Background
Type 1 autoimmune pancreatitis (AIP) is associated with the enlargement of the pancreatic parenchyma, abundant lymphoplasmacytic infiltration and fibrosis, and frequent elevations in the serum immunoglobulin (Ig)-G4 levels. Although the precise pathogenesis of AIP has not yet been determined, AIP is clinically characterized by a response to steroid therapy, and it has a favorable prognosis [
1‐
6]. The remission rate of steroid-treated AIP is 98 %, which is significantly higher than 74 % of patients without steroid treatment [
7]. However, many patients will experience disease relapse in type 1 AIP, and the relapse rate for this type is 15–64 %, according to various studies [
7‐
10]. For most patients in previous reports, relapses occurred after steroid discontinuation [
7,
11]. Kamisawa et al. reported that continued maintenance treatment with low-dose prednisolone for 6 months to 3 years is also recommended to prevent relapse in type 1 AIP [
7]. Patients who resumed steroid treatment continued to respond favorably with a high remission rate. In addition, some patients with relapse were treated with an immunomodulator [
9,
11]. Although there is general agreement that long-term steroid therapy is the ideal initial treatment for preventing disease relapse, the incidence of steroid-related side effects is a major concern. If predictive factors of relapse or non-relapse in patients with type 1 AIP exist, some patients may not require long-term steroid maintenance therapy, and the incidence of treatment-related side effects may decrease. However, factors that may predict relapse have not yet been established. In this context, the Ehime Pancreato-Cholangiology (EPOCH) Study Group conducted a retrospective study to identify the predictive factors of relapse in patients with type 1 AIP by focusing on the volume changes in the pancreas.
Discussion
The histologic pattern of type 1 AIP is called lymphoplasmacytic sclerosing pancreatitis, which is characterized by a periductal lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative venulitis [
3,
4]. In our study, the pancreatic volume on CT significantly reduced by steroid therapy in all patients. However, when the relapse and non-relapse groups were compared, the change in pancreatic volume after steroid therapy was significantly different. These findings may suggest that the pancreatic volume change after steroid therapy reflects the histological findings in the pancreas. According to the histological findings previously reported, the pancreatic parenchyma was replaced by massive or extensive interlobular fibrosis with lymphoplasmacytic infiltrates to varying degrees in advanced stages of type 1 AIP [
14]. However, the pancreatic volumetric blood flow of perfusion CT was attenuated in AIP, which improved after steroid treatment [
15]. The pancreatic volumetric blood flow after steroid treatment may reflect the histological disease stage of type 1 AIP. Ko et al. reported that the number of IgG4-positive plasma cells in pancreatic tissue was decreased by steroid treatment, indicating a reduction in inflammation [
16]. Nevertheless, changes in the histopathology after steroid treatment for AIP are still unclear. Matsubayashi et al. reported a reduction in the splenic volume by steroid therapy in cases with AIP [
17]. In our study, although the volume of the spleen was reduced by steroid therapy, it did not differ between the relapse and non-relapse groups.
In an analysis of 463 patients with AIP among 15 institutes in eight countries, Kamisawa et al. reported that the relapse rate in patients treated with steroid ranged 15–64 % [
10]. The relapse rates in Western countries were higher than those in Asian countries (United States, 64 % vs. Japan, 15 %). The difference in the relapse rate was presumably due to the period from administration to cessation of steroid therapy (United States, 3 months vs. Japan, 1–2 years). Indeed, the majority of relapse episodes occurred in steroid-treated subjects following steroid discontinuation compared to those in whom the steroid dose was being tapered or were on steroid maintenance therapy [
7,
11]. Continued maintenance treatment with low-dose prednisolone for 6 months to 3 years is also recommended to prevent relapse [
7]. Although there is general agreement that long-term steroid therapy is the ideal initial treatment for preventing disease relapse, the incidence of steroid-related side effects is a major concern. Shimizu et al. reported that the cumulative dose of corticosteroids was significantly higher in patients with serious side effects than in those without [
18]. In our cases, maintenance steroid therapy was given to all patients, and steroid therapy was discontinued in only 4 patients. Some relapsed patients are treated with an immunomodulator such as azathioprine [
9,
11], and these steroid-sparing approaches are attractive for preventing complications from long-term steroid exposure [
19‐
22].
There are some reports regarding the relapse factors in AIP. Diffuse pancreatic swelling was a predictive factor of relapse [
11]. The relapse rate of AIP was higher in patients with IgG4-related sclerosing cholangitis (SC) than in those without IgG4-related SC (56.1 % vs. 25.7 %, respectively) [
11]. IgG4 seropositivity and jaundice are at a higher risk of relapse, and IgG4 seronegativity have a high likelihood of spontaneous remission [
23]. Diffuse pancreatic swelling and proximal biliary involvement are predictive of relapse in type 1 AIP [
8], whereas distal biliary involvement was not predictive in cases of type 1 AIP [
11]. Additionally, positive staining of the duodenal papilla for IgG4 and a swollen duodenal papilla had a favorable response to steroid therapy [
24]. However, factors that may predict relapse have not been well defined, and some are still controversial. Indeed, our study failed to show that the diffuse type IgG4 seropositivity and jaundice were predictive factors of relapse. Moreover, these factors are examined at the time of diagnosis, and they are not intended to reflect the course of treatment.
Over the course of treatment, our findings suggest that early pancreatic volume changes after steroid therapy may be a useful prognostic value, because patients with AIP with a high post-treatment pancreatic volume (50 cm3<) or low pancreatic volume reduction (<35 %) showed a significant relapse. Reduction of steroids in these cases must be observed carefully with consideration of immunomodulator use, such as azathioprine.
On the other hand, patients who had a post-treatment pancreatic volume ≤50 cm
3 and a percent reduction in the pancreatic volume 35 % ≤ had a significantly lower relapse rate. In other words, a low post-treatment pancreatic volume and a high pancreatic volume reduction may predict non-relapse in patients with AIP. Therefore, these measures may be useful for selecting suitable candidates for steroid discontinuation to prevent treatment-related side effects. However, Masuda et al. reported that AIP patients with pancreatic atrophy after steroid therapy have a high incidence of diabetes mellitus [
25]. Although our cases did not fit into the definition of pancreatic atrophy proposed by Hirano et al. [
26] at the time of CT measurement after steroid therapy, some cases might further reduce their pancreatic volume with a longer period of steroid therapy and develop diabetes. These reports also support the abovementioned idea to discontinue steroid in selected patients.
As is common for studies with retrospective designs, our study has the following limitations: small sample size; not all patients underwent a histological examination; and the steroid treatment regimen, period of steroid therapy, and timing of CT were not uniform. To overcome these limitations, further long-term prospective studies in a larger cohort are needed to examine the relationship between the pancreas volume reduction and relapse in AIP treated with steroids. Nevertheless, we believe that our findings currently present one of the best factors for predicting relapse in patients with AIP.
Acknowledgement
Not applicable.