Management of biliary stricture in patients with IgG4-related sclerosing cholangitis.

BACKGROUND: We aimed to determine the optimal approach with endoscopic biliary drainage (EBD) and corticosteroid (CS) for the treatment of IgG4-related sclerosing cholangitis (ISC).
METHODS: To evaluate the safety of EBD for treatment of biliary stricture caused by ISC, we assessed the risk of stent dislodgement and sought to determine the most appropriate time for stent removal. We also assessed the safety of treatment with CS alone for patients with obstructive jaundice, and the rate of and risk factors for biliary tract complications.
RESULTS: Sixty-nine patients with ISC treated with CS were enrolled. Twenty-eight patients (40.6%) were treated with EBD for biliary stricture before CS initiation. Intentional stent removal was performed in thirteen (46.4%) after confirming CS-induced improvement. Eleven of thirteen patients (84.6%) underwent stent removal within 1 month after CS initiation and all their stent removals were safely carried out without early (within two weeks) recurrence of obstructive jaundice. Ten of twenty-eight patients (35.7%) experienced spontaneous stent dislodgement after CS initiation, and seven (70%) of them developed stent dislodgement two weeks to two months after CS initiation. Among forty-one patients treated with CS alone without EBD, 10 patients had obstructive jaundice at the time of CS initiation and all of them achieved clinical improvement without biliary tract infection. During the follow-up, three patients (4.3%), all of whom had undergone EBD, developed bile-duct stones, while none of those treated with CS alone developed bile-duct stones (p = 0.032). Long-term biliary stenting was a risk factor for bile-duct stones.
CONCLUSIONS: Biliary stent removal should be carried out within 2 weeks after CS initiation if biliary stricture improves to prevent stent dislodgement. Obstructive jaundice can be treated safely with CS alone in patients without infection. Clinicians should be aware of the possibility of bile-duct stones in patients treated with EBD.

Introduction

IgG4-related sclerosing cholangitis (ISC) is characterized by an elevated serum IgG4 level and IgG4-positive plasma cell infiltration of the bile-duct wall[1]. ISC is one of the many phenotypes of systemic IgG4-related diseases. ISC is frequently associated with autoimmune pancreatitis (AIP)[2], although some patients with ISC do not have involvement of other organs[3].

ISC frequently causes biliary stricture and obstructive jaundice as sequelae to fibro-inflammatory changes in the bile-duct wall. Similar to AIP, ISC displays a good response to corticosteroid (CS) therapy[4,5]. The clinical and radiological features of ISC are resolved by CS in most patients. However, CS may worsen obstructive jaundice and trigger biliary tract infection. Therefore, most patients with obstructive jaundice undergo endoscopic biliary drainage (EBD) before CS initiation[6,7].

EBD and CS play an important role in the treatment of biliary stricture in patients with ISC, and they influence the short- and long-term prognosis. The optimal timing of stent removal, to prevent spontaneous stent dislodgement due to improved biliary stricture or early recurrence of obstructive jaundice caused by residual biliary stricture, is unclear. Data regarding the safety and effectiveness of treatment with CS alone (i.e., without EBD) for obstructive jaundice are insufficient. Also, the risk of biliary tract complications during long-term management of ISC is unknown. We aimed to determine the optimal approach for management of biliary stricture in patients with ISC.

Methods

Subjects

This retrospective study was approved by the Ethics Committee of Kanazawa University Hospital (the approval number is 2016–191). We enrolled patients diagnosed with ISC and treated with CS in our hospital or its affiliated institutes from January 2008 to December 2018. The diagnosis of ISC was based on the 2012 clinical criteria of the Japanese working group[8]. The enrolled patients satisfied the criteria for definite or probable ISC and were followed up for > 6 months. Patients who underwent surgical resection or received other immunosuppressive agents were excluded. The medical records of the patients were reviewed, and their clinical data were collected. We evaluated the following clinical parameters: age, sex, serum total bilirubin (TB) level, IgG and IgG4 level, endoscopic retrograde cholangiography (ERC) findings (type 1/2/3/4) based on ISC-specific diagnostic criteria[1], the incidence and type (diffuse/local) of AIP, treatment modality (EBD and/or CS), and the incidence of complications during the follow-up.

Treatment and follow-up of ISC

The enrolled patients underwent ERC for diagnosis of biliary stricture, exclusive diagnosis of biliary tract cancer, and/or treatment with EBD. In this study, patients who received endoscopic nasobiliary drainage (ENBD) as initial treatment with EBD were excluded because the status of ENBD insertion must not have let us evaluate the incidence of spontaneous stent dislodgement and its precise time after CS initiation.

CS was started after ISC diagnosis in almost all patients, while some received CS as an optional adjunct treatment. CS therapy started with prednisolone at 20–40 mg/day, which was tapered by 2.5–10 mg every 1–4 weeks. We evaluated clinical improvement during tapering of the prednisolone dose by assessing the thickness of the bile-duct wall using computed tomography (CT) and/or according to the degree of biliary stricture by ERC within 1 month of initiating CS. A variety of CS regimens were used for maintenance therapy, based on the patient’s condition; maintenance therapy was defined as continuous administration of CS for > 6 months after initiation. A maintenance dose was defined as a dose of daily prednisolone administered for the longest period during the follow-up.

After CS initiation in patients with ISC treated with EBD using a plastic stent for biliary stricture, many of them underwent planned stent removal after improvement of ISC; in other cases the stent was not removed. Some of the patients with prolonged biliary stenting experienced spontaneous stent dislodgement (confirmed by radiological imaging) during the follow-up. To evaluate the effectiveness and safety of EBD, we noted the time from CS initiation to planned stent removal or spontaneous stent dislodgement. We could not determine the precise time of spontaneous stent dislodgement, so it was defined as the halfway point between the last time a biliary stent was seen and the first time its dislodgement was confirmed.

We assessed the rate of clinical relapse of ISC, which was defined as reappearance of symptoms and/or repeated elevation of serum biliary enzyme levels in addition to exacerbation of biliary stricture on radiological imaging after CS-induced improvement. We also noted the occurrence of biliary tract complications, such as bile-duct stones, biliary tract cancer, and infectious diseases, during the follow-up.

Statistical analysis

Categorical variables were compared by chi-squared test, and continuous variables by Student’s t-test or the Mann–Whitney U test. Differences with p-values < 0.05 were considered statistically significant. Statistical analysis was performed using StatView software (SAS Institute, Cary, NC, USA).

Results

Characteristics of the patients with ISC

This study included 69 patients with ISC treated with CS. The median follow-up period was 65.3 months (range: 7.0–192.1 months). The clinical characteristics of the patients are listed in Table 1. Based on the 2012 clinical criteria[8], 68 patients (98.6%) were judged to have definitive ISC and 1 patient (1.4%) to have probable ISC. Thirty-two patients (46.4%) had obstructive jaundice with a serum TB level of > 3.0 mg/dL. The serum IgG level was elevated to > 1,800 mg/dL in 39 of 66 patients (59.1%), and the serum IgG4 level was elevated to > 135 mg/dL in all 69 of the patients (100%) examined. Regarding the cholangiographic type of ISC, type 1 was detected in 55 patients (79.7%), type 2 in 5 (7.2%), type 3 in 7 (10.1%), and type 4 in 2 patients (2.9%). That is, extrapancreatic biliary stricture was seen in 14 patients (20.3%). Forty-eight (69.6%) and twenty (29.0%) patients developed diffuse and focal AIP, respectively.

Table 1

The clinical characteristics of patients with IgG4-related sclerosing cholangitis.

Parameter (n = 69)
Age, mean ± SD, years	66.1 ± 10.5
Sex, male / female (%)	60 (87.0) / 9 (13.0)
Accuracy of diagnosis, definite / probable	68 (98.6) / 1 (1.4)
Obstructive jaundice†, present / absent (%)	32 (46.4) / 37 (53.6)
Serum IgG level, median (range), mg/dl	1871.5 (950–5963)
Serum IgG4 level, median (range), mg/dl	484 (145–4080)
Cholangiography findings, type 1 / 2 / 3 / 4	55 / 5 / 7 / 2
Concurrence of autoimmune pancreatitis, diffuse / focal / absent	48 / 20 / 1
Endoscopic biliary drainage, present / absent (%)	28 (40.6) / 41 (59.4)
CS maintenance therapy‡, present / absent (%)	64 (92.8) / 5 (7.2)
Maintenance dose of prednisolone, median (range), mg/day	5 (1–10)
Follow-up period§, median (range), months	65.3 (7.0–192.1)

† Serum total bilirubin level of > 3.0 mg/dL with dilation of bile-duct.

‡ Maintenance therapy was defined as continuous administration of CS for > 6 months after initiation.

§ Follow-up period counts from CS initiation.

CS, corticosteroid therapy.

Treatment with EBD and/or CS

Twenty-eight patients (40.6%) were treated with EBD for biliary stricture before CS initiation (Table 1) and received placement of 7-French straight-type plastic stents. Of the patients treated with EBD, type 1 was seen in 23 patients, type 2 in 2, and type 3 in 3 patients classified by ERC findings. Of the 5 patients of type 2 or 3 ISC, who had multiple biliary stricture, 3 received placement of long plastic stents that reached the intrahepatic bile-duct because drainage for severe extrapancreatic biliary stricture that caused obstructive jaundice was necessary. No patient had symptoms of purulent cholangitis such as fever or chills before EBD.

The management of EBD is detailed in Table 2. Intentional stent removal was performed in 13 of 28 patients (46.4%) after confirming CS-induced improvement. The median time from CS initiation to stent removal was 16 days (range: 10–143 days). Eleven of thirteen patients (84.6%) underwent stent removal within 1 month of CS initiation. The median daily prednisolone dose at the time of stent removal was 30 mg (range: 10–40 mg). Stent removal was safely carried out without early (within 2 weeks) recurrence of obstructive jaundice in all 11 patients who underwent stent removal within 1 month of CS initiation. Fifteen of 28 patients (53.6%) underwent prolonged biliary stenting and twelve (42.9%) experienced spontaneous stent dislodgement. Two and ten of those twelve patients experienced spontaneous stent dislodgement before and after CS initiation, respectively. The estimated median time from CS initiation to spontaneous stent dislodgement in the 10 patients was 39 days (range: 9–154 days), and the median daily prednisolone dose at the estimated time of spontaneous stent dislodgement was 15 mg (range: 5–30 mg). Seven of those ten patients (70%) developed spontaneous stent dislodgement 2 weeks to 2 months after CS initiation. None of the patients developed complications associated with stent dislodgement; e.g., intestinal perforation.

Table 2

The management of biliary stricture for IgG4-related sclerosing cholangitis using endoscopic biliary drainage.

Stent removal / dislodgement	Time from CS initiation to stent removal / stent dislodgement, median (range), days	Daily prednisolone dose at the time of stent removal / dislodgement, median (range), mg/day
Removal (n = 13)	16 (10–143)	30 (10–40)
Dislodgement (n = 10)	39 (9–154) †	15 (5–30)

† The time of spontaneous stent dislodgement was defined as the halfway point between the last time a biliary stent was seen and the first time its dropout was confirmed.

CS, corticosteroid therapy.

All 69 patients were treated with CS for a median of 34.4 months (range: 1.4–160.7 months). Sixty-four patients (92.8%) received CS maintenance therapy for > 6 months. The median maintenance dose of oral prednisolone was 5 mg (range: 1–10 mg). Forty-one patients (59.4%) were treated with CS alone. The differences in clinical characteristics between the patients treated with CS alone and CS in addition to EBD are shown in Table 3. The serum TB level in the patients who underwent EBD and received CS was significantly higher than that in patients treated with CS alone (p < 0.001). There was no significant difference in age, sex, serum IgG or IgG4 level, or the presence of extrapancreatic biliary stricture between the two treatment groups. Forty-one patients treated with CS alone did not undergo EBD for the following reasons: no or mild elevation of biliary enzyme levels without obstructive jaundice in 31 patients; physician’s judgement that CS initiation should be preferred over EBD despite obstructive jaundice with a serum TB level of > 3.0 mg/dL in 9 patients; and EBD failure because of obstructive jaundice due to type 2 diffuse intrahepatic biliary stricture in 1 patient (Fig 1). The 10 patients with obstructive jaundice had no symptoms of suppurative cholangitis at the time of CS initiation and achieved clinical improvement without biliary tract infection.

Table 3

The differences in clinical characteristics between the patients treated with CS alone and CS in addition to EBD.

Parameter (n = 69)	CS alone (n = 41)	EBD and CS (n = 28)	p value
Age, mean ± SD, years	65.2 ± 10.1	67.4 ± 11.2	0.285
Sex, male / female	36 / 5	24 / 4	0.800
Obstructive jaundice†, present / absent	10 / 31	22 / 6	< 0.001
Serum IgG level, median (range), mg/dl	1826 (950–5963)	1945 (1191–2968)	0.707
Serum IgG4 level, median (range), mg/dl	465.5 (145–4080)	547 (148–3805)	0.348
Extrapancreatic biliary strictures, present / absent	9 / 32	5 / 23	0.678
Development of bile-duct stones, present / absent	0 / 41	3 / 25	0.032
Development of biliary tract cancer, present / absent	0 / 41	0 / 28	N/A

† Serum total bilirubin level of > 3.0 mg/dL with dilation of bile-duct.

EBD, endoscopic biliary drainage; CS, corticosteroid therapy, N/A; not available.

Fig 1

Magnetic resonance cholangiopancreatography images of a patient with IgG4-related sclerosing cholangitis who showed obstructive jaundice.

(a) An image obtained before corticosteroid (CS) initiation showing both intrapancreatic and diffuse intrahepatic biliary strictures with a serum total bilirubin (TB) level of 11.1 mg/dL. Accordingly, endoscopic biliary drainage was considered ineffective. (b) An image obtained 2 months after CS initiation showing cholangiopancreatographic improvement. The serum TB level decreased to 2.1 mg/dL, without symptoms of biliary tract infection.

Clinical relapse and biliary tract complications

During the follow-up, relapse of ISC occurred in 11 patients (15.9%) after CS-induced improvement. Table 4 shows the clinical characteristics of the patients who did and did not relapse. No clinical factor was significantly predictive of ISC relapse before CS initiation. Neither maintenance therapy (p = 0.797) nor a daily maintenance dose of prednisolone (p = 0.320) was associated with relapse. However, patients who discontinued CS during the clinical course were more likely to experience relapse than those who continued CS maintenance therapy (p = 0.089).

Table 4

The differences in clinical characteristics between the patients who experienced relapse and not.

Parameter (n = 69)	Relapse (+) (n = 11)	Relapse (-) (n = 58)	p value
Age, mean ± SD, years	71.1 ± 11.5	65.1 ± 10.1	0.103
Sex, male / female	9 / 2	51 / 7	0.581
Obstructive jaundice†, present / absent	5 / 6	27 / 31	0.947
Serum IgG level, median (range), mg/dl	1772 (950–3010)	1910 (1191–5963)	0.140
Serum IgG4 level, median (range), mg/dl	423 (145–1740)	538 (155–4080)	0.157
Extrapancreatic biliary strictures, present / absent	3 / 8	11 / 47	0.530
Treatment with EBD, present / absent	5 / 6	23 / 35	0.720
Initial dose of prednisolone, median (range), mg/day	30 (20–40)	30 (5–45)	0.288
CS maintenance therapy‡, present / absent	10 / 1	54 / 4	0.797
Maintenance dose of prednisolone, median (range), mg/day	4 (1–10)	5 (1–10)	0.320
Maintenance prednisolone dose of ≥ 5 mg/day, present / absent	5 / 6	40 / 18	0.133
CS discontinuation, present / absent	7 / 4	21 / 37	0.089

† Serum total bilirubin level of > 3.0 mg/dL with dilation of bile-duct.

‡ Maintenance therapy was defined as continuous administration of CS for > 6 months after initiation.

EBD, endoscopic biliary drainage; CS, corticosteroid therapy.

Regarding biliary tract complications during the follow-up, three patients (4.3%), all of whom had undergone EBD, developed bile-duct stones, while none of those treated with CS alone developed bile-duct stones (p = 0.032) (Table 3). Furthermore, 2 of the 3 patients had not undergone stent removal, compared to 1 of 25 patients without bile-duct stones (p < 0.001) (Table 5). The median duration of EBD in patients with bile-duct stones was 7.9 months, which is longer than that in patients without bile duct-stones (1.5 months, p = 0.063). Liver abscess occurred in one patient who had not undergone stent removal after CS-induced improvement. None of the patients developed biliary tract cancer during the follow-up.

Table 5

The differences in the management of EBD between the patients who developed bile-duct stones and not.

Parameter (n = 28)	Bile-duct stones (+) (n = 3)	Bile-duct stones (-) (n = 25)	p value
Prolonged biliary stenting, present / absent	2 / 1	1 / 24	<0.001
The duration of EBD, median (range), months	7.9 (1.7–10.1)	1.5 (0.3–31.6)	0.063

EBD, endoscopic biliary drainage.

Discussion

In large-scale retrospective studies, > 70% of cases of obstructive jaundice secondary to AIP received EBD before CS initiation to prevent biliary tract infection[6,7]. Although some reports and reviews have described the short- or long-term prognosis of biliary stricture accompanying AIP, few reports focused on ISC irrespective of the presence of AIP. Japanese researchers recently published clinical practice guidelines for ISC[9], which describe the appropriate management of biliary stricture in patients with ISC. However, some aspects of ISC treatment by EBD followed by CS are unclear.

The clinical and radiological features of ISC are usually resolved by CS, which is typically followed by safe removal of the stent. If the stent is not removed, improvement of the biliary stricture due to amelioration of inflammation of the bile-duct wall could cause spontaneous stent dislodgement, which is associated with a risk of intestinal perforation[10]. Therefore, stent removal after CS-induced improvement, and the timing thereof, is important. In this study, stent dislodgement occurred in 42.9% of the patients. Notably, in most of those patients stent dislodgement was estimated to occur 2 weeks to 2 months after the CS initiation. On the other hand, premature stent removal may cause recurrence of obstructive jaundice due to residual biliary stricture if the CS-induced improvement is insufficient. It is preferable to avoid repeat EBD after stent removal from the point of view of procedure-related costs and the risk of complications. In this study, none of patients who underwent intentional stent removal after CS-induced improvement of biliary stricture caused by ISC required repeat EBD due to early recurrence of obstructive jaundice within 2 weeks. Therefore, we suggest that stent removal should be performed within 2 weeks after CS initiation in patients with obstructive jaundice. If CS-induced improvement of biliary stricture seemed to be insufficient on ERC after stent removal, stent reinsertion might be necessary to prevent recurrence of obstructive jaundice. In that case, it is important to determine the appropriate timing for stent removal with closely monitoring. Noteworthy, two patients developed spontaneous stent dislodgement before CS initiation in our study. Although we placed a straight-type plastic stent in patients with ISC, the insertion of a double-pigtail plastic stent would likely be safer because of the lower risk of stent dislodgement and related complications. ENBD is also useful and safe for treating purulent cholangitis and/or multiple biliary strictures like type 2–3, while endoscopic ultrasound guided-fine needle aspiration (EUS-FNA), which is necessary for pathological differentiation from pancreatic cancer in patients with focal-type AIP, is difficult to perform during insertion of ENBD. Each method of EBD has advantages and disadvantages as mentioned above, so an appropriate strategy of EBD should be selected according to the patient's condition.

Ten patients with obstructive jaundice achieved improvement with CS alone in this study, and none of them developed purulent cholangitis. Clinical practice guidelines for ISC recommend performing EBD in cases involving obstructive jaundice, while they also state that CS can be initiated without EBD in cases involving mild jaundice without purulent cholangitis in patients for whom the diagnosis of ISC is definite and pathological examinations for biliary stricture are unnecessary[9,11,12]. Some reports indicated obstructive jaundice secondary to AIP may be safely managed using CS alone[13,14]. In our opinion, prior CS initiation may be acceptable in patients with obstructive jaundice caused by multiple biliary stricture like type 2–3 for which effective EBD is impossible as shown in Fig 1, of course, under the condition of close monitoring by an experienced physician. However, there are a small number of studies about treatment with CS alone for ISC involving obstructive jaundice, and we cannot conclude the safety of it. Furthermore, patients with ISC who undergo ERC followed by transpapillary bile-duct biopsy and/or brushing cytology should be treated with short term EBD to relieve cholestasis and prevent cholangitis even without obstructive jaundice. Of course, in patients who did not undergo ERC at the time of initial diagnosis, if radiological or laboratory findings do not improve rapidly even after CS initiation, ERC should be performed again to determine the validity of the pretreatment diagnosis[13,15].

We also investigated the long-term prognosis, including the incidence of clinical relapse and biliary tract complications, of patients with ISC. Reports from Western countries suggest that relapse occurs in 30–57% of patients during CS maintenance therapy or after CS discontinuation[7,16]. In a Japanese retrospective cohort study, relapse of biliary stricture occurred in 19% of patients[4], similar to our finding. The difference in results between Western and Japanese studies seems to be due to the duration of CS administration. Patients received CS for a median of 5.5 months, and only 47% received CS for > 6 months, in a large cohort study from the United Kingdom[16]. The consensus in Japan is that long-term (3-year) prednisolone maintenance therapy at a daily dose of approximately 5 mg is desirable to prevent relapse[17]. Furthermore, Hirano et al. recommended that long-term maintenance therapy with CS should be continued beyond 3 years, because relapse occurred in 48% of patients with AIP who discontinued CS after 3 years in a prospective trial[18]. In this study, patients who discontinued CS maintenance therapy were more likely to experience relapse.

Prediction of ISC relapse based on the clinical characteristics of patients before CS initiation would enable the appropriate duration of CS administration to be determined, with the aim of preventing relapse. Although no clinical factor has been shown to predict ISC relapse, some risk factors have been suggested, including a high serum IgG4 level, the presence of extrapancreatic or multiple biliary strictures, and a thickened bile-duct wall during the initial attack[7,19,20]. Unfortunately, in this study no clinical factor was significantly predictive of relapse before CS initiation. Considering the difficulty of identifying patients who will experience ISC relapse based on a single clinical value, a system for scoring the disease activity of ISC based on multiple parameters with high sensitivity and specificity is needed for predicting relapse. This would enable identification of patients at high risk of relapse, to whom long-term CS maintenance therapy should be administered.

Biliary tract complications may become a clinical issue during the follow-up. Our results revealed that bile-duct stones were likely to develop in patients treated with EBD, particularly if biliary stenting was prolonged. ISC causes chronic inflammation of the bile-duct wall and its accessory glands, while the injury to the bile-duct epithelium itself is relatively mild[3,21]. The mucosal surface of the bile-duct in patients with ISC is macroscopically smooth (and its lumen patent), unlike in those with primary sclerosing cholangitis or cholangiocarcinoma. Therefore, the risk of bile-duct stones in patients with ISC is relatively low after improvement of cholestasis by CS. In this study, patients treated with CS alone did not develop bile-duct stones. Erosions or ulcers in the bile-duct epithelium of patients with ISC frequently result from long-term biliary stenting and increase the risk of bile-duct stones due to sludge formation. In fact, the biliary stent remained in situ for a prolonged period in patients who developed bile-duct stones in this study. However, the long-term incidence of bile-duct stones in patients with ISC is unclear. Since three patients with bile-duct stones are too few for statistical analysis, the result may vary if patients with ISC increase and are observed for a longer follow-up period. One patient who had not undergone stent removal developed liver abscess during CS maintenance therapy. Both EBD-related retrograde cholangitis and CS-induced immunosuppression may lead to liver abscess. The long-term management of ISC requires caution because biliary tract infection is likely to develop in patients who undergo EBD. In this study, none of the patients developed biliary tract cancer during the follow-up. While there have been previous reports of cholangiocarcinoma concurrent with ISC at disease onset, there has been no case report of the development of biliary tract cancer during the course of ISC[22-25]. Kamisawa et al. reported the presence of KRAS mutations in epithelial cells in the pancreas, common bile-duct, and gallbladder of patients with AIP[26]. Although ISC complicated by bile-duct cancer is rare, clinicians should be aware of the possibility.

This study had several limitations. First, it was not a prospective study. Second, the results were derived from a small number of patients seen at only a few institutions, which could have caused bias. Third, there is no standardized indication for EBD, initial and maintenance doses of prednisolone. Especially with regard to EBD, we enrolled only patients treated with EBD by placement of plastic stent for before CS initiation. However, ENBD may be suitable for patients with symptoms of purulent cholangitis. Furthermore, there may be differences in the optimal strategy for EBD between type 1 ISC and the others including type 2, 3 and 4, which have extrapancreatic biliary stricture. Showing the results of this study using this retrospective cohort may not be convincing. To find the best treatment method, this study should have used a prospective observational design.

In conclusion, we investigated recent advances in the treatment of ISC. Biliary stent removal should be carried out within 2 weeks after CS initiation if CS improves biliary stricture to prevent spontaneous stent dislodgement. Obstructive jaundice due to biliary stricture can be treated safely by CS alone in limited patients without purulent cholangitis. Long-term management requires caution because bile-duct complications are likely in patients who undergo EBD. Therefore, further prospective investigations are needed to evaluate the disease activity of ISC and methods for reducing the risk of biliary tract complications.

12 Mar 2020

PONE-D-20-06103

Management of biliary stricture in patients with IgG4-related sclerosing cholangitis

PLOS ONE

Dear Dr. Masaki Miyazawa,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript within 60 days. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Gianfranco D. Alpini

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2)  We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This retrospective study is neat with great clinical significance, regarding to the management of biliary stricture in IgG4-related sclerosing cholangitis (ISC). It presents a profile of 69 patients with ISC, who underwent corticosteroid (CS) therapy or endoscopic biliary drainage (EBD) combined with CS. ISC is a rare disease that belongs to a subgroup of sclerosing cholangitis. The diagnosis of ISC is complicate and difficult. Distinguish from PSC, cholangiocarcinoma and pancreatic cancer should always be considered. The treatment is not easy even though CS is commonly effective. In ISC patients with biliary obstruction and jaundice, EBD may play an important role except for CS. This research focused on this special situation and indicated the safety and efficacy of two treatment methods.

Due to the low prevalence of ISC, it is difficult to design and undertake prospective randomized clinical trials. A well-designed retrospective study is valuable for the clinical reference. The sample size of this study is large enough considering the rarity of ISC. The criteria for the enrollment and exclusion are rigorous. The statistics analysis is sound. The results are convincing and described in every detail. In the discussion section, it shows the novelty of this study and the differences from some others. Overall, this article would be useful for specialists carrying out EBD combined with CS therapy.

I have only two questions/suggestions for the manuscript:

1. The abstract was written not clearly enough, sometimes a little confusing. I don’t understand it until I read through the paper, especially the following descriptions in the results. The manuscript would be perfect if the abstract is modified properly.

2. The authorship is confusing. Did not see the “*” after author’s names. All “¶” contributed equally? First 5 authors and last 6 authors?

Reviewer #2: In this study, the authors aimed to determine the optimal approach with endoscopic biliary drainage (EBD) and corticosteroid (CS) for the treatment of lgG4-related sclerosing cholangitis (ISC). 69 patients with ISC treated with CS were enrolled. Twenty-eight patients (40.6%) were treated with EBD for biliary stricture before CS initiation. Stent removal was carried out safely without early (within 2 weeks) recurrence of obstructive jaundice in all eleven patients who underwent stent removal within a month of CS initiation. Ten patients (35.7%) experienced spontaneous stent dislodgement after CS initiation, and seven (70%) of them developed stent dislodgement 2 weeks to 2 months after CS initiation. All ten patients with obstructive jaundice treated with CS alone did not develop biliary tract infection. All three patients with bile duct stones had received EBD. Long-term biliary stenting was a risk factor for bile duct stones. The manuscript is very well written, and the data clearly support the conclusions.

1. My concern is that sample size is too small, only three patients who had undergone EBD, developed bile-duct stones which is hard to draw rigorous conclusions.

2. Logistic regression can predict the risk of developing a given disease, which is based on observed characteristics of the patient. Therefore, the authors should use Logistic regression to predict the risk for bile duct stones.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

1 Apr 2020

Response to Reviewers

Reviewer #1:

1. The abstract was written not clearly enough, sometimes a little confusing. I don’t understand it until I read through the paper, especially the following descriptions in the results. The manuscript would be perfect if the abstract is modified properly.

• I modified the descriptions in the results to make the abstract easier to understand.

2. The authorship is confusing. Did not see the “*” after author’s names. All “¶” contributed equally? First 5 authors and last 6 authors?

• I rewrote the title page as shown in the policy. Symbol * means corresponding author and was marked in author’s name. Roles of authors with symbol ¶ were investigation and supervision. A Role of authors with symbol & was investigation.

Reviewer #2:

1. My concern is that sample size is too small, only three patients who had undergone EBD, developed bile-duct stones which is hard to draw rigorous conclusions.

• As you say, I think the sample size is too small for three patients who developed bile-duct stones. The result may vary if patients of ISC increase and are observed for longer follow-up period. I add the above statement to the discussion part.

2. Logistic regression can predict the risk of developing a given disease, which is based on observed characteristics of the patient. Therefore, the authors should use Logistic regression to predict the risk for bile duct stones.

• The results of univariate analysis to determine the risk factors for bile-duct stones showed that EBD administration, sustained biliary stenting and duration of EBD were risk factors. Other clinical parameters were not risk factors of bile-duct stones. Logistic regression analysis was attempted, but the number of patients who developed bile-duct stones was too small to be analyzed. The result may vary if patients of ISC increase.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

8 Apr 2020

Management of biliary stricture in patients with IgG4-related sclerosing cholangitis

PONE-D-20-06103R1

Dear Dr. Masaki Miyazawa,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Gianfranco D. Alpini

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

21 Apr 2020

PONE-D-20-06103R1

Management of biliary stricture in patients with IgG4-related sclerosing cholangitis

Dear Dr. Miyazawa:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Gianfranco D. Alpini

Academic Editor

PLOS ONE