Objective.Because it is uncertain whether immunoglobulin G4–related disease (IgG4-RD) is associated with malignancy, we evaluated the incidence of cancer development in a large cohort of patients with IgG4-RD.Methods.The study enrolled 158 patients diagnosed as having IgG4-RD between 1992 and 2012. We calculated the standardized incidence ratio (SIR) and cumulative rate of malignancies in this group and searched for risk factors associated with the occurrence of tumors.Results.A total of 34 malignancies were observed in the patients with IgG4-RD over a mean followup period of 5.95 ± 4.48 years. The overall SIR of malignancies was 2.01 (95% CI 1.34–2.69). The SIR of patients who exhibited a tumor within 1 year after IgG4-RD diagnosis was 3.53 (95% CI 1.23–5.83), while that of subjects forming a malignancy in subsequent years was 1.48 (95% CI 0.99–1.98). The cumulative rate of malignancy development was significantly higher in patients with IgG4-RD within 12 years after diagnosis than in the Japanese general population. Comparable results were obtained for an autoimmune pancreatitis subgroup. The serum concentrations of several disease activity markers at diagnosis were significantly higher in patients with malignancies than in those without.Conclusion.We identified a close association between IgG4-RD and malignancy formation within 12 years after diagnosis, particularly during the first year. An active IgG4-RD state is presumed to be a strong risk factor for malignancy development.

Autoimmune pancreatitis (AIP) has been recognized as a distinct type of pancreatitis that is possibly caused by autoimmune mechanisms. AIP is characterized by high serum IgG4 and IgG4-positive plasma cell infiltration in affected pancreatic tissue. Acute phase AIP responds favorably to corticosteroid therapy and results in the amelioration of clinical findings. However, the long-term prognosis and outcome of AIP remain unclear. We have proposed a working hypothesis that AIP can develop into ordinary chronic pancreatitis resembling alcoholic pancreatitis over a long-term course based on several clinical findings, most notably frequent pancreatic stone formation. In this review article, we describe a series of study results to confirm our hypothesis and clarify that: 1) pancreatic calcification in AIP is closely associated with disease recurrence; 2) advanced stage AIP might have earlier been included in ordinary chronic pancreatitis; 3) approximately 40% of AIP patients experience pancreatic stone formation over a long-term course, for which a primary risk factor is narrowing of both Wirsung’s and Santorini’s ducts; and 4) nearly 20% of AIP patients progress to confirmed chronic pancreatitis according to the revised Japanese Clinical Diagnostic Criteria, with independent risk factors being pancreatic head swelling and non-narrowing of the pancreatic body duct.

Objectives. The recent International Consensus Diagnostic Criteria (ICDC) for autoimmune pancreatitis (AIP) and its Japanese amendment developed by the Japanese Pancreas Society (JPS 2011) may have overcome the drawbacks of earlier criteria and achieved a higher diagnostic ability for AIP. The aim of the present study is to evaluate this possibility and identify the underlying causes of this change. Methods. We compared the diagnostic abilities of the ICDC and JPS 2011 with those of the Japanese diagnostic criteria 2006 (JPS 2006), Korean diagnostic criteria (Korean), Asian diagnostic criteria (Asian), and HISORt diagnostic criteria in 110 patients with AIP and 31 patients with malignant pancreatic cancer. Results. The ICDC achieved the highest diagnostic ability in terms of accuracy (95.0%), followed by JPS 2011 (92.9%), Korean (92.2%), HISORt (88.7%), Asian (87.2%), and JPS 2006 (85.1%). Nearly all criteria systems exhibited a high specificity of 100%, indicating that the enhanced diagnostic ability of the ICDC and JPS 2011 likely stemmed from increased sensitivity brought about by inclusion of diagnostic items requiring no endoscopic retrograde pancreatography. The diagnostic ability of JPS 2011 was nearly equivalent to that of the ICDC. Conclusions. The ICDC and JPS 2011 have improved diagnostic ability as compared with earlier criteria sets because of an increase in sensitivity.

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Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterized by high serum IgG4 concentration and a variety of complicating extra-pancreatic lesions. In particular, lachrymal/salivary gland lesions tend to manifest in a highly active AIP disease state, and several genes are speculated to be associated with the onset of this complication. We therefore searched for candidate susceptibility genes related to lachrymal/salivary gland lesions in a genome-wide association study (GWAS) with the GeneChip Human Mapping 500k Array Set (Affymetrix, CA) that was followed by fine mapping of additional single nucleotide polymorphisms (SNPs) in strongly significant genes with TaqMan assays. Venous blood samples were obtained from 50 type 1 AIP patients with lachrymal/salivary gland lesions (A group) and 53 type 1 AIP patients without (B group). The mean values of IgG and IG4 were both significantly different (P<0.05) between the groups. SNPs that showed a significant association with the A group at the genome-wide level (P<0.0001) were identified and subsequently used in fine SNP mapping of candidate genes. In total, five SNPs had a positive association with complicated AIP (most notably rs2284932 [P=0.0000021]) and five SNPs possessed a negative association (particularly rs9371942 [P=0.00000039]). Among them, KLF7, FRMD4B, LOC101928923, and MPPED2 were further examined for complication susceptibility using additional SNPs that were not included in the GWAS. Individual genotyping of KLF7 rs2284932 revealed that the frequency of the minor C allele was significantly increased (P=0.00062, Pc=0.0018, OR=2.98, 95%CI=1.58-5.65) in group A. The minor T allele of rs4473559 in FRMD4 demonstrated a significant association in the A group (P=0.00015, OR=3.38, 95%CI=1.77-7.65). In the LOC101928923 gene, the frequency of the minor C allele of rs4379306 was significantly decreased in group A in both TaqMan and GWAS analyses. Lastly, the minor C allele of MPPED2 rs514644 carried a significantly increased risk of complications. These four genes may be linked with the onset of lachrymal/salivary gland lesions in type 1 AIP patients and require further study.

BackgroundAlthough most patients with autoimmune pancreatitis (AIP) respond favorably to prednisolone therapy, some individuals who later suffer from pancreatic calculi may require additional extracorporeal shock wave lithotripsy (ESWL) treatment. This study compares the efficacy of ESWL for calculi in AIP with that in ordinary chronic pancreatitis (CP) and proposes a new treatment approach for pancreatic duct stones occurring in AIP.MethodsWe examined the clinical records of 8 patients with chronic stage AIP and 92 patients with ordinary CP who received ESWL for pancreatic calculi.ResultsThe AIP group was significantly older than the CP group (69.0 vs. 56.5 years, P = 0.018). With regard to the indications for ESWL, chronic pain was significantly less frequent in the chronic stage AIP group (0% vs. 45.7%, P = 0.001), whereas preservation of pancreatic function was significantly more frequent (75% vs. 19.6%, P = 0.001). Compared with the CP group, the AIP group tended to exhibit pancreatic duct stenosis proximal to pancreatic calculi and had a lower rate of complete extraction of stones from the main pancreatic duct. Histopathological analysis of a patient with chronic stage AIP revealed widely distributed nodular pancreatitis, which was characteristic of ordinary CP, along with isolated areas of lymphoplasmacytic sclerosing pancreatitis.ConclusionsDifferent approaches are needed for the treatment of pancreatic calculi in chronic stage AIP and ordinary CP. Specifically, it appears that intensive ESWL therapy can be avoided or delayed in AIP if the patient displays: (1) advanced age, (2) little or no chronic pain or pancreatitis, and (3) pancreatic duct stenosis proximal to pancreatic stones. In such cases, the benefit of ESWL treatment may be outweighed by the risks involved in this procedure.

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Type 1 autoimmune pancreatitis (AIP) is characterized by a high serum IgG4 concentration and is closely associated with the HLA-DRB1 * 04:05-DQB1 * 04:01 haplotype, for which family studies may disclose its immunogenetic significance. In the present study, we encountered two male siblings with type 1 AIP who exhibited diffuse pancreatic swelling with a capsule-like rim and diffuse pancreatic duct stricture. The younger brother also displayed characteristic IgG4-related sialadenitis and retroperitoneal fibrosis. Contrary to our expectations, the siblings showed only normal or slightly elevated values of serum IgG4 and no HLA DRB1 * 04: 05-DQB1 * 04:01 haplotype, suggesting that type 1 autoimmune pancreatitis is associated with multiple immunogenetic factors.