Pancreatology xxx (2016) 1e9

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Pancreatology
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Original article

Diagnosis, treatment and long-term outcomes of autoimmune

pancreatitis in Spain based on the International Consensus
Diagnostic Criteria: A multi-centre study
Antonio Lo
pez-Serrano*, Javier Crespo, Isabel Pascual, Silvia Salord, Federico Bolado,

s J. del-Pozo-García, Lucas Ilzarbe, Enrique de-Madaria, Eduardo Moreno-Osset,
Andre
Members of the Autoimmune Pancreatitis in Spain Study Group
Department of Gastroenterology, Hospital Universitari Dr. Peset, University of Valencia, Valencia, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that has been reported
Available online xxx worldwide for the last two decades. The aim of this study is to analyse the clinical profile of patients from
Spain with AIP, as well as treatments, relapses and long-term outcomes.
Keywords: Methods: Data from 59 patients with suspected AIP that had been diagnosed in 15 institutions are
Autoimmune diseases retrospectively analysed. Subjects are classified according to the International Consensus Diagnostic
Diagnosis
Criteria (ICDC). Patients with type 1 AIP (AIP1) and type 2 AIP (AIP2) are compared. KaplaneMeier
Immunoglobulin G
methodology is used to estimate the overall survival without relapses.
Pancreatitis
Chronic
Results: Fifty-two patients met ICDC, 45 patients were AIP1 (86.5%). Common manifestations included
Therapeutics abdominal pain (65.4%) and obstructive jaundice (51.9%). Diffuse enlargement of pancreas was present in
51.0%; other organ involvement was present in 61.5%. Serum IgG4 increased in 76.7% of AIP1 patients vs.
20.0% in AIP2 (p ¼ 0.028). Tissue specimens were obtained in 76.9%. Initial successful treatment with
steroids or surgery was achieved in 79.8% and 17.3%, respectively. Maintenance treatment was given in
59.6%. Relapses were present in 40.4% of AIP1, with a median of 483 days. Successful long-term remission
was achieved in 86.4%.
Conclusions: AIP1 is the most frequent form of AIP in Spain in our dataset. Regularly, ICDC allows AIP
diagnosis without the need for surgery. Steroid and chirurgic treatments were effective and safe in most
patients with AIP, although maintenance was required many times because of their tendency to relapse.
Long-term serious consequences were uncommon.
Copyright © 2016, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All
rights reserved.

Introduction
Autoimmune pancreatitis (AIP) is an inflammatory disorder re-
ported recently. AIP is responsible for chronic pancreatitis in 5e10% of
patients [1,2], predominantly in Asian countries. Although some
overlap exists, AIP consists of two distinct clinical and histopatho-
logical forms of pancreatitis [3,4]. Type 1 AIP (AIP1) is a pancreatic
manifestation of immunoglobulin-G4 (IgG4)-related systemic disease
* Corresponding author. Servicio de Medicina Digestiva, Hospital Universitari Dr.
Peset, Av. Gaspar Aguilar, 90, 46007 Valencia, Spain. Tel.: þ34 963861913; fax: þ34
963862501.
E-mail address: lopez_antser@gva.es (A. Lo
pez-Serrano).
[5], while type 2 AIP (AIP2) is a pancreas-specific disorder that is not
associated with IgG4 [6]. Diagnosis of AIP requires a combination of
different data. Recently, many diagnostic criteria for AIP have been
proposed in the literature [7e14]. The Asian criteria and the revised
HISORt criteria have been used most frequently [11,12]. In 2010, the
International Association of Pancreatology described the Interna-
tional Consensus Diagnostic Criteria (ICDC) [5]. According to ICDC, the
diagnosis of AIP is based on the values of one or more of the following
factors: pancreatic parenchyma and pancreatic duct imaging, serum
IgG4 level, other organ involvement, histology of the pancreas and
response to steroid treatment. Criteria and algorithms for two types
of AIP were independently developed, and the classification catego-
rized AIP into two levels of confidence according to the reliability of
the test results.

http://dx.doi.org/10.1016/j.pan.2016.02.006
1424-3903/Copyright © 2016, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
j.pan.2016.02.006
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2
pez-Serrano et al. / Pancreatology xxx (2016) 1e9
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Table 1
Demographic and clinical characteristics of patients with autoimmune pancreatitis (AIP).

Variable Type of AIP p valueF

1 (N ¼ 45) 2 (N ¼ 5)

Age* (years) 64.4 (12.9) 53.2 (17.3) NST

Age at diagnosis* (years) 60.2 (11.6) 44.4 (18.0) 0.009T
Diagnostic delayy (weeks) 36.6 (2.5e17.5) 54.4 (1.5e133.5) NS
Sex
Female 12 (26.7) 0 NS
Male 33 (73.3) 5 (100.0)
Main manifestations
Obstructive jaundice 23 (51.1) 3 (60.0) NS
Abdominal pain 30 (66.7) 3 (60.0) NS
Weight loss 15 (33.3) 2 (40.0) NS
Acute pancreatitis 14 (31.1) 1 (20.0) NS
Hypertransaminasemia 16 (35.6) 0 e
Dissociate cholestasis 8 (17.8) 1 (20.0) NS
Steatorrhoea 4 (8.9) 0 e
Acute cholangitis 4 (8.9) 0 e
Pruritus 4 (8.9) 0 e
Hyperamylasaemia 16 (35.6) 1 (20.0) NS
Vomiting 1 (2.2) 0 e
Asymptomatic 1 (2.2) 0 e
Other organ involvement 25 (55.6) 5 (100) NS
Proximal biliary stenosis 8 (17.8) 1 (20.0) NS
Mediastinal and/or abdominal lymph nodes swelling 8 (17.8) 0 e
Thyroiditis 4 (8.9) 0 e
Ulcerative colitis 2 (4.4) 2 (40.0) e
Crohn disease (colonic) 0 3 (60.0)
Retroperitoneal fibrosis 3 (6.7) 0 e
Interstitial nephritis 3 (6.7) 0 e
Dacryoadenitis 3 (6.7) 0 e
Sialadenitis 3 (6.7) 0 e
Aortitis 2 (4.4) 0 e
Dermatologic disease 1 (2.2) 0 e
Autoimmune hepatitis 1 0 e
Gastric IgG4 involvement 1 0 e
Duodenal papilla IgG4 involvement 1 0 e
Mesenteric panniculitis 1 0 e
Cervical Neuropathy 1 0 e
Follow up* (days) 1428 (1547) 3160 (1415) 0.021T

Results are expressed as number of patients (percentage); *mean (standard deviation); or ymedian (interquartile range).
T ¼ Student's t test. F ¼ Fisher's exact test. IgG4 ¼ immunoglobulin-G4.

Over the last decade, several series of AIP cases have been reported
throughout Europe [13,15e23]. In our area, there are few reports on
patients with AIP [24e27], probably because of the low incidence of
the disease. The present study aim to know the clinical characteristics
of patients with AIP diagnosed at several tertiary care centres in Spain
using the ICDC [5], with particular emphasis on diagnosis, affected
organs, response to treatment, and long-term outcomes.
Methods
Patients
This paper presents an observational, retrospective and multi-
centre study. The first step was to design a protocol to collect data
from patients with AIP diagnosis performed in tertiary centres in
Spain through December 2014. Members of the Spanish Pancreatic
Association were invited to participate. Researches retrospectively
reviewed paper and/or electronic medical records for data collection,
including personal history, clinical manifestations, imaging studies,
laboratory tests, pathological diagnosis, treatment, relapses and
outcomes of the patients. Dr. Peset University Hospital carried out
coordination tasks. Data collection forms were submitted to the lead
investigator (A.L-S) for analysis. According to ICDC, those patients
classified as either definite or probable (type 1 or type 2) AIP or non-
specific AIP (Ns-AIP) were selected for the study [5].
Diagnostic delay was defined as the period from the beginning
of the symptoms to the AIP diagnosis; follow-up period was the
time from AIP diagnosis until death or the last visit. Focal or
mass-forming lesion was defined as focal-type AIP, and the
swollen pancreas extending from the pancreatic head to tail as
diffuse-type AIP [13]. Other organ involvement (OOI) was the
presence of extra-pancreatic disease (this did not include the
intra-pancreatic biliary tract involvement or distal biliary steno-
sis). Proximal biliary stenosis was the involvement of either hilar/
intrahepatic bile ducts or the extrahepatic common bile duct
proximal to the head of the pancreas; when it occurred in the
context of AIP1 it was referred to as IgG4-related sclerosing
cholangitis (IgG4-SC). Normal serum IgG4 levels were recognized
as those below the upper limit of normal for the laboratory that
performed the test. Remission was defined as the disappearance
of symptoms and imaging manifestations after the initial treat-
ment. Relapse was defined as the recurrence of symptoms of AIP
after initial resolution and/or radiological manifestations in the
pancreas or extra-pancreatic organs after excluding other dis-
eases [28,29].
The study was approved by the Clinic Investigation Ethical
Committee of Dr. Peset University Hospital and by the local com-
mittees of all the participating institutions, and was in compliance
with the Declaration of Helsinki. All patients (or their relatives in
their absence) gave written consent.

Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
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pez-Serrano et al. / Pancreatology xxx (2016) 1e9
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Statistical analysis Results

Basic descriptive statistics were obtained including mean, me-
dian, standard deviation (SD) and/or interquartile range (IQR) for
continuous variables, together with absolute frequency and per-
centage for discrete variables. Comparisons were made between
patients with AIP1 and patients with AIP2. Before performing
parametric tests, normal distribution of the continuous variables
was tested using the KolmogoroveSmirnov test or was assumed
when the sample size was >30 individuals. Nonparametric quan-
titative variables were compared using the ManneWhitney U test.
Continuous parametric variables differences were assessed using
Student's t test. Categorical data were compared using Chi-square
test and Fisher's exact test (when the expected frequency in cells
was <5). KaplaneMeier method was used to estimate and visually
assess overall patient survival without relapses from AIP diagnosis
to the end of follow up period. The log-rank statistic was used to
compare survival profiles for different groups of patients: AIP1 vs.
non-AIP1; presence or absence of OOI; focal vs. diffuse pancreatitis;
and medical treatment vs. surgery. Statistical analysis was per-
formed using the Statistical Package for Social Sciences (SPSS
version 17.0, Chicago, IL). All tests performed were bilateral and p
values <0.05 were considered as statistically significant.
Patient characteristics and clinical presentation
In response to the questionnaire, we collected information on 59
patients from 15 hospitals with suspected AIP attended between
February 1997 and December 2014. A detailed inspection detected
misclassification in 25 (42.4%) patients. Seven (11.9%) patients
without criteria of AIP according to ICDC were excluded from the
study. A total of 52 patients were included in the study. According
to ICDC, 45 (86.5%) patients were AIP1 (definitive, 38; probable, 7
patients); 5 (9.6%) patients were AIP2 (definitive, 1; probable, 4
patients), and 2 (3.8%) patients were Ns-AIP. The male-to-female
ratio was 3.2:1. Forty-seven patients (90.4%) were Spanish, and
the remaining five were from Morocco, India, Germany, Colombia
and Philippines, respectively. Table 1 shows the demographic and
clinical characteristics of AIP1 and AIP2 patients. Autoimmune
diseases were present in 13 patients (25.0%). Twenty-eight patients
had history of smoking; among them, 14 patients (50.0%) were ex-
smokers (>6 months) at the moment of the AIP diagnosis. Eight
patients had a history of alcohol consumption, with a median
(range) of 15 (5e50) g/day of alcohol consumption for 20 (1e45)
years.

Table 2
Imaging data of patients with autoimmune pancreatitis (AIP).

Imaging Type of AIP Area of pancreatic Diffuse narrowing of Localized narrowing Biliary extrahepatic stenosis Other
technique enlargement: the pancreatic duct of the pancreatic duct: distal/proximal/multiple
Diffuse/Localized head/body/tail/multiple
head/Localized
body or tail

CT 1 (43) 26/12/2 3 2/0/0/0 17/1/1 Adenopathy (5)

Pancreatic calcifications (3)
Pancreatic atrophy (1)
Mesenteric Panniculitis (1)
2 (4) 2/0/0 e e 1/1/0 Pancreatic atrophy (1)
Non-specific (2) 0/1/0 e 0/0/1/0 e Mesenteric Panniculitis (1)
Pancreatic atrophy (1)
Pancreatic calcifications (1)
MRI 1 (29) 14/6/2 4 1/1/1/1 4/1/1 Biliary dilation (6)
Portal thrombosis (1)
2 (2) 1/1/0 e 1/0/0/0 e Biliary dilation (1)
Non-specific (2) 0/1/0 2 e e e
MRCP 1 (28) e 1 3/2/1/1 7/1/3 Intrahepatic biliary
irregularity (6)
Pancreas Divisum (1)
2 (2) e e e 1/1/0 e
Non-specific (2) e 2 1/0/0 e
AUS 1 (40) 6/17/1 1 e 4/3/0 Biliary dilation (19)
Cholelithiasis (7)
Hepatic Cyst (1)
2 (3) 0/1/0 e e 0/1/0 Biliary dilation (1)
Non-specific (1) 0/1/0 e e Biliary dilation (1)
EUS 1 (20) 6/9/0 1 e e Pancreatic calcifications (2)
Adenopathy (1)
2 (2) 1/0/1 e e e e
Non-specific (1) e e e e e
ERCP 1 (19) e e 2/0/0/0 11/0/2 e
2 (1) e e e 1/0/0 e
Non-specific (1) e e 1/0/0/0 1/0/0 e
18F-FDG PET/CT 1 (3) 0/1a/1a e e e Lung hilum (1)
Thyroid gland (1)
2 (1) e e e e e

Results are expressed as number.

CT ¼ computed tomography. MRI ¼ magnetic resonance imaging. MRCP ¼ magnetic resonance cholangiopancreatography. AUS ¼ abdominal ultrasonography.
EUS ¼ endoscopic ultrasound. ERCP ¼ endoscopic retrograde cholangiopancreatography. 18F-FDG PET/CT ¼ Positron emission tomography with 2-deoxy-2-[fluorine-18]
fluoro-D-glucose integrated with computed tomography.
a
The same patient presented pathologic uptake at the head and tail of the pancreas.

Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
j.pan.2016.02.006
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4
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Table 3 (Table 4). Pathologic studies confirmed AIP1 only in 8 patients,

Laboratory tests of patients with autoimmune pancreatitis (AIP). when haematoxylineeosin staining of specimens revealed lym-
Variable Type of AIP p valueF phoplasmacytic pancreatitis. In addition, one patient presented
1 (N ¼ 45) 2 (N ¼ 5)
lymphoplasmacytic infiltration with fibrosis in the intra-pancreatic
z
biliary tree. None of these patients showed granulocyte epithelial
Serum IgG4 33/43 (76.7) 1/5 (20.0) 0.028
lesions. IgG4 immuno-histochemical analyses showed marked
Serum IgGz 18/38 (47.4) 0/3 e
Auto antibodies (other than IgG/IgG4) 24/45 (53.3) 3/5 (60.0) NS infiltration (>10 IgG4 positive plasma cells per high-power field) in
Antinuclear antibody 13/36 (36.1) 2/4 (50.0) NS the pancreas in 2 patients. One patient showed lymphoplasmacytic
Anti-carbonic anhydrase II antibody 10/17 (58.8) 1/4 (25.0) NS infiltration with IgG4-positive plasma cells in stomach and gall-
Anti-smooth muscle antibody 4/25 (16.0) 0/2 e
bladder [30].
Anti-thyroglobulin antibody 2/5 (66.7) 0/1 e
Anti-thyroid peroxidase antibody 1/2 (50.0) 0/1 e
Rheumatoid factor 0/15 1/2 (50.0) e Treatment and follow-up
Anti-mitochondrial antibody 0/26 0/2 e
Anti-neutrophil cytoplasmic antibody 0/12 0/1 e
Main treatment
Hyperbilirubinemiaz 23/45 (51.1) 3/5 (60.0) NS
Alanine aminotransferasex 16/45 (35.6) 0/5 e The main treatment and outcomes of the patients are shown in
Pancreatic exocrine insufficiency** 15/42 (35.7) 2/5 (40.0) NS Table 5. One patient with AIP1 presented spontaneous remission.
Diabetes mellitus 16/45 (35.6) 2/5 (40.0) NS Initial surgical resection for suspicion of focal pancreatic cancer or
Results are expressed as number of patients (percentage); *mean (standard devia- cholangiocarcinoma was performed in 7 and 2 patients, respec-
tion); or ymedian (interquartile range). tively. The surgical procedures included pancreato-duodenectomy
F ¼ Fisher's exact test. IgG4 ¼ immunoglobulin-G4. IgG ¼ immunoglobulin-G. (6 patients), segmental pancreatectomy (2 patients) and distal
z
>1 time above the standard limit.
x pancreatectomy (1 patient). Surgery was performed frequently if
>2 times above the standard limit.
**
Pancreatic exocrine insufficiency tests performed: Van der Kamer test, 7; faecal previous endoscopic ultrasonography-guided fine needle aspira-
elastase-1, 8; 13C-mixed triglycerides breath test, 4; and nutritional status, 2 tion (EUS-FNA) was not performed in focal pancreatitis (6/8; 75.0%),
patients. whereas only 3/15 (20.0%) patients with previous EUS-FNA were
operated (p ¼ 0.017). In contrast, 42 (80.7%) patients received
successful initial steroid treatment. Clinical improvement was
Imaging examinations observed at week 2 in 59.5% (25/42) of the patients (range: 1e6
weeks). Improvement in laboratory parameters was seen at week 4
Imaging findings of the reported patients are summarized in in 38.1% (16/42) of patients. Improvement in IgG4 levels was
Table 2. According to the pre-treatment examinations, 94.2% of pa- observed in 11/13 (84.6%) of the cases, 50% of them within the
tients (49/52) had enlargement of their pancreas: 51.0% (25/49) initial 5 weeks of treatment. Radiological improvement in pancre-
diffuse-AIP and 49.0% (24/49) focal-AIP. Main pancreatic duct ste- atic parenchyma was seen in 21/29 (72.4%) of patients, with a
nosis was seen in 15/52 (28.8%) patients. Twenty (38.4%) patients median (range) of 5 (2e36) weeks; controls to assure improvement
had biliary stricture in the lower part of the common bile duct, while on radiological lesions were performed using computed tomogra-
7 (13.4%) patients showed that in the hilar/intrahepatic bile ducts. phy (CT) in 20/42 (47.6%), magnetic resonance chol-
angiopancreatography (MRCP) in 5/42 (11.9%) and magnetic
Laboratory tests resonance imaging (MRI) in 4/42 (9.5%) of patients.

Results of laboratory tests performed to the patients are showed in Relapses

Table 3. Serum IgG4 level was >2 times above the standard limit only
in AIP1 patients (18/43; 41.9%); in 44.0% (11/25) of diffuse AIP vs. 27.3%
(6/22) of focal AIP (p ¼ NS); in 50.0% (5/10) of patients operated vs.
32.5% (13/40) of non-operated (p ¼ NS); and in 9/21 (42.9%) of pa-
tients without OOI vs. 8/28 (28.6%) of patients with OOI (p ¼ 0.059).
Nineteen out of 28 (67.9%) patients with positive autoimmune anti-
bodies (other than IgG4) showed an elevated level of serum IgG4.
Pathology
Tissue specimens were obtained from various organs in 40/52
(76.9%) patients, including the pancreas in 29/40 (72.5%) patients
At the end of follow-up period, 21 (50%) patients had suffered at
least one relapse: 16/42 (38.1%) after steroid treatment, 4/9 (44.4%)
after surgery and one without previous treatment (Table 5). One
relapse occurred in 14 patients, and 2e5 relapses in 7 patients.
Relapses occurred only in AIP1 patients (Fig. 1). In steroid treated
subjects, relapses occurred more often following steroid discon-
tinuation (9/16; 56.2%), than either during the steroid tapering (5/
16; 31.2%) or while on maintenance steroids (4/17; 23.5%). Relapses
occurred in 16 patients at the pancreas, at the extra-pancreatic
organs in 12 patients, and in 6 patients both at the pancreas and
at extra-pancreatic organs. Patients with initial high levels of serum
IgG4 had more relapses (18/34; 52.9%) than those with normal

Table 4
Histological examinations of patients with autoimmune pancreatitis (AIP).

Organs Procedures Type of AIP

1 (N ¼ 35) 2 (N ¼ 3) Non-specific (N ¼ 2)

Pancreas EUS-FNA 24 (68.6) 1 (33.3) e

Resection 11 (31.4) 1 (33.3) e
Percutaneous FNA 2 (5.7) 1 (33.3) e
Duodenal papilla Endoscopic biopsy 7 (20.0) e 1 (50.0)
Bile duct Cytology brush 6 (17.1) e 1 (50.0)
Lymph nodes swelling Percutaneous biopsy 1 (2.9) e e

Results are expressed as number (%).

EUS-FNA ¼ endoscopic ultrasonography-guided fine needle aspiration.
FNA ¼ guided fine needle aspiration.

Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
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pez-Serrano et al. / Pancreatology xxx (2016) 1e9
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Table 5
The main treatment of patients with autoimmune pancreatitis (AIP) until follow-up endpoint.

Initial treatment Type of AIP Treatment after relapse

1 (N ¼ 45) 2 (N ¼ 5) Non-specific (N ¼ 2)

Steroid 36 (20/16) 4 (4/0) 2 (2/0)

Steroid alone 26 (11/15a) 4 (4/0) 2 (2/0) Steroid þ azathioprine 11 (8/3b)
Surgery 2 (2/0)
Steroid alone 1 (1/0)
Steroid þ infliximab 1 (1/0)
BDPT þ steroid 9 (8/1) e e Surgery 1 (1/0)
PDPT þ steroid 1 (1/0) e e e e
Surgery 8 (4/4) 1 (1/0) e
Surgery alone 5 (2/3) e e Steroid alone 3 (3/0)
BDPT þ surgery 2 (1d/1) 1 (1/0) e Steroid alone 1 (0/1c)
Steroid þ surgery 1 (1/0) e e e e
None 1 (0/1) e e Steroid alone 1 (1/0)

Results are expressed as number (remissions/relapse).

BDPT ¼ prosthesis at the biliary duct.
PDPT ¼ preoperative prosthesis at the main pancreatic duct.
a
7/15 patients relapsed during steroid treatment.
b
Relapses were treated with methotrexate, 6-mercaptopurine, and etanercept, respectively.
c
Relapse was treated with steroid alone.
d
1 patient in remission with steroid þ AZA after surgery.

levels (3/16; 18.8%) (p ¼ 0.022). Six out of the 9 subjects with IgG4- diagnosis. No statistically significant differences were found in the
SC had at least one relapse. median to first relapse between patients with or without OOI (463
The median (IQR) time to relapse was 483 (537) days. Fifty per vs. 455 days); diffuse AIP or focal AIP (469 vs. 630 days); or initial
cent of AIP1 patients had no relapse within 748 days from surgery or medical treatment (155 vs. 487 days). Fifty per cent of

Fig. 1. Plots of KaplaneMeier product limit estimates of survival without relapses in patients with autoimmune pancreatitis (AIP) and comparisons of survival profiles for different
groups: (A) patients with type 1 AIP (AIP1) vs. patients without AIP1 (Non-AIP1); (B) patients with other organ involvement (OOI) vs. patients without OOI; (C) patients with diffuse
vs. focal AIP; and (D) patients with initial medical treatment vs. surgery.

Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
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patients with or without OOI were relapse free within 487 and 455
days from diagnosis, respectively; 1111 and 4606 days in diffuse or
focal AIP patients; and 729 and 483 days in patients with or without
surgery, respectively (Fig. 1).
Successful remission was achieved in 19/21 (90.54%) of patients
with relapses. Azathioprine median (range) doses in 12 patients
were 100 (50e150) mg/day, and it was prescribed during a mean
(SD) of 11.5 (12.6) months. Complete response was achieved in 9
patients. Azathioprine was removed in 4 patients due to occurrence
of hepatitis, herpes zoster infection, gastric intolerance and meta-
static colon neoplasia, respectively; in 3 patients, it was replaced by
methotrexate, 6-mercaptopurine or etanercept, respectively. Be-
sides, one patient needed morphine-derived treatment because of
recurrent epigastric pain.
Steroid treatment
Steroid was initially given orally to all patients except for three
with transient intravenous catheter. Median (range) prednisone initial
doses were 40 (16e80) mg/24 h. Steroid doses were tapered (median)
5.0 mg weekly (range: 2.5e15.0 mg). Steroid withdrawal was
completely achieved before the 15th week (range: 1e153) in half of
the patients, while in 80% of them that was achieved before to 15th
month. Median (range) duration of steroid treatment was 15 (1e153)
weeks and the response rate was 80.9% after the first course of
treatment. Median (range) withdrawal week of steroids was 4 (1e19).
Maintenance steroid treatment was given in 31/42 (73.8%) patients,
with a median (range) doses of 5 (1e30) mg. Reasons for prolonged
steroid treatment were high risk of recurrence or recurrence in 7 and
24 of patients, respectively. Complications related to steroid treatment
included increase of blood glucose levels in 14 patients, infections in 2
patients, and secondary suprarenal insufficiency in one patient.
Late complications
Cancer was diagnosed during follow-up period in 3 patients:
pancreatic, parotid and bladder cancer, after 6 months, 13 years and 17
years since diagnosis, respectively. Two patients were dead at the end
of the study period: a 64 year-old patient because of advanced
pancreatic carcinoma; and a 74 year-old patient because of pneumonia.
Discussion
In this study, we aim to characterize the short-term and long-
term clinical outcomes for patients with AIP in our area according
to ICDC. Our findings support previous results of the clinical profile
of AIP [3,8,12,23,31e33]. AIP1 has been the most frequent form of
AIP, predominantly affecting men older than 50 years of age.
Obstructive jaundice was the predominant initial symptom and
biliary stricture in the lower part of the bile duct was the most
common radiological finding. However, mild acute pancreatitis
occurred in 30% of our patients, predominantly in AIP1, whereas
other studies with a larger number of patients have shown that
acute pancreatitis is more common in AIP2 [33]. IgG4 was used to
allow the diagnostic of IAP mainly in AIP1 [34]. CT was the main
imaging technique performed, although MRI was frequently used.
Steroids were the leading treatment used; however, long-term
treatments were required in many patients in spite of their good
initial response.
AIP is a type of pancreatitis that has been reported for the last
two decades [35]. AIP has been extensively reported worldwide,
but the epidemiology of AIP is not fully known. Surveys from Japan
indicate that incidence and prevalence rates of AIP are increasing
[32,36]. Two multicentre, international series of patients with AIP
from Europe, Asia and USA have been reported [37,38]. Hart et al.
conducted an analysis on 1064 patients with AIP diagnosed ac-
cording to ICDC from 10 different countries [38]. The proportion of
Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
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patients with AIP2 was lower in Asia (3.7%) than in both Europe
(12.9%) and North America (13.7%). In our dataset, 10.4% of patients
presented AIP2, which is in line with that reported for other
western countries.
Two previous studies of patients with probable AIP have been
carried out in Spain, in the setting of patients with idiopathic
chronic pancreatitis [24,25]. Their main objective was to know the
clinical utility of antibodies against to carbonic anhydrase and/or
IgG4 for the diagnosis of AIP. However, our study registers the
largest series of AIP in Spain and analyses the clinical features,
diagnosis, treatment and outcomes of these patients.
AIP is a complex disease whose diagnosis raises a challenge that
requires diagnostic scores. According to a recent study on 61 AIP
patients, out of the five major diagnostic criteria (ICDC, HISORt,
revised Japanese Pancreas Society e JPS e criteria, Asian and
Korean), ICDC was found to be the most accurate for the diagnosis
of AIP [39]. However, the ICDC diagnostic is very elaborate and
somewhat troublesome for a general use [40]. In our dataset, 42.4%
(25/59) of patients were misclassified by the researchers. Seven
patients did not meet ICDC, and they were excluded from the study
(one-seventh in the recent study of Van Heerde et al.) [40]. In ICDC,
the presence of OOI and the elevation of serum IgG4 level are the
main determining factors in the choice of which algorithms to
follow (AIP1 vs. AIP2). However, their absence does not necessarily
imply diagnosis of AIP2, as AIP1 can also be seronegative and
without OOI. In our study, we have found that the most common
source of misdiagnosis of AIP was serum IgG4. In the absence of
significantly elevated IgG4 levels, our patients were frequently not
classified as AIP1: 15/30 (48.3%) patients with correct diagnosis had
high IgG4 levels (>2 times above the upper limit of normal),
whereas levels were lower in 20/25 (80.0%) of misdiagnosed pa-
tients. In 9/25 (36.0%) patients not categorized as AIP1, the final
diagnosis was AIP1 when diagnostic criteria other than serology
were verified, while there was 2/27 (7.4%) patients categorized as
AIP1 that definitely were not an AIP. In addition, in the absence of
significantly high IgG4 levels the distinction between probable
AIP1, probable AIP2 and Ns-AIP is often ambiguous; for these rea-
sons, some experts have proposed that they could be merged into a
single entity called “probable AIP” [41]. On the other hand,
mistaken allocation of patients was more likely in absence of OOI
(14/26; 53.8%) than when that is present (13/33; 39.4%). Similarly to
other studies, OOI was present in 61.5% of patients in our data
[42,43]. Half of OOI lesions appeared after the diagnosis of the
disease. OOIs are often an important clue for diagnosis, like IBD to
the diagnostic to AIP2 [33]. IBD was present in 13.5% of our patients.
AIP1 may be mistakenly classified as AIP2 due to accompanying
IBD. The latter occurred in 1 patient in our data. Certainly this does
not affect the initial treatment selection, but it may have an impact
on predicting recurrence or on decision for a maintenance therapy.
Following ICDC, the diagnosis of AIP also requires the existence
of pancreatic enlargement and/or the presence of obstructive
jaundice. This is because ICDC was developed for the preoperative
diagnosis of AIP to avoid unnecessary surgeries. A patient in our
study with jaundice had a postoperative diagnosis of AIP1, without
prior images of pancreatic involvement. Van Heerde et al. pre-
sented a retrospective comparative study including 114 patients
with AIP [40]. Only 68% of patients met the ICDC (88.1% in our
global series). They showed that, if pancreatic abnormalities are not
present in abdominal CT, HISORt was the only scoring system that
could establish a diagnosis of AIP. These authors recommend the
use of HISORt criteria, and complementary, the use of the Asian
diagnostic scoring system if a pancreatogram is available (optional)
or if IgG4 level is normal (mandatory), and ICDC if diagnosis is still
not confirmed. Similar recommendations have been made in Japan.
Provided that in Japanese cases with AIP2 are extremely rare, the

pez-Serrano et al. / Pancreatology xxx (2016) 1e9
A. Lo
JPS 2011 criteria are recommended for the diagnosis of AIP1 [9],
with special emphasis in excluding malignancy by endoscopic
retrograde cholangiopancreatography (ERCP) and/or EUS-FNA; in
this case, the ICDC are required to diagnose cases of Ns-AIP or AIP2.
Nonetheless, a more simplified and unified algorithm that allows
the diagnosis of AIP in the initial stage of the disease is required
[41].
Using ICDC, 4 patients in our dataset (3 with diffuse-AIP, and one
with focal-AIP) were definitely AIP1 because a good response to
steroids was achieved, in addition to additional criteria such as
pancreatic enlargement with or without ductal affection that were
also satisfied. The latter was important to avoid pancreatic resec-
tion, a situation that represents a failure of ICDC; although extreme
caution is required even when EUS-FNA is performed to rule out
pancreatic cancer [5]. When a EUS-FNA was performed, patients
were more frequently managed with conservative treatment (87%),
whereas 72% of surgeries were performed in non-EUS-FNA pa-
tients. Perhaps, the general expansion of EUS in tertiary centres in
Spain in the last decade allows us to rule out pancreatic cancer
more often, which is very important in patients with obstructive
jaundice and signs of possible AIP. Although some reports
emphasize the usefulness of EUS-FNA for the diagnosis of AIP
[32,44,45], a histological diagnosis of AIP using the small samples
obtained by EUS-FNA is somewhat difficult. In our study, EUS-FNA
was performed in 48.0% of patients, and in any case was helpful for
the diagnosis of AIP. Obtaining samples with endoscopic ultraso-
nography core biopsy (EUS-CB) is a promising test to improve tissue
acquisition [46], but its utility in AIP has not been shown so far. An
alternative to EUS-CB may be biopsy of the ampulla for IgG4 im-
munostaining in presumed AIP1 patients [5,45]. IgG4-positive
lymphoplasmacytic infiltrate was seen in a resected stomach in
our cases; so, gastroscopy may have an important role in the study
of these patients [47]. Only two patients showed complete histo-
logic features of AIP1, including infiltration of IgG4-positive plasma
cells.
Although abdominal ultrasonography in AIP patients is effective
for detecting the enlarged pancreas, similarly to previous studies
[48], we did not found dilatation of the main pancreatic duct in
most cases. CT, MRI and MRCP may be also useful in the diagnostic
of AIP and in evaluating the resolution of lesions [28]. However, the
role of ERCP in the diagnosis of AIP is contradictory around different
guidelines [31,49,50]. In our study, ductal changes have been
studied using MRCP, a non-invasive modality that is inferior to
ERCP in detecting the subtle ductal changes in AIP [51], but with the
advantage of avoiding the risk of post-ERCP pancreatitis. However,
in previous studies, there was no post-ERCP pancreatitis in patients
with AIP [33,52,53]. Nowadays, MRCP-enhanced secretin may be an
alternative to ERCP [42], but so far no study has been documented
in this setting. It has been suggested that Fluorine-18 fluorodeox-
yglucose positron emission tomography (FDG-PET) may be used to
allow a more rapid and objective assessment of the response to
steroids [54] and to discriminate between AIP and pancreatic
cancer [55,56]. PET was performed in 4 patients in our study
outside on acute period of the disease to check the presence of
extra-pancreatic lesions, and a pathologic uptake was detected in
the pancreatic area in one patient.
IgG4-SC and lymphadenopathy were the leading extra-
pancreatic lesions. According to ICDC, in our study distal bile duct
stricture was regarded as a part of AIP caused by biliary extrinsic
compression and was not diagnosed as IgG4-SC. However, Japanese
authors advocate for the inclusion of all type of biliary affection as
IgG4-SC because resection specimens of patients with isolated
intra-pancreatic common bile duct stricture often show that ductal
wall thickening spreads continuously from intra-pancreatic com-
mon bile duct to the supra-pancreatic middle bile duct [57].
Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
j.pan.2016.02.006
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2016. Elsevier Inc. Todos los derechos reservados.
7
Additionally, Japanese researchers have suggested that both IgG4-
related biliary inflammation and pancreatic head swelling affect
lower bile duct stricture [58]. For that reason, consensus on an
accurate definition of bile duct involvement as OOI would be
necessary [41]. High levels of serum IgG4 are present in 68e81% of
AIP patients, similar to our study [12,59,60]. Other autoimmune
antibodies were excluded from ICDC because none of them
appear to be disease specific [25,61,62].
Although spontaneous improvement of AIP is seen in some
patients, the standard therapy for AIP is oral steroids [63]. In the
present study, steroids were given to 42 patients as the main
treatment, with an initial prednisone dose of 30e40 mg in 33
(78.6%) patients. Nine patients with distal biliary stenosis received
temporarily prosthesis at the biliary duct (BDPT) previously to
steroid treatment, and another 9 patients with (extra-pancreatic)
IgG4-SC resolved with steroid treatment. In addition, pancreatic
lesions display a good response to steroid therapy. So, BDPT may be
unnecessary in distal biliary if carefully steroid trial to allow AIP
diagnosis is performed [64]. Nonetheless, unresponsive biliary
affectation may be due to advanced fibrous scarring in the late
course of the disease [65].
Recent studies have reported that the relapses are more com-
mon in type 1 (31e50%) than in type 2 AIP (0e15%) [33,38,50]. The
location of the recurrence is predominantly in pancreas [38], as in
our study. Most relapses occur after steroids reduction or discon-
tinuation and often require the reintroduction of such treatment.
Proximal bile duct involvement (like in 8/9 patients in our series)
and persistent increase of serum IgG4 levels may be associated to
relapses [38,66]. A rapid decrease in IgG4 level is seen in our pa-
tients after corticosteroid treatment, but this has been studied in 11
patients only. Diffuse AIP, another risk factor of relapses [6], is more
frequently associated in our series with earlier relapse than focal
AIP. In relapsed cases, re-administration or dose-up of steroid, and
administration of immunomodulators or B-cell depletion therapy
using rituximab may be effective [38,66,67]. Complications related
to steroid treatment (they appeared in 63.5% of the patients) and
the high degree of relapses lead us to conclude that alternative
treatments to steroids should be used in a large proportion of AIP1
patients. One patient with active Crohn disease and relapsed AIP
responded to anti-tumour necrosis factor therapy (anti-TNF), and
that may be a promising treatment for recurrent AIP. Relapses
affected two patients with pancreatic calcifications, a possible
sequel of chronic pancreatitis described in AIP [68]. On the contrary,
previous pancreatectomy may be associated with lower frequency
of disease relapse [67]. In fact, in our study, relapses after surgery
occurred fewer than relapses after medical treatment.
Long term prognosis of the disease is unknown. AIP is often
associated with pancreatic exocrine and endocrine dysfunction.
Similar to other studies [69e71], diabetes mellitus was present in
many patients at AIP presentation, but some patients showed
exacerbation of pre-existing diabetes with the onset of AIP and/or
with the steroid treatment. Furthermore, AIP is in many cases
associated with pancreatic exocrine dysfunction [69]. The onset of
chronic pancreatitis in AIP could favour its development [68]. The
prevalence of exocrine pancreatic insufficiency in our series was
36%, slightly lower than those reported in the literature. These
differences may be due to the absence of suspicion of this situation,
and for that reason their existence was not investigated.
Patients with AIP occasionally develop various types of cancer
[63,72]. Two retrospective studies have documented pancreatic
cancer in AIP [38,73], in many cases diagnosed synchronously with
AIP or detected during the first year of follow-up [38]. K-ras mu-
tations in pancreas tissue may explain it [66], although some au-
thors have proposed that type 1 AIP is a paraneoplastic condition
[74]. In our study, a pancreatic cancer was detected 6 months
8
pez-Serrano et al. / Pancreatology xxx (2016) 1e9
A. Lo
after the AIP diagnosis. Previous FNA was negative to malignancy,
but there is a possibility that an un-sampled neoplastic disease may
coexist in the same lesion. For this reason, a high serum IgG4
concentration and diffuse enlargement of pancreas cannot preclude
the presence of pancreatic cancer. Hence, other criteria such us
response to steroid should be added, a recommendation proposed
in ICDC algorithm to diagnose AIP [5]. Further studies are needed to
conclude whether or not that increases the risk of cancer compared
with the general population.
The current study has several limitations. It is a retrospective
study of a rare disease over 17 years. Diagnostic strategies and
management of AIP have changed over this period of time. So,
variability in the data and the low number of patients included
prevent us from obtaining far-reaching conclusions. Comparisons
between groups are not statistically different in overall survival
without relapses. These analyses are often complicated when we
have partial information, which is fairly common in retrospective
studies. However, the KaplaneMeier estimate is the simplest way
of computing the survival over time in spite of difficulties associ-
ated with subjects or situations [75]. Predictive factors for both the
response and the disease recurrence following treatment should be
the main objective of future studies in AIP. Even so, given the lack of
similar studies in our area, this study probably will allow us to
know more accurately the profile of patients with AIP and to apply a
more adequate treatment.
Conclusion
In conclusion, AIP1 is the most frequent form of AIP in our area,
often presented with obstructive jaundice and with elevated serum
IgG4. Clinical manifestations, laboratory tests, imaging and patho-
logical examinations could increase the diagnostic rate of AIP.
Although the use of ICDC is complex, it may allow AIP diagnosis
without the need for surgery in many cases. Steroid and chirurgic
treatments are effective and safe at the beginning of the disease but
they have an elevate rate of relapses. So, maintenance treatment
including immunomodulators is often required. Long-term serious
consequences are uncommon. Further investigation is necessary to
clarify the pathogenic mechanisms, including more definite sero-
logical markers and identification of the best diagnostic and ther-
apeutic strategies.
Contributions of authors
ALS: study concept and design; acquisition of data; analysis and
interpretation of data; drafting of the manuscript; critical revision
of the manuscript for important intellectual content; statistical
analysis. JC, SS, FB, IP, LI, EdM: acquisition of data, critical revision of
the manuscript for important intellectual content. EMO: critical
revision of the manuscript for important intellectual content. All
authors approved the final version.
Acknowledgements
The authors thank other Members of the Autoimmune Pancre-
atitis in Spain Study Group for their work to include patients:

n, Spain), Alonso C (Hospital
Almela P (Hospital General de Castello
Universitario Marque
s de Valdecilla, Santander, Spain), Aparisi L
(Hospital Universitari Clínic, Valencia, Spain), Casi MA (Complejo

n M (Hospital
Hospitalario de Navarra, Pamplona, Spain), Concepcio
de la Santa Creu i Sant Pau, Barcelona, Spain), García N (Hospital
Universitari Clínic, Valencia, Spain), Garrido C (Hospital Son Espa-
ses, Palma de Mallorca, Spain), Higo
n MD (Hospital Universitari i
Politecnic La Fe, Valencia, Spain), Marra-Lo
pez C (Hospital Uni-
versitario Araba-Sede Txagorritxu, Vitoria-Gasteiz, Spain),
Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
Descargado de ClinicalKey.es desde Biblioteca Nacional de Salud y Seguridad Social, BINASSS mayo 12, 2016.
j.pan.2016.02.006Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2016. Elsevier Inc. Todos los derechos reservados.
Pleguezuelo M (Hospital Reina Sofía, Co
rdoba, Spain), Rodríguez M
(Hospital Universitario Central de Asturias, Oviedo, Spain), Seca-
nella L (Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat,
Spain).
We would like to acknowledge with appreciation Dr. Francisco J.
Santonja (Department of Statistics and Operations Research, Fac-
ulty of Mathematics, University of Valencia, Spain) for the statistical
analysis of the study.
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Please cite this article in press as: Lo
pez-Serrano A, et al., Diagnosis, treatment and long-term outcomes of autoimmune pancreatitis in Spain
based on the International Consensus Diagnostic Criteria: A multi-centre study, Pancreatology (2016), http://dx.doi.org/10.1016/
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