The levels of IL-1ß and soluble IL-1 receptors in patients with IgG4-related periaortitis/periarteritis.

PURPOSE: IgG4-related disease (IgG4-RD) is a chronic fibrotic inflammatory and an immune-mediated disease characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system, and its pathogenesis and characteristics remain unclear. The inflammatory cytokine IL-1ß is involved in a variety of cellular activities including inflammation, fibrosis, and angiogenesis. The present study compared the levels of the inflammatory cytokine IL-1ß and two soluble IL-1 receptors, IL-1R1 and IL-1R2, between IgG4-RD patients with and without IgG4-related periaortitis/periarteritis. METHODS: The patients with IgG4-related periaortitis/periarteritis (n â€‹= â€‹38), those without (n â€‹= â€‹66) and healthy (n â€‹= â€‹33) were recruited to measure cytokines of IL-1ß and soluble receptors (sIL-1R1 and sIL-1R2) in sera by ELISA assay. RESULTS: Serum IgG4 was significantly higher in patients with periaortitis/periarteritis compared to non-periaortitis/periarteritis (p â€‹= â€‹0.0074), while serum IL-1ß was significantly lower in patients with periaortitis/periarteritis (p â€‹= â€‹0.00037). The three groups did not show significant difference in sIL1-R1, while sIL-1R2 in the periaortitis/periarteritis and healthy group was higher than in the group without periaortitis/periarteritis (p â€‹= â€‹0.00001). CONCLUSIONS: The characteristic changes in IL-1ß, sIL-1R1, and sIL-1R2 levels in IgG4-RD patients with and without IgG4-related periaortitis/periarteritis may indicate an active phase of the inflammatory process in these diseases.

The differential diagnosis of IgG4-related disease based on machine learning.

INTRODUCTION: To eliminate the disparity and maldistribution of physicians and medical specialty services, the development of diagnostic support for rare diseases using artificial intelligence is being promoted. Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a rare disorder often requiring special knowledge and experience to diagnose. In this study, we investigated the possibility of differential diagnosis of IgG4-RD based on basic patient characteristics and blood test findings using machine learning. METHODS: Six hundred and two patients with IgG4-RD and 204 patients with non-IgG4-RD that needed to be differentiated who visited the participating institutions were included in the study. Ten percent of the subjects were randomly excluded as a validation sample. Among the remaining cases, 80% were used as training samples, and the remaining 20% were used as test samples. Finally, validation was performed on the validation sample. The analysis was performed using a decision tree and a random forest model. Furthermore, a comparison was made between conditions with and without the serum IgG4 concentration. Accuracy was evaluated using the area under the receiver-operating characteristic (AUROC) curve. RESULTS: In diagnosing IgG4-RD, the AUROC curve values of the decision tree and the random forest method were 0.906 and 0.974, respectively, when serum IgG4 levels were included in the analysis. Excluding serum IgG4 levels, the AUROC curve value of the analysis by the random forest method was 0.925. CONCLUSION: Based on machine learning in a multicenter collaboration, with or without serum IgG4 data, basic patient characteristics and blood test findings alone were sufficient to differentiate IgG4-RD from non-IgG4-RD.

IL1R1 gene variants associate with disease susceptibility to IgG4-related periaortitis/periarteritis in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated disorder characterized by high serum IgG4 concentration and IgG4-bearing plasma cell infiltration in affected organs. IgG4-related periaortitis/periarteritis is a recently identified disease entity in IgG4-RD that affects the cardiovascular system. Since the genetic factors related to disease onset are unclear, we examined the genetic associations with IgG4-related periaortitis/periarteritis susceptibility. METHODS: A small scale of genome-wide association analysis identified that interleukin 1 receptor type 1 (IL1R1) gene variants were correlated with the development of IgG4-related periaortitis/periarteritis in 75 patients with IgG4-RD. Accordingly, 8 single nucleotide polymorphisms (SNPs) in the IL1R1 gene were selected and genotyped in 124 patients with IgG4-RD (43 with periaortitis/periarteritis and 81 without periaortitis/periarteritis) and 344 healthy subjects. RESULTS: The minor allele frequencies of 6 SNPs (rs2287049, rs3917273, rs2160227, rs951192, rs3917318, rs7582198) were significantly increased in IgG4-related periaortitis/periarteritis patients compared with those without periaortitis/periarteritis (corrected P < 0.05). In addition, the frequency of the AGAAA haplotype, comprised of 5 SNPs (rs3917273, rs2160227, rs951192, rs3917318, rs7582198), was significantly higher in patients with periaortitis/periarteritis (OR = 2.41, 95% CI:1.42-4.10). CONCLUSION: Our findings indicated that IL1R1 genetic polymorphisms contributed to IgG4-related periaortitis/periarteritis and the possibility of certain genetic factors influencing the risk of specific IgG4-RD manifestations.

Cut-off values of serum IgG4 among three reagents, including a novel IgG4 reagent: a multicenter study.

Elevated serum IgG4 is a useful marker of IgG4-related disease (IgG4-RD) activity. However, there is no uniformity in the cut-off values of IgG4 among the various reagents. The aim of this study was to compare the measured and cut-off values of IgG4 assessed using three different reagents. This study enrolled 466 IgG4-RD and non-IgG4-RD patients who required measurement of serum IgG4 levels to diagnose or treat IgG4-RD. Serum IgG4 was measured using three reagents: N-assay LA IgG4 Nittobo (Nittobo), BS-NIA IgG4 (TBS), and N Latex IgG4 (Siemens). The values obtained using the three reagents were compared, and cut-off values were calculated for each. Although there was good correlation among the results with the three reagents, the measured and cut-off values were all different. The Nittobo values were 1.4 times the TBS values and the TBS values were almost half those of the Siemens values. ROC curve analysis showed cut-off values for the Nittobo, TBS, and Siemens reagents of 1.42, 1.31, and 2.38 g/L, respectively. The measured and cut-off values of serum IgG4 vary depending on the reagents used for the assay, although there is good correlation among the values measured by the three reagents.

Immunostaining With Immunoglobulin G Subclass Antibody Cocktail for Diagnosis of Type 1 Autoimmune Pancreatitis.

BACKGROUND.: Immunoglobulin (Ig) G4-related diseases (RDs) are systemic diseases in which serum IgG4 levels are frequently elevated. They can cause diffuse or focal tumor formation, organ swelling, and tissue thickening in organs infiltrated by IgG4+ plasma cells. The diagnostic criteria for IgG4-RDs include an IgG4/IgG ratio >40%, but counting IgG+ cells can be difficult because of the weakness of IgG staining density. We hypothesized that an antibody cocktail of mixed IgG1, IgG2, IgG3, and IgG4 (AC-IgG) might give immunohistochemistry results comparable with those of IgG in IgG4-RD. METHODS.: We compared AC-IgG reactivity with IgG expression in type 1 autoimmune pancreatitis (AIP), a representative IgG4-RD. We compared immunohistochemistry results using AC-IgG and IgG-only in 10 cases of AIP. The coefficient of variation (Cv) was used to analyze differences between AC-IgG and IgG findings in AIP by 13 board-certified pathologists. RESULTS.: Although mean values for IgG+ cells did not significantly differ between AC-IgG (34.3; range = 27.4-37.1) and IgG (30.0; range = 23.0-45.6; P = .6254), Cv was lower for AC-IgG (33.4%) than for IgG (51.4%; regression equation; y[IgG] = 0.988x + 0.982; correlation coefficient = 0.907). The data showed that the results of both methods were largely consistent. CONCLUSION.: AC-IgG could replace IgG to count IgG+ cells because of its lower Cv.

A comparison of the features of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) between IgG4-related disease with bilateral hilar lymphadenopathy and sarcoidosis.

We aimed to show the differentiation of the degree and distribution on Fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) between patients with immunoglobulin G4-related disease (IgG4-RD) and sarcoidosis, though both diseases frequently show bilateral hilar lymphadenopathy (BHL). The clinical records were retrospectively reviewed in 25 patients with IgG4-RD with BHL and 15 patients with sarcoidosis (stage I-II) diagnosed at Shinshu University Hospital. All patients underwent FDG-PET at Aizawa Hospital from January 2004 to December 2015. The FDG accumulation pattern and maximum standardized uptake value (SUVmax) of the hilar lymph nodes were compared between the two groups. The IgG4-RD group (21 men; median age 69 years) showed a significant male predominance and older age compared with the sarcoidosis group (3 men, median age 55.4 years). The IgG4-RD group showed a significantly higher incidence of FDG accumulation in the lachrymal gland, submandibular gland, pancreas, prostate and periurethral and periarterial regions compared with the sarcoidosis group. In contrast, the sarcoidosis group showed a significantly higher incidence of FDG accumulation in the supraclavicular and abdominal lymph nodes, muscle and soft tissues compared with the IgG4-RD group. Furthermore, the SUVmax of the hilar lymph nodes was significantly higher in the sarcoidosis group (median 7.20) than in the IgG4-RD group (median 4.20, p=0.002). In conclusion, significant differences were observed in the FDG accumulation patterns and SUVmax values of the hilar lymph nodes between IgG4-RD with BHL and sarcoidosis, although both diseases develop through the lymphatic routes of the lungs and are frequently associated with BHL.

Impaired expression of innate immunity-related genes in IgG4-related disease: A possible mechanism in the pathogenesis of IgG4-RD.

Background: IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. The pathogenesis of this disease is not clear. Transcriptome analysis was performed to identify genes over- and under-expressed in patients with IgG4-RD.Method: DNA microarray analysis was performed using RNA from peripheral blood mononuclear cells of two patients with IgG4-RD and four healthy individuals. Genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy were identified. Four genes related to innate immunity such as transcobalamin I (TCN1), secretory leukocyte peptidase inhibitor (SLPI), bactericidal/permeability-increasing protein (BPI) and lactotransferrin (LTF) were assessed by real-time PCR in 15 IgG4-RD patients and 13 healthy individuals.Result: DNA microarray analysis identified 30 genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy. Real-time RT-PCR showed that the levels of mRNAs encoding TCNI and SLPI, except for BPI and LTF, were significantly lower in patients with IgG4-RD than in healthy people. The levels of all four mRNAs in patients with IgG4-RD were significantly increased after steroid treatment.Conclusion: These results indicate that reduction in expression of innate immunity-related genes may participate in the pathogenesis of IgG4-RD that steroid treatment may rectify impaired innate immunity as well as acquired immunity.

Evaluation of a novel serum IgG4 assay and determination of reference interval for the Japanese population.

BACKGROUND: IgG4-related disease (IgG4-RD) is a new syndrome characterized by elevated serum IgG4 concentration and tissue infiltration of IgG4-positive plasma cells. Here, we evaluated the analytical performance of a new IgG4 assay reagent featuring a wide dynamic range, highly specific monoclonal antibody, and the reversed passive latex agglutination assay and determined the IgG4 reference interval (RI) for the Japanese population. METHODS: Performance evaluations were conducted on precision, linearity, sensitivity, interference, and method comparison with The Binding Site (TBS) and Siemens reagents. The RI was derived by the parametric method from 619 apparently healthy Japanese 18 to 65 years of age. RESULTS: Between-day precisions ranged from 1.99 to 5.52 CV%. Linearity was confirmed up to 5.0 g/l. The limit of quantitation was 0.085 g/l. Interfering substances did not significantly influence values. Method comparison among the 3 reagents yielded correlation coefficients between 0.973 and 0.988. Values for the new reagent matched those of TBS reagent except at a higher concentration range, where reactivity dissociated. The RI was 0.11-1.21 g/l without distinction by sex and age. CONCLUSION: The novel IgG4 assay reagent demonstrated satisfactory analytical performance for clinical use. Because of matched value with TBS reagent at low concentrations, it is possible to use the IgG4-RD cut-off value determined by TBS reagent.

Validity and safety of endoscopic biliary stenting for biliary stricture associated with IgG4-related pancreatobiliary disease during steroid therapy.

Background Patients with IgG4-related sclerosing cholangitis and autoimmune pancreatitis frequently develop obstructive jaundice, which requires endoscopic biliary stenting (EBS) during steroid therapy to prevent bile duct infection from cholestasis and adverse steroid effects. However, it is controversial whether EBS during steroid therapy is advisable, because the procedure itself carries a risk of cholangitis and procedure-related adverse events. This study aimed to clarify the validity and safety of EBS for patients with biliary stricture associated with IgG4-related pancreatobiliary disease (IgG4-PBD) during steroid therapy. Methods We enrolled 59 patients who presented with biliary stricture exhibiting jaundice or liver dysfunction and who were treated with EBS. The incidences of recurrent biliary obstruction and acute cholangitis were compared for EBS cases with and without steroid administration. Results EBS was present in 55 periods with steroid administration and 110 periods without. The incidence of recurrent biliary obstruction was significantly lower in cases with steroids than in those without (1-month no obstruction rate: 100 % vs. 82 %; log-rank test P  = 0.0015). The incidence of acute cholangitis related to stenting was significantly lower in cases with steroids than in those without (1-month no acute cholangitis rate: 100 % vs. 90 %; log-rank test P  = 0.0278). Biliary stents could be removed without acute cholangitis, liver dysfunction, or stent replacement in 96 % of patients who underwent endoscopic retrograde cholangiopancreatography 1 month after commencing steroid administration. Conclusions EBS during steroid administration was both valid and safe in patients with biliary stricture associated with IgG4-PBD. Stents could be safely removed 1 month after steroid initiation.

Effectiveness of steroid therapy for pancreatic cysts complicating autoimmune pancreatitis and management strategy for cyst-related complications.

Objectives: Autoimmune pancreatitis (AIP) sometimes becomes complicated with pancreatic cysts, although their detailed characteristics and management strategy have not been fully determined. We aimed to clarify the efficiency of steroid therapy and the risk factors for cyst formation and cyst-related complications. Methods: One hundred sixty-three AIP patients were retrospectively analyzed for relevant factors of cyst formation. We compared subjects with and without steroids to evaluate drug effectiveness on cyst size change and investigated the factors associated with cyst-related complications. Results: Thirty-two patients (19.6%) had complicating pancreatic cyst formation, and 40 cystic lesions of ≥10 mm in size were detected. Multivariate analysis revealed a drinking habit, abdominal/back pain, and elevated serum amylase to be significantly associated with cyst formation. Steroid-treated cysts became significantly reduced in size in the short-term and disappeared significantly more frequently within 1-year as compared with non-treated ones, which was confirmed by multivariate analysis. Six of 40 cysts exhibited cyst-related complications significantly associated with multilocular morphology and larger size. Conclusions: Steroid therapy is an effective choice for cysts developing in AIP to promote the release of pancreatic juice stasis. Larger lesions with multilocular morphology should be monitored closely for cyst-related complications and be considered strong candidates for steroid therapy.

Comparison of the chemokine profiles in the bronchoalveolar lavage fluid between IgG4-related respiratory disease and sarcoidosis: CC-chemokine ligand 1 might be involved in the pathogenesis of sarcoidosis.

BACKGROUND: We previously reported that the cytokine profiles in the bronchoalveolar lavage fluid (BALF) of IgG4-related respiratory disease (IgG4-RRD) more closely resemble the T-helper (Th) 2 response than sarcoidosis. The present study aimed to assess the chemokines in the BALF of IgG4-RRD and sarcoidosis in order to evaluate any possible associations between these chemokines and other markers. METHODS: We examined 12 chemokines using a MILLIPLEX® MAP Kit (Millipore, Darmstadt, Germany) in the same BALF samples of the same 44 patients (IgG4-RRD, n = 11; sarcoidosis, n = 33) in which we had previously evaluated the cytokines. RESULTS: The levels of CC-chemokine ligand (CCL)26 in the BALF of IgG4-RRD patients (median 24.5, range 3.1-401.1 pg/mL) were significantly higher than those in the BALF of sarcoidosis patients (median 3.1, range 3.1-155.6 pg/mL, p < 0.05). Interestingly, the BALF levels of CCL1 in the sarcoidosis patients (median 13.1, range 0.1-106.9 pg/mL) were significantly higher than those of the IgG4-RRD patients (median 9.8, range 0.1-14.7 pg/mL, p < 0.05). Furthermore, the CCL1 levels in the BALF were correlated with the total cell count (ρ = 0.539, p < 0.001), lymphocyte fraction (R = 0.406, P < 0.05), lymphocyte count (R = 0.686, P < 0.001), TNF-α level, (R = 0.748, P < 0.001), and IL-2 level (R = 0.757, P < 0.001) in the BALF of sarcoidosis patients. CONCLUSIONS: CCL1 might reflect disease activity and its involvement in the pathogenesis of sarcoidosis might be more closely related to Th1 than to Th2.

Predictive Factors for Autoimmune Pancreatitis Relapse After 3 Years of Maintenance Therapy.

OBJECTIVES: Oral corticosteroid treatment is the standard therapy for autoimmune pancreatitis (AIP) and is highly effective. However, relapse may occur during maintenance therapy (MT). We aimed to clarify the predictive factors for relapse after 3 years of MT for use in deciding on the continuation of long-term MT. METHODS: Among 56 retrospectively recruited AIP patients who received corticosteroid remission induction therapy followed by MT for a minimum of 5 years, 38 subjects were enrolled after exclusion criteria and divided into the relapse group of patients who experienced relapse after 3 years of MT and the nonrelapse group of patients who did not. RESULTS: According to multivariate analysis, at least 4 other organ involvement numbers at diagnosis (hazard ratio, 5.82; 95% confidence interval, 1.203-28.192) and IgG of 1400 mg/dL or greater at 3 years of MT (hazard ratio, 4.41; 95% confidence interval, 1.096-17.790) were predictive factors for relapse after MT for 3 years, with patients exhibiting both predictive factors having a higher cumulative relapse rate than those with 1 or fewer predictive factor. CONCLUSIONS: We uncovered 2 predictive factors for AIP relapse after 3 years of MT. These findings will assist in deciding corticosteroid therapy regimens at 3 years of MT to minimize AIP relapse risk and adverse corticosteroid effects.

Promoter hypomethylation of SKI in autoimmune pancreatitis.

The relationship between methylation abnormality and autoimmune pancreatitis (AIP)-a representative IgG4-related disease-has not yet been elucidated. We identified SKI might have a significant methylation abnormality in AIP through methylation array analysis using the Illumina Infinium Human Methylation 450K BeadChip array, and investigated the relationship of SKI with AIP clinicopathological features. The methylation rate of SKI was assessed by quantitative SYBR green methylation-specific PCR, and the degree of SKI expression in tissue specimens was assessed by immunohistochemistry in 10 AIP cases, 14 cases of obstructive pancreatitis area in pancreatic ductal adenocarcinoma (PDA) without a history of AIP, and 9 normal pancreas (NP) cases. The SKI methylation ratio was significantly lower in AIP than in PDA and NP. Additionally, the immunohistochemical staining-index (SI) score for SKI was significantly higher in AIP than NP, although there was no significant difference between AIP and PDA. There was a strong negative correlation between SI score and SKI methylation ratio, and between the serum concentrations of IgG4 and the SKI methylation ratio. There was a moderate positive correlation between the serum concentrations of IgG4 and SI. SKI is thought to be an oncogene indicating that SKI hypomethylation and carcinogenesis might be linked to AIP. Furthermore, the correlation between serum concentrations of IgG4 and SKI methylation levels suggest SKI might be involved in the pathogenesis of AIP. However, the role of SKI has not been clearly elucidated. Further studies are needed to understand further the function of SKI.

Immunoglobulin G4-related dacyroadenitis presenting as bilateral chorioretinal folds from severely enlarged lacrimal glands.

PURPOSE: To describe a case of immunoglobulin G4 (IgG4)-related dacyroadenitis presenting as bilateral chorioretinal folds from eyeball compression by massively enlarged lacrimal glands. OBSERVATIONS: A 51-year-old woman with severely enlarged bilateral lacrimal glands was diagnosed as having IgG4-related dacryoadenitis. The glands strongly compressed the globes, forming chorioretinal folds resembling those found in orbital malignancy. Eventual treatment with oral prednisolone dramatically reduced the volume of the lacrimal glands and released globe compression on magnetic resonance imaging. However, the chorioretinal folds remained in the right fundus and symptoms of blurred vision improved but persisted. CONCLUSIONS AND IMPORTANCE: This is the first account of chorioretinal fold formation by severely enlarged lacrimal glands appearing in IgG4-related dacryoadenitis. Chorioretinal fold formation by an enlarged lacrimal gland occurring bilaterally may represent a basis for suspecting IgG4-related dacryoadenitis. Prompt treatment is recommended for patients presenting with very large lacrimal glands to avoid visual impairment.

IgG4-related Disease - A Systemic Disease that Deserves Attention Regardless of One's Subspecialty.

IgG4-related disease (IgG4-RD) is an inflammatory condition characterized by a high serum IgG4 concentration and the abundant infiltration of lymphocytes and IgG4-positive plasma cells in the tissue, as well as spatial (diverse clinical manifestations) and temporal (the possibility of recurrence) multiplicities. Since the initial documentation of IgG4-related disease in patients with autoimmune pancreatitis in 2001, a growing body of evidence has been accumulating to suggest that various-virtually all-organs can be affected by IgG4-RD. In general, steroid therapy is effective and is considered to be the first-line treatment for IgG4-RD. The precise mechanism underlying this systemic disorder has remained unknown. Considering that IgG4-RD was specified as being an intractable disease in 2015, further studies are needed to clarify whether IgG4-RD is indeed a distinct disease entity or a complex of disorders of different etiologies and clinical conditions.

Clinical features of IgG4-related periaortitis/periarteritis based on the analysis of 179 patients with IgG4-related disease: a case-control study.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic condition characterized by high serum immunoglobulin G4 (IgG4) concentration and IgG4-bearing plasma cell infiltration in affected organs. Although it has become evident that IgG4-RD also involves the systemic aortic/arterial system, the precise details of this condition remain unclear. The present study sought to clarify the clinical features of IgG4-related periaortitis/periarteritis. METHODS: Among 223 patients with IgG4-RD, 179 (131 male, median onset age 67 years) were recruited for this study. Periaortitis/periarteritis was defined as vessel wall thickness with circumferential enhancement on contrast-enhanced computed tomography. RESULTS: Periaortitis/periarteritis was identified in 65 (36.3%; 53 male) of 179 IgG-RD patients. The distribution of IgG4-related periaortitis/periarteritis could be broadly classified into five types, with the most prevalent Type 2 (44.6%) being localized at the infra-renal artery portion of the abdominal aorta and continuing to the iliac arteries. The infra-renal artery region of the abdominal aorta was most frequently involved (>80%) among IgG4-related periaortitis/periarteritis cases. Comparisons of clinical parameters between IgG4-RD patients with and without periaortitis/periarteritis revealed significantly higher propensities for older IgG4-RD onset age and highly active disease state featuring elevated serum IgG, IgG4, circulating immune complex, and soluble interleukin-2 receptor. All patients showed improvement of wall thickening after steroid therapy, although nine patients (20.9%) exhibited worsening of luminal dilatation. The main risk factor for this manifestation was prior luminal dilatation according to multivariate analysis. CONCLUSION: IgG4-related periaortitis/periarteritis predominantly occurred at the infra-renal artery portion of the abdominal aorta, affected older IgG4-RD onset patients, and was prevalent in highly active disease states. As reported previously, the main risk factor for worsening luminal dilation after corticosteroid therapy was the existence of luminal dilation beforehand.

Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single-nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio (OR)=0.68; corrected P=0.025). Haplotype 2 (rs2238154 A, rs11065904 T and rs739496 G) was associated with resistance to AIH (OR 0.67, P=0.021) as well as to autoimmune pancreatitis (OR=0.70, P=0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.

Usefulness of three-dimensional magnetic resonance cholangiopancreatography with partial maximum intensity projection for diagnosing autoimmune pancreatitis.

PURPOSE: To compare three-dimensional magnetic resonance cholangiopancreatography (MRCP) with/without partial maximum intensity projection (MIP) and endoscopic retrograde cholangiopancreatography (ERCP) in patients with autoimmune pancreatitis (AIP). MATERIALS AND METHODS: Three-dimensional MRCP and ERCP images were retrospectively analyzed in 24 patients with AIP. We evaluated the narrowing length of the main pancreatic duct (NR-MPD), multiple skipped MPD narrowing (SK-MPD), and side branches arising from the narrowed portion of the MPD (SB-MPD) using four MRCP datasets: 5 original images (MIP5), 10 original images (MIP10), all original images (full-MIP), and a combination of these three datasets (a-MIP). The images were scored using a 3- or 5-point scale. The scores of the four MRCP datasets were statistically analyzed, and the positive rate of each finding was compared between MRCP and ERCP. RESULTS: The median scores for SB-MPD on MIP5 and a-MIP were significantly higher than those on MIP10 and full-MIP. In other words, partial MIP is superior to full-MIP for visualization of detailed structures. The positive rate for SB-MPD on full-MIP was significantly lower than that on ERCP, whereas the positive rate on MIP5, MIP10, and a-MIP was not significantly different from that on ERCP. Moreover, the positive rate for NR-MPD and SK-MPD on the MRCP images was significantly higher than that on the ERCP images. CONCLUSION: Partial MIP is useful for evaluating the MPD and is comparable with ERCP for diagnosing AIP.

Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis.

OBJECTIVES: Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP. METHODS: Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing. RESULTS: Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP. CONCLUSIONS: These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis.

OBJECTIVE: Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP. DESIGN: We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5-7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis. RESULTS: Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed. CONCLUSIONS: Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks. TRIAL REGISTRATION NUMBER: UMIN000001818; Results.