ORIGINAL ARTICLE
Nationwide Epidemiological Survey of Autoimmune Pancreatitis in Japan in 2011 Atsushi Kanno, MD, PhD,* Atsushi Masamune, MD, PhD,* Kazuichi Okazaki, MD, PhD,† Terumi Kamisawa, MD, PhD,‡ Shigeyuki Kawa, MD, PhD,§ Isao Nishimori, MD, PhD,|| Ichiro Tsuji, MD, PhD,¶ and Tooru Shimosegawa, MD, PhD,* for the Research Committee of Intractable Diseases of the Pancreas Objectives: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, a nationwide epidemiological survey was conducted. Methods: Patients with AIP who had visited selected hospitals in 2011 were surveyed. Autoimmune pancreatitis was diagnosed according to the revised clinical diagnostic criteria for AIP (Japan Pancreas Society 2011). The study consisted of 2 stage surveys; the number of patients with AIP was estimated by the first questionnaire, and their clinical features were assessed by the second questionnaire. Results: The estimated total number of AIP patients in 2011 was 5745 (95% confidence interval, 5325–6164), with an overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP was estimated to be 1808 (95% confidence interval, 1597–2018), with an annual incidence rate of 1.4 per 100,000 population. The sex ratio (male to female) was 3.2, and the mean age was 66.3 (11.5). Among the 936 patients whose detailed clinical information was obtained, 86.4% of the patients presented high serum immunoglobulin G4 levels (≥135 mg/dL), and 82.3% received steroid therapy. Conclusions: The data represent the current clinical features of AIP in Japan. Key Words: pancreatitis, IgG4, steroid, sclerosing cholangitis, epidemiology Abbreviations: AIP - autoimmune pancreatitis, EUS-FNA - endoscopic ultrasonography fine-needle aspiration, IBD - inflammatory bowel disease, IgG - immunoglobulin G, JPS - Japan Pancreas Society, MPD - main pancreatic duct (Pancreas 2015;44: 535–539)
A
utoimmune pancreatitis (AIP) is a rare disease that has recently emerged as a unique type of pancreatitis with a presumed autoimmune etiology. Although almost 20 years have passed since AIP was proposed as a diagnostic entity by Yoshida et al,1 the epidemiology, pathology, and optimal treatment of this disease remain largely unknown. In 2002, the Japan Pancreas
From the *Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai; †Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka; ‡Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo; §Center of Health, Safety, and Environmental Management, Shinshu University, Matsumoto; ||Nishimori Clinic, Kochi; and ¶Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. Received for publication July 16, 2014; accepted October 30, 2014. Reprints: Tooru Shimosegawa, MD, PhD, Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574 Japan (e‐mail: [email protected]). This work was supported in part by the Research Committee of Intractable Diseases of the Pancreas, and by the Ministry of Health, Labor, and Welfare of Japan. The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 4, May 2015
Society (JPS) proposed the world's first clinical diagnostic criteria for AIP (JPS 2002),2 which was revised in 2006 (JPS 2006).3 The Research Committee of Intractable Diseases of the Pancreas, supported by the Ministry of Health, Labor, and Welfare of Japan, has conducted nationwide epidemiological surveys of AIP in 20034 and 20075 according to the JPS 2002 and JPS 2006, respectively. Subsequently, the International Consensus Diagnostic Criteria (ICDC) were proposed in 2010.6 Autoimmune pancreatitis was classified to 2 subtypes according to the ICDC: type 1 related to immunoglobulin G4 (IgG4) (lymphoplasmacytic sclerosing pancreatitis) and type 2 with granulocytic epithelial lesions (idiopathic duct-centric chronic pancreatitis). Because Japanese cases of type 2 AIP are extremely rare, the JPS and the Research Committee of Intractable Diseases of the Pancreas revised the diagnostic criteria as the clinical diagnostic criteria for AIP 2011 (JPS 2011).7 To estimate the precise number of AIP patients in Japan and to elucidate their clinical features, we undertook the third nationwide epidemiological survey based on the JPS 2011.
MATERIALS AND METHODS We conducted a 2-staged postal survey. The first survey aimed to estimate the number of patients with AIP, and the second survey aimed to elucidate the clinicoepidemiological characteristics of AIP. This study was approved by the Ethics Committee of Tohoku University School of Medicine (article number 2012-1-460).
The Diagnosis of AIP In this study, AIP was diagnosed according to the JPS 2011.7 The JPS 2011 consisted of 5 major findings (parenchyma, narrowing of the main pancreatic duct [MPD], serum IgG4 level [≥135 mg/dL], other organ involvement, and steroid responsiveness). The JPS 2011 adopted as much as possible the basic concepts of both the previous Japanese criteria and the following criteria concerning type 1 in the ICDC: (1) simple to use by general physicians; (2) diffuse/segmental/focal classification on pancreatic imaging; (3) IgG4 alone as a serological marker; (4) sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis as other organ involvements; (5) no classifications of level 1/2 in serum IgG4 and other organ involvement; and (6) optional steroid trial only after excluding malignancy by endoscopic ultrasonographyguided fine-needle aspiration (EUS-FNA).8 Endoscopic retrograde cholangiopancreatography is basically required in the focal/ segmental type because the findings of the pancreatic duct are important in the differential diagnosis from pancreatic cancer. In the general clinical practice in Japan, the JPS 2011 criteria are recommended for the diagnosis of AIP; however, the ICDC are required to diagnose cases of AIP not otherwise specified or type 2 AIP.
First-Stage Survey Our target subjects were patients with AIP who visited the selected hospitals in 2011. The list of hospitals for the survey is www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
535
Pancreas • Volume 44, Number 4, May 2015
Kanno et al
TABLE 1. Summary of the First Survey
Strata
Total No. Departments in Japan
Sampling Rate, %
No. Surveyed Departments
No. Responded Departments
Response Rate, %
Total No. Reported Cases
No. Newly Diagnosed Patients
487
100
487
264
54.2
753
164
391
100
391
209
53.5
482
137
865 799 1506 1903 5291 5572 16,814
100 80 40 20 10 5
865 640 603 381 529 279 4175
424 286 210 158 220 113 1884
49.0 44.7 34.8 41.5 41.6 40.5 45.1
441 127 88 42 23 3 1959
135 49 34 15 8 2 544
Special departments University hospital ≥500 beds 400–499 beds 300–399 beds 200–299 beds 100–199 beds ≤99 beds Total
based on the hospital yearbook 2012 (R&D Co, Ltd, Japan). The departments of internal medicine, gastroenterology, surgery, digestive surgery, and emergency were listed and subjected to stratified random sampling. The sampling rates were approximately 5%, 10%, 20%, 40%, 80%, 100%, and 100% for the stratum of hospitals with less than 100 beds, 100 to 199 beds, 200 to 299 beds, 300 to 399 beds, 400 to 499 beds, 500 or more beds, and the affiliated university hospitals, respectively. Several departments treating many pancreatic disease patients were classified as a special stratum, and all of them were selected for the survey. In the first survey, a simple questionnaire was sent to each department requesting the number of patients with AIP who visited during 2011. This questionnaire was directly mailed in June 2012 to 4175 departments randomly chosen as described previously. After the collection of the first questionnaire, the number of patients with AIP was estimated as previously described.9–11
Second-Stage Survey In December 2012, we sent the second questionnaire to departments reporting that they had AIP patients in 2011 on the first questionnaire. The second questionnaire was collected by October 2013. Because some items of the questionnaire were unanswered, the numbers of patients subjected for analyses were different among the items.
RESULTS
collected. Two hundred twenty-eight patients were newly diagnosed in 2011, and 699 patients had been already diagnosed as AIP before 2011 (including 9 unknown patients). All patients were Japanese. The male-to-female ratio was 3.7. The mean (SD) age was 66.3 (11.5) years (67.0 [11.1] in males and 64.0 [12.4] in females). The most affected ages were 70 to 79 years in males and 60 to 69 years in females (Fig. 1).
Clinical Profile Clinical profiles of the reported patients are summarized in Table 2. The definitions of enlargement of the pancreas and ductal imaging were revised in the ICDC6 and JPS 2011.5 The enlargement of the pancreas or narrowing of MPD to less than one third of the whole pancreas was defined as focal, and that with more than one third but less than two thirds was defined as segmental. Approximately 90% of the cases had enlargement of the pancreas. Among them, nearly 50% cases showed localized enlargement, suggesting focal or segmental enlargement in the JPS 2011.7 Main pancreatic duct narrowing was seen in about 90% cases, but approximately 50% of the cases showed narrowing to within two thirds of the entire length. IgG4 was elevated in 739 (86.4%) of 855 patients (mean [SD], 533.0 [540.9] mg/dL). Two hundred sixty-three (33.5%) of 785 patients were positive for antinuclear antibodies, 486 (56.4%) of 862 had high levels of IgG, and 125 (21.7%) of 576 were positive for rheumatoid factors.
First Survey The results of the first survey are summarized in Table 1. Of 4175 departments, 1884 departments responded to the questionnaire in the first-stage survey (response rate, 45.1%), and 1959 patients with AIP were identified. Among them, 544 cases (27.8%) were newly diagnosed as having AIP in 2011. We estimated that the total number of patients diagnosed as having AIP in 2011 was 5745 (95% confidence interval, 5325–6164), which means an estimated overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP in 2011 was estimated to be 1808 (95% confidence interval, 1597–2018), from which the annual incidence rate was calculated to be 1.4 per 100,000 population.
Second Survey From the second survey, the clinical data of 936 patients (703 males, 217 females, and 16 patients of unknown sex) were
536
www.pancreasjournal.com
FIGURE 1. Age distribution of patients with AIP. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 4, May 2015
Nationwide Survey of AIP in Japan
TABLE 2. Clinical Profiles of the Reported AIP Patients
TABLE 4. Extrapancreatic Lesions (Including Overlapping Cases)
Pancreatic Imaging
Extrapancreatic Lesion (%)
Enlargement Diffuse enlargement Segmental enlargement Focal enlargement Atypical N/A MPD narrowing Diffuse (≥2/3) Segmental (1/3≤
Nationwide Epidemiological Survey of Autoimmune Pancreatitis in Japan in 2011 Atsushi Kanno, MD, PhD,* Atsushi Masamune, MD, PhD,* Kazuichi Okazaki, MD, PhD,† Terumi Kamisawa, MD, PhD,‡ Shigeyuki Kawa, MD, PhD,§ Isao Nishimori, MD, PhD,|| Ichiro Tsuji, MD, PhD,¶ and Tooru Shimosegawa, MD, PhD,* for the Research Committee of Intractable Diseases of the Pancreas Objectives: To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, a nationwide epidemiological survey was conducted. Methods: Patients with AIP who had visited selected hospitals in 2011 were surveyed. Autoimmune pancreatitis was diagnosed according to the revised clinical diagnostic criteria for AIP (Japan Pancreas Society 2011). The study consisted of 2 stage surveys; the number of patients with AIP was estimated by the first questionnaire, and their clinical features were assessed by the second questionnaire. Results: The estimated total number of AIP patients in 2011 was 5745 (95% confidence interval, 5325–6164), with an overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP was estimated to be 1808 (95% confidence interval, 1597–2018), with an annual incidence rate of 1.4 per 100,000 population. The sex ratio (male to female) was 3.2, and the mean age was 66.3 (11.5). Among the 936 patients whose detailed clinical information was obtained, 86.4% of the patients presented high serum immunoglobulin G4 levels (≥135 mg/dL), and 82.3% received steroid therapy. Conclusions: The data represent the current clinical features of AIP in Japan. Key Words: pancreatitis, IgG4, steroid, sclerosing cholangitis, epidemiology Abbreviations: AIP - autoimmune pancreatitis, EUS-FNA - endoscopic ultrasonography fine-needle aspiration, IBD - inflammatory bowel disease, IgG - immunoglobulin G, JPS - Japan Pancreas Society, MPD - main pancreatic duct (Pancreas 2015;44: 535–539)
A
utoimmune pancreatitis (AIP) is a rare disease that has recently emerged as a unique type of pancreatitis with a presumed autoimmune etiology. Although almost 20 years have passed since AIP was proposed as a diagnostic entity by Yoshida et al,1 the epidemiology, pathology, and optimal treatment of this disease remain largely unknown. In 2002, the Japan Pancreas
From the *Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai; †Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka; ‡Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo; §Center of Health, Safety, and Environmental Management, Shinshu University, Matsumoto; ||Nishimori Clinic, Kochi; and ¶Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. Received for publication July 16, 2014; accepted October 30, 2014. Reprints: Tooru Shimosegawa, MD, PhD, Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574 Japan (e‐mail: [email protected]). This work was supported in part by the Research Committee of Intractable Diseases of the Pancreas, and by the Ministry of Health, Labor, and Welfare of Japan. The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 4, May 2015
Society (JPS) proposed the world's first clinical diagnostic criteria for AIP (JPS 2002),2 which was revised in 2006 (JPS 2006).3 The Research Committee of Intractable Diseases of the Pancreas, supported by the Ministry of Health, Labor, and Welfare of Japan, has conducted nationwide epidemiological surveys of AIP in 20034 and 20075 according to the JPS 2002 and JPS 2006, respectively. Subsequently, the International Consensus Diagnostic Criteria (ICDC) were proposed in 2010.6 Autoimmune pancreatitis was classified to 2 subtypes according to the ICDC: type 1 related to immunoglobulin G4 (IgG4) (lymphoplasmacytic sclerosing pancreatitis) and type 2 with granulocytic epithelial lesions (idiopathic duct-centric chronic pancreatitis). Because Japanese cases of type 2 AIP are extremely rare, the JPS and the Research Committee of Intractable Diseases of the Pancreas revised the diagnostic criteria as the clinical diagnostic criteria for AIP 2011 (JPS 2011).7 To estimate the precise number of AIP patients in Japan and to elucidate their clinical features, we undertook the third nationwide epidemiological survey based on the JPS 2011.
MATERIALS AND METHODS We conducted a 2-staged postal survey. The first survey aimed to estimate the number of patients with AIP, and the second survey aimed to elucidate the clinicoepidemiological characteristics of AIP. This study was approved by the Ethics Committee of Tohoku University School of Medicine (article number 2012-1-460).
The Diagnosis of AIP In this study, AIP was diagnosed according to the JPS 2011.7 The JPS 2011 consisted of 5 major findings (parenchyma, narrowing of the main pancreatic duct [MPD], serum IgG4 level [≥135 mg/dL], other organ involvement, and steroid responsiveness). The JPS 2011 adopted as much as possible the basic concepts of both the previous Japanese criteria and the following criteria concerning type 1 in the ICDC: (1) simple to use by general physicians; (2) diffuse/segmental/focal classification on pancreatic imaging; (3) IgG4 alone as a serological marker; (4) sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis as other organ involvements; (5) no classifications of level 1/2 in serum IgG4 and other organ involvement; and (6) optional steroid trial only after excluding malignancy by endoscopic ultrasonographyguided fine-needle aspiration (EUS-FNA).8 Endoscopic retrograde cholangiopancreatography is basically required in the focal/ segmental type because the findings of the pancreatic duct are important in the differential diagnosis from pancreatic cancer. In the general clinical practice in Japan, the JPS 2011 criteria are recommended for the diagnosis of AIP; however, the ICDC are required to diagnose cases of AIP not otherwise specified or type 2 AIP.
First-Stage Survey Our target subjects were patients with AIP who visited the selected hospitals in 2011. The list of hospitals for the survey is www.pancreasjournal.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
535
Pancreas • Volume 44, Number 4, May 2015
Kanno et al
TABLE 1. Summary of the First Survey
Strata
Total No. Departments in Japan
Sampling Rate, %
No. Surveyed Departments
No. Responded Departments
Response Rate, %
Total No. Reported Cases
No. Newly Diagnosed Patients
487
100
487
264
54.2
753
164
391
100
391
209
53.5
482
137
865 799 1506 1903 5291 5572 16,814
100 80 40 20 10 5
865 640 603 381 529 279 4175
424 286 210 158 220 113 1884
49.0 44.7 34.8 41.5 41.6 40.5 45.1
441 127 88 42 23 3 1959
135 49 34 15 8 2 544
Special departments University hospital ≥500 beds 400–499 beds 300–399 beds 200–299 beds 100–199 beds ≤99 beds Total
based on the hospital yearbook 2012 (R&D Co, Ltd, Japan). The departments of internal medicine, gastroenterology, surgery, digestive surgery, and emergency were listed and subjected to stratified random sampling. The sampling rates were approximately 5%, 10%, 20%, 40%, 80%, 100%, and 100% for the stratum of hospitals with less than 100 beds, 100 to 199 beds, 200 to 299 beds, 300 to 399 beds, 400 to 499 beds, 500 or more beds, and the affiliated university hospitals, respectively. Several departments treating many pancreatic disease patients were classified as a special stratum, and all of them were selected for the survey. In the first survey, a simple questionnaire was sent to each department requesting the number of patients with AIP who visited during 2011. This questionnaire was directly mailed in June 2012 to 4175 departments randomly chosen as described previously. After the collection of the first questionnaire, the number of patients with AIP was estimated as previously described.9–11
Second-Stage Survey In December 2012, we sent the second questionnaire to departments reporting that they had AIP patients in 2011 on the first questionnaire. The second questionnaire was collected by October 2013. Because some items of the questionnaire were unanswered, the numbers of patients subjected for analyses were different among the items.
RESULTS
collected. Two hundred twenty-eight patients were newly diagnosed in 2011, and 699 patients had been already diagnosed as AIP before 2011 (including 9 unknown patients). All patients were Japanese. The male-to-female ratio was 3.7. The mean (SD) age was 66.3 (11.5) years (67.0 [11.1] in males and 64.0 [12.4] in females). The most affected ages were 70 to 79 years in males and 60 to 69 years in females (Fig. 1).
Clinical Profile Clinical profiles of the reported patients are summarized in Table 2. The definitions of enlargement of the pancreas and ductal imaging were revised in the ICDC6 and JPS 2011.5 The enlargement of the pancreas or narrowing of MPD to less than one third of the whole pancreas was defined as focal, and that with more than one third but less than two thirds was defined as segmental. Approximately 90% of the cases had enlargement of the pancreas. Among them, nearly 50% cases showed localized enlargement, suggesting focal or segmental enlargement in the JPS 2011.7 Main pancreatic duct narrowing was seen in about 90% cases, but approximately 50% of the cases showed narrowing to within two thirds of the entire length. IgG4 was elevated in 739 (86.4%) of 855 patients (mean [SD], 533.0 [540.9] mg/dL). Two hundred sixty-three (33.5%) of 785 patients were positive for antinuclear antibodies, 486 (56.4%) of 862 had high levels of IgG, and 125 (21.7%) of 576 were positive for rheumatoid factors.
First Survey The results of the first survey are summarized in Table 1. Of 4175 departments, 1884 departments responded to the questionnaire in the first-stage survey (response rate, 45.1%), and 1959 patients with AIP were identified. Among them, 544 cases (27.8%) were newly diagnosed as having AIP in 2011. We estimated that the total number of patients diagnosed as having AIP in 2011 was 5745 (95% confidence interval, 5325–6164), which means an estimated overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP in 2011 was estimated to be 1808 (95% confidence interval, 1597–2018), from which the annual incidence rate was calculated to be 1.4 per 100,000 population.
Second Survey From the second survey, the clinical data of 936 patients (703 males, 217 females, and 16 patients of unknown sex) were
536
www.pancreasjournal.com
FIGURE 1. Age distribution of patients with AIP. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 4, May 2015
Nationwide Survey of AIP in Japan
TABLE 2. Clinical Profiles of the Reported AIP Patients
TABLE 4. Extrapancreatic Lesions (Including Overlapping Cases)
Pancreatic Imaging
Extrapancreatic Lesion (%)
Enlargement Diffuse enlargement Segmental enlargement Focal enlargement Atypical N/A MPD narrowing Diffuse (≥2/3) Segmental (1/3≤
