Autoimmunity Reviews 5 (2006) 314 318

www.elsevier.com/locate/autrev

Lupus-associated pancreatitis
Gabriel S. Breuer a,b,, Asher Baer a , David Dahan a , Gideon Nesher a,b
a
Department of Internal Medicine, Shaare-Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel
b
Rheumatology Service, Shaare-Zedek Medical Center, Jerusalem, Israel
Received 17 October 2005; accepted 10 November 2005
Available online 27 January 2006

Abstract

A number of lupus patients develop episodes of acute idiopathic pancreatitis, unrelated to the known causes of mechanical
obstruction of the pancreatic duct or toxic-metabolic etiologies. This lupus-associated pancreatitis is rare. The estimated annual
incidence was 0.41.1/1000 lupus patients. A literature search found detailed descriptions of this condition in 77 lupus patients.
Their median age was 27, and 88% were females. Abdominal pain was the most frequent pancreatitis-related symptom (88%).
In 97% the diagnosis of pancreatitis was based on laboratory evidence of elevated serum amylase or lipase. Most cases were
unrelated to treatment with steroids or azathioprine. Most of the patients (84%) had active lupus at the time of pancreatitis.
Mortality rate was 27%, higher than in non-SLE associated pancreatitis. Active lupus and several biochemical abnormalities,
but not treatment with steroids or azathioprine, were significantly associated with increased mortality. Treatment with steroids
lowered the mortality by 67% compared to non-treated patients.
2006 Elsevier B.V. All rights reserved.

Keywords: Pancreatitis; Lupus; Steroids; Azathioprine; Mortality

Contents

1. Incidence of lupus-associated pancreatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

2. Relationship of pancreatitis to SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
3. Relationship of the onset of pancreatitis to treatment with steroids or azathioprine . . . . . . . . . . . . . . . . . 315
4. Clinical and laboratory manifestations of acute lupus-associated pancreatitis . . . . . . . . . . . . . . . . . . . . . 315
5. Pathology and etiology-pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
6. Treatment, pancreatitis complications, and outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

Involvement of the pancreas in systemic lupus ery-

Corresponding author. Department of Internal Medicine, Shaare-
Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. Tel.:
+972 2 6555 687; fax: +972 2 6666 049.
E-mail address: gbreuer@szmc.org.il (G.S. Breuer).
1568-9972/$ - see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2005.11.004
thematosus (SLE) is rare. The common causes of pan-
creatitis in the general population are mechanical
obstruction of the pancreatic duct (most frequently a
result of choledocholithiasis) and toxic-metabolic
 G.S. Breuer et al. / Autoimmunity Reviews 5 (2006) 314318
(secondary to alcohol intake, certain drugs, hypercalce-
mia, or hypertriglyceridemia) [1,2]. SLE patients may
certainly develop acute pancreatitis as a result of those
etiologies, however a number of patients develop idio-
pathic pancreatitis, where no etiology other than SLE
itself could be identified. A literature search found
detailed descriptions of this condition in 77 lupus
patients [336]. Their median age was 27, and 88% were
females.
1. Incidence of lupus-associated pancreatitis
The annual incidence of this idiopatic or lupus-
associated pancreatitis is estimated to be 0.41.1 per
1000 lupus patients. Saab et al. [3] found 8 cases of
pancreatitis among 891 SLE cases over a period of
9 years, giving an annual incidence of 1/1000. Pascual-
Ramos et al. [37] reported pancreatitis in 35 of 895
SLE patients over a period of 17 years, an annual
incidence of 2.3 / 1000. However, more than a half of
these patients had mechanical or toxic-metabolic
etiologies, so the annual incidence of idiopathic
pancreatitis was 1.1 / 1000. Derk and DeHoratius [38]
reported pancreatitis in only 25 of 2947 SLE patients
over a period of 20 years, giving an annual incidence of
0.4 / 1000.
2. Relationship of pancreatitis to SLE
In 22% of the patients the acute pancreatitis was
among the presenting symptoms of SLE. In some cases it
was the sole presenting symptom. In additional 22% of
the patients pancreatitis occurred within 1 year of the
diagnosis of SLE. Similarly, in one series [37] 60% of
the lupus patients with pancreatitis developed this
manifestation within 2 years of the diagnosis of SLE.
However, in another series the median SLE disease
duration was longer (5.5 years) at the time of pancreatitis
[38].
Acute pancreatitis was associated with active SLE.
At the time of pancreatitis, only 10 patients did not
have any manifestation of lupus. Pascual-Ramos et al.
[37] compared SLE activity scores between patients
with pancreatitis associated with mechanical or toxic-
metabolic etiologies, and patients with idiopathic
pancreatitis. The SLE disease activity index was
significantly increased in the patients with idiopathic
pancreatitis.
Among patients with SLE manifestations, skin
involvement was the most common, followed by joint
and renal involvement. Most of the patients also had
laboratory evidence of active lupus (see below).
315
3. Relationship of the onset of pancreatitis to
treatment with steroids or azathioprine
Steroids and azathioprine are included in the group of
medications implicated as potentially causing pancrea-
titis [1,2]. Fifty-one patients (66%) were on steroid
treatment and 10 (13%) were also on azathioprine at the
onset of pancreatitis. In a few cases these medications
were considered by the respective authors as causing the
episode of acute pancreatitis, although this was not
proven in any of them. Among the patients on steroids
and azathioprine, these medications were continued
during the episode of pancreatitis, in 82% and 50% of
the patients, respectively. Twenty-six patients were not
on steroid or azathioprine therapy at the onset of pan-
creatitis. Among these patients, steroids were started in
22, and azathioprine in 3.
Pascual-Ramos et al. [37] compared the frequency of
steroid therapy at the onset of pancreatitis between the
idiopathic (SLE-associated) group and the group with
mechanical or toxic-metabolic etiologies. There was no
difference in the frequency of steroid administration or
in the dosing. Furthermore, four patients who had SLE-
associated acute pancreatitis were rechallenged with
those medications. None developed further episodes of
pancreatitis.
Although the role of steroids and azathioprine as
etiological factors in acute pancreatitis is difficult to
ascertain or to disprove, these data suggest that in most
cases steroids and azathioprine are not associated with
triggering acute pancreatitis.
4. Clinical and laboratory manifestations of acute
lupus-associated pancreatitis
Abdominal pain was the most frequent pancreatitis-
related symptom (88% of the patients). In only 23% of
the patients the pain radiated to the back. Two thirds of
the patients had nausea or vomiting, and a half of them
had fever. Diarrhea was uncommon (9%). A few pa-
tients had panniculitis.
In all but 2 patients the diagnosis of acute pan-
creatitis was based on laboratory evidence of elevated
serum amylase or lipase. Imaging studies abdominal
ultrasonography, computerized tomography (CT) of
the abdomen and endoscopic retrograde cholangio-
pancreatography (ERCP) were performed in 41
patients to aid in diagnosing the cause of the
abdominal symptoms. However, the sensitivity of CT
and ultrasonography for diagnosing pancreatitis in
these cases was not high 76% for CT and 55% for
ultrasonography.
316 G.S. Breuer et al. / Autoimmunity Reviews 5 (2006) 314318
Table 1
The more common complications of acute pancreatitis in 77 SLE
patients
Outcome/complication Number (%) of patients
Respiratory insufficiency 17 (22)
Recurrent pancreatitis 17 (22)
Ascites 15 (19)
Pleural effusion 14 (18)
Infection 14 (18)
Acute renal failure 11 (14)
Circulatory shock 9 (12)
Pancreatic pseudocyst 9 (12)
Additional complications were peritoneal hemorrhage, chronic
pancreatitis, pericardial effusion, panniculitis, disseminated intravas-
cular coagulation, and thrombotic thrombocytopenic purpura.
Additional biochemical abnormalities included hy-
poalbuminemia (in 78%), abnormal liver function tests
(in 65%), elevated serum creatinine (44%), and hypo-
calcemia (23%). Abnormalities in blood counts were
also common: anemia, leukopenia, and thrombocytope-
nia were relatively common (81%, 59%, and 48%,
respectively), while leukocytosis was infrequent (only
15%). It should be noted that in non-SLE pancreatitis
(e.g. those related to mechanical or toxic-metabolic
etiologies) leukocytosis is much more common. Urinal-
ysis showed proteinuria in 81%. The biochemical and
blood count abnormalities that were found in these
patients probably reflected both the lupus activity and the
acute pancreatitis itself.
Anti-nuclear antibodies (ANA) were present in 98%
of the patients. Laboratory markers of lupus activity
were present in the majority of the patients: anti-DNA in
73%, and low complement was reported in 75% of the
patients. In addition, anti-phospholipid antibodies
(APLA) were reported in 13 cases, anti-SSA in 8,
anti-Sm in 7, and anti-RNP and positive Coombs test in
3 cases each.
5. Pathology and etiology-pathogenesis
Histological specimens of pancreatic tissue were
obtained in 16 cases: 10 were obtained at autopsy and 6
during surgery. All showed evidence of inflammation or
necrosis. Surprisingly, vascular lesions were present in
very few cases: thrombosis in 3 cases (two had APLA),
intimal proliferation in one, and vasculitis in only one
case. It is possible that in cases of SLE with acute
pancreatitis, an autoimmune reaction involving abnor-
mal cellular immune response or autoantibody reaction,
rather than vasculitis, is responsible for this intense
inflammatory reaction. However, it is difficult to draw
conclusions from such autopsy reports, since the
inflammatory pancreatic changes may reflect a gener-
alized and terminal disease, and the initial cause may be
obscured.
In addition to the idiopathic or lupus-associated
pancreatitis, it should be remembered that SLE patients
may develop pancreatitis secondary to the other non-
SLE related causes. In the series of Pascual-Ramos et
al. [37] mechanical or toxic-metabolic etiologies were
found in one-half of their lupus patients with pan-
creatitis. Derk and DeHoratius [38] also reported hy-
pertriglyceridemia, biliary sludge or gallstones and
alcohol ingestion in a substantial number of their
patients.
6. Treatment, pancreatitis complications, and
outcome
Treatment of the lupus-associated pancreatitis con-
sisted of steroids in 64 patients (83%), with the addition
of azathioprine in 8 patients, and cyclophosphamide in
6. Six patients were treated with plasmapheresis, and 2
with intravenous gamma-globulin.
Complications of pancreatitis were reported in 44 of
these patients (Table 1). Many of the complications were
fatal, and the mortality rate was 27% (21 patients). The
time of death in relation to the day of admission was
reported in 13 of the cases: the median time was 7 days
(range 221). A similar mortality rate of 22% was
reported by Pascual-Ramos et al. [38]. This was in
contrast to the low mortality rate of 3% in their non-
SLE controls with acute pancreatitis. Derk and DeHor-
atius [37] reported 18% mortality among their SLE
patients.
Lupus activity was significantly associated with
increased mortality. There were no cases of mortality
among patients without SLE symptoms at the onset of
pancreatitis, compared to 40% mortality among those
Table 2
Clinical parameters associated with mortality in SLE patients with
pancreatitis
Patient characteristics (n) % Mortality p
SLE symptoms at the time of pancreatitis
Any symptom (53) 40
None (10) 0 0.023
Treatment during pancreatitis
Steroids (alone or with other agents a) (64) 20
No immunosuppressive treatment (13) 61 0.005
a
In addition to steroids, other immunosuppressive therapies were:
azathioprine (8 patients), cyclophosphamide (6), and intravenous
immunoglobulin (2).
 G.S. Breuer et al. / Autoimmunity Reviews 5 (2006) 314318
with SLE manifestations. Increased serum creatinine,
hypoalbuminemia, anti-DNA antibodies, thrombocyto-
penia, and low complement were all associated with
increased mortality, but only the last two parameters
reached statistical significance.
In acute pancreatitis in the general population,
mortality is associated with several biochemical abnor-
malities, such as hypocalcemia, hyperglycemia, increas-
ing blood urea levels, and elevated liver enzymes [1,2].
In this collective group of 77 lupus patients there was
also a significant association between hypocalcemia and
mortality. Hypocalcemia carried 55% mortality, com-
pared to only 17% mortality rate in patients with
normocalcemia.
Mortality rate was 45% among patients who
developed pancreatitis complications (Table 1), com-
pared to only 3% in patients not developing these com-
plications. In regard to specific complications, 100%
mortality rate was reported in patients developing circu-
latory shock or acute renal failure, and 87% in patients
developing respiratory insufficiency.
Prior immunosuppressive therapy did not affect the
outcome of pancreatitis. At the onset of pancreatitis,
51 patients were already on steroid therapy. Mortality
rate in this group was 25%, compared to 31% in patients
who were not on steroids at that time (Table 2). Similar
data were reported by Pascual-Ramos et al. [37].
64 patients were treated with steroids following the
diagnosis of pancreatitis. Mortality rate in this group
was 20%, compared to 61% among those who were not
treated with steroids for their pancreatitis. Eight patients
were treated with azathioprine (in addition to steroids)
and none of them died. In addition, a few patients were
given azathioprine later on as treatment of other lupus
manifestations, without causing recurrence of acute
pancreatitis. This suggests that the assumed toxic
effect of these agents on the pancreas is probably
negligible, while their immunosuppressive effect is
crucial for recovery in patients with lupus-associated
pancreatitis.
Take-home messages
Although uncommon, pancreatitis should be sus-
pected in any SLE patient with abdominal pain. Acute
idiopathic pancreatitis is often associated with
increased SLE activity.
Mechanical obstruction (most frequently a result of
choledocholithiasis) and toxic-metabolic etiologies
(secondary to alcohol intake, certain drugs, hypercal-
cemia, or hypertriglyceridemia) should be ruled out.
317
In most cases, the onset of pancreatitis appears
unrelated to current treatment with steroids or
azathioprine. Moreover, treatment with these medica-
tions improves prognosis.
Mortality rate appears to be higher than in non-SLE
associated pancreatitis.
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Autoantibodies to human manganese superoxide dismutase (MnSOD) in children with facial palsy due to
neuroborreliosis.

Acute peripheral facial palsy due to neuroborreliosis is associated with a distal neuritis. In patients with Lyme
disease the activity of antioxidant enzymes is decreased. With respect to the pathogenesis of neuroborreliosis,
Eiffert H. et. al. (Neuropediatrics 2005; 36: 386-8) investigated sera of children with acute peripheral facial palsy
for the presence of autoantibodies against human manganese superoxide dismutase (MnSOD), which were
suspected of raising the oxidative injury of infected tissues. Sera of 20 children with acute peripheral palsy with
neuroborreliosis, sera of 20 children with facial palsy without reference to Lyme disease and sera of 14 blood
donors were tested for antibodies against human MnSOD using an ELISA. The concentration of IgM
autoantibodies to MnSOD of the children with neuroborreliosis were significantly increased compared with the
two control groups. The authors propose that the antibodies detected block the protective effects of MnSOD
resulting in an increased oxidative inflammation.