Pancreatitis as a rare manifestation of Behçet disease

Behçet disease (BD) is a chronic idiopathic vasculitis characterized as a triad of papulopustular skin lesions, uveitis, and genital-oral ulcers.1Sakane T. Takeno M. Suzuki N. Inaba G. Behçet's disease.N Engl J Med. 1991; 341: 1284-1291Crossref Scopus (1584) Google Scholar Gastrointestinal (GI) manifestations of BD are associated with significant morbidity and mortality, as mucosal inflammation and large vessel disease result in intestinal ischemia and infarction.2Skef W. Hamilton M. Arayssi T. Gastrointestinal Behçet's disease: A review.World J Gastroenterol. 2015; 21: 3801-3812Crossref PubMed Scopus (99) Google Scholar Although the incidence of GI involvement varies, rates are reported to be as high as 60% in Japan.3Ebert E. Gastrointestinal manifestations of Behçet's disease.Dig Dis Sci. 2009; 54: 201-207Crossref PubMed Scopus (87) Google Scholar Pancreatitis is a rare manifestation of BD that has scarce documentation in the literature. It has been suggested that Behçet pancreatitis may be underdiagnosed, as an autopsy series of 170 cases from Japan found 5 previously undiagnosed cases of pancreatitis.4Lakhanpal S. Tani K. Lie J. Pathological features of Behcet's syndrome: a review of japanese autopsy registry data.Hum Pathol. 1985; 16: 790-795Abstract Full Text PDF PubMed Scopus (357) Google Scholar We report on a 56-year-old man with BD who presented with acute pancreatitis requiring repeated hospital admission. Per the International Study Group Criteria for BD, the patient initially had BD diagnosed in 2005 after a 5-year history of various cutaneous lesions and recurrent genital-oral ulcers.5Criteria for diagnosis of Behcet's disease. International study group for Behcet's disease.Lancet. 1990; 335: 1078-1080Abstract PubMed Scopus (4191) Google Scholar He had 2-mm inflamed follicular papules on his face and numerous 0.5- to 1-cm indurated deep red papulopustular lesions along his chest, back, thigh, and buttocks (Fig 1). Subsequent punch biopsies found a dense dermal neutrophil infiltrate, which was in keeping with BD (Figs 2 and 3). His BD was well controlled while being treated with topical corticosteroids and varying regimens of colchicine, dapsone, and methotrexate.Fig 2Punch biopsy shows dense dermal suppurative neutrophilic infiltrate with surface ulceration. (Hematoxylin-eosin stain; original magnification: ×25.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3High-power examination shows dense dermal neutrophilic infiltrate. (Hematoxylin-eosin stain; original magnification: ×200.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient was initially admitted in 2011 after presenting with severe abdominal pain and a concurrent flare of his BD in which he had an increasing number of cutaneous lesions. Although both endoscopy and computed tomography (CT) enterography were normal, a CT of the abdomen showed pancreatic fat stranding, which was suggestive of pancreatitis. However, because the lipase was not significantly elevated, an exact cause was not determined. The rheumatology service attributed his presentation to BD, and he was started on azathioprine, 50 mg daily. After resolution of his pancreatitis, the patient was seen in follow-up, and it was noted that his cutaneous lesions were also resolving. Although the patient self-stopped the medication after 6 weeks because of increasing fatigue, he did not have any recurrence of abdominal pain until 2015. In 2015, the patient was admitted again after having a 2-week duration of worsening right upper quadrant pain that radiated to the back and was worse after meals. Although he had no other GI symptoms, he also experienced night sweats, chills, malaise, and general weakness. The patient again noted a concurrent flare of his BD with an increased number of erythematous papulopustular lesions along his trunk and extremities (Fig 1). There was no evidence of oral or genital lesions during this admission. Initial investigations found a leukocyte count of 12.3 × 109/L with an elevated C-reactive protein level at 175 mg/L (normal, 0-10 mg/L). Although liver enzymes were normal, the lipase level was elevated at 69 U/L and was as high as 185 U/L (normal, 0-60 U/L) the day before admission. Upper endoscopy was normal, but CT enterography did show pancreatic fat stranding, which is a sign of inflammation. There were no findings to suggest gallstones, biliary sludge, microlithiasis, or biliary obstruction as the cause of his pancreatitis. In the hospital, the patient's symptoms were treated conservatively. He rapidly improved as his abdominal pain settled and C-reactive protein and lipase returned to normal. Two searches using Discovery Service for University of Alberta Libraries and Pubmed were performed in July 2015. Of 45 articles, 6 studies were case reports of Behçet pancreatitis. Because an obvious cause for pancreatitis was not found, other etiologies were considered. Autoimmune pancreatitis was ruled out because IgG-4 was within normal limits.6Zhang L. Smyrk T.C. Autoimmune pancreatitis and IgG4-related systemic diseases.Int J Clin Exp Pathol. 2010; 3: 491-504PubMed Google Scholar Review of the patient's medications found frequent use of ranitidine, which has been implicated in some cases of pancreatitis.7Herrmann R. Shaw R.G. Fone D.J. Ranitidine-associated recurrent acute pancreatitis.Aust N Z J Med. 1990; 20: 243-244Crossref PubMed Scopus (26) Google Scholar However, a retrospective cohort study suggests that there is no association between pancreatitis and ranitidine.8Eland I.A. Alvarez C.H. Stricker B.H. Rodriguez L.A. The risk of acute pancreatitis associated with acid-suppressing drugs.Br J Clin Pharmacol. 2000; 49: 473-478Crossref PubMed Scopus (41) Google Scholar Another possible culprit was azathioprine, which has been associated with idiosyncratic pancreatitis (relative risk, 8), typically with onset of acute pancreatitis 3 to 5 weeks after starting azathioprine and resolution after cessation of therapy.9Floyd A. Pedersen L. Nielsen G.L. Thorlacius-Ussing O. Sorensen H.T. Risk of acute pancreatitis in users of azathioprine: a population-based case-control study.Am J Gastroenterol. 2003; 98: 1305-1308PubMed Google Scholar, 10Moran G.W. Dubeau M.F. Kaplan G.G. et al.Clinical predictors of thiopurine-related adverse events in crohn's disease.World J Gastroenterol. 2015; 21: 7795-7804Crossref PubMed Scopus (24) Google Scholar, 11Lopez-Martin C. Chaparro M. Espinosa L. Bejerano A. Mate J. Gisbert J.P. Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease.Gastroenterol Hepatol. 2011; 34: 385-392Crossref PubMed Scopus (25) Google Scholar In this case, the patient had stopped azathioprine 4 years prior, making azathioprine an unlikely cause. Other risk factors were also absent: the patient is a nonsmoker and consumes alcohol only on a social basis, there were no preceding infections, calcium value was within normal limits, and triglycerides were only mildly elevated.12Murad M.H. Hazem A. Coto-Yglesias F. et al.The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis.BMC Endocr Disord. 2012; 12: 2Crossref PubMed Scopus (65) Google Scholar Because no other etiology was apparent, the patient's concurrent flare of BD and pancreatitis suggests that there is an association between the 2 disease processes. Despite the high prevalence of intestinal BD, similar cases of associated pancreatitis are rare in the literature. To our knowledge, our patient is the 11th reported case of pancreatitis in patients with BD (Table I).4Lakhanpal S. Tani K. Lie J. Pathological features of Behcet's syndrome: a review of japanese autopsy registry data.Hum Pathol. 1985; 16: 790-795Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 13O'Duffy J.D. Carney J.A. Deodhar S. Behcet's disease. Report of 10 cases, 3 with new manifestations.Ann Intern Med. 1971; 75: 561-570Crossref PubMed Scopus (227) Google Scholar, 14Le Thi Huong D. Wechsler B. Dell'Isola B. et al.Acute pancreatitis in Behcet's disease.Dig Dis Sci. 1992; 37: 1452-1453Crossref PubMed Scopus (21) Google Scholar, 15Backmund M. Schomerus P. Acute pancreatitis and pericardial effusion in Behcet's disease.Gastroenterology. 1999; 117: 286Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar, 17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar Clinically, symptoms suggestive of pancreatitis such as epigastric pain, vomiting, or diarrhea are also common in intestinal BD.18Grigg E.L. Kane S. Katz S. Mimicry and deception in inflammatory bowel disease and intestinal Behcet disease.Gastroenterol Hepatol (N Y). 2012; 8: 103-112PubMed Google Scholar In reviewing these cases, we find that there is no predilection for gender (Table I).4Lakhanpal S. Tani K. Lie J. Pathological features of Behcet's syndrome: a review of japanese autopsy registry data.Hum Pathol. 1985; 16: 790-795Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 13O'Duffy J.D. Carney J.A. Deodhar S. Behcet's disease. Report of 10 cases, 3 with new manifestations.Ann Intern Med. 1971; 75: 561-570Crossref PubMed Scopus (227) Google Scholar, 14Le Thi Huong D. Wechsler B. Dell'Isola B. et al.Acute pancreatitis in Behcet's disease.Dig Dis Sci. 1992; 37: 1452-1453Crossref PubMed Scopus (21) Google Scholar, 15Backmund M. Schomerus P. Acute pancreatitis and pericardial effusion in Behcet's disease.Gastroenterology. 1999; 117: 286Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar, 17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar In addition, the age of onset seems to be in young adults with an average age of 31 (median, 32). The most common presenting complaint was epigastric pain radiating to the back followed by significant weight loss. Other GI symptoms are uncommon, as vomiting was only present in 1 patient. Thus, patients with BD that present with unexpected epigastric pain and weight loss may warrant additional workup for pancreatitis. Because lipase was elevated in 83% (5 of 6), bloodwork should include lipase in addition to other inflammatory markers such as leukocyte count and C-reactive protein (Table I).13O'Duffy J.D. Carney J.A. Deodhar S. Behcet's disease. Report of 10 cases, 3 with new manifestations.Ann Intern Med. 1971; 75: 561-570Crossref PubMed Scopus (227) Google Scholar, 14Le Thi Huong D. Wechsler B. Dell'Isola B. et al.Acute pancreatitis in Behcet's disease.Dig Dis Sci. 1992; 37: 1452-1453Crossref PubMed Scopus (21) Google Scholar, 15Backmund M. Schomerus P. Acute pancreatitis and pericardial effusion in Behcet's disease.Gastroenterology. 1999; 117: 286Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar The single patient with a normal lipase level had a history of chronic, rather than acute, abdominal pain, which may explain his normal lipase level.16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar Imaging the pancreas by CT enterography may be helpful, as 80% of cases (4 of 5) had positive CT findings (Table I).14Le Thi Huong D. Wechsler B. Dell'Isola B. et al.Acute pancreatitis in Behcet's disease.Dig Dis Sci. 1992; 37: 1452-1453Crossref PubMed Scopus (21) Google Scholar, 15Backmund M. Schomerus P. Acute pancreatitis and pericardial effusion in Behcet's disease.Gastroenterology. 1999; 117: 286Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar, 17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar Endoscopic ultrasound scan (EUS) may help confirm the diagnosis of pancreatitis and rule out biliary stone disease and examine for vasculopathy.Table IPancreatitis in patients with BD: Review of the literatureStudyNo. of patientsAgeGenderClinical presentationDiagnostic findingsTreatmentO'Duffy et al13O'Duffy J.D. Carney J.A. Deodhar S. Behcet's disease. Report of 10 cases, 3 with new manifestations.Ann Intern Med. 1971; 75: 561-570Crossref PubMed Scopus (227) Google Scholar143FSharp midepigastric pain radiating to the back, 30-lb weight loss↑Amylase—Lakhanpal et al4Lakhanpal S. Tani K. Lie J. Pathological features of Behcet's syndrome: a review of japanese autopsy registry data.Hum Pathol. 1985; 16: 790-795Abstract Full Text PDF PubMed Scopus (357) Google Scholar5——No preclinical data availableAutopsy data—Le et al14Le Thi Huong D. Wechsler B. Dell'Isola B. et al.Acute pancreatitis in Behcet's disease.Dig Dis Sci. 1992; 37: 1452-1453Crossref PubMed Scopus (21) Google Scholar124MVomiting, epigastric pain, 13-kg weight loss↑ Amylase (77)↑ Lipase (537)U/S, CT normalEUS findingsPrednisone, 60 mg daily × 3 monthsBackmund and Schomerus15Backmund M. Schomerus P. Acute pancreatitis and pericardial effusion in Behcet's disease.Gastroenterology. 1999; 117: 286Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar132MFever, mild epigastric pain↑ Amylase (1054-2146)↑ Lipase (8333)U/S, CT findingsCortisone, pentoxifylline prednisoloneAlkim et al16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar137M2-year duration of epigastric pain radiating to back,12-year history of 100 to 150 g/w of alcoholNormal lipaseU/S, CT findingsPseudoaneurysm of superior mesenteric arteryPancreatic sphincterotomyYaghlene et al17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar118FSevere epigastric pain,7 kg weight loss↑Lipase (4-5x N)U/S, CT findings,EUS confirmedpseudoaneurysms of celiac arteriesPrednisolone, 1 mg/kg/d × 5 months;cyclophosphamide, 900 mg q3w × 6 cyclesColchicine/aspirinq3w, Every 3 weeks; U/S, ultrasound. Open table in a new tab q3w, Every 3 weeks; U/S, ultrasound. In previous cases, the main treatment was oral steroids; however, immunosuppressives, colchicine, and symptomatic treatment were also effective (Table I).4Lakhanpal S. Tani K. Lie J. Pathological features of Behcet's syndrome: a review of japanese autopsy registry data.Hum Pathol. 1985; 16: 790-795Abstract Full Text PDF PubMed Scopus (357) Google Scholar, 13O'Duffy J.D. Carney J.A. Deodhar S. Behcet's disease. Report of 10 cases, 3 with new manifestations.Ann Intern Med. 1971; 75: 561-570Crossref PubMed Scopus (227) Google Scholar, 14Le Thi Huong D. Wechsler B. Dell'Isola B. et al.Acute pancreatitis in Behcet's disease.Dig Dis Sci. 1992; 37: 1452-1453Crossref PubMed Scopus (21) Google Scholar, 15Backmund M. Schomerus P. Acute pancreatitis and pericardial effusion in Behcet's disease.Gastroenterology. 1999; 117: 286Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar, 17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar Currently, however, there is no consensus for treating pancreatitis associated with BD. Of note, 2 of the case reports documented the presence of pseudoaneurysms in the celiac and superior mesenteric artery.16Alkim H. Gurkaynak G. Sezgin O. Oguz D. Saritas U. Sahin B. Chronic pancreatitis and aortic pseudoaneurysm in Behcet's disease.Am J Gastroenterol. 2001; 96: 591-593PubMed Google Scholar, 17Ben Yaghlene L. Hammel P. Palazzo L. et al.Acute pancreatitis revealing Behcet disease.Gastroenterol Clin Biol. 2005; 29: 294-296Crossref PubMed Scopus (4) Google Scholar These observations suggest that the underlying large vessel vasculitis found in intestinal BD may also contribute to acute pancreatitis in BD such that systemic therapies for intestinal BD may also be effective for pancreatitis.18Grigg E.L. Kane S. Katz S. Mimicry and deception in inflammatory bowel disease and intestinal Behcet disease.Gastroenterol Hepatol (N Y). 2012; 8: 103-112PubMed Google Scholar, 19Vaiopoulos A.G. Sfikakis P.P. Kanakis M.A. Vaiopoulos G. Kaklamanis P.G. Gastrointestinal manifestations of Behcet's disease: advances in evaluation and management.Clin Exp Rheumatol. 2014; 32: S140-S148PubMed Google Scholar We report a rare case of acute and recurrent pancreatitis associated with BD. Because GI symptoms are nonspecific to both pancreatitis and intestinal BD, we suggest that pancreatitis should be considered in the differential diagnosis in patients with BD who present with abdominal pain. With better recognition, more data will be available to generate higher-quality studies, allowing current therapeutic strategies to be refined. Because intestinal BD is often severe enough to require hospitalization, controlling and preventing GI manifestations of BD may improve overall morbidity and mortality.

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