Introduction

Autoimmune pancreatitis (AIP) was defined by Yoshida et al. as pancreatitis caused by irregular narrowing of the pancreatic duct, pancreatic swelling, or infiltration and fibrillation of lymphocytes, with such events related to autoimmune mechanisms [1]. Hamano et al. reported rising levels of serum IgG4 in patients with AIP [2]. The 2010 International Consensus Diagnostic Criteria (ICDC) for Autoimmune Pancreatitis [3] define pancreatitis as “Type 1” when other organ involvement and elevated serum IgG4 are present and lymphoplasmacytic sclerosing pancreatitis (LPSP) is histologically the distinguishing characteristic; or “Type 2” when elevated serum IgG4 is not present, the symptoms accompany inflammatory bowel disease, and idiopathic duct-centric chronic pancreatitis (IDCP) / granulocytic epithelial lesion (GEL) are histologically the distinguishing characteristics. Due to growing recognition of AIP, the number of reported cases has increased. Steroid therapy is the standard treatment, but relapse is reported to occur in 10–53% of cases [4–7].

Steroid pulse therapy produces local immunosuppression after organ transplantation and is effective for systemic lupus erythematosus (SLE), intestinal pneumonia, and several autoimmune diseases [8–10], but has not become established therapy for AIP. Matsushita et al. suggested that steroid pulse therapy can be used for lower bile duct stricture and is useful for following the therapeutic outcome because of the lack of a need for tapering [11]. In 2011, Tomiyama et al. reported significant improvements of γ-guanosine triphosphate (GTP) at 2 weeks after steroid pulse therapy, alanine aminotransferase (ALT) at 2 and 8 weeks, and glycosylated hemoglobin at 7 months after therapy [12]. In addition, γ-GTP at 2 and 8 weeks after therapy were improved in a subset of patients with diffuse pancreatic swelling.

Oral steroid therapy with prednisolone (PSL) and steroid pulse therapy with methylprednisolone (mPSL) are administered for AIP in our hospital. The goal of this study was to retrospectively review the efficacy of steroid pulse therapy for AIP.

Patients and Methods

Patients

This study was approved by the Ethics Committee of Fukushima Medical University Hospital. Patients were not required to give informed consent to the study because the analysis uses anonymous clinical data obtained after each patient agreed to treatment by written consent. For full disclosure, the details of the study are published on the home page of Fukushima Medical University. Among 39 patients with AIP treated at our hospital from July 2003 to July 2013, 24 AIP type 1 patients with traceable treatment histories of ≥12 months and initial elevated serum IgG4 ≥135 mg/dl who were initially treated with steroid therapy were selected for the study (Fig 1). Patients with normal serum IgG4 (n = 5), surgery as initial treatment (n = 2), no treatment (n = 1), history of steroid treatment (n = 1), or a traceable history < 12 months (n = 6) were excluded from the study. The normal range of serum IgG4 is 4.8–105 mg/dl in our hospital.

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Fig 1. Breakdown of AIP patients in our hospital.

https://doi.org/10.1371/journal.pone.0138604.g001

All patients were classified as “unconfirmed diagnosis” or higher based on the 2010 International Consensus Diagnostic Criteria for Autoimmune Pancreatitis (confirmed diagnosis: 22 cases, quasi-confirmed diagnosis: 2 cases). All underwent endoscopic ultrasonograpy-guided fine needle aspiration (EUS-FNA) for the purpose of cytology to rule out pancreatic cancer, therefore, there were no diagnoses of LPSP based on EUS-FNA specimens.

Results

There were no significant differences between the oral and pulse groups for age (56.0±9.4 vs. 60.0±9.6, P = 0.41), gender (men 8, women 0 vs. men 14, women 2, P = 0.43), type of pancreatic swelling (diffuse 3, partial 5 vs. diffuse 5, partial 11, P = 0.55), serum IgG4 before treatment (367.5±287.2 vs. 476.0±409.3 mg/dl, P = 0.27), other organ involvement (4 vs. 9, P = 0.56), involvement of obstructive jaundice (4 vs. 8, P = 0.67), and PSL dosage until serum IgG4 reached a minimum level (3744.5±2690.9 vs. 4156.9±3344.5 mg, P = 0.33), the number of patients with elevated HbA1c after steroid therapy (one patient in the oral group had 1.0% elevation, and one in the pulse group had 0.9% elevation, P = 0.57) (Table 1). No other adverse events were seen.

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Table 1. Background of patients^a.

https://doi.org/10.1371/journal.pone.0138604.t001

The serum IgG4 level was significantly reduced from 367.5±287.5 mg/dl before treatment to 124.3±129.3 mg/dl after treatment in the oral group (p = 0.012) (Fig 2A), and from 476.0±409.3 mg/dl before treatment to 110.3±147.6 mg/dl after treatment in the pulse group (p<0.001) (Fig 2B).

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Fig 2. Serum IgG4 before and after steroid therapy.

Serum IgG4 improved significantly in the oral group (A) and pulse group (B).

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The 5-year cumulative relapse-free survival rate did not differ significantly between the oral and pulse groups (46.9% vs. 77.8%, p = 0.098) (Fig 3A). However, in a subset of cases with diffuse pancreatic swelling, this rate was significantly lower in the oral group (33.3% vs. 100.0%, p = 0.046) (Fig 3B)

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Fig 3. Cumulative relapse free survival rate.

(A) There was no significant difference between the oral and pulse groups. (B) A significant difference was found in a comparison limited to patients with diffuse pancreatic swelling.

https://doi.org/10.1371/journal.pone.0138604.g003

Discussion

In this study, the long term prognoses of patients who received oral steroid therapy or steroid pulse therapy were not significantly different, but a protective effect against relapse was found after steroid pulse therapy in patients with diffuse pancreatic swelling.

Steroid therapy has become standard therapy for AIP; however, regarding the time until relapse, a report from the Mayo Clinic found a 53% relapse rate after 3 months when steroid treatment was stopped at 11 weeks [13], whereas Kubota et al. found a relapse rate of 25.9% when steroid treatment was continued for ≥12 months [14]. Predictive factors for relapse of AIP include patient background factors and serum IgG4 levels. Patients with AIP in whom serum IgG4 did not elevate were excluded from the current study because these cases do not tend to relapse and can improve spontaneously [14]. In fact, the 5 cases in our hospital with serum IgG4 that was not elevated did not relapse. Among patient background factors, IgG4-related sclerosing cholangitis, obstructive jaundice, immune complex value, diffuse pancreatic ductal changes, and sclerosing sialadenitis have been proposed as relapse factors [6, 15–18]. Studies of the serum IgG4 level have proposed the following predictive factors for relapse: high serum IgG4 at initial diagnosis [11, 19–21], a high level before and after treatment [4], and resurgence of serum IgG4 in the remission phase after treatment [22].

In reports of IgG4-related conditions that were not limited to AIP, the serum IgG4 level was lowered by steroid treatment in all patients, but normalization was only achieved in about half of the patients, and patients with persistent high values were reported to be at risk for relapse [23]. The role of IgG4 in IgG4-related diseases is unclear, but Tabata et al. suggested that the serum IgG4 level reflects the disease activity of AIP [24]. In the current study, serum IgG4 improved in the oral and pulse groups, which suggests that the two treatments do not differ in their ability to reduce disease activity.

Steroid pulse therapy for AIP is useful for subsequent evaluation of the therapeutic effect due to the absence of a need for tapering [11] and may also improve liver function (ALT, γ-GTP) and HbA1c [12]. Steroid pulse therapy was found to be effective in a patient with AIP in whom lower bile duct stricture did not improve after oral steroid therapy, and improved γ-GTP on a long-term basis in this patient [12]. Our study indicated no significant difference in the effect on disease activity between steroid pulse therapy and oral steroid therapy. However, steroid pulse therapy was more effective than oral steroid therapy in patients with diffuse pancreatic swelling, and these patients may be suitable candidates for steroid pulse therapy.

The regimen of steroid pulse therapy in previous studies was mPSL 500 mg/day×3days. However, several adverse effects of this therapy have been reported: Zonana-Nacach et al. found a relationship between steroid pulse therapy (mPSL 1 g×3days) and dementia in a cohort study of 539 patients with SLE [25], and Haugeberg et al. showed that steroid pulse therapy (6.6–10 mg/kg) elevated the risk of osteoporosis [26]. There may also be an increased risk of failure of the circulatory system following administration of mPSL 500 mg within 10 minutes [27] and of liver dysfunction with steroid pulse therapy of mPSL at 500 mg/day [28]. For these reasons, as low a steroid dose as possible is preferable, and a regimen of steroid pulse therapy of (mPSL 250 mg or 125 mg/day) may be an option.

The limitations of the current study are the small number of patients and the steroid tapering dose not being perfectly in accord with the daily moving average, due to the retrospective nature of the study. However, the steroid dose tapering mostly used the methods referred to above and any deviation is likely to have had little influence on the results because all steroid doses during the period of serum IgG4 reduction did not differ significantly between the oral and pulse groups. As described above, steroid pulse therapy (mPSL 500 mg/day) is effective for therapeutic diagnosis of AIP [11]. We did not examine the effective dose of steroid pulse therapy (mPSL 125 or 250 mg/day) because all patients in the pulse group underwent steroid tapering. A future study on the effect of steroid pulse (mPSL 125 or 250 mg) without tapering is required to examine safer therapeutic diagnosis. However, further accumulation of patients is needed to confirm the results. Within these limitations, we conclude that steroid pulse therapy for AIP does not show a stronger effect than oral steroid therapy for prevention of relapse or on long-term prognosis, but pulse therapy may be an effective treatment for patients with diffuse swelling of the pancreas.