ranitidine induced hepatitis

letters to the editor
Ranitidine induced hepatitis
To the Editor,
Ranitidine and other H2-receptor antagonists (H2RA) are
considered extremely safe, resulting in utilization without
requiring a prescription [1]. Despite this, ranitidine rarely can
be associated with severe hepatotoxicity [2]. We describe a
case of ranitidine induced hepatitis with a clinical evaluation
eliminating alcohol, viral, biliary tract, primary liver disease
and other medications as potential confounders.
A 27 year old male, without significant past medical
history, presented to our emergency room with jaundice and
mild right upper quadrant discomfort of three days duration.
No active alcohol or illicit drug use was reported. Medication
history at presentation revealed only over-the-counter
ranitidine for intermittent epigastric pain and heartburn.
Physical examination was significant for jaundice and mild
right upper quadrant tenderness without hepatosplenomegaly.
Laboratory data revealed a WBC count of 4,300/mm3, AST
1385 U/L, ALT 2544 U/L, total bilirubin of 10.7 mg/dl, direct
bilirubin of 7.5 mg/dL, alkaline phosphatase 199 U/L, ferritin
>1650 ng/ml, iron saturation of 62.1%, PT 14.5 seconds,
and INR 1.47. Acute viral hepatitis panel on admission was
negative for hepatitis A, B and C. Abdominal CT revealed
a 6 mm stone in the gallbladder.
Further serologic evaluation during admission revealed
negative CMV and EBV serologies along with the absence
of anti-mitochondrial, anti-nuclear and anti-smooth muscle
antibodies. Alpha-1-antitrypsin and ceruloplasmin serum
levels were normal. Hemochromatosis genetic testing was
negative. Endoscopic retrograde cholangiopancreatography
(ERCP) showed a normal cholangiogram without ductal
dilation, choledocholithiasis or sludge. Percutaneous liver
biopsy revealed mild portal inflammation of predominantly
small lymphocytes, a few eosinophils with mild lobular
inflammation and steatosis (Figs. 1, 2). Intra-hepatic
cholestasis was present, but no viral cytopathic effect or
evidence of iron overload was noted. Trichrome stain
J Gastrointestin Liver Dis
September 2010 Vol. 19 No 3, 337-342
Fig 1. Portal inflammation with piecemeal
necrosis. Eosinophils are present (H&E x 40).
Fig. 2. Mild lobular inflammation with
macrovesicular and microvesicular steatosis
(H&E x 40).
demonstrated minimal portal fibrosis. These findings were
histologically consistent with drug-induced hepatitis.
Ranitidine was discontinued at admission and the patient
slowly improved, resulting in discharge on day 7. All
laboratory abnormalities returned to normal spontaneously
over the following 7 weeks. Sequential liver function testing
was performed for 12 months after resolution, with all values
remaining in the normal range.
The mechanism of hepatotoxicity due to ranitidine
remains unclear. Based on the clinical characteristics of
hepatitis and its rarity, these episodes were presumed to be
idiosyncratic in origin [1]. Recently, investigations have
338
been performed to determine the molecular mechanism
underlying ranitidine hepatotoxicity, suggesting a role for
lipopolysaccharides [3].
Many reports available in the literature did not
contain sufficient detail to confirm ranitidine as the cause.
Hepatotoxic medication use, recent blood transfusion and/or
alcohol use appeared as confounders in multiple situations
[4-6]. Others did not perform a complete evaluation,
including autoimmune hepatitis serology [4, 7], hepatobiliary imaging (ERCP, ultrasound) [7] and/or liver biopsy
[7, 8]. Hepatitis onset after introduction of ranitidine can
vary from days to months [2, 4].
In contrast, our patient was not found to have any other
plausible cause for acute hepatitis. Endoscopic, histologic
and radiologic evaluation only revealed changes consistent
with drug-induced hepatitis. Therefore, a thorough history
should be obtained, including over-the-counter medications,
to determine if ranitidine is a potential cause for an episode
of acute hepatitis.
Tae Hoon Lee1, Kenneth J. Vega2,
Joe Gerges El Khoury3
1) Department of Internal Medicine, Marshall
University Joan C. Edwards School of Medicine,
Huntington, WV; 2) Division of Digestive Diseases
and Nutrition, University of Oklahoma Health
Sciences Center, Oklahoma City, OK; 3) Section of
Gastroenterology, Marshall University Joan C. Edwards
School of Medicine, Huntington, WV, U.S.A.
References
1. Dobbs JH, Muir JG, Smith RN. H2-antagonists and hepatitis. Ann
Intern Med 1986; 105: 803.
2. Ramrakhiani S, Brunt EM, Bacon BR. Possible cholestatic injury
from ranitidine with a review of the literature. Am J Gastroenterol
1998; 93: 822-826.
3. Yokoyama M, Yokoyama A, Mori S, et al. Inducible histamine
protects mice from P. acnes-primed and LPS-induced hepatitis
through H2-receptor stimulation. Gastroenterology 2004; 127: 892902.
4. Halparin LS. Adverse effects of ranitidine therapy. Can Med Assoc
J 1984; 130: 668, 672.
5. Hiesse C, Cantarovich M, Santelli C, et al. Ranitidine hepatotoxicity
in renal transplant patient. Lancet 1985; 1: 1280.
6. Lauritsen K, Havelund T, Rask-Madsen J. Ranitidine and
hepatotoxicity. Lancet 1984; 2: 1471.
7. Graham DY, Opekun AR, Smith JL, Schwartz JT. Ranitidine and
hepatotoxicity. Ann Intern Med 1985; 102: 416.
8. Devuyst O, Lefebvre C, Geubel A, Coche E. Acute cholestatic
hepatitis with rash and hypereosinophilia associated with ranitidine
treatment. Acta Clin Belg 1993; 48: 109-114.
More on serum markers of liver
fibrosis: are they still clinically limited?
To the Editor,
We read with much interest the article by Parsian et
al. on serum hyaluronic acid (HA) and laminin (LN) as
Letters to the editor
biomarkers in liver fibrosis appearing in the June issue of the
Journal [1]. They suggest that measurement of HA and LN
concentrations in patients with chronic viral or autoimmune
hepatitis can discriminate between individuals with and
without liver fibrosis, and those with small and large fibrotic
lesions assessed by using the modified Knodell scoring
system [2]. Unfortunately, patients with higher serum HA
and LN concentrations had also greater inflammation grades,
so there may be a hesitation regarding whether one is
measuring the former or the latter. Moreover, because the
Knodell scoring system [2, 3] measures fibrosis extent semiquantitatively, an overlap between these different degrees
of fibrotic changes is possible and may be responsible for
the still limited sensitivity and specificity of serum HA and
LN observed in the Dr Parsian article.
We encountered the same problem. Hoping to overcome
this potential bias, at our Institution we assessed the extent
of liver fibrosis by computerized histomorphometry (Zeiss
Kontron Videoplan analysis system), measuring the ratio of
the mean values of the areas of portal tracts in the specimen
of the entire liver biopsy in a group of 54 children with
chronic hepatitis B. Although the degree of portal tract
fibrosis correlated significantly with serum HA and LN (r=
0.49, p < 0.0001 and r = 0.50, p < 0.0001, respectively),
no cut-off value patently discriminated between patients
with little or extensive lesions. Although elevated HA
concentration (> 100 ng/ml) identified a subgroup of patients
with histology or laparoscopy-proven liver cirrhosis, several
other cirrhotic children would however be missed with this
cut-off because of considerable values’ overlap. Furthermore,
serum concentration of LN could only differentiate patients
with cirrhosis from the controls [4]. We still think this finding
might depend also on poor LN degradation associated with
impaired hepatic function rather than on hepatic fibrosis
alone.
Pending more extensive studies, we believe that these
biomarkers’ estimations, despite the statistical significance
of the results, are still clinically limited and remain therefore
of largely experimental interest.
Pietro Vajro, MD
Department of Pediatrics
Pediatric Hepatology
University of Naples “Federico II”
Naples, Italy
References
1. Parsian H, Rahimipour A, Nouri M, et al. Serum hyaluronic acid and
laminin as biomarkers in liver fibrosis. J Gastrointestin Liver Dis.
2010;19:169-174
2. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R. Formulation
and application of a numerical scoring system for assessing
histological activity in asymptomatic chronic active hepatitis.
Hepatology 1981;1:431–435
3. Desmet VJ. Knodell RG, Ishak KG, et al. Formulation and application
of a numerical scoring system for assessing histological activity in
asymptomatic chronic active hepatitis [Hepatology 1981;1:431-435].
J Hepatol. 2003 ; 38:382-386.
Letters to the editor
4. Vajro P, De Chiara C, D’Armiento M et al. Serum hyaluronic acid
and laminin in children with chronic hepatitis B. Eur J Gastroenterol
and Hepatol 1994; 6:1023-1026.
339
that these non invasive tests will assist physicians in the
precise diagnosis of liver fibrosis in the future.
Hadi Parsian, PhD
Department of Biochemistry
and Biophysics Faculty of Medicine
Babol, Iran
Reply,
We are grateful to Dr. Pietro Vajro for his interest in our
paper. According to the data reported, a strong correlation
between serum hyaluronic acid (HA) and laminin (LN)
concentrations with hepatic necroinflammatory lesions was
found and an increase in serum HA and LN concentrations
above the predictive value was associated with liver
fibrosis.
As demonstrated, the Knodell scoring system measures
fibrosis extent semi-quantitatively and an overlap between
the fibrotic stages may occur. At present the use of liver
biopsy and Knodell scoring system for the assessment of the
liver biopsy fragments is an important diagnostic tool in our
area and our study was an attempt to clarify the relationship
between the serum non invasive tests and liver biopsies. We
tried to reduce the confounding variables; for example, two
independent pathologists studied the specimens blindly and
the analysis of samples was also blind and the data were
pooled.We categorized our patients in two groups: stage
0-2 as mild fibrosis and stage 3-6 as advanced fibrosis and
we calculated the cut-off values for each group in order to
decrease the data overlap. In clinical care, we wish to know
whether our patients have mild or advanced liver disease, and
exact staging is less important. Therefore, the determination
of fibrosis stage does not need to be as exact as the pathologic
scoring systems [1]: an overlap between some stages of liver
fibrosis can occur, but it is not so important.
Despite the statistical significance of the results, use
of these tests is clinically limited. At present this is a big
problem for researchers, because LN and various ECM
components such as HA are not liver specific biomarkers,
since elevations occur in other diseases (lung fibrosis,
rheumatoid diseases etc.). They are non-specific and when
used in the diagnosis of hepatic fibrosis, other diseases should
be ruled out. We concluded that serum fibrosis markers can
reflect abnormal metabolism of ECM, because the ECM
is an active tissue and matrix synthesis and degradation
appears in it, in a dynamic process. The imbalance between
synthesis and degradation of the ECN components can lead
to fibrosis and progress to cirrhosis. Although we found a
strong correlation between serum HA and LN concentrations
with hepatic necroinflammatory lesions, we can not rely only
on these two tests in clinical practice. Physicians should
take into consideration all liver function tests, history and
clinical manifestations (liver biopsy) in the assessment of
the diagnostic value of these fibrosis tests in the staging of
hepatic fibrosis. At present all research into liver disorders
are dependent on liver biopsy and we also used the liver
biopsy as a gold standard [2-4]. As noted, larger studies
are required before the abolishing of liver biopsy in liver
disease assessment. These tests are still considered to be in
their infancy, but with more extensive research we are sure
References
1. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis.
Gastroenterology 2008; 134: 1670-81.
2. Grigorescu M. Noninvasive biochemical markers of liver fibrosis. J
Gastrointestin Liver Dis 2006; 15:149-159.
3. Rossi E, Adams L, Bulsara M, Jeffrey GP. Assessing Liver Fibrosis
with Serum Marker Models. Clin Biochem Rev 2007; 28: 3–10.
4. Friedman SF. Liver fibrosis – from bench to bedside. J Hepatol 2003;
38:S38–S53.
Is it untrue that ultrasonography
guidance is superior to the blind
method for liver biopsy?
To the Editor,
We read with great interest the article by Akkan Çetinkaya
et al [1] published in issue 1 of J Gastrointestin Liver Dis
2010. The authors retrospectively analyzed 205 consecutive
patients that had underwent liver biopsies (LB) during a
12-month period. Liver biopsy was performed via the blind
method in 152 patients, and via ultrasound (US)-guidance in
53 patients. They concluded that US-guided biopsy was not
superior to the blind biopsy. The authors also suggested that
gastroenterologists/hepatologists should be encouraged to
perform LB via the blind method. However, there are several
important points that need to be addressed. We believe this
paper advocates potentially unsafe messages. From our
point of view, after a long experience in performing LB
via ultrasound guidance, we consider that direct US control
of the needle pathway during the procedure represents
the guarantee that the hepatic fragment obtained by LB is
adequate for histological analysis and additionally reduces
the complication rates. The opinion that the blind method
of LB (without visual inspection of the needle pathway)
has the same chance for a successful outcome is simply not
realistic (especially regarding safety of the intervention and
its complication rate).
In the current study, there were no statistically significant
differences between the two groups in terms of the number of
biopsy specimens, specimen fragmentation or the number of
portal tracts and central veins in each specimen. There was
no mortality or major complications in their study.
Yet, these results should be cautiously interpreted.
Our main concern is the sample size, although authors
did mention this issue. It is widely reported that LB is an
invasive procedure associated with mild complications in
30% of cases and responsible for serious complications,
including severe bleeding and death in 0.5% of cases [2].
340
Letters to the editor
Bearing in mind these numbers, the minimum sample
for adequate comparison between two groups in terms of
serious complications rates should be much higher (several
thousands). Also it is surprising that the rates of minor
complications are not recorded. Indisputably, sampling in
both types of procedure is widely confirmed to be adequate
– safety is the main concern behind utilization of US
and therefore all complications should be monitored and
reported.
Several studies showed that complications have appeared
more often in “blind” than in “US-guided” biopsies [3- 6].
In a prospective study, Riley et al [7] reported that US
examination before the LB forced a change of the site of
biopsy in 15.1% of the cases due to interposition of lung,
gallbladder, large central vessel, ascites, colonic loop, and
slim liver edge.
In many countries ultrasound examination is performed
both by radiologists and by clinicians. In other countries,
the US examination is performed only by radiologists.
Therefore, we think that blind biopsy is acceptable for
clinicians (gastroenterologists/hepatologists) in the countries
where only radiologists perform ultrasound examination. In
the countries where clinicians perform US examination, we
cannot recommend blind biopsies because the US guided
method is likely to reduce the risk of complications and could
improve the quality of specimens obtained, as recommended
by the AASLD guidelines [8].
Enver Zerem, Nermin Salkić, Predrag Jovanović
The University Clinical Center, Tuzla,
Bosnia and Herzegovina
References
1. Akkan Cetinkaya Z, Sezikli M, Güzelbulut F, Benek YZ, Ozkara S,
Gökden Y, Yaşar B, Ovünç Kurdaş O. Liver biopsy: ultrasonography
guidance is not superior to the blind method. J Gastrointestin Liver
Dis. 2010;19:49-52.
2. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France:
results of a prospective nationwide survey. For the Group of
Epidemiology of the French Association for the Study of the Liver
(AFEF). Hepatology 2000;32:477-481.
3. Younossi ZM, Teran JC, Ganiats TG, Carey WD.Ultrasound-guided
liver biopsy for parenchymal liver disease: an economic analysis.
Dig Dis Sci 1998; 43: 46-50
4. Farrell RJ, Smiddy PF, Pilkington RM, Tobin AA, Mooney EE,
Temperley IJ, McDonald GS, Bowmer HA, Wilson GF, Kelleher
D. Guided versus blind liver biopsy for chronic hepatitis C: clinical
benefits and costs. J Hepatol 1999; 30: 580-587
5. Pasha T, Gabriel S, Therneau T, Dickson ER, Lindor KD. Costeffectiveness of ultrasound-guided liver biopsy. Hepatology 1998;
27: 1220-1226
6. Sporea I, Popescu A, Sirli R. Why, who and how should perform
liver biopsy in chronic liver diseases. World J Gastroenterol 2008;
14: 3396-3402.
7. Riley TR 3rd. How often does ultrasound marking change the liver
biopsy site? Am J Gastroenterol 1999; 94: 3320-3322
8. Rockey, DC, Caldwell, SH, Goodman, ZD, et al. Liver biopsy.
Hepatology 2009; 49:1017.
Reply,
We read the letter by Zerem et al and first of all we thank
them for their interest. As we stated in the title, ultrasound
(US)-guided biopsy was not superior to the blind method
in our study. In the text, we also stated that complication
rates and adequacy of specimens had been more acceptable
with US-guided method and we supported these findings
with literature [1-4]. However, we can conclude that the
blind method may yield satisfactory results in terms of
complication rates and adequacy of specimens with prior
exclusion of contraindications such as congenital anomalies
and mass lesions by US examination.
There might be some reasons for this unexpected result.
Firstly, all the patients in our study had compensated liver
disease. Secondly, all patients underwent US prior to
the blind biopsy procedure to exclude contraindications.
Coagulation tests were performed on all patients. Thirdly,
the number of patients was low in our study.
It is not logical to advocate the blind method for
every patient without prior examination. However, the
complication rate was low and specimens were adequate for
the histologic examination when conditions were as in our
study. As stated by Zerem et al, US-guided biopsy is more
suitable [5]. However, the blind method is another option
following examination via US and hematologic parameters
especially when US-guided biopsy is not available. There is
a need for more extensive studies to verify these results.
Züleyha Akkan Çetinkaya1, Mesut Sezikli1
Fatih Güzelbulut1, Yusuf Ziya Benek2
Selvinaz Özkara3, Yasemin Gökden1
Bülent Yaşar1, Oya Övünç Kurdaş1
1) Gastroenterology Department; 2) Radiology
Department 3) Pathology Department, Haydarpaşa
Numune Research and Education Hospital
Istanbul, Turkey
References
1. Riley TR 3rd. How often does ultrasound marking change the liver
biopsy site? Am J Gastroenterol 1999 ;94:3320-3322.
2. Lindor KD, Bru C, Jorgensen RA et al. The role of ultrasonography
and automatic-needle biopsy in outpatient percutaneous liver biopsy.
Hepatology 1996 ;23:1079-1083.
3. Younossi ZM, Teran JC, Ganiats TG, Carey WD. Ultrasound-guided
liver biopsy for parenchymal liver disease: an economic analysis.
Dig Dis Sci 1998; 43: 46-50.
4. Farrell RJ, Smiddy PF, Pilkington RM, Tobin AA, Mooney EE,
Temperley IJ, McDonald GS, Bowmer HA, Wilson GF, Kelleher
D. Guided versus blind liver biopsy for chronic hepatitis C: clinical
benefits and costs. J Hepatol 1999; 30: 580- 587.
5. Rockey, DC, Caldwell, SH, Goodman, ZD, et al. Liver biopsy.
Hepatology 2009; 49:1017.
Letters to the editor
341
Primary neuroendocrine tumor of the
extrahepatic biliary tree mimicking
Klatskin tumor
To the Editor,
A 77-year-old man during his scheduled follow up for
colon cancer underwent blood tests and radiological imaging.
The patient had been subjected to a sigmoidectomy 12 years
before for colon cancer and had remained asymptomatic. The
blood tests showed elevated liver enzymes and conjugated
bilirubin. Tumor markers (CEA, CA19.9, AFP) were
negative. The abdominal CT revealed a circumscribed mass
in the porta hepatis, dilated intrahepatic bile ducts and atrophy
of the left liver lobe. Due to the doubtful interpretations of
the radiological findings, magnetic resonance imaging
(MRI and MRCP) was carried out (Fig. 1). In addition, an
intrahepatic bile duct dilation was described at the source of
the lesion, which led to the suspicion of a Klatskin tumor.
This could not be confirmed by Fine Needle Aspiration due
to its position.
Fig 1. MRI of the upper abdomen revealing a
centrally located single nodule and intrahepatic
biliary dilatation.
The patient underwent an uncomplicated left hepatectomy
(segments II, III and IV), excision of the extrahepatic
biliary tree with portal lymphadenectomy and right Rouxen-Y hepaticojejunal anastomosis with an uneventful
postoperative clinical course (Fig. 2). The pathological
examination described two nodules originating from
neuroendocrine cells. We undertook a more thorough
investigation to rule out the possibility that the tumor was
metastatic. This workup included octreotide scintigraphy
using 111In-pentetreotide (octreotide scan), upper and lower
gastrointestinal endoscopy, a small bowel series, abdominal
US, and chest and abdominal CT scans. All were negative.
Fig 2. Tumor surgical specimen - opened
Neuroendocrine tumors are slow-growing neoplasms
derived from the neuroendocrine system. About 54.5% of
neuroendocrine tumors arise within the gastrointestinal
system [1]. Neuroendocrine tumors of the bile duct
are rare and account for 0.2–2% of all gastrointestinal
neuroendocrine tumors [2]. The most common presenting
symptom is jaundice and the most common anatomic sites
where they occur are the common bile duct (58%), perihilar
region (28%), cystic duct (11%), and common hepatic duct
(3%) [3]. Similar to other tumors of the biliary tree, these
lesions are difficult to diagnose and almost impossible to
distinguish from cholangiocarcinoma.
In our case, the solitary lesion of the confluence and
left hepatic duct was an incidental finding. The patient did
not have any symptoms, in contrast to all the previously
15 reported cases of hilar neuroendocrine tumors [3, 4],
where jaundice is the most common, and perhaps the only
presenting symptom in 93% of cases. The circumscribed
mass in the porta hepatis was diagnosed as a Klatskin
tumor and this diagnosis was suggested by the intrahepatic
biliary dilatation of the left liver lobe. Therefore the patient
was subjected to a left hepatectomy (segments II, III and
IV), excision of the extrahepatic biliary tree and right
hepaticojejunal anastomosis.
In conclusion, biliary neuroendocrine tumors can be
very difficult to diagnose preoperatively. However, since
aggressive surgical resection is the primary treatment for
biliary neuroendocrine tumors and the only therapy that
offers a chance of cure, they should be differentiated from
non-neuroendocrine tumors for therapeutic strategy.
Konstantinos Tsalis1, Georgios Vrakas1,
Triantafyllos Geroukis2, Angeliki Cheva3,
Georgios-Nikolaos Roidos1, Charalampos Lazarides1
1) 4th Surgical Department, Aristotle University
2) Radiology Department; ‘G. Papanikolaou’ Hospital,
3) Pathology Department, ‘G. Papanikolaou’
Hospital,Thessaloniki, Greece
References
1. Maggard MA, O’Connell JB, Ko CY. Updated population based
review of carcinoid tumors. Ann Surg 2004; 240: 117-122.
2. Kirschbaum JD, Kozoll DC. Carcinoma of the gall bladder and
extrahepatic bile ducts. SGO 1941; 73: 740–753.
3. Chamberlain RS, Blumgart LH. Carcinoid tumors of the extrahepatic
342
bile duct. A rare cause of malignant biliary obstruction. Cancer 1999;
86: 1959-1965.
4. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. ZollingerEllison syndrome due to primary gastrinoma of the extrahepatic
biliary tree: three case reports and review of literature. Endocr Pract
2009; 15: 737-749.
Emergence of Crohn’s disease in
Juvenile Idiopathic Arthritis during
treatment with etanercept: a causal link
or a mere coincidence?
To the Editor,
Anti-tumor necrosis factor-α (anti-TNF-α) biological
agents (etanercept, infliximab and adalimumab) are widely
used for the treatment of several autoimmune diseases,
showing varying efficacy [1]. We present a case report
of Crohn’s disease (CD) onset in a patient with Juvenile
Idiopathic Arthritis (JIA) during treatment with etanercept,
suggesting a possible causative role of this anti-TNF-α agent
in CD occurrence.
A 17-year-old female was admitted to our department
and diagnosed with CD, based on standard criteria. She had
had a history of oligoarticular JIA from the age of 2 and
had been previously treated with NSAIDs, methotrexate and
cyclosporine. At the age of 13, treatment with etanercept and
leflunomide was initiated, limiting the relapses during the last
4 years. In order to succeed efficacy for both JIA and CD,
therapy with infliximab was introduced. An allergic reaction
appeared and infliximab was discontinued. Treatment with
adalimumab, at conventional doses, was started, with an
excellent response. During a 12-month follow-up, the patient
has remained on adalimumab therapy, steroid-free, with
clinical remission of both CD and JIA.
Etanercept is a recombinant dimer of human tumor
necrosis factor (TNF) receptor proteins fused and bound to
human IgG1 that acts competitively to inhibit the binding of
TNF to its cell surface receptor. Numerous studies confirm
the efficacy of etanercept in spondyloarthropathies and
JIA [1,2], while others indicate low efficacy of etanercept
in CD [3]. However, the new onsets as well as flares of
inflammatory bowel disease (IBD) reported during treatment
with etanercept have raised a number of questions regarding
the triggering role of etanercept in gut inflammation [1-5].
Braun et al reported that patients with ankylosing spondylitis
treated with etanercept had more flares and even some
new onsets of IBD, as compared with those treated with
infliximab and adalimumab [4]. Although there is a wellknown genetic linkage between spondyloarthropathies and
IBD [6], it is difficult to establish whether etanercept had
an unambiguous causative role. Juvenile idiopathic arthritis,
on the other hand, has no clear genetic linkage with IBD;
recent reports, though, have identified the occurrence of
IBD in at least 15 patients with JIA during treatment with
etanercept [2,5].
A different TNF-binding pattern seems to be responsible
for the low efficacy of etanercept in CD, compared to other
Letters to the editor
anti-TNF agents [3]. Haraui et al demonstrated possible
pathways responsible for both its low efficacy in CD and
its triggering role in new onsets of CD: etanercept dimer
binds to 2 of the 3 binding sites of the TNF molecule,
while infliximab fills all 3 binding sites. At the same time,
etanercept soluble TNF complexes are less stable relatively
to infliximab. Furthermore, infliximab binds specifically to
TNF-α, whereas etanercept binds and neutralizes both TNF-α
and lymphotoxin-α [1]. Etanercept, in addition, cannot bind
to peripheral blood cells and lamina propria mononuclear
cells derived from CD patients and cannot induce caspace3 activation and apoptosis of inflammatory cells via
direct binding to the tmTNF (membrane bound TNF),
whereas infliximab and adalimumab can [1]. Infliximab
and etanercept also have different effects on the cytokine
production of T lymphocytes upon nonspecific stimulation
[7,8], possibly inducing CD in genetically predisposed
patients [1]. The binding patterns outlined above, may be
responsible for the low efficacy of etanercept in IBD and the
increased probability of IBD development in patients with
JIA during treatment with etanercept. However, the exact
IBD-triggering pathways warrant further research.
Konstantinos A Oikonomou, Andreas N Kapsoritakis,
Fotios D Tsiopoulos, Antonios N Tsikouras,
Spyros Potamianos,
Department of Gastroenterology,
University of Thessaly, School of Medicine
Thessaloniki, Greece
References
1. Haraoui B, Krelenbaum M. Emergence of Crohn’s Disease During
Treatment with the Anti-Tumor Necrosis Factor Agent Etanercept
for Ankylosing Spondylitis: Possible Mechanisms of Action. Semin
Arthritis Rheum 2009; 39: 176-81.
2. Quartier P, Taupin P, Bourdeaut F, et al. Efficacy of etanercept for
the treatment of juvenile idiopathic arthritis according to the onset
type. Arthritis Rheum 2003; 48: 1093-1101.
3. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active
Crohn’s disease: a randomized, double-blind, placebo-controlled
trial. Gastroenterology 2001; 121: 1088-1094.
4. Braun J, Baraliakos X, Listing J, et al. Differences in the incidence of
flares or new onset of inflammatory bowel diseases in patients with
ankylosing spondylitis exposed to therapy with anti-tumor necrosis
factor alpha agents. Arthritis Rheum 2007; 57: 639-647.
5. Dallocchio A, Canioni D, Ruemmele F, et al; the SOFREMIP.
Occurrence of inflammatory bowel disease during treatment of
juvenile idiopathic arthritis with etanercept: a French retrospective
study. Rheumatology (Oxford) 2010; May 14 (Epub ahead of
print).
6. Cohen R , Robinson D Jr, Paramore C, Fraeman K, Renahan K, Bala
M. Autoimmune disease concomitance among inflammatory bowel
disease patients in the United States, 2001-2002. Inflamm Bowel
Dis 2008; 14: 738-743.
7. Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Downregulation of the nonspecific and antigen-specific T cell cytokine
response in ankylosing spondylitis during treatment with infliximab.
Arthritis Rheum 2003; 48: 780-790.
8. Zou J , Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Up
regulation of the production of tumour necrosis factor alpha and
interferon gamma by T cells in ankylosing spondylitis during
treatment with etanercept.Ann Rheum Dis 2003; 62: 561-564.