ORIGINAL ARTICLES LIVER, PANCREAS, AND BILIARY TRACT

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7: ORIGINAL ARTICLES LIVER, PANCREAS, AND BILIARY TRACT Presentation and Management of Post-treatment Relapse in Autoimmune Pancreatitis/Immunoglobulin G4-Associated Cholangitis NEOMAL S. SANDANAYAKE,*, NICHOLAS I. CHURCH,* MICHAEL H. CHAPMAN,*, GAVIN J. JOHNSON,* DIPOK K. DHAR, ZAHIR AMIN, MAESHA G. DEHERAGODA, MARCO NOVELLI, ALISON WINSTANLEY, MANUEL RODRIGUEZ JUSTO, ADRIAN R. W. HATFIELD,* STEPHEN P. PEREIRA,*, and GEORGE J. M. WEBSTER*, Departments of *Gastroenterology, Histopathology, and Radiology, University College Hospital, London; and Institute of Hepatology, University College London, London, United Kingdom Podcast interview: see related article, Chari ST et al, on page 1097 in this issue of CGH; see Editorial on page BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is a multisystem disorder that often has extrapancreatic manifestations such as immunoglobulin G4 associated cholangitis (IAC). Patients respond rapidly to steroids but can relapse after therapy. We assessed the clinical management of relapse in a group of patients with AIP/IAC. METHODS: We performed a prospective study of patients diagnosed with AIP from who received steroids. Treatment outcome was defined clinically, radiologically, and biochemically as response to steroids, remission after steroids, failure to wean steroids, and relapse. Steroids azathioprine (AZA) were used to treat patients who failed, relapsed, or could not be weaned from steroids. RESULTS: Twenty-eight patients with AIP were studied; 23 (82%) had IAC. All patients responded within 6 weeks to prednisolone therapy. Twenty-three patients achieved remission after a median of 5 months of treatment (range, months), whereas 5 patients (18%) could not be weaned because of a disease flare. Of the patients who achieved remission, 8 of 23 (35%) subsequently relapsed. Overall, 13 of 23 patients (57%) with AIP/IAC relapsed, compared with 0 of the 5 with isolated AIP (P.04, Fisher exact test). Steroids were increased/restarted in all patients who relapsed; 10 also received AZA. Remission was achieved and maintained in 7 patients; they remain on AZA monotherapy at a median of 14 months (range, 1 27 months). CONCLUSIONS: Relapse or failure to wean steroids occurred in 46% of patients with AIP. Patients with IAC are at particularly high risk of relapse. AZA appears to be effective in patients with post-treatment relapse or who cannot be weaned from steroids. View this article s video abstract at Autoimmune pancreatitis (AIP) is a fibroinflammatory disease of unknown etiology, which is characterized histologically by an IgG4-positive lymphoplasmacytic infiltrate. Extrapancreatic involvement is frequently seen, and sclerosing cholangitis related to AIP has recently been termed IgG4-associated cholangitis (IAC). 1 The treatment of AIP has been the subject of much debate. There have been no placebo-controlled trials of steroid therapy, and spontaneous improvement of the disease might occur without treatment. 2 Nevertheless, case series have shown uniformly favorable clinical, radiologic, and serologic responses within a few weeks of commencing steroids, 3 6 and patients treated with steroids seem to develop fewer long-term complications. 7 However, the dosage and duration of steroid treatment have not been defined, and clinical relapse after stopping steroids has recently been reported, often involving extrapancreatic tissues We report here the frequency and clinical management of relapse in a prospectively followed group of patients with AIP/IAC. Patients and Methods This was a prospective case series and included all patients who were diagnosed with AIP in our center between February 2004 and December 2007 and who received a course of steroid therapy. The diagnosis was based on recognized international criteria, including those from the Japan Pancreas Society 12 and, since 2006, the HISORt criteria from the Mayo Clinic. 4 Features included a focal pancreatic mass or a diffusely enlarged pancreas (characteristically termed sausage pancreas); focal or diffuse pancreatic duct stricturing; raised levels of serum IgG4; extrapancreatic involvement (including sclerosing cholangitis); a lymphoplasmacytic infiltrate within the pancreas and/or involved extrapancreatic tissues, including elevated levels of IgG4-positive plasma cells ( 10 per high-power field); and a subsequent prompt response to steroid therapy. Data were obtained by case note review and prospective patient follow-up. Pancreatic protocol computed tomography Abbreviations used in this paper: AIH, autoimmune hepatitis; AIP, autoimmune pancreatitis; AZA, azathioprine; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; IAC, IgG4-associated cholangitis; MRCP, magnetic resonance cholangiopancreatography; PSC, primary sclerosing cholangitis by the AGA Institute /09/$36.00 doi: /j.cgh

2 1090 SANDANAYAKE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 (CT) was performed in all patients. Patients with obstructive jaundice underwent endoscopic retrograde cholangiopancreatography (ERCP), biliary brushing for cytologic analysis, and polyethylene stenting to optimize biliary drainage when indicated. In patients with biliary obstruction but no jaundice (at diagnosis or on follow-up), magnetic resonance cholangiopancreatography (MRCP) was performed, with or without subsequent ERCP. In cases in which biliary intervention was necessary but ERCP was not possible (eg, prior hepaticojejunostomy), percutaneous transhepatic intervention was performed. Histology from the pancreas or involved extrapancreatic tissues was obtained via endoscopy, endoscopic ultrasound, guided percutaneous approaches, or from surgical specimens. After diagnosis, prednisolone 30 mg daily was commenced, with a reducing regimen tailored to clinical response. The usual regimen was a reduction by 5 mg every 2 weeks after the first 2 weeks, with steroid cessation after 3 4 months. Response to treatment was assessed in terms of presteroid and poststeroid symptoms, liver biochemistry, serologic IgG4 levels, and radiologic appearance. Patients were then followed up in an outpatient setting initially monthly for 3 months and then according to clinical course. Blood samples were taken at each clinic visit for full blood count, urea and electrolytes, biochemistry, glucose, and serum C-reactive protein. Serum IgG4 levels were measured every 3 6 months. Follow-up imaging was performed according to clinical need. Patients who required biliary stents for obstructive jaundice underwent repeat ERCP usually within 3 months of initiation of steroid therapy or earlier if clinically indicated. Stents were either replaced or removed, depending on cholangiographic appearances and/or liver biochemistry. Four treatment outcomes were defined. (1) Disease response referred to symptomatic, biochemical, and radiologic improvement after the commencement of treatment. (2) Disease remission was defined as the maintenance of symptomatic, biochemical, and radiologic disease control after cessation of prednisolone and the removal of previously sited biliary stents. (3) Disease relapse was defined as recurrence of disease activity after achievement of remission and cessation of steroids. (4) Failed weaning was defined by a flare of disease activity while tapering initial steroid course, or an inability to wean steroids completely as a result of biochemical and/or radiologic deterioration. Of note, in this study we did not define or manage response, remission, or relapse serologically (ie, according to serum IgG4 level). Serologic data were analyzed for statistical significance by using SPSS version 14 (SPSS Inc, Chicago, IL). Differences between groups were evaluated by using the Mann Whitney U test. The significance between categorical variables was deter- Table 1. Patient Profile and Clinical Features at Diagnosis Extrapancreatic disease Elevated IgG4 Patient no. Age (y) Sex Pancreatic disease Biliary Other organs involved Serum ( 1.3 g/l) Tissue ( 10 IgG4 plasma cells/hpf) Follow-up after diagnosis (mo) 1 55 M Y Y K Y Y M Y Y K/RPF Y Y M Y Y K Y Y M Y Y N N N M Y Y N Y n/a M Y Y N Y Y M Y Y K Y Y M Y Y N Y n/a M Y Y N n/a Y M Y Y N Y n/a F Y Y N Y N M N Y N Y Y M Y Y N N Y M Y Y K/Neuro Y Y M Y Y RPF Y Y M Y Y N N Y M Y Y N n/a Y F Y N N N Y M Y N N Y Y F Y Y Sal N N M Y Y N N Y M Y Y N Y N F Y N N n/a Y M Y N N N N M Y Y N Y Y M Y N K Y Y M Y Y N Y N M Y Y K N Y 6 RPF, retroperitoneal fibrosis; K, kidney involvement; Neuro, neurologic involvement; Sal, salivary gland involvement; HPF, high-power field; n/a, not available.

3 October 2009 POST-TREATMENT RELAPSE IN AIP/IAC 1091 mined by using Fisher exact test. A P value less than.05 was considered significant. Results Patient Profile and Clinical Disease at Diagnosis AIP was diagnosed in 28 patients (M:F, 24:4) with median age at diagnosis of 61 years (range, years) (Table 1). The initial presentation included obstructive jaundice in 23 of 28 patients (82%), whereas 4 (14%) presented with abdominal/back pain alone. In 1 patient an incidental pancreatic mass was noted on follow-up imaging for an abdominal aortic aneurysm. Five patients (18%) had undergone surgery after their initial presentation (before the diagnosis of AIP) in view of the suspicion of pancreatic cancer (pancreaticoduodenectomy in 2 patients; biliary bypass in 2 patients, choledochoduodenostomy in 1 patient). Presteroid Imaging Pancreatic disease. Twenty-two of 28 patients (79%) had abnormalities of pancreatic parenchyma on cross-sectional imaging. Twelve of 28 (43%) patients had a focal pancreatic mass at presentation, and 10 of 28 (36%) patients had diffuse pancreatic enlargement. Pancreatic atrophy was noted in 3 of 28 (11%) patients. Small pancreatic cysts associated with atrophy were noted in 1 patient, and pancreatic calcification was seen in 1 of 28 (4%) patients. Pancreatic ductal disease was seen on MRCP and/or ERCP in 17 of 28 (61%) patients. Focal pancreatic duct were noted in 12 of 28 (43%) patients, whereas diffuse stricturing was seen in 5 of 28 (18%). One patient had pancreas divisum, a normal pancreas on cross-sectional imaging, but diffuse intrahepatic. Extrapancreatic disease. MRCP and/or ERCP were performed in all 28 patients. Strictures of the intrapancreatic portion of the common bile duct were found in 15 of 25 (60%) patients who had not undergone pancreaticobiliary surgery, usually in association with a pancreatic mass and obstructive jaundice. In addition, 23 of 28 (82%) had proximal, hilar, or intrahepatic biliary stricturing. The biliary tree was radiologically normal in 4 of 28 (14%). All the patients who had undergone surgery had developed intrahepatic biliary by the time of a definitive diagnosis of AIP. Six of 28 (21%) patients had renal involvement with infiltrates and abnormal perfusion on CT, and 2 of 28 (7%) had retroperitoneal fibrosis on CT. Serology The median serum IgG4 level before treatment, available in 25 patients, was 1.65 g/l (range, g/l; normal range, 1.3 g/l). Raised levels of serum IgG4 were found in 17 of 25 (68%) patients before steroids, with a median IgG4 of 2.06 g/l (range, g/l) in this group (Table 1). Histology Biopsies were obtained for histology in 25 of 28 (89%) patients, with positive IgG4 immunostaining demonstrated in 20 of 25 (80%) patients. A lymphoplasmacytic infiltrate associated with 10 IgG4-positive plasma cells per high-power field was demonstrated within the pancreas in 10 patients (with histology obtained via percutaneous biopsy in 3 patients, endoscopic ultrasound in 3 patients, and after surgery in 4 patients). One percutaneous pancreatic biopsy demonstrated marked fibrosis but a sparse plasma cell infiltrate; thus, immunostaining was deemed negative, whereas another patient had normal histology on an endoscopic ultrasound guided biopsy. Lymphoplasmacytic infiltration with IgG4-positive plasma cells was also seen in nonpancreatic biopsies including liver (n 8), kidney (n 2), salivary glands (n 1), bone marrow (n 1), major ampulla (n 2), stomach (n 1), and gallbladder (n 3) biopsies. The 5 patients who underwent surgery all had positive IgG4-plasma cells on subsequent immunostaining of specimens obtained at surgery. Figure 1. Response and outcome to treatment. *Recent relapse; **low-dose steroids for polyarthritis.

4 1092 SANDANAYAKE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 Figure 2. Disease relapse and response to treatment in AIP/IAC. Sequential MRCP scans of patient 10. (A) Taken at diagnosis, a complex hilar stricture with subsegmental intrahepatic caused by obstruction at hilum (arrow) is shown. After an excellent clinical response to 9 months of steroids, marked improvement is seen in biliary stricturing at 18 months (B). Note dilated pancreatic duct and features of chronic pancreatitis (thick arrow). Ten months later (C) patient presented with fatigue, biliary obstruction, and elevated serum IgG4 level. After reintroduction of steroids and AZA, marked improvement of biliary stricturing again is seen (D). Initial Steroid Therapy and Response Median follow-up from the start of the initial steroid course was 29 months (range, 6 53 months). All 28 patients exhibited a disease response within 4 6 weeks of starting steroids, as defined by improvements in symptoms, liver biochemistry, and radiologic abnormalities (Figure 1). Steroids were reduced and stopped after disease remission in 23 of 28 (82%) patients after a median of 5 months of therapy (range, months). Five patients (18%) failed weaning of their initial steroid course. Disease Relapse Of the 23 patients who achieved remission, 8 (35%) relapsed at a median of 4 months (range, 1 29 months) after ceasing the initial course of prednisolone. The median duration of the initial prednisolone course had been 6 months (range, months). All 8 patients were noted to have had extrapancreatic or proximal biliary at the time of diagnosis. Seven of the 8 patients re-presented clinically and radiologically with symptoms of biliary obstruction caused by worsening biliary stricturing, with a median bilirubin of 31 mol/l (range, mol/l) and alkaline phosphatase 749 IU/L (range, IU/L). One patient remained largely asymptomatic 20 months after completing steroids but had significantly deranged liver function test results and progressive biliary stricturing on MRCP (Figure 2). No patient experienced a relapse within the pancreas. Failure to Wean Steroids In 5 patients (18%) it was not possible to wean and stop the initial prednisolone course as a result of a flare of their disease. Patients had been taking prednisolone for a median of 13 months (range, 3 22 months) until their flare. The event at the time of their flare was renal impairment in 2 of 5 (40%), obstructive jaundice in 1 of 5 (20%), deranged liver biochemistry in 1 of 5 (20%), and neurologic impairment in 1 of 5 (20%). All 5 patients who failed to wean their initial steroid course also had proximal biliary. Serum Immunoglobulin G4 and Response to Treatment Serum IgG4 was measured during treatment and after completion of steroids. The normal laboratory value for serum IgG4 at our institution was 1.3 g/l. The median serum IgG4 after treatment in the 11 of 15 patients with available samples who achieved and maintained remission was 0.81 g/l (range, g/l). The median serum IgG4 of the combined relapse/failure to wean steroid group after initial treatment was 1.35 g/l (range, g/l). There was no statistical difference in these 2 groups (Figure 3). Treatment of Patients Who Relapsed All 8 patients who relapsed were commenced on 30 mg prednisolone at the time of their relapse (Table 2). Blood thiopurine S-methyltransferase levels were measured (normal levels in all), and 7 of 8 patients were also commenced on 1 mg/kg azathioprine (AZA) daily, with a target dose of 2 mg/kg. Six of the relapsed patients (75%) were able to cease their second course of steroids at a median of 6 months (range, 3 9 months). The median duration of second remission has been 15 months to date (range, 2 29 months). Patient 4 was treated with a 4-month course of steroids and declined the use of AZA but remains in remission 17 months after stopping steroids. Patients 10 and 22 relapsed recently and have begun a second course of prednisolone and commenced AZA. Patient 16 presented with panhypopituitarism and diabetes insipidus after stopping steroids while on AZA 1 mg/kg/day (nausea having prompted dose reduction). Magnetic resonance imaging brain scan revealed an inflammatory mass related to the pituitary/pituitary stalk, which subsequently resolved on reintroducing prednisolone 30 mg daily and AZA 1.5 mg/kg/

5 October 2009 POST-TREATMENT RELAPSE IN AIP/IAC 1093 Figure 3. Serum IgG4 before and after treatment. Box and whisker plot of serum IgG4 in pretreatment cohort, after treatment in the relapse/failure to wean steroid group, and the nonrelapse groups. ULN, upper limit of normal (1.3 g/l). day. The patient s pancreaticobiliary disease remained in remission throughout. Treatment of Patients Who Failed Weaning Three of the 5 patients who failed weaning of their initial treatment steroids had their prednisolone dose increased to 20 mg per day, whereas 2 were given 30 mg. Three patients were commenced on AZA, with a target dose of 2 mg/kg. Patients 21 and 2 were subsequently weaned off steroids after 4 and 14 months and remain in remission 11 and 22 months, respectively, on AZA monotherapy (Table 3). Patient 3 was treated with AZA and 20 mg prednisolone. His deranged liver biochemistry, biliary, and associated elevated creatinine responded and did not flare on weaning steroids. However, he had a polyarthropathy, which was exacerbated with a prednisolone dose less than 5 mg. He has thus been on long-term low dose ( 7.5 mg) prednisolone. Patient 14 developed neurologic deterioration with global cerebral dysfunction 2 weeks after coronary bypass grafting, while receiving prednisolone 5 mg. Investigations showed no evidence of an infective cause or a thromboembolic event, and imaging suggested an immunemediated encephalopathy. No significant response was seen to high-dose immunosuppression, including steroids, and the patient subsequently died 6 months later, without recovering preoperative cerebral function. Discussion It is now generally accepted that AIP represents one aspect of a multisystem disease characterized by the involvement of affected tissues by an IgG4-positive plasma cell infiltrate The term IgG4-related sclerosing disease 16 has also been advocated, and IAC has been used to describe the biliary disease with which AIP is frequently associated. 10 Although spontaneous improvement of pancreatic masses and biliary can occur, 3,17,18 a rapid response to steroid therapy is often seen, 4,5,19 and fewer complications appear to occur in those who have received steroids, compared with those Table 2. Clinical Profile and Management of 8 Patients Who Relapsed Continued treatment Duration of 2 nd remission (mo) Duration of 2 nd steroid course (mo) IgG4 at relapse (g/l) (0 1.3) ALP (IU/L) (40 129) Bilirubin ( mol/l) (0 20) Duration of 1 st remission (mo) IgG4 at remission (g/l) (0 1.3) Event at relapse Duration of initial steroids (mo) Patient no Nil Jaundice/hilar mass stricture 6 5 Un Jaundice/hilar stricture AZA 9 3 Un Recurrent abdominal AZA pain/diffuse cholangiopathy Hilar stricture N/A Steroids AZA Diffuse cholangiopathy AZA AZA Right hepatic duct mass stricture AZA Jaundice/hilar N/A Steroids AZA Low CBD and hilar ALP, alkaline phosphatase; CBD, common bile duct; N/A, not applicable because patients recently relapsed; Un, unavailable.

6 1094 SANDANAYAKE ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 10 Table 3. Clinical Profile and Management of 5 Patients Who Failed Steroid Weaning Continued treatment Duration of follow-up post-flare (mo) Duration of 2 nd steroid course (mo) Treatment of flare IgG4 at disease flare (g/l) (0 1.3) ALP (IU/L) (40 129) Bilirubin ( mol/l) (0 20) Hilar biliary stricture Duration of steroids before flare (mo) Event at flare Patient no. 1 8 Renal impairment Yes Steroids Steroids 2 13 Recurrent abdominal Yes Steroids AZA AZA pain and hilar 3 22 Renal impairment Yes Steroids AZA Steroids AZA Encephalitis Yes Steroids 4 6 Died Yes Steroids AZA 4 15 AZA 21 3 Jaundice and diffuse intrahepatic ALP, alkaline phosphatase. who have not. 7 Serum IgG4 levels fall in response to treatment, 20 and tissue infiltration by IgG4-positive plasma cells has been shown to resolve after prednisolone use. 21 Despite the absence of placebo-controlled studies, a response to steroids is an established component of the diagnostic criteria for AIP. 4,17,22 24 Nevertheless, the dose and duration of steroid therapy and long-term outcome after treatment have not been clarified. Several studies have recently demonstrated a relapse rate of 19% 55% after an initial favorable response to steroids. 4,5,7,8,10,19,25,26 The clinical pattern of this relapse and its optimal management remain to be defined. In this study, all 28 patients had a rapid response to initial steroid treatment, with improvement in symptoms, liver biochemistry, and biliary. All patients treated with steroids who underwent biliary stenting for obstructive jaundice remained non-icteric after removal of stents. We defined 2 groups that collectively represent disease relapse. In one group, 8 of 23 (35%) patients relapsed after successful steroid cessation and the development of clinical remission. In the other group, 5 of 28 (18%) patients failed to wean and stop their initial prednisolone course as a result of a flare of disease activity on steroid reduction. This represents a combined relapse/failure to wean rate of 46%. All patients who relapsed experienced worsening hilar biliary /IAC, with obstructive jaundice occurring in 7 of 8 (88%) patients. IAC was also a feature in the 5 patients in whom steroid weaning failed, and additional features included deterioration of renal function in 2 patients. The significant neurologic deterioration seen on steroid reduction in one patient could not be established (and did not respond to increased immunosuppression), and the conclusion drawn was that this most closely fitted an immune mediated encephalopathy. Neurologic complications of AIP/IgG4 systemic disease have recently been reported. 27 Certain factors appear to be associated with poststeroid relapse/failure to wean. Of the 23 patients with sclerosing cholangitis/iac before initial steroids, 13 (57%) subsequently relapsed or failed to wean, in comparison with none of the 5 patients without sclerosing cholangitis/iac. The absence of relapse in any AIP patient without associated IAC at the time of diagnosis is surprising, although our numbers are small. It has been shown that levels of serum IgG4 fall in response to steroid therapy, 20 and that a persistently raised serum IgG4 might be associated with relapse 6 and failure of disease control with steroids. 28 We did not find any statistically significant correlation between serum IgG4 levels and relapse. We believe that further studies will be necessary before the monitoring of serum IgG4 levels can be used in clinical practice to tailor therapy, and that there is insufficient evidence to support the continuation or reintroduction of immunosuppression on the basis of serum IgG4 alone. An interesting observation was that no patient in our series developed a relapse within the pancreas. The explanation for this is uncertain, but the frequent observation of pancreatic atrophy on imaging after steroids and of endocrine/exocrine insufficiency suggests that fibrosis might be established early. The presence of dense pancreatic fibrosis has previously been shown. 29 The fact that relapse predominantly occurs outside the pancreas lends further support for the concept that the pancreas is just one target (perhaps the first in AIP) of a multisystem IgG4 systemic disease. 8,13,30 The finding also suggests that longer-term immunosuppression for this disease

7 October 2009 POST-TREATMENT RELAPSE IN AIP/IAC 1095 should not have preservation of pancreatic function/anatomy as its primary goal, but that treatment of extrapancreatic tissues, such as the intrahepatic biliary tree, should be a particular focus. The reintroduction of immunosuppression in response to relapse of AIP/IAC allowed effective disease control in most cases, with improvements in cholangiography and liver biochemistry. This is in contrast to classic primary sclerosing cholangitis (PSC), which, despite similar radiologic appearances to IAC, does not respond to immunosuppression. 31 The explanation for this is unclear but might relate to disease duration. Biliary disease in AIP/IAC might evolve rapidly, suggesting a predominant inflammatory rather than fibrotic disease at presentation, which might be partially reversible with treatment. It is of note that steroids have been shown to be of some benefit in children with PSC 32 and in younger adults with a presumed shorter duration of disease. 33 Although the 9% of patients with PSC and increased serum IgG4 level 34 appear to have more rapidly progressive disease; further studies will be needed to elucidate whether steroids improve the outcome. It is clear that disease activity might vary significantly in different organs at any one time, perhaps related to cycles of inflammation and fibrosis (similar to other systemic diseases such as sarcoidosis). Equally, control of disease in one organ in response to treatment might not be reflected in another. For example, our patient who developed panhypopituitarism had excellent control of intrahepatic biliary disease on AZA monotherapy at the same time as developing an inflammatory pituitary mass. If longer-term immunosuppression is needed, what medical therapies might be considered? Maintenance oral steroid use has been proposed, as has pulsed intravenous methylprednisolone. 26 Disease control might be achieved with long-term steroids, but the side-effect profile necessitates that alternatives are considered. In view of the high prevalence of pancreatic exocrine insufficiency and biliary disease in patients with AIP/ IAC, steroid-induced osteoporosis would also be of concern. Case reports or small series have reported a beneficial role for mycophenolate, 10 5-mercaptopurine, 10 AZA, 5,10 and rituximab 35 in AIP. Although pancreatitis is reported to complicate approximately 1.5% of cases of AZA use (usually mild and occurring during the first few weeks), 36,37 there is no reason to suspect these risks to be increased in AIP. An analogy with the management of autoimmune hepatitis (AIH) is pertinent, because a rapid response to steroid therapy is predictably seen, but the high relapse rate necessitates longer-term immunosuppression. AZA has an established role in maintaining remission in AIH 38 and in preserving hepatic structure and function. In contrast to AIH, however, relapse of AIP after an initial steroid course appears to be frequent but not universal. In view of this, there is insufficient evidence to support prolonged immunosuppression from the outset in all patients with AIP. The duration of steroids after the introduction of AZA, parameters for guiding steroid reduction, and the possible role of low-dose maintenance steroids in combination with AZA remain to be clarified. It is difficult to set specific criteria by which to define disease control on treatment (and therefore the timing of treatment reduction or cessation). A necessity of complete normalization of liver biochemistry and resolution of all biliary stricturing might ignore the fact that some disease is irreversible and might lead to inappropriate prolongation of treatment. Whereas normalization of liver function test results and resolution of active hepatitis on liver biopsy might be used to guide cessation of immunosuppression in AIH, we do not believe that we have such reliable parameters in AIP/IAC as yet. In this study the presence of extrapancreatic disease, in particular IAC, predicted lack of maintained disease control after an initial steroid course. The biliary changes in AIP/IAC are dynamic, with progression to end-stage liver failure and portal hypertension reported, 10 yet a favorable clinical and radiologic response to treatment has been shown. 5,10 We have shown that remission and radiographic improvement might be achieved with AZA-based therapy after disease relapse. The timing, choice, and duration of longer-term immunosuppression in AIP/IAC merit further study. 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