Abstract
Objective
Steroid pulse therapy is a regimen involving the intravenous administration of supra-pharmacological doses of corticosteroids in the short term. It is used to treat various inflammatory and autoimmune conditions. However, the strengths and limitations of steroid pulse therapy for induction of remission in type 1 autoimmune pancreatitis (AIP) are unknown.
Methods
Depending on the steroid therapy regimen administered, the 104 patients with type 1 AIP included in this retrospective study were divided into three groups: conventional oral prednisolone (PSL) regimen (PSL group), intravenous methylprednisolone (IVMP) pulse followed by oral PSL regimen (Pulse+PSL group), and IVMP pulse-alone regimen (Pulse-alone group). We then examined the relapse rate and adverse events among the three groups.
Results
The Kaplan-Meier estimates of the relapse rate at 36 months after steroid therapy were 13.6% in the PSL group, 13.3% in the Pulse+PSL group, and 46.2% in the Pulse-alone group. The log-rank test revealed that the relapse-free survival in the Pulse-alone group was significantly shorter than that in the PSL (p=0.024) and Pulse+PSL groups (p=0.014). The exacerbation of glucose tolerance after steroid therapy was less frequently observed in the Pulse-alone group (0%) than in the PSL group (17%, p=0.050) and Pulse+PSL groups (26%, p=0.011).
Conclusion
Although treatment with IVMP pulse alone resulted in unsatisfactory relapse prevention outcomes compared with conventional steroid therapy, the IVMP pulse-alone regimen might be an alternative treatment strategy for type 1 AIP from the perspective of avoiding adverse events from steroids.
Keywords: autoimmune pancreatitis, steroid pulse therapy, long-term outcome, relapse, diabetes
Introduction
Autoimmune pancreatitis (AIP) was first proposed as a novel clinical entity by Yoshida et al. in 1995 (1). The radiological features of AIP include focal or diffuse pancreatic enlargement and irregular narrowing of the main pancreatic duct (2).
To date, two subtypes of AIP have been recognized: type 1 and type 2 AIP. Patients with type 1 AIP are often elderly men with elevated serum IgG4 levels and extrapancreatic lesions (e.g., sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis), and the disease is considered a pancreatic manifestation of IgG4-related disease (IgG4-RD) (3).
Since AIP is therapeutically characterized by a dramatic response to steroids, the Japanese and European guidelines recommend initial oral steroid therapy with prednisolone (PSL) at a dose of 0.6 mg/kg body weight/day for 2-4 weeks or 0.6-0.8 mg/kg body weight/day for 1 month for the induction of remission, respectively. After assessing the response to the initial treatment, the dose of PSL is then gradually tapered (4,5). Evidence concerning the effectiveness of maintenance steroid therapy for reducing the relapse rate was also recently provided in a randomized controlled trial study (6).
Steroid pulse therapy, a regimen of intravenous administration of high doses of corticosteroids in the short term, is widely used to initiate treatment in various inflammatory and autoimmune conditions, such as rapidly progressive and immunologically mediated disorders, including rapidly progressive glomerulonephritis and vasculitis, systematic lupus erythematosus, acute renal allograft rejection, multiple sclerosis, and pemphigus (7). Steroid pulse therapy can thus be expected to not only elicit more rapid and strong effects but to also lead to less cumulative toxicity than conventional oral steroid treatment.
We previously reported that steroid pulse therapy with intravenous methylprednisolone (IVMP) was more effective in inducing the remission of type 1 AIP than conventional steroid therapy with oral PSL because of a significant improvement in the biliary stricture associated type 1 AIP (8,9). However, the long-term outcomes after steroid pulse therapy are unclear at present.
In the present study, we examined the relapse rate and adverse events in type 1 AIP patients receiving steroid pulse therapy compared with patients treated with conventional oral steroid therapy.
Materials and Methods
Patients
This retrospective study that conformed to the Declaration of Helsinki was approved by the Ethics Committee of Kansai Medical University (No. 2009601).
One hundred and fifty-one patients diagnosed with type 1 AIP according to the clinical diagnostic criteria (2) were extracted from our single-center prospective database of Kansai Medical University from 2004 to 2019. The diagnosis of AIP was made by a consensus of patients' attending doctors and gastroenterological experts (KO, MT, KU, TI, HM, and TM) who had at least 10 years of career experience in clinical practice for pancreatic disease.
Of the 151 patients with type 1 AIP, we excluded 47 for the following reasons: no treatment for type 1 AIP (n=15), insufficient clinical data at the diagnosis of type 1 AIP (n=11), surgical resection (n=10), follow-up less than 6 months (n=8), and initiation of steroid therapy for diseases other than type 1 AIP (n=3) (Fig. 1). Consequently, we enrolled 104 patients who had received steroid treatment for clinical manifestations associated with IgG4-RD and retrospectively retrieved the patient data from the clinical records.
Figure 1.
Flow diagram of the study. AIP: autoimmune pancreatitis
Steroid therapy
All analyzed patients with type 1 AIP were treated with any of three steroid regimens as initial pharmacological therapy (Fig. 2). The decision on which regimen to administer as the initial therapy (oral or IVMP) for the induction of remission was made at random in 20 patients (19%) treated from November 2004 to May 2009 (8). The initial steroid therapy regimen (oral or IVMP) in the remaining 84 patients (82%) treated after June 2009 and whether maintenance therapy following the initial therapy was left to the discretion of gastroenterological experts (KO, MT, KU, TI, HM, and TM) depending on the patients' symptoms, co-morbidities, and medication adherence.
Figure 2.
Regimens of steroid therapy performed in this study. A: Conventional oral PSL (PSL group), B: Intravenous mPSL pulse followed by oral PSL (Pulse+PSL group), C: Intravenous mPSL pulse alone without PSL (Pulse-alone group). PSL: prednisolone, mPSL: methylprednisolone, Tx: therapy
In the conventional oral PSL regimen (PSL group), PSL was administered at an initial dose of 0.6 mg/kg body weight/day for at least 2 weeks and subsequently gradually tapered by 5 mg every 2-4 weeks until the maintenance dosage was reached (Fig. 2A). In the IVMP pulse followed by oral PSL regimen (Pulse+PSL group), methylprednisolone (mPSL) was intravenously administered at a dose of 125-500 mg/day for 3 consecutive days/week for 2 weeks. Following the IVMP pulse, we prescribed prednisolone 20 mg/day, and it was gradually tapered (Fig. 2B). Finally, in the IVMP pulse-alone regimen (Pulse-alone group), mPSL was intravenously administered at a dose of 125-500 mg/day for 3 consecutive days/week for 2 consecutive weeks. After steroid pulse therapy, no corticosteroid treatment was administered (Fig. 2C). In patients in whom PSL was administered (PSL and Pulse+PSL groups), maintenance steroid therapy with PSL at a dose of 2.5-5.0 mg/day was continued to prevent relapse (4,6).
All patients received prophylactic pharmacological treatment of steroid-induced pathological fractures and peptic ulcers.
Definition
Diabetes mellitus (DM) was defined as HbA1c ≥6.5% or the use of glucose-lowering medications prior to steroid therapy (10). To assess the incidence of new-onset DM and the exacerbation of pre-existing DM after starting steroid therapy, HbA1c levels and use of diabetic medications were reviewed before and within three months after starting steroid therapy. The patient was considered to have exacerbated glucose tolerance if there was a need for an increased dose or introduction of insulin/anti-diabetic agents, an increased HbA1c level by ＞0.5%, or if there was new-onset DM within three months after initiation of steroid treatment (11).
Other organ involvement associated with type 1 AIP was defined as a typical abnormality on a physical or radiological examination in the proximal bile duct, retroperitoneum, kidney, or salivary/lacrimal glands (2).
Remission of the disease was defined as the disappearance of clinical symptoms and resolution of pancreatic and/or extrapancreatic manifestations on imaging studies (12).
Disease relapse was defined as the reappearance of symptoms with the development or reappearance of pancreatic and/or extrapancreatic (including bile duct, salivary gland, and retroperitoneum) abnormalities on imaging studies without suspicion of cancer during steroid therapy or after steroid discontinuation (12). Abnormality of serological parameters alone, including re-elevation of serum IgG4, was not considered to indicate relapse (13).
Statistical analyses
Continuous variables were presented as the mean±standard error in a normal distribution or the median (interquartile range) in a non-normal distribution. Significant differences pertaining to continuous variables were assessed using unpaired t-test in a normal distribution or Mann-Whitney U test in a non-normal distribution. The comparison of proportions was performed using the chi-square test. The cumulative relapse-free survival rate calculated using the Kaplan-Meier method was compared by a log-rank test. Univariate and multivariate analyses were performed to assess the predictors of disease relapse using a Cox proportional hazards regression model. Values of p＜0.05 were considered statistically significant. Statistical analyses were performed using the STATA software program, version 14 (Stata, College Station, USA).
Results
Clinical profile of the analyzed patients
The details of the 104 patients are shown in Table 1. The median age at the diagnosis was 66 (interquartile range, 59.5-72) years old, and 85 patients (82%) were men. The median observation period was 61.5 (interquartile range, 39.5-100.5) months. All patients presented with improvement åof clinical symptoms and pancreatic swelling at the assessment two to four weeks after starting steroid therapy; therefore, remission of type 1 AIP was deemed to have been achieved in all patients.
Table 1.
Characteristics of the 104 Patients.
| n=104 | |
|---|---|
| Age (years) | |
| Median | 66 |
| Interquartile range | 59.5-72 |
| Male | 85 (82%) |
| Observation period (months) | |
| Median | 61.5 |
| Interquartile range | 39.5-100.5 |
| Drinkers | 19 (18%) |
| Smokers | 43 (41%) |
| Diabetes | 44 (42%) |
| Enlargement of pancreas | |
| Diffuse | 54 (52%) |
| Focal | 49 (47%) |
| None | 1 (1%) |
| Narrowing of MPD | |
| Long or multiple stricture | 45 (43%) |
| Focal narrowing | 55 (53%) |
| None | 4 (4%) |
| Serum IgG4 | |
| <135 mg/dL | 10 (10%) |
| 135-270 mg/dL | 21 (20%) |
| >270 mg/dL | 73 (70%) |
| Other organ involvement | |
| Biliary tract | 67 (64%) |
| Retroperitoneum | 8 (8%) |
| Salivary gland | 27 (26%) |
| Kidney | 7 (7%) |
| Steroid therapy | |
| Oral PSL | 23 (22%) |
| Intravenous mPSL pulse followed by oral PSL | 61 (59%) |
| Intravenous mPSL pulse alone | 20 (19%) |
| Relapse | 36 (35%) |
MPD: main pancreatic duct, PSL: prednisolone, mPSL: methylprednisolone
Regarding the steroid therapy regimen, conventional oral PSL, IVMP pulse followed by oral PSL, and intravenous mPSL pulse alone without PSL were performed in 23 (22%), 61 (59%), and 20 (19%) patients, respectively. Of the 84 patients who received oral PSL, 79 (94%) underwent maintenance steroid therapy for a median duration of 30 months.
Disease relapse was observed in 36 patients (35%) during steroid therapy (n=12) or after steroid discontinuation (n=24). The relapse organs were the pancreas (n=27), kidney (n=4), retroperitoneum (n=3), and proximal bile duct (n=2). In all relapsed patients, remission was eventually achieved with re-administration or an increase in the dose of steroids.
None of the patients experienced severe adverse events induced by steroids, such as infection, bone fracture, femoral head necrosis, or cardiovascular diseases.
Comparing the clinical features among the PSL, Pulse+PSL, and Pulse-alone groups
Table 2 shows the comparison of clinical characteristics among the three groups categorized according to the initial steroid therapy regimen. The prevalence of DM at the onset of type 1 AIP in the Pulse-alone group (65%) was significantly higher than that in the PSL (30%) and Pulse+PSL groups (39%) (Pulse-alone group vs. PSL group, p=0.023, Pulse-alone group vs. Pulse+PSL group, p=0.046). There was a statistically significant difference in the involvement of the biliary tract between the Pulse+PSL group and Pulse group (p=0.004). The exacerbation of glucose tolerance after starting steroid therapy was less frequently observed in the Pulse-alone group than in the PSL group (p=0.050) and Pulse+PSL group (p=0.011).
Table 2.
Comparison of Clinical Features.
| PSL n=23 | Pulse+PSL n=61 | Pulse alone n=20 | p value | |||
|---|---|---|---|---|---|---|
| PSL vs. Pulse+PSL |
PSL vs. Pulse alone |
Pulse+PSL vs. Pulse alone |
||||
| Age ≥64 | 12 (52%) | 36 (59%) | 10 (50%) | 0.572 | 0.887 | 0.480 |
| Male | 19 (83%) | 51 (84%) | 5 (25%) | 0.913 | 0.541 | 0.390 |
| Drinkers | 7 (32%) | 10 (16%) | 2 (10%) | 0.124 | 0.085 | 0.485 |
| Smokers | 13 (59%) | 23 (38%) | 7 (35%) | 0.083 | 0.118 | 0.828 |
| DM | 7 (30%) | 24 (39%) | 13 (65%) | 0.451 | 0.023 | 0.046 |
| Diffuse enlargement of pancreas | 9 (39%) | 36 (59%) | 9 (45%) | 0.190 | 0.697 | 0.424 |
| Long or multifocal narrowing of MPD | 8 (35%) | 28 (46%) | 9 (45%) | 0.654 | 0.772 | 0.939 |
| Serum IgG4 >270 mg/dL | 20 (87%) | 40 (66%) | 13 (65%) | 0.053 | 0.089 | 0.963 |
| Other organ involvement | ||||||
| Biliary tract | 13 (57%) | 46 (75%) | 8 (40%) | 0.091 | 0.280 | 0.004 |
| Retroperitoneum | 0 (0%) | 6 (10%) | 2 (10%) | 0.115 | 0.120 | 1.000 |
| Salivary gland | 5 (22%) | 15 (25%) | 7 (35%) | 0.784 | 0.334 | 0.364 |
| Kidney | 2 (9%) | 3 (5%) | 2 (10%) | 0.514 | 0.883 | 0.412 |
| Exacerbation of glycemic control after steroid Tx | 4 (17%) | 16 (26%) | 0 (0%) | 0.396 | 0.050 | 0.011 |
PSL: patients group, DM: diabetes mellites, MPD: main pancreatic duct, Tx: therapy
Relapse rates in the PSL, Pulse+PSL, and Pulse-alone groups
The relapse rate and median duration from the initiation of steroid therapy to relapse in the PSL, Pulse+PSL, and Pulse-alone group were 39% (9/23), 28% (17/61), and 50% (10/20), and 65 (26-74), 43 (21-61), and 13 (8-26) months, respectively. In contrast, 61% (14/23), 72% (44/61), and 50% (10/20) did not exhibit relapse during the median follow-up period of 93 (46-139), 43 (23-73), and 52 (42-57) months in the PSL, Pulse+PSL, and Pulse-alone groups, respectively.
The Kaplan-Meier curves for disease relapse grouped by the steroid therapy regimen are presented in Fig. 3. The Kaplan-Meier estimates of the relapse rate at 36 and 60 months after the beginning of steroid treatment were 13.6% [95% confidence interval (CI), 4.5-34.8%] and 19.4% (95% CI, 7.4-42.1%) in the PSL group, 13.3% (95% CI, 6.4-25.7%) and 27.7% (95% CI, 16-43.5%) in the Pulse+PSL group, and 46.2% (95% CI, 25.9-67.7%) and 52.9% (95% CI, 30.8-73.9%) in the Pulse-alone group, respectively. Analyses using the log-rank test revealed that the relapse-free survival in the Pulse-alone group was significantly shorter than that in the PSL group (p=0.024) and Pulse+PSL group (p=0.014), whereas there was no significant difference between the PSL and Pulse+PSL groups (p=0.623).
Figure 3.
Kaplan-Meier curve of the relapse-free survival rates of three groups. The median relapse-free survival was 65 months in the PSL group, 43 months in the Pulse+PSL group, and 13 months in the Pulse-alone group. The relapse-free survival in the Pulse-alone group was significantly shorter than that in the PSL group and Pulse+PSL group. PSL: prednisolone
Identification of relapse predictors in all patients included in the study
To examine whether or not treatment with IVMP pulse alone was an independent factor associated with disease relapse, we performed univariate and multivariate analyses using a Cox proportional hazards regression model (Table 3). The univariate Cox regression model demonstrated the following 4 candidate variables associated with relapse (p＜0.1): older age (＞65 years old), elevated IgG4 level (＞270 mg/dL), involvement of the biliary duct, and IVMP pulse alone. In the multivariate Cox regression model, the only significant variable associated with relapse was IVMP pulse alone [hazard ratio (HR) 2.74; 95% CI, 1.20-6.26; p=0.016].
Table 3.
Predictors for Relapse in Patients Who Receive Steroid Therapy.
| Univariable | Multivariable | ||||
|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | ||
| Age >65 years | 0.52 (0.26-1.01) | 0.053 | 0.55 (0.28-1.08) | 0.082 | |
| Male | 0.65 (0.25-1.69) | 0.380 | |||
| Diabetes | 0.61 (0.30-1.22) | 0.162 | |||
| Diffuse enlargement of pancreas | 0.93 (0.49-1.75) | 0.820 | |||
| Long or multifocal narrowing of MPD | 0.92 (0.51-1.67) | 0.787 | |||
| Serum IgG4 >270 mg/dL | 2.22 (0.92-5.34) | 0.075 | 2.41 (0.95-6.09) | 0.064 | |
| Serum IgG >1,800 | 1.14 (0.54-2.43) | 0.724 | |||
| Serum IgE >320 U/L | 2.19 (0.72-6.63) | 0.165 | |||
| Eosinophil >500/μL | 0.812 (0.29-0.30) | 0.694 | |||
| Other organ involvement | |||||
| Biliary tract | 0.48 (0.24-0.95) | 0.035 | 0.82 (0.38-1.76) | 0.604 | |
| Retroperitoneum | 1.49 (0.45-4.94) | 0.517 | |||
| Salivary gland | 1.80 (0.88-3.65) | 0.106 | |||
| Kidney | 1.99 (0.60-6.57) | 0.259 | |||
| Intravenous mPSL pulse alone | 2.90 (1.35-6.21) | 0.006 | 2.74 (1.20-6.26) | 0.016 | |
HR: hazard ratio, CI: confidence interval, DM: diabetes mellites, MPD: main pancreatic duct, mPSL: methylprednisolone
Subgroup analyses of 20 patients undergoing pulse therapy alone
We conducted a subgroup analysis of 20 patients in the Pulse group to clarify the presence of predictors for relapse after IVMP pulse alone (Table 4). Univariate analyses using a Cox proportional hazards regression model demonstrated that candidate variables associated with relapse (p＜0.2) were DM at the onset of type 1 AIP, elevated IgG4 (＞270 mg/dL), involvement of the biliary duct, and a single dose of mPSL in pulse therapy (500 mg). In the multivariate Cox regression model, DM at the onset of type 1 AIP showed the smallest p values, but there was no statistically significant association with relapse (HR 0.26; 95% CI, 0.07-1.14; p=0.079).
Table 4.
Predictors for Relapse in the Population Limited to Patients Receiving Intravenous Methyl-prednisolone Pulse Alone.
| Univariable | Multivariable | ||||
|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | ||
| Age >65 years | 0.53 (0.15-1.88) | 0.322 | |||
| Male | 0.68 (0.14-3.24) | 0.632 | |||
| Diabetes | 0.21 (0.06-0.78) | 0.020 | 0.28 (0.07-1.14) | 0.071 | |
| Diffuse enlargement of pancreas | 0.74 (0.74-2.59) | 0.639 | |||
| Long or multifocal narrowing of MPD | 1.21 (0.43-3.44) | 0.715 | |||
| Serum IgG4 >270 mg/dL | 3.45 (0.70-17.05) | 0.129 | 2.84 (0.56-14.4) | 0.207 | |
| Serum IgG >1,800 | 0.69 (0.12-3.78) | 0.665 | |||
| Serum IgE >320 U/L | 1.49 (0.15-14.41) | 0.729 | |||
| Eosinophil >500/μL | 3.27 (0.38-28.04) | 0.280 | |||
| Other organ involvement | |||||
| Biliary tract | 0.33 (0.07-1.58) | 0.166 | 0.69 (0.13-3.57) | 0.661 | |
| Retroperitoneum | 0.86 (0.11-6.80) | 0.885 | |||
| Salivary gland | 1.07 (0.30-3.83) | 0.916 | |||
| Kidney | 1.07 (0.13-8.57) | 0.951 | |||
| A single dose of mPSL in pulse Tx | |||||
| 125 mg/250 mg | Reference | ||||
| 500 mg | 2.57 (0.74-8.94) | 0.137 | 1.63 (0.45-5.97) | 0.457 | |
HR: hazard ratio, CI: confidence interval, DM: diabetes mellites, MPD: main pancreatic duct, mPSL: methylprednisolone, Tx: therapy
Next, in the 9 patients in whom data on the serum interleukin (IL)-6 levels before steroid therapy were available, we compared serum IL-6 levels between the relapse (n =4) and non-relapse (n =5) groups. The mean levels of IL-6 in the non-relapse groups (4.4±1.7 pg/mL) were significantly higher than those in the relapse group (1.8±0.6 pg/mL) (p=0.048) (Fig. 4). In addition, we examined the relationship between the serum IL-6 levels and candidate factors associated with relapse, such as DM at the onset of type 1 AIP, high IgG4 levels, and biliary dust involvement. As results of a univariate analysis, we noted no significant difference in serum IL-6 levels between patients with and without DM (4.0±0.9 pg/mL in patients with DM vs. 1.8±0.5 pg/mL in patients without DM, p=0.174) or between patients with and without high IgG4 levels (＞270 mg/dL) (2.5±0.6 pg/mL in patients with high IgG4 vs. 4.2±1.3 pg/mL in patients without high IgG4, p=0.280), whereas serum levels of IgG4 in patients with biliary tract involvement (5.1±0.9 pg/mL) tended to be higher than those in patients without biliary tract involvement (1.8±0.3 pg/mL) (p=0.051).
Figure 4.
A comparison of serum interleukin-6 levels at the onset of type 1 autoimmune pancreatitis between patients with and without relapse after intravenous methylprednisolone pulse alone. Among patients treated with intravenous methylprednisolone pulse alone, the mean levels of IL-6 in those without relapse were significantly higher than in those with relapse. IL: interleukin
Discussion
In the present study, we examined differences in long-term disease relapse rates in patients with type 1 AIP treated with conventional oral PSL, IVMP pulse followed by oral PSL, and IVMP pulse alone without PSL. The relapse-free survival in the Pulse-alone group was significantly poorer than that in the PSL and Pulse+PSL groups, and the relapse-free survival of the PSL group and Pulse+PSL group was comparable. In addition, treatment with IVMP pulse alone was a significant predictor of relapse. In contrast, half of the patients receiving IVMP pulse alone did not exhibit relapse during a median follow-up period of 52 months. Furthermore, none of the patients receiving IVMP pulse alone exhibited an exacerbation of glucose tolerance, whereas glucose tolerance was aggravated in approximately 20% of patients receiving continuous treatment with PSL. This is the first paper reporting the strengths and limitations of steroid pulse therapy in type 1 AIP from an experience at a high-volume center.
Steroid therapy is the first-line treatment for the remission of type 1 AIP unless there are contraindications for steroid use. According to clinical guidelines and previous studies, oral administration of PSL at sufficient doses is recommended as initial therapy, followed by a gradual dose reduction (4,5,14,15). Steroid pulse therapy has also been introduced as another initial regimen for remission induction (8,9). The steroid pulse therapy regimen involves the intravenous administration of high doses of steroids in a short span of time for quicker and better efficacy in the initial management of type 1 AIP. In our previous study, steroid pulse therapy yielded a significant improvement in serum γ-guanosine triphosphate levels at two weeks and alanine aminotransferase levels at two and eight weeks after steroid therapy compared with oral steroid therapy, indicating that steroid pulse therapy was a beneficial alternative to oral steroid therapy in the initial treatment for type 1 AIP (7).
However, there are limited published data concerning the long-term outcomes of IVMP pulse therapy for type 1 AIP. Sugimoto et al. (16) investigated the efficacy of steroid pulse therapy for type 1 AIP, and reported that the 5-year cumulative relapse-free survival rates did not differ significantly between patients treated with oral PSL and those treated with IVMP pulse therapy followed by oral PSL (46.9% vs. 77.8%); however, this study was limited by the small number of patients (16 patients treated with IVMP pulse followed by oral PSL and 8 treated with oral PSL). In addition to the larger study population, our study has an advantage in that the long-term outcome of patients in whom IVMP pulse alone was administered without PSL was examined for the first time.
In the present study, IVMP pulse alone without PSL was inferior to conventional oral PSL and IVMP pulse alone followed by oral PSL at preventing disease relapse. However, there was no marked difference in the relapse-free survival rate between oral PSL and IVMP pulse followed by oral PSL. These findings suggest that maintenance therapy with oral PSL plays an important role in reducing relapses regardless of whether steroid pulse therapy is performed as initial treatment. IVMP pulse alone without oral PSL was identified as an independent factor associated with disease relapse in this setting, although previous studies have identified some risk factors for relapse, including diffuse pancreatic enlargement (17), elevated serum IgG4 level before steroid therapy (18,19), and a persistently elevated, low reduction rate, or re-elevated serum IgG4 level after steroid treatment (12,20).
Our study revealed that IVMP pulse alone without PSL was insufficient to prevent relapses because the 3- and 5-year cumulative relapse rates of the Pulse-alone group were higher, accounting for 46.2% and 52.9%, respectively, than those in the PSL group (13.6% and 19.4%, respectively) and Pulse+PSL group (13.3% and 27.7%, respectively). However, remission was still achieved in about 50% of patients receiving IVMP pulse alone during a median follow-up of over 4 years.
Regarding the glycemic control, no patient showed exacerbation of pre-existing DM after initiation of steroid therapy in the Pulse-alone group, although the prevalence of DM in the Pulse-alone group was higher than in the PSL group and Pulse+PSL group. Furthermore, there was no adverse effect on the risk of new-onset DM in patients receiving IVMP pulse alone, as these patients did not receive persistent doses of oral PSL. Previous studies have reported that 42-71% of AIP patients had DM or endocrine dysfunction at the onset of AIP (10,11,21,22). In the short term (3 months), after starting daily oral administration of PSL, 33% of AIP patients had increased HbA1c levels (23), and 13% of AIP patients with DM showed worsening of DM (11). The most recent prospective study also demonstrated that glucose tolerance was aggravated in 15% of patients with AIP after steroid therapy (6). Long-term steroids are also associated with other debilitating side effects, such as osteoporosis, Addison-like adrenal insufficiency, fatty liver, brittle skin, muscle weakness, and infection (24,25). Although no severe adverse events induced by steroids were observed in any patients included in our study, IVMP pulse alone might be an alternative treatment strategy for type 1 AIP that can minimize the adverse events associated with steroid therapy. In addition, based on the results of the subgroup analysis (Table 4), it is notable that a single dose of mPSL in pulse therapy seems not to be associated with disease relapse. That suggests that a regimen of decreased IVMP dose, so-called mini-pulse therapy, can provide similar efficacy for relapse prevention to conventional IVMP pulse in patients treated with steroid pulse therapy.
IL-6 is a principal mediator of inflammation and immunity. Regarding the immune response, IL-6 promotes the expansion and activation of T cells and the differentiation of B cells, thus playing an important role in the linking of innate to acquired immune response (26). Although the pathophysiology of type 1 AIP is still incompletely understood, abnormal innate and acquired immunity may be involved in the development of type 1 AIP (27). Some patients with IgG4-RD (include type 1 AIP) exhibit elevated serum IL-6 (28,29); in addition, they tend to show severe clinical manifestations related to acute inflammatory reaction at the onset of the disease (29). In the present study, the mean serum level of IL-6 was significantly elevated in patients without relapse compared to patients with relapse in a subset of patients treated by IVMP pulse alone, suggesting pulse therapy alone might be an advantageous treatment in patients with high levels of IL-6 who are high risk for the incidence of adverse events associated with continuous steroid therapy. As corticosteroids exert not only immunosuppressive effects but also anti-inflammatory effects induced by suppressing pro-inflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor-α (TNF-α) (7), steroid pulse therapy with high-dose intravenous corticosteroids seems to be more effective than oral steroid therapy in patients with a relatively high level of serum IL-6. As type 1 AIP patients with hyper-IL-6 might have different clinical characteristics (e.g., tendency of higher prevalence of biliary tract involvement) and steroid responsibility from typical type 1 AIP patients, further studies are needed to clarify the precise role of IL-6 in the pathogenesis of type 1 AIP.
One limitation of this study is that it was a retrospective single-center study with an inherent selection bias. However, in the comparison of clinical features among the PSL, Pulse+PSL, and Pulse-alone groups, there were no significant differences in parameters that have already been reported as predictors of relapse. Furthermore, the patients included in the study were treated with a relatively unified treatment strategy for each steroid therapy regimen based on the consensus of our department. This helped minimize the bias.
In conclusion, compared with conventional oral PSL and IVMP pulse followed by oral PSL, treatment with IVMP pulse alone resulted in unsatisfactory relapse prevention outcomes. However, despite treatment with IVMP pulse alone, some patients achieved sustained long-term remission. IVMP pulse alone might serve as an alternative treatment strategy to conventional oral steroid therapy, especially in patients who are at a high risk of developing adverse events associated with steroids.
The authors state that they have no Conflict of Interest (COI).
Financial support
This study was partially supported by (1) Grant-in-Aid for Scientific Research (C) of the Ministry of Culture and Science of Japan (20590810, 23591017, 24591020, 12008507, 17877850, 17K09468, 15K09052, 19K17476); (2) the Research Program on Intractable Diseases, from the Ministry of Labour and Welfare of Japan; (3) grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; (4) the Research Program from the Japan Medical Research and Development (AMED) (17824893); (5) the branding program as a world-leading research university on intractable immune and allergic diseases supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan; and (6) a research grant from Kansai Medical University.
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