HEPATOLOGY Elsewhere
15273350, 2000, 4, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.510320429 by INASP/HINARI - INDONESIA, Wiley Online Library on [29/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
JACQUELYN MAHER, EDITOR
San Francisco General Hospital
Building 40, Room 4102
1001 Potrero Avenue
San Francisco, CA 94110
MEDICAL TREATMENT FOR PRIMARY SCLEROSING
CHOLANGITIS: RISK VERSUS BENEFIT
Schramm C, Schirmacher P, Helmreich-Becker I, Gerker G,
Meyer zum Buschenfelde KH, Lohse AW. Combined therapy
with azathioprine, prednisolone, and ursodiol in patients with
primary sclerosing cholangitis. A case series. Ann Intern Med
1999;131:943-946. Reprinted with permission.
ABSTRACT
Background: No established medical therapy alters the
progressive course of primary sclerosing cholangitis. Objec-
tive: To explore the potential usefulness of combined ther-
apy with azathioprine, steroids and ursodeoxycholic acid
(UDCA) in primary sclerosing cholangitis. Design: Case se-
ries. Setting: University hospital in Mainz, Germany. Pa-
tients: 15 patients with primary sclerosing cholangitis. In-
terventions: Azathioprine (1 to 15 mg/kg of body weight per
day), prednisolone (1 mg/kg per day initially, tapering to 5
to 10 mg per day) and UDCA (500 to 750 mg per day).
Measurements: Clinical and laboratory evaluation, liver bi-
opsy, and endoscopic retrograde cholangiography (a >30%
change in stenosis was considered significant). Results: Af-
ter a median observation period of 41 months (range, 3 to 81
months), liver enzyme levels declined significantly in all
patients. Six of 10 patients with follow-up liver biopsies
showed histologic improvement. Significant radiologic de-
terioration was seen in only 1 of 10 patients who had endo-
scopic retrograde cholangiography. In 7 patients previously
treated with UDCA alone, liver enzyme levels declined sig-
nificantly only after immunosuppressive therapy was
added. Adverse drug reactions led to the withdrawal of
study medication in 2 patients. Conclusions: Combined im-
munosuppressive therapy may alter the progression of pri-
mary sclerosing cholangitis. Our observations suggest a ben-
efit from adding immunosuppressive drugs to UDCA
therapy. A randomized trial is warranted.
COMMENTS
Primary sclerosing cholangitis (PSC), a chronic cholestatic
liver disease characterized by progressive destruction of intra-
hepatic and/or extrahepatic bile ducts usually leads to biliary
cirrhosis and its inherent complications. The etiology of PSC
has remained poorly understood since the earliest description
of the disease. Current thinking is that PSC occurs as a con-
sequence of a genetically determined dysregulated immune
system, resulting in an uncontrolled inflammatory response
in the bile ducts with destruction and fibrosis and ultimately
biliary cirrhosis. The allo- and/or auto-antigen(s) that trigger
this restricted inflammatory response in the bile ducts are
871
ADVISORY COMMITTEE
LAURIE DELEVE, Los Angeles, CA
DAVID CRABB, Indianapolis, IN
ADRIAN DIBISCEGLIE, St. Louis, MO
EMMET KEEFE, Palo Alto, CA
JOEL LAVINE, San Diego, CA
MICHAEL NATHANSON, New Haven, CT
DON ROCKEY, Durham, NC
DWAIN THIELE, Dallas, TX
unknown. Putative agents include bacterial antigens absorbed
through a diseased bowel mucosa, particularly in patients
with underlying inflammatory bowel disease, as well as cyto-
toxic bile acids, viral infections, and ischemic injury. Over the
last two decades, several treatments have been evaluated in
controlled and uncontrolled trials in patients with PSC.
Agents have included immunosuppressant and anti-inflam-
matory and antifibrotic drugs as well as bile acids. Unfortu-
nately, none of these medications has shown a convincing
long-term benefit. The multiple medications evaluated in the
treatment of PSC clearly reflects our lack of understanding of
the pathogenesis of this condition, along with the need for
effective medical therapy. So far, liver transplantation is the
only life-extending therapeutic alternative for patients with
end-stage PSC.1,2
Although initially perceived by clinicians as a rare disease,
PSC is diagnosed with increasing frequency and currently
represents one of the most common chronic cholestatic liver
diseases in adults. To date, no medical, endoscopic or surgical
intervention other than liver transplantation has been shown
to significantly impact the natural history of this condition.
Most patients with PSC seem destined to progress and suc-
cumb to liver-related complications if transplantation is not
performed. Hence, efforts to identify promising drugs or com-
binations as treatment for PSC are enthusiastically endorsed
by the medical community dealing with these patients. Ur-
sodeoxycholic acid is widely used and is as effective as mono-
therapy for primary biliary cirrhosis.3 The combination of
azathioprine and prednisone, which is effective for autoim-
mune hepatitis,4 has been evaluated in selected patients with
PSC.5-7 This two-drug combination offered some improve-
ment in liver tests and the degree of inflammation on liver
biopsy. Because of its safety profile and good patient compli-
ance, ursodeoxycholic acid is the drug that has received the
most attention in PSC. Ursodeoxycholic acid at a dose be-
tween 10 to 15 mg/kg/d has consistently improved liver tests
in several controlled trials.8-11 None of these studies, however,
showed significant improvement in the natural history of the
disease. This was the rationale for Schramm et al. to try ur-
sodeoxycholic acid in combination with azathioprine and
prednisolone.
Schramm et al. observed improvement in serum alkaline
phosphatase activity and aminotransferases with the combi-
nation of azathioprine, prednisolone, and ursodeoxycholic
acid. The results were similar to those observed when these
medications were used as monotherapy. The improvement in
serum bilirubin (27%), however, which is an important prog-
nostic marker in PSC, was less impressive. Although some
patients were said to have “histologic improvement” with
combination therapy, it is uncertain what the authors meant

872 HEPATOLOGY Elsewhere
since detailed histologic information was not provided. Tab-
ular data clearly imply that the degree of fibrosis, the most
worrisome histologic feature in patients with PSC and the one
that provides most of the basis for disease staging,12 was not
significantly affected by combination therapy. Similarly, the
small sample size along with the lack of a comparative group
make it difficult to assume that the lack of progression of bile
duct involvement on cholangiography was attributable to the
combination therapy. It is intriguing that none of the patients
had biochemical improvement with ursodeoxycholic acid
alone before azathioprine and prednisolone were added. A
significant improvement in liver tests, at least in the short
term, is usually seen in PSC patients treated with ursodeoxy-
cholic acid alone, although the dose used by Schramm et al.
was low. The combination of azathioprine, prednisolone, and
ursodeoxycholic acid was said to be well tolerated, but bone
density was not quantified in the study and consequently the
effect of corticosteroids on bone mass cannot be determined.
PSC is a slowly progressive disease over many years. Hence,
any drug evaluated for the treatment of this condition should
be given for a number of years to see effects that go beyond
improvements in biochemical liver tests and tissue inflamma-
tion to include benefits in liver fibrosis and clinical disease
progression. Adverse events associated with study medica-
tions should also be factored into overall assessments of ther-
apeutic benefit. This has not typically been the case with cor-
ticosteroids in the treatment of chronic cholestatic liver
diseases including PSC.13-15 Corticosteroid-associated ad-
verse events, particularly worsening of bone disease, are usu-
ally of sufficient magnitude to preclude the use of these agents
as long-term therapy for PSC. This is especially true if one
considers that most PSC patients will eventually undergo liver
transplantation. Spontaneous fractures in the posttransplan-
tation period, which are a significant cause of morbidity, oc-
cur almost exclusively in PSC patients who are already os-
teopenic at the time of transplantation.16
Before combination therapy can be considered routinely for
patients with PSC, the promising results of Schramm et al.
must be reproduced in larger, controlled series with clinically
relevant end points and extended follow-up. In addition,
given the fact that medical treatment needs to continue for a
number of years in order to determine its impact on PSC
progression, combination therapy must have an acceptable
risk/benefit ratio.
In summary, the report by Schramm et al. has called our
attention once again to the need for effective medical treat-
ment for patients with PSC. The authors emphasize that treat-
ments identified as promising in pilot studies must ultimately
be scrutinized in controlled trials. Indeed, candidate treat-
ments with good short-term results can have serious adverse
effects over the long term. Further data will be critical for
15273350, 2000, 4, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.510320429 by INASP/HINARI - INDONESIA, Wiley Online Library on [29/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY October 2000
assessing the overall utility of combination therapy in patients
with PSC.
PAUL ANGULO, M.D.
KEITH D. LINDOR, M.D.
Division of Gastroenterology and Hepatology
Mayo Clinic and Foundation
Rochester, MN
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