Introduction

Although there are no prospective randomized studies on steroid use in autoimmune pancreatitis (AIP), it is evident that this disease is exquisitely responsive to steroid therapy regardless of its subtypes (21). As a result, steroid therapy has become the standard therapy for AIP (7). In some patients with AIP, spontaneous resolution of symptoms and radiological abnormalities has been reported (8). The use of steroid, however, may bring about remission consistently and more quickly than in AIP cases without steroid therapy. In a recent large retrospective study in Japan, the remission rate was significantly higher in the group with steroid therapy compared to those without steroid therapy (7). Likewise, significantly fewer patients who received steroid therapy experienced a relapse compared to those who received only supportive care (7). Hirano et al. reported that unfavorable events related to AIP including obstructive jaundice due to a bile duct stricture, pancreatic pseudocyst or other extrapancreatic manifestations were significantly lower in patients receiving steroid therapy compared to those who received only supportive care (4). In addition, a recent study has shown that early therapeutic intervention has been clinically and histopathologically demonstrated to be important for the preservation of gland function (19).

In the following review, we discuss steroid therapy for type 1 AIP.

Definition of Treatment Outcomes

Remission

The treatment goal of AIP is to achieve and maintain remission. So far, there is no generally accepted consensus on the specific parameters that define remission, including specific radiological, biochemical or serological variables; neither is there consensus concerning the extent to which the outcome should be interpreted as remission. Since remission is also related to the timing of the steroid tapering after the initial high-dose steroid is administered, some patients may be under-treated. Differences in definitions of remission may account, at least in part, for the differences in the reported frequency of disease remission for patients on steroid and the relapse rates among different studies (5). Thus, clearly defining remission is an important cornerstone in discussions on treatment and relapse.

Remission may be defined as the resolution or normalization of symptoms, biochemical abnormalities, radiological abnormalities, and pancreas/extrapancreatic organ histology (10). In a practical setting, the end point of treatment is often symptomatic remission along with radiological remission because histological remission is difficult to confirm (10). After steroid therapy, persistently elevated serum IgG4 levels may be observed in patients without symptoms or residual radiological abnormalities (15). However, it is unclear as to whether this represents subclinical disease activity.

Relapse

In practice, relapse is generally defined as the recurrence of radiological manifestations of AIP with or without symptoms in the pancreas or extrapancreatic organs after remission has been achieved (10). It should be discerned from failed weaning of the steroid, which is defined by a flare of disease activity during the initial steroid course (18). Usually isolated elevation of serum IgG4, without symptoms or radiological abnormalities, is not regarded as relapse.

Similar to remission, the definition of relapse is not uniform among studies. Since the lack of consensus on the definition of relapse may be related to the different relapse rates among studies, a consensus definition of relapse is important (18).

Treatment

Indication for steroid therapy

In the initial inflammatory phase of AIP, the aim of treatment is to alleviate symptoms and improve radiological and biochemical abnormalities (13). In general, the indications for steroid therapy in type 1 AIP include symptoms, such as obstructive jaundice or abdominal pain, and the presence of symptomatic extrapancreatic lesions (6, 23).

A major determinant of treatment responsiveness may be the degree of fibrosis within the pancreas (22). Similar to other autoimmune diseases, which are characterized by an active phase and then an inactive burnt-out phase, it is generally agreed that steroids should be offered to AIP patients with active disease (16). There does not appear to be a role for steroids in patients who present in the post-acute phase with pancreatic atrophy.

Steroid regimen

Current practice in the treatment of type 1 AIP is shown in Figure 1. To date, although the International Consensus Diagnostic Criteria defines the starting dose of steroid for induction of remission as 0.6 to 1 mg/kg per day, a steroid regimen for type 1 AIP has not been standardized, and there is no consensus on the duration of induction, the tapering schedule, and the optimal dose and duration of maintenance therapy (20). In the clinical setting, most clinicians in Japan, Korea, and the United States use 30–40 mg of prednisolone (or prednisone) daily as an induction therapy (7, 11, 17, 18). Some European doctors use an initial prednisolone dose of 60 mg per day (1).

Different patterns of steroid tapering have been proposed by medical centers around the world. In the United States, in which a relatively short overall course of initial steroid therapy with selective maintenance therapy is used, the starting dose of prednisolone is 40 mg per day for 4 weeks, after which the dose is tapered by 5 mg per week with an attempt to withdraw the steroid completely without an extended tapering period or maintenance therapy (i.e., 4 weeks of induction therapy plus 8 weeks of tapering) (17). In Japan, the initial daily dose of prednisolone (0.6 mg/kg) is given for 2-4 weeks and then reduced by 5mg every 1-2 weeks. After reaching the prednisolone dose of 15 mg the dose is reduced more slowly, by 2.5-5 mg every 2-8 weeks, until a maintenance dose of 2.5-5 mg per day is reached (6, 7). In Korea, remission is usually achieved on a regimen of prednisolone 30 mg per day for 1-2 months, followed by a gradual tapering of 5-10 mg per month to the maintenance dose of 5 mg per day, which is continued for several months and then completely stopped. The goal of tapering is not to achieve remission, but to avoid possible cortisol deficiency resulting from the suppression of the hypothalamic-pituitary-adrenal axis while maintaining sustained remission. Therefore, induction of remission should be confirmed before steroid tapering is begun.

Figure 1. Current principles in steroid treatment of type 1 autoimmune pancreatitis.

From our experience, resolution of pancreatic abnormalities is achieved relatively quickly, whereas extrapancreatic lesions, such as retroperitoneal fibrosis or proximal bile duct stricture and ductal wall thickening, take more time. In some patients, complete resolution of these abnormalities may take several months. In the United States and Japan, however, the duration of induction therapy with high dose steroids does not exceed 1 month (7, 17). After only a month of steroids a considerable portion of the abnormalities might still remain. In this situation, remaining abnormalities represent persistent disease activity rather than a true disease relapse. Therefore, the duration of the initial induction therapy with high-dose steroid may need to be tailored to each patient according to the disease activity of the specific organs involved.

Maintenance therapy

Maintenance therapy is used to prevent disease relapse while maintaining remission. The Japanese guidelines for AIP suggest that maintenance therapy with low-dose steroids (2.5-5 mg/day) should be administered to all patients, with the aim of stopping steroid therapy within 3 years (6). According to the study by Kamisawa et al., patients with maintenance steroid therapy were less likely to relapse, and most relapses occurred in the first 3 years following initial diagnosis (7). Therefore, medical centers in Japan routinely use a prolonged maintenance therapy for up to 3 years with the logic that most relapses occur within that timeframe. Low-dose steroids (2.5-5mg/day), however, may be insufficient to prevent relapses because it is only a physiological dose of steroid. Additional outcome data are needed to establish the risk-benefit before endorsing this practice.

Unlike the Japanese practice of using maintenance therapy in most patients, in the United States maintenance therapy is used only in those patients who relapse after an initial course of steroids (3, 14). The rationale against the universal use of maintenance steroids is that nearly half of patients did not relapse even after a short-course of steroid therapy (13).

Unfortunately, the different approaches to patient selection for maintenance therapy have not been directly compared. It remains to be proven whether maintenance therapy should be used for all patients or restricted to those who relapse or those who are likely to relapse after an initial steroid course.

Steroid-related side effects

The exact rates of the side effects of steroid therapy in AIP have not been established (13). A recent multicenter study on steroid therapy for AIP reported several cases of glucose intolerance, osteoporosis (10/459), spinal compression fracture (5/459), avascular necrosis of femoral head (3/459), and pneumonia (3/459) (7). In general, cosmetic changes including moon face, dorsal hump formation, abdominal striae, weight gain, acne, and alopecia are relatively common after long-term steroid therapy (9). Aggravated glycemic control and labile hypertension can also occur. Serious side effects requiring discontinuation of steroids include osteoporosis with compression fracture, avascular necrosis, steroid-induced psychosis, and opportunistic infections (4, 7). Patients on long-term steroid therapy, especially those with individual risk factors, including the use of other medications or comorbidities, should be closely monitored for side effects of long-term steroid use.

Treatment of Relapse

Patients may experience relapse of AIP, either during maintenance steroid therapy or after a complete discontinuation of steroid (10). Most patients with disease relapse need a full course of therapy similar to the initial therapy, but isolated serological relapse can be observed without a specific therapy (23).

Currently, there are three options for managing patients suffering from a relapse of type 1 AIP (Figure 2) (3). The remission rates achieved using steroids at disease relapse remains very high and is similar to rates achieved at the time of initial disease presentation (2, 13). For patients who relapse, steroids are often given at a higher induction dose which is tapered more gradually, and maintenance therapy is often more prolonged (10, 12). Unfortunately, it is uncertain as to how long the steroid treatment should be continued in patients with relapsing AIP.

Summary

There are a variety of steroid treatment regimens which differ according to the dose and duration of induction therapy, and whether or not maintenance therapy is administered.  These regimens are based on institutional experiences, are not standardized, and have not been systematically compared. Developing a consensus regarding definitions of remission, and the optimal treatment regimen including need for and the duration of maintenance treatment may help to increase complete remission rate and lower relapse rates. Additional studies are needed to advance our understanding of the role of steroids in the optimal management of AIP.

Figure 2. A current algorithm for treatment of relapsed type 1 autoimmune pancreatitis.

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