Correspondence
A Novel Antibody Associated with Autoimmune Pancreatitis
N Engl J Med 2010; 362:759-761February 25, 2010
- Article
To the Editor:
Frulloni et al. (Nov. 26 issue)1 report on a new serologic marker for autoimmune pancreatitis. A total of 5 of 110 patients with pancreatic cancer had a positive test for antibodies, with a sensitivity of 94%. I agree with the authors that this is an imperfect test to rule out the diagnosis. Were the levels of IgG4 normal in these five patients? Perhaps the diagnostic value of the antibody test could be improved if it were combined with the IgG4 levels.
Also, there is increasing evidence that autoimmune pancreatitis is a risk factor for pancreatic cancer.2 For example, a recent study by Kamisawa et al. showed a high frequency of K-ras mutations in autoimmune pancreatitis.3 In reviewing these five cases, is there histopathologic evidence of autoimmune pancreatitis? It might be that the presumed false positive antibody tests were in fact markers of an underlying autoimmune pancreatitis.
Gijs W. Landman, M.D.
Isala Clinics, Zwolle, the Netherlands
g.w. d. landman@isala. nl No potential conflict of interest relevant to this letter was reported.
3 References1
Frulloni L ,Lunardi C ,Simone R , et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med 2009;361:2135-2142
Full Text | Web of Science | Medline2
Fukui T ,Mitsuyama T ,Takaoka M ,Uchida K ,Matsushita M ,Okazaki K . Pancreatic cancer associated with autoimmune pancreatitis in remission. Intern Med 2008;47:151-155
CrossRef | Web of Science | Medline3
Kamisawa T ,Tsuruta K ,Okamoto A , et al. Frequent and significant K-ras mutation in the pancreas, the bile duct, and the gallbladder in autoimmune pancreatitis. Pancreas 2009;38:890-895
CrossRef | Web of Science | Medline
To the Editor:
Frulloni et al. identify an antibody against plasminogen-binding protein (PBP) of Helicobacter pylori in most patients with autoimmune pancreatitis and in 5% of patients with pancreatic cancer. Their findings not only help to discriminate autoimmune pancreatitis from pancreatic cancer but also provide a link between H. pylori infection and autoimmune pancreatitis. However, two issues deserve discussion. First, although healthy controls were not positive for anti–PBP antibodies, patients with active H. pylori infection may have had false positive results. Therefore, the authors should have enrolled another control group of patients with H. pylori infection to validate the diagnostic accuracy of this assay. Second, H. pylori has been suggested as a cause of autoimmune pancreatitis,1,2 and the authors found a homology between the peptide AIP1-7 and the PBP of H. pylori. To clarify the role of H. pylori in the pathogenesis of autoimmune pancreatitis, they should describe the status of H. pylori infection in the patients with autoimmune pancreatitis and pancreatic cancer.
Chia-Chi Wang, M.D.
Buddhist Tzu Chi General Hospital, Taipei, TaiwanJia-Horng Kao, M.D., Ph.D.
National Taiwan University College of Medicine, Taipei, Taiwan
kaojh@ntu.edu. tw No potential conflict of interest relevant to this letter was reported.
2 References1
Guarneri F ,Guarneri C ,Benvenga S . Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med 2005;9:741-744
CrossRef | Web of Science | Medline2
Kountouras J ,Zavos C ,Gavalas E ,Tzilves D . Challenge in the pathogenesis of autoimmune pancreatitis: potential role of Helicobacter pylori infection via molecular mimicry. Gastroenterology 2007;133:368-369
CrossRef | Web of Science | Medline
To the Editor:
Frulloni et al. report the identification of anti–PBP peptide antibodies associated with autoimmune pancreatitis. We have concerns about this study. In a previous article by Frulloni and colleagues,1 from January 2000 through March 2008, a total of 58 patients received a diagnosis of autoimmune pancreatitis. However, in this study, from January 2002 through November 2008, serum samples were obtained from only 20 patients with autoimmune pancreatitis. Even though data on the validation group may have been derived from the same study periods, serologic findings in a substantial portion of the entire cohort may not have been evaluated. Therefore, the selectively accrued cohort may lead to conflicting results in external validation studies. The previous study by Frulloni et al.1 might have included a fair proportion of patients with idiopathic duct-centric chronic pancreatitis,2 and this result suggests that the anti–PBP peptide antibodies might be related to idiopathic duct-centric chronic pancreatitis rather than autoimmune pancreatitis. Because the IgG1 immune complex may be related to both IgG4-negative autoimmune pancreatitis and idiopathic duct-centric chronic pancreatitis,3 further detailed comments on the subtype of IgG antibodies against the PBP peptide may be needed to elucidate the role of this antibody in autoimmune pancreatitis.
Do Hyun Park, M.D., Ph.D.
University of Ulsan College of Medicine, Seoul, South KoreaJ. Yoonoo Hwang, M.D.
Asan Medical Center, Seoul, South KoreaMyung-Hwan Kim, M.D., Ph.D.
University of Ulsan College of Medicine, Seoul, South Korea
mhkim@amc.seoul. kr No potential conflict of interest relevant to this letter was reported.
3 References1
Frulloni L ,Scattolini C ,Falconi M , et al. Autoimmune pancreatitis: differences between the focal and diffuse forms in 87 patients. Am J Gastroenterol 2009;104:2288-2294
CrossRef | Web of Science | Medline2
Sugumar A ,Kloppel G ,Chari ST . Autoimmune pancreatitis: pathologic subtypes and their implications for its diagnosis. Am J Gastroenterol 2009;104:2308-2310
CrossRef | Web of Science | Medline3
Park DH ,Kim MH ,Chari ST . Recent advances in autoimmune pancreatitis. Gut 2009;58:1680-1689
CrossRef | Web of Science | Medline
Author/Editor Response
Landman asks whether the IgG4 levels in the five patients with pancreatic cancer and a positive antibody test were normal, suggesting that cancer may have arisen from previously undiagnosed autoimmune pancreatitis. In these five patients, the IgG4 levels were normal. We are reviewing the five cases to evaluate the possibility that these patients might have had previously undiagnosed autoimmune pancreatitis.
Combining antibody testing and IgG4 levels may improve the diagnostic value, since among the patients with autoimmune pancreatitis, 2 patients who were negative for anti–PBP peptide antibodies had elevated IgG4 levels and 16 patients with normal IgG4 levels had a positive antibody test. Prospective studies may confirm the clinical usefulness of the combined serologic tests.
Wang and Kao suggest that the patients with active H. pylori infection may have had false positive results for anti–PBP peptide antibodies. We believe the possibility of false positive results in subjects with active H. pylori infection is quite remote, since the response to the described epitope of PBP protein was limited mainly to patients with autoimmune pancreatitis and possibly related to a particular genetic background. Indeed, previous observations suggest that the immune response to an infectious agent in a particular autoimmune disease involves the presence of a subgroup of antibodies directed against a particular epitope. Such a response is not detected in normal subjects and in patients with other autoimmune diseases.1,2 However, at the beginning of the study, we did not know that the identified AIP peptide shared a homology with an H. pylori–derived protein. Therefore, we cannot say whether the patients with autoimmune pancreatitis and pancreatic cancer in our study had active H. pylori infection.
Park et al. are concerned about the selection of patients considered in this study. The patients enrolled were consecutive. The numbers of patients are smaller than in the previous study because the period is slightly different and some patients were observed more than 1 month after the clinical onset of the disease and were not included.
Experts from the United States and Europe consider idiopathic duct-centric chronic pancreatitis to be a type II form of autoimmune pancreatitis3 on the basis of clinical, radiologic, and pathological findings and, in particular, on the basis of a similar response to corticosteroids. The estimated prevalence of type II autoimmune pancreatitis in Italy, based on surgical specimens, is 40%.4 Therefore, we disagree that anti–PBP peptide antibodies might be related to idiopathic duct-centric chronic pancreatitis. We are analyzing the IgG subtype of anti–PBP peptide antibodies; however, we doubt that this analysis will elucidate the role of the antibody in autoimmune pancreatitis.
Luca Frulloni, M.D., Ph.D.
Claudio Lunardi, M.D.
University of Verona, Verona, ItalyAntonio Puccetti, M.D., Ph.D.
Giannina Gaslini Institute, Genoa, Italy
antonio.puccetti@unige. it Since publication of their article, the authors report no further potential conflict of interest.
4 References1
Lunardi C ,Bason C ,Navone R , et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med 2000;6:1183-1186
CrossRef | Web of Science | Medline2
Bason C ,Corrocher R ,Lunardi C , et al. Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis. Lancet 2003;362:1971-1977
CrossRef | Web of Science | Medline3
Chari ST ,Longnecker DS ,Klopper G . The diagnosis of autoimmune pancreatitis: a Western perspective. Pancreas 2009;38:846-848
CrossRef | Web of Science | Medline4
Zamboni G ,Luttges J ,Capelli P , et al. Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study of 53 resection specimens and 9 biopsy specimens. Virchows Arch 2004;445:552-563
CrossRef | Web of Science | Medline
