Amendment of the Japanese Consensus Guidelines for Autoimmune Pancreatitis, 2013 I. Concept and diagnosis of autoimmune pancreatitis

Background

In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese consensus guidelines for managing AIP required revision.

Methods

Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Fifteen specialists for AIP extracted the specific clinical statements from 1,843 articles published between 1963 and 2012 (obtained from Pub Med and a secondary database, and developed the CQs and statements. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid.

Results

The professional committee created 13 CQs and statements for the current concept and diagnosis of AIP, 6 for extra-pancreatic lesions, 6 for differential diagnosis, and 11 for treatment.

Conclusion

After evaluation by the moderators, amendments to the Japanese consensus guidelines for AIP have been proposed for 2013.     

Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP

Steroid therapy appeared to be a standard treatment for autoimmune pancreatitis (AIP), although some AIP patients improve spontaneously. The indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, and back pain, and the presence of symptomatic extrapancreatic lesions. Before steroid therapy, jaundice should be managed by biliary drainage in patients with obstructive jaundice, and blood glucose levels should be controlled in patients with diabetes mellitus. For the initial oral prednisolone dose for induction of remission, 0.6 mg/kg/day is recommended. The initial dose is administered for 2–4 weeks, and the dose is tapered by 5 mg every 1–2 weeks, based on changes in the clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5–5 mg/day) over a period of 2–3 months. Steroid therapy should be stopped based on the disease activity in each case. Stopping of maintenance therapy should be planned within at least 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapses. The prognosis of AIP appears to be good over the short-term with steroid therapy. It is unclear whether the long-term outcome is good because there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.     

Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis

In 2002, the Japan Pancreas Society (JPS) was the first in the world to propose diagnostic criteria for autoimmune pancreatitis (AIP). Since the concept of AIP has changed with the accumulation of AIP cases, the Research Committee of Intractable Pancreatic Diseases (RCIPD) provided by the Ministry of Health, Labour and Welfare of Japan and the JPS issued revised clinical diagnostic criteria of AIP in 2006. The Asan Medical Center of Korea also proposed diagnostic criteria for AIP in 2006. However, there are subtle but clinically challenging differences between the Japanese and Korean criteria. This inconsistency makes it difficult to compare data in studies from different centers and elucidate the characteristics of AIP. To reach a consensus on AIP, the RCIPD and the Korean Society of Pancreatobiliary Diseases established the following Asian criteria for the diagnosis of AIP: I-1. Imaging studies of pancreatic parenchyma show a diffuse/segmental/focally enlarged gland, occasionally with a mass and/or a hypoattenuation rim. I-2. Imaging studies of pancreaticobiliary ducts show diffuse/segmental/focal pancreatic ductal narrowing, often with stenosis of the bile duct. (Both I-1 and I-2 are required for diagnosis). II. Elevated level of serum IgG or IgG4, and detection of autoantibodies. III. Common lymphoplasmacytic infiltration and fibrosis, with abundant IgG4-positive cell infiltration. AIP should be diagnosed when criterion I and one of the other two criteria are satisfied, or when histology shows the presence of lymphoplasmacytic sclerosing pancreatitis in the resected pancreas. A diagnostic trial of steroid therapy can be applied carefully by expert pancreatologists only in patients fulfilling criterion I alone with negative diagnostic work-up results for pancreatobiliary cancer.     

Japanese consensus guidelines for management of autoimmune pancreatitis: I. Concept and diagnosis of autoimmune pancreatitis

As the number of patients with autoimmune pancreatitis (AIP) is increasing in Japan, practical guidelines for managing AIP need to be established. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee of moderators] were organized. Fifteen AIP specialists extracted specific clinical statements from a total of 871 articles in the literature using a PubMed search (1963–2008) and a secondary database, and developed the CQs and statements. The expert panelists individually rated these clinical statements using a modified Delphi approach in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. The professional committee developed 13, 6, 6, and 11 CQs and statements for the concept and diagnosis, extra-pancreatic lesions, differential diagnosis and treatment, respectively. The expert panelists regarded them as valid after two-round modified Delphi approaches. After evaluation by the moderators, the Japanese clinical guidelines for AIP were established. The digest versions of the present guidelines have been published in the official journal of the Japan Pancreas Society, “Pancreas.” Full versions divided into three series are scheduled to be published in the present and followings two issues in the Journal of Gastroenterology with approval of Professor Go VLW, the Editor-in-Chief of "Pancreas.”     

A proposal of a diagnostic algorithm with validation of International Consensus Diagnostic Criteria for autoimmune pancreatitis in a Japanese cohort

BackgroundAmong many diagnostic criteria for autoimmune pancreatitis (AIP), the International Consensus Diagnostic Criteria (ICDC) first enabled us to diagnose and compare type 1 and type 2 AIP, which permitted tailoring individual diagnostic algorithms depending on local expertise. We compared them and validated ICDC with special reference to levels 1 and 2, and proposed a diagnostic algorithm for AIP in Japan.MethodsThe diagnostic sensitivity of 5 major criteria (ICDC, Korean, Japanese-2011, Asian, and HISORt criteria) was compared, using 61 patients with AIP. Fifty six patients with pancreatic cancer served as a control. Pancreas imaging on computed tomography (CT) and endoscopic retrograde pancreatography (ERP) were independently evaluated by 3 pancreatologists (5, 10, and 20 years of career experience) and each diagnostic criterion of ICDC was validated with special reference to levels 1 and 2.ResultsThe sensitivities of 5 major criteria were 95.1% (ICDC), 90.2% (Korean), 86.9% (Japanese), 83.6% (Asian), and 83.6% (HISORt) with 100% of specificity in each. In the evaluation of pancreas imaging, diagnostic sensitivities of combination with CT and ERP in segmental/focal type AIP were significantly higher than single imaging (26% in CT (P < 0.01) or 35% in ERP (P < 0.05) vs 63% in CT + ERP), but not significantly different in the diffuse type.ConclusionsOf the 5 criteria, ICDC is the most sensitive and useful for diagnosing AIP. We have proposed a diagnostic algorithm with CT for the diffuse type of AIP, and combination with CT + ERP followed by EUS-FNA for the segmental/focal type.     

Long-term prognosis of autoimmune pancreatitis with and without corticosteroid treatment

Objectives

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis, and has a favourable response to corticosteroid treatment (CST). Little is known, however, about the long‐term outcome of AIP. This study aimed to document the prognosis without and with CST, and to examine the indication for CST.

Patients and methods

The prognosis and clinical features of 23 patients without CST and 19 patients treated with CST from onset were investigated. In addition, factors concerning the late occurrence of unfavourable events related to AIP were examined.

Results

The patients without CST were 19 men and four women, with an average age of 66 years. After an average observation period of 25 months, 16 patients (70%) developed unfavourable events including obstructive jaundice as a result of distal bile duct stenosis in four, growing pseudocyst in one, sclerogenic changes of extrapancreatic bile duct in nine, hydronephrosis as a result of retroperitoneal fibrosis in one, and interstitial nephritis in one. Patients with obstructive jaundice at onset showed a higher cumulative event occurrence rate (p = 0.025). The patients treated with CST were 16 men and three women, with an average age of 64 years. After an average observation period of 23 months, six patients (32%) developed unfavourable events consisting of interstitial pneumonia in three, and a recurrence of obstructive jaundice in three. In multivariate analysis, CST (HR 0.33, 95% CI 0.12–0.89, p = 0.029) and obstructive jaundice at onset (HR 3.09, 95% CI 1.14–8.32, p = 0.026) were significant predictive factors for unfavourable events.

Conclusion

CST could reduce AIP‐related unfavourable events. The early introduction of CST is recommended especially for patients with obstructive jaundice.     

Interferon-Gamma Treatment Accelerates and Aggravates Autoimmune Pancreatitis in the MRL/Mp-Mouse

Background: T helper 1 cell-released pro-inflammatory cytokines have been implicated in the pathogenesis of autoimmune pancreatitis (AIP), but the experimental database is small. Here, we have directly tested the effects of interferon-γ (IFN-γ) by applying it to AlP-prone MRL/Mp mice. Methods: MRL/Mp-mice were treated for 4 weeks with IFN-γ. Severity of AIP was assessed by histopathology, laboratory findings and gene expression analysis. Results: Using a histopathological score from 0 (healthy pancreas) to 4 (severe AIP), we found that IFN-γ treatment strongly increased severity of pancreatic lesions. IFN-γ also caused pancreatic accumulation of CD4-, CD8-, C11b- and CD138-positive cells, and enhanced pancreatic mRNA expression of interleukin (IL)-Iß, transforming growth factor-ß and IFN-γ itself. In the serum of IFN-γ-treated mice, higher lipase activities but normal glucose levels were observed. Discussion: IFN-γ accelerates and aggravates AIP in MRL/Mp mice. IFN-γ-enhanced AIP of MRL/Mp mice may serve to study pathophysiology, and to test diagnostic/therapeutic approaches.     

自身免疫性胰腺炎激素治疗的疗效及预后研究

目的 探讨自身免疫性胰腺炎(AIP)激素治疗的远期疗效、预后及激素治疗的给药方法.方法 分析2004年8月至2008年8月北京协和医院确诊并随访的13例AIP患者临床资料.结果 13例AIP患者中男12例、女1例,平均年龄58.7岁,平均随访30个月.合并胆管病变11例,其中9例放置胆管支架且均已取出.11例患者接受激素治疗,平均起始剂量为每日0.6 mg/kg.10例患者临床治愈,已停用激素,平均激素治疗时间为9.2个月,其中6例联合胆管支架置入者平均激素治疗时间为7.9个月,4例单纯激素治疗者则为13.4个月,差异有统计学意义(P=0.023).激素治疗后患者各血清学指标于5.3～8.8周内恢复正常.经激素治疗后第1次影像学复查时(1.0～11.3周)患者胰腺肿大均获改善,9例患者平均经16.6周激素治疗后胰腺大小恢复正常.随访期间所有患者无影像学胰腺炎复发表现.8例合并新发糖尿病的患者经激素治疗后4例血糖恢复正常.2例合并自身免疫性肝病患者随访结束时出现早期肝硬化表现.1例患者在停用激素6个月时颌下腺肿大复发.结论 AIP患者对激素治疗反应良好,放置胆管支架可缩短激素治疗时间,合并胆管病变及新发糖尿病者在激素治疗后部分可获缓解,但合并自身免疫性肝病者预后相对较差.     

Autoimmune pancreatitis, pancreatic mass, and lower gastrointestinal bleed.

Autoimmune pancreatitis (AIMP) is a recently described clinical entity causing chronic pancreatitis. It often presents with diffuse enlargement of the pancreas and/or a focal mass at the head of the pancreas causing common bile duct obstruction and jaundice. In most instances, AIMP is mistaken for pancreatic cancer. A number of laboratory abnormalities such as positive antinuclear antibody, hypergammaglobulinemia, and antibody to carbonic anhydrase are often present in these patients. Currently, pancreatic biopsy demonstrating characteristic histopathologic changes is essential to establish the diagnosis. We report the first case of AIMP presenting as a pancreatic tail mass and lower gastrointestinal bleed.     

International Consensus Guidelines for Risk Factors in Chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology,the American Pancreatic Association,the Japan Pancreas Society,and European Pancreatic Club

BackgroundChronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP.MethodsAn international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach’s alpha reliability coefficient.ResultsStrong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers.ConclusionsBoth genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.