Background Sclerosing pancreatitis is a unique form of pancreatitisthat is characterized by irregular narrowing of the main pancreaticduct, lymphoplasmacytic inflammation of the pancreas, and hypergammaglobulinemiaand that responds to glucocorticoid treatment. Preliminary studiessuggested that serum IgG4 concentrations are elevated in thisdisease but not in other diseases of the pancreas or biliarytract.
Methods We measured serum IgG4 concentrations using single radialimmunodiffusion and an enzyme-linked immunosorbent assay in20 patients with sclerosing pancreatitis, 20 age- and sex-matchednormal subjects, and 154 patients with pancreatic cancer, ordinarychronic pancreatitis, primary biliary cirrhosis, primary sclerosingcholangitis, or Sjögren's syndrome. Serum concentrationsof immune complexes and the IgG4 subclass of immune complexeswere determined by means of an enzyme-linked immunosorbent assaywith monoclonal rheumatoid factor.
Results The median serum IgG4 concentration in the patientswith sclerosing pancreatitis was 663 mg per deciliter (5th and95th percentiles, 136 and 1150), as compared with 51 mg perdeciliter (5th and 95th percentiles, 15 and 128) in normal subjects(P<0.001). The serum IgG4 concentrations in the other groupsof patients were similar to those in the normal subjects. Inpatients with sclerosing pancreatitis, serum concentrationsof immune complexes and the IgG4 subclass of immune complexeswere significantly higher before glucocorticoid therapy thanafter four weeks of such therapy. Glucocorticoid therapy inducedclinical remissions and significantly decreased serum concentrationsof IgG4, immune complexes, and the IgG4 subclass of immune complexes.
Conclusions Patients with sclerosing pancreatitis have highserum IgG4 concentrations, providing a useful means of distinguishingthis disorder from other diseases of the pancreas or biliarytract.
In developed countries, most patients with chronic pancreatitishave a long history of alcohol abuse. Alcohol-induced chronicpancreatitis is characterized by recurrent attacks of abdominalpain, irregular dilatation of the pancreatic duct with stoneformation, atrophy of the pancreatic parenchyma, and pancreaticexocrine and endocrine insufficiency. A unique form of chronicpancreatitis characterized by infrequent attacks of abdominalpain, irregular narrowing of the pancreatic duct, and swellingof the pancreatic parenchyma has been described. It has beenreferred to as sclerosing pancreatitis,1 primary inflammatorypancreatitis,2,3 lymphoplasmacytic sclerosing pancreatitis,4autoimmune pancreatitis,5,6,7,8 chronic pancreatitis with diffuseirregular narrowing of the main pancreatic duct,9 and sclerosingpancreaticocholangitis.10 Sclerosing pancreatitis, the termused in this article, is associated with lymphoplasmacytic inflammationof the pancreas and hypergammaglobulinemia and responds to glucocorticoidtreatment. It can be mistaken for pancreatic cancer on endoscopicretrograde cholangiopancreatography or other imaging studies.1,4,5,7,9,10The clinicopathologic features of sclerosing pancreatitis mimicthose of pancreatitis associated with Sjögren's syndrome,primary biliary cirrhosis, and primary sclerosing cholangitis.11,12,13,14,15
We previously found that the serum of some patients with sclerosingpancreatitis had a polyclonal band in the rapidly migratingfraction of gamma globulins. Immunoprecipitation assays confirmedthat this band was caused by a high serum concentration of theIgG4 fraction of gamma globulins. IgG4 is the rarest of theIgG subclasses and accounts for only 3 to 6 percent of totalIgG in the serum of normal subjects. It is unique among theIgG subclasses in its inability to bind Clq complement and,therefore, activate the classic pathway of complement16 andin its low affinity for target antigen. Because high serum IgG4concentrations are found in only a limited number of conditions,such as atopic dermatitis,17 some parasitic diseases,18 andpemphigus vulgaris and pemphigus foliaceus,19 we sought to determinewhether serum IgG4 concentrations are high in patients withsclerosing pancreatitis but not in patients with other diseasesof the pancreas or biliary tract.
Methods
Study Subjects
Between September 1994 and February 1999, we obtained serumsamples from 20 patients with sclerosing pancreatitis, 15 menand 5 women, who were 38 to 73 years of age (mean [±SD]age, 61± 11). We also obtained serum samples from 20age- and sex-matched normal subjects and 45 patients with ordinarychronic pancreatitis (alcoholic in 36 cases and idiopathic in9 cases), 70 patients with pancreatic cancer, 20 patients withprimary biliary cirrhosis, 8 patients with primary sclerosingcholangitis, and 11 patients with Sjögren's syndrome. Allserum samples were stored at –20°C.
All 20 patients with sclerosing pancreatitis had irregular narrowingof the main pancreatic duct and sonolucent swelling of the pancreasthat responded to glucocorticoid treatment, obstructive jaundice,hypergammaglobulinemia, and high serum IgG concentrations; 4patients had high serum IgE concentrations.2,5,7,8,14 The conditionof all 20 patients improved after treatment with 40 mg of prednisoloneper day for four weeks, followed by a gradual reduction of 5mg per week over a period of seven weeks until a daily doseof 5 mg was reached. The patients were followed for 10 to 63months after treatment was discontinued. Two patients had recurrencesof their pancreatitis.
All 45 patients with ordinary chronic pancreatitis had eithermarked irregular dilatation of the main pancreatic duct or markedcalcification of the pancreas,20 features that were not foundin patients with sclerosing pancreatitis. The diagnosis of primarybiliary cirrhosis was confirmed by histologic evaluation ofliver-biopsy specimens. The diagnosis of primary sclerosingcholangitis was confirmed by cholangiographic examination andliver biopsy. The diagnosis of Sjögren's syndrome was confirmedby the finding of diminished function of the lacrimal and salivaryglands and by the presence of Sjögren's syndrome A andSjögren's syndrome B antibodies in serum. The diagnosisof pancreatic cancer was confirmed on the basis of histologicfindings in 26 patients and on the basis of both typical findingson imaging procedures and the clinical course in 44 patients.
All subjects provided written informed consent for invasivetests such as endoscopic retrograde cholangiopancreatographyand liver biopsy. This retrospective analysis was not reviewedby an institutional review committee, but all tests and treatmentswere performed in accordance with institutional guidelines.
Laboratory Tests
Because there is no widely accepted method of measuring theconcentrations of subclasses of IgG, we measured serum IgG4and the other subclasses of IgG in the patients with sclerosingpancreatitis and the normal subjects using two methods: singleradial immunodiffusion (Binding Site, Birmingham, United Kingdom)and enzyme-linked immunosorbent assay (ELISA)21 (Yoshitomi PharmaceuticalIndustries, Osaka, Japan). We found a close correlation betweenthe results of single radial immunodiffusion and those of ELISAfor each serum IgG subclass. Serum IgG4 concentrations in theother patients were measured by single radial immunodiffusion.Serum total IgG, IgA, and IgM concentrations were measured byturbidimetric immunoassay, and serum IgE concentrations weremeasured by ELISA. We determined the cutoff values for serumIgG4 and IgG by analyzing receiver-operating-characteristiccurves.
We measured circulating immune complexes with an ELISA kit withmonoclonal rheumatoid factor (Immune complex mRF Nissui, NissuiPharmaceutical, Tokyo, Japan).22 We used the manufacturer'srecommended cutoff value, which was the mean plus 2 SD of valuesin normal subjects. To detect circulating immune complexes containingIgG4, we designed a new ELISA system using monoclonal rheumatoidfactor–coated plates and peroxidase-labeled antihumanIgG4 antibody (AU009, Binding Site) as a tracer antibody. Thisantihuman IgG4 antibody was the same as that used in singleradial immunodiffusion for IgG4. The serum samples were treatedwith EDTA solution according to the instructions for the circulatingimmune-complex–assay system. Peroxidase-labeled antihumanIgG4 antibody was diluted 1:5000 with phosphate-buffered salinecontaining 0.5 percent bovine serum albumin, and specimens werestained with 3,3',5,5'-tetramethylbenzidine (Behring Diagnostics,Marburg, Germany). Optical density was measured at 450 nm witha microplate reader (Bio-Rad Laboratories, Hercules, Calif.).We tentatively defined the cutoff value for the serum concentrationof the IgG4 subclass of immune complexes as an optical-densityunit of 0.1, because serum samples from all 20 normal subjectshad lower values.
Statistical Analysis
Statistical analyses were performed with the Mann–Whitneytest to compare the serum concentrations of each IgG subclass,IgA, IgM, and IgE in patients with sclerosing pancreatitis withthose in normal subjects. The Wilcoxon matched-pairs signed-ranktest was used to compare serum IgG concentrations, serum IgG4concentrations, the ratio of serum IgG4 to serum IgG, serumconcentrations of circulating immune complexes, and serum concentrationsof the IgG4 subclass of circulating immune complexes in patientswith sclerosing pancreatitis before and after four weeks ofglucocorticoid therapy. Data were analyzed with the use of SPSSsoftware (version 6.1, SPSS, Chicago).23 All reported P valuesare two-sided. To differentiate sclerosing pancreatitis fromother pancreatic diseases (ordinary chronic pancreatitis andpancreatic cancer), we analyzed receiver-operating-characteristiccurves for serum IgG and IgG4 values with the use of the statisticalsoftware package Stat Flex (version 5.0, Artech, Osaka, Japan).24,25
Results
According to both assay methods, the patients with sclerosingpancreatitis had serum IgG4 concentrations that were significantlyhigher than those in the normal subjects (P<0.001) (Table 1).The patients with sclerosing pancreatitis also had slightlybut significantly higher serum IgG1 concentrations and lowerserum IgG2 concentrations as determined by ELISA but not bysingle radial immunodiffusion. There were no significant differencesbetween these two groups with respect to the concentrationsof other serum IgG subclasses or of serum IgA, IgM, or IgE (Table 1).
Table 1. Age, Sex, and Serum Immunoglobulin Concentrations of Normal Subjects and Patients with Sclerosing Pancreatitis.
The results of measurements of serum IgG4 and total IgG in thepatients with sclerosing pancreatitis and the other groups areshown in Figure 1. Serum IgG4 concentrations were elevated onlyin the patients with sclerosing pancreatitis (Figure 1A). Althoughserum total IgG concentrations were slightly higher in the patientswith sclerosing pancreatitis, there was considerable overlapwith the other groups (Figure 1B). The use of a cutoff valuefor serum IgG4 concentrations of 135 mg per deciliter resultedin a high rate of accuracy (97 percent), sensitivity (95 percent),and specificity (97 percent) for the differentiation of sclerosingpancreatitis from pancreatic cancer. The respective values forthe use of a cutoff value of 1883 mg per deciliter for serumIgG were 80 percent, 65 percent, and 81 percent.
Figure 1. Serum IgG4 Concentrations as Determined by Single Radial Immunodiffusion (Panel A) and Serum Total IgG Concentrations (Panel B) in 70 Patients with Pancreatic Cancer, 45 Patients with Ordinary Chronic Pancreatitis, 20 Patients with Sclerosing Pancreatitis, 20 Patients with Primary Biliary Cirrhosis, 8 Patients with Primary Sclerosing Cholangitis, and 11 Patients with Sjögren's Syndrome.
Serum IgG4 and total IgG concentrations above 135 mg per deciliter and 1883 mg per deciliter, respectively (dotted lines), were considered elevated, as determined by an analysis of receiver-operating-characteristic curves.
To determine the relation between serum IgG4 concentrationsand disease activity in patients with sclerosing pancreatitis,we measured serum IgG4 in 12 patients after four weeks of glucocorticoidtherapy. All of the patients had remission of symptoms and resolutionof abnormalities on imaging studies after four weeks of treatment(Figure 2). Both the serum IgG4 concentration and the serumIgG4:IgG ratio were significantly lower than their respectivebase-line values (Table 2); there was also a significant decreasein the median serum IgG concentration. These findings suggestthat the change in the serum IgG4 concentration is a specificeffect of glucocorticoid treatment, not a nonspecific effectof treatment on the overall production of immunoglobulins.
Figure 2. Findings on Endoscopic Retrograde Cholangiopancreatography and Ultrasonography (Insets) in a 72-Year-Old Woman with Sclerosing Pancreatitis.
Before therapy (Panel A), there is irregular narrowing of the main pancreatic duct and sonolucent swelling of the pancreas. The dimension of the main pancreatic duct (D1) is 1.2 mm, and the dimension of the pancreatic body (D2) is 14.0 mm. After four weeks of glucocorticoid therapy (Panel B), the abnormalities have resolved. The dimension of the pancreatic head (D1) is 9.7 mm, and the dimension of the pancreatic body (D2) is 8.7 mm.
Table 2. Serum IgG and IgG4 Concentrations, Serum IgG4:IgG Ratio, and Serum Concentrations of Immune Complexes and Immune Complexes of the IgG4 Subclass in 12 Patients with Sclerosing Pancreatitis before and after Four Weeks of Glucocorticoid Therapy.
To examine whether the high serum IgG4 concentrations were relatedto high serum concentrations of immune complexes and the IgG4subclass of immune complexes, we measured these concentrationsbefore and after four weeks of glucocorticoid therapy in 12patients with sclerosing pancreatitis. The serum concentrationsof immune complexes before treatment exceeded the cutoff valueof 4.2 µg per milliliter in 92 percent of the patientswith sclerosing pancreatitis. The concentrations decreased significantlyafter four weeks of glucocorticoid therapy (Table 2). Similarto the serum concentration of immune complexes, the serum concentrationof the IgG4 subclass of immune complexes was elevated in 92percent of the patients with sclerosing pancreatitis beforetherapy and decreased significantly after four weeks of therapy(Table 2).
Discussion
We found high serum IgG4 concentrations in patients with sclerosingpancreatitis but not in patients with ordinary chronic pancreatitis,primary biliary cirrhosis, primary sclerosing cholangitis, orSjögren's syndrome. These findings suggest that sclerosingpancreatitis differs immunologically from these other diseasesand that it is a distinct disease entity.
If sclerosing pancreatitis is misdiagnosed, patients may beassumed to have pancreatic cancer and may undergo unnecessarysurgery.1,4,5,7,9,10 At least 5 percent of patients who undergosurgery for cancer of the head of the pancreas are found tohave benign inflammatory disease,26 which may include sclerosingpancreatitis. We found that measurements of serum IgG4 can beused to distinguish sclerosing pancreatitis from pancreaticcancer. Our findings suggest that increased awareness of sclerosingpancreatitis as a discrete entity and the measurement of serumIgG4 in patients suspected of having pancreatic cancer may helpreduce the incidence of unnecessary surgery.
In conditions associated with high serum IgG4 concentrations,the IgG4 subclass is usually categorized as a pathologic antibody.In patients with atopic dermatitis, asthma, and some parasiticdiseases, high serum concentrations of IgE and IgG4 are a directresponse to exogenous antigen,17,18 and the increase in serumIgG4 antibodies has been postulated to block the access of solubleantigens to IgE-coated mast cells.18 Patients with pemphigusvulgaris and pemphigus foliaceus, autoimmune skin diseases characterizedby the presence of IgG4 autoantibodies against the cell-adhesionmolecules desmoglein 3 and desmoglein 1, also have high serumIgG4 concentrations,27,28,29 and passive transfer of these IgG4autoantibodies induces skin disease in animals.29 In patientswith membranous nephropathy, immune complexes containing IgG4have been detected in serum,30 and IgG4 is predominantly depositedalong the epithelial surface of the glomerular basement membrane.31
It is unlikely that the serum concentration of IgG4 increasedin our patients with sclerosing pancreatitis as a direct responseto exogenous antigen. A parallel increase in the serum IgE concentrationwas found in only 20 percent of patients, and the median serumIgE concentrations were similar in the patients with sclerosingpancreatitis and the normal subjects.
We found that the patients with sclerosing pancreatitis hadelevated serum concentrations of immune complexes and the IgG4subclass of immune complexes and that these concentrations decreasedsignificantly during glucocorticoid therapy. These findingssuggest that the pathogenesis of sclerosing pancreatitis isclosely related to the immune complexes. Important clinicalfindings of immune-complex disease are nephritis and vasculitis.We have not found any renal involvement in patients with sclerosingpancreatitis, but we have not excluded the possibility of vasculardamage. Because IgG4 is unique among the IgG subclasses in itsinability to fix Clq complement and its low affinity for targetantigens,30 the characteristic features of sclerosing pancreatitismay be closely associated with the IgG4 subclass of immune complexes.The role of immune complexes containing IgG4 differs from thatof immune complexes containing other IgG subclasses. In thepathogenesis of membranous nephropathy, for example, these characteristicsof IgG4 may account for the slow rate of clearance of this subclassof immune complex from the circulation and for the formationof membrane-attack complexes in tissues as a result of the fixingof complement by means of the alternative pathway.32
In conclusion, we found that patients with sclerosing pancreatitishave high serum IgG4 concentrations and that the values areclosely associated with disease activity.
Supported in part by a Grant-in-Aid for Scientific Researchfrom the Ministry of Education, Science, Sports, and Cultureof Japan (11877089).
We are indebted to Ms. Sachiko Akanuma and Mr. Hiroya Hidakaof Central Clinical Laboratories for technical assistance withthe serum IgG4 determinations; to Dr. Eiji Tanaka, Dr. KanameYoshizawa, Dr. Tetsuya Ichijyo, and Dr. Akihiro Matsumoto ofthe Second Department of Internal Medicine for assistance withsample collection and statistical analysis; to Ms. Ayumi Nakazawaof the Department of Anatomy for technical assistance with histologicanalysis; to Dr. Osamu Hasebe, Dr. Masuo Tokoo, and Dr. SeiichiFuruta of Nagano Municipal Hospital, Dr. Kenji Matsuzawa ofMaruko Central Hospital, Dr. Kenji Mukawa of Suwa Red CrossHospital, Dr. Shinya Maejima of Chushin Matsumoto Hospital,and Dr. Yoshiyuki Nakamura and Dr. Shinji Okaniwa of Iida MunicipalHospital for clinical assistance; and to Dr. Kiyoshi Ichiharaof Kawasaki Medical School for assistance with the statisticalanalysis.
Source Information
From the Second Department of Internal Medicine (H.H., S.K., A.H., H.U., N.F., T.A., K.K.) and the Departments of Laboratory Medicine (M.F.), Obstetrics and Gynecology (T.N.), Organ Generation (T.N.), and Anatomy (K.N.), Shinshu University School of Medicine, Matsumoto, Japan; and the Department of Anatomy, Fujita Health University School of Medicine, Toyoake, Japan (N.U.).
Address reprint requests to Dr. Kawa at the Second Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan, or at skawapc{at}hsp.md.shinshu-u.ac.jp.
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