease activity is completely lost. Once the disease recurred, additional steroid treatment was required, and a greater amount of steroids eventually had to be used to achieve remission again in the relapse group (6.94±2.63 vs 4.43±2.19 g, P=0.011).

Taken together, elevated serum IgG4 levels before initial treatment may reflect higher disease activity and may be associated with higher risk of recurrence. However, it is not clear whether a high serum IgG4 level is a specific marker for predicting recurrence, because serum IgG4 levels immediately before recurrence were not found to be increased in our study (P=0.594), in contrast to the findings of a previous report.8 Given the possible correlation between the initial serum IgG4 levels and recurrence, we believe that it would be worth considering more aggressive treatment for a longer period for patients with elevated serum IgG4 levels before treatment to reduce the risk of recurrence. The value of long-term low-dose maintenance corticosteroid therapy to avoid recurrence in autoimmune pancreatitis, a subtype of IgG4-RD, is well known.24 However, the duration of maintenance therapy has not yet been established.25 The results of our study showed the systemic maintenance of corticosteroids over 5 months could be suggested for initial treatment to reduce the risk of recurrence, and further prospective studies are needed to establish effective regimens of long-term low-dose corticosteroids to prevent recurrence.

Our study has several limitations. First, the study was retrospectively designed, and we could not evaluate all potential factors. Second, the number of cases was insufficient to draw firm conclusions. Moreover, all patients were diagnosed with IgG4-ROD by histopathological criteria for IgG4-RD (reported by the Research Programme for Intractable Disease of the Ministry of Health, Labour, and Welfare of Japan),9 and some patients were referred to us after receiving short-term steroid treatment elsewhere. Previous treatment could influence clinical characteristics, such as serum IgG4 levels. Finally, we included patients who had been observed for >6 months, but this time period may have been insufficient to assess relapse accurately.

In conclusion, most patients responded well to systemic corticosteroids, and elevated serum IgG4 levels before initial treatment was associated with a good response to initial steroid treatment, and with an increased recurrence rate. Our results highlight that enlargement of bilateral lacrimal glands is a key clinical feature of IgG4-ROD, and that sufficient duration (5 months or more) of initial systemic steroid therapy would be necessary to reduce the risk of recurrence as well as the total use of steroids. Patients with IgG4-ROD responded well to systemic steroid treatment, but recurrence was common, particularly among those with elevated serum IgG4 levels and a shorter duration of initial steroid treatment. Low-dose maintenance treatment with systemic steroids should be considered to avoid recurrence in patients with elevated serum IgG4 levels.

References

Footnotes

  • Contributors All authors take responsibility for the integrity of the data and the accuracy of the data analysis. JWH: analysis and interpretation of data, writing the article, proof and revising the article. SK: design of the study, acquisition and analysis of data. MKS, CJA: analysis and interpretation of data. H-SS: design of the study, analysis and interpretation of data, proof and revising the article.

  • Disclaimer The authors have no proprietary interests in or financial support for the development or marketing of instruments or equipment mentioned in this article or any competing instruments or equipment.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board of Asan Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Linked Articles

  • At a glance
    Keith Barton James Chodosh Jost B Jonas