Research
Dr. Marshall
Kaplan
Chief, Division of Gastroenterology
Dr. Kaplan gives us his thoughts on
the following article
Methotrexate and transplantation
WESTPORT, Aug 30 (Reuters Health)
- In patients with primary biliary cirrhosis, the
risk of death or transplantation is increased nearly threefold with long-term
use of low-dose methotrexate, according to the
results of a 6-year, placebo-controlled study.
Dr. Mark T.
Hendrickse and colleagues at
Patients treated with
methotrexate had significantly lower "...serum
alkaline phosphatase,
gamma-glutamyltransferase,
[IgM], IgG, and (after
24 months) aspartate
aminotransferase and
alanine aminotransferase
levels..." than controls. On the other hand, clinical factors, such as
Knodell inflammatory scores and
pruritus scores, were not significantly different
between the two groups.
Moreover, patients randomized to low-dose
methotrexate actually had an increased risk of
death or liver transplantation, with a relative
risk of 2.9, though this association did reach statistical significance.
The findings, published in the August
issue of Gastroenterology, indicate that use of
methotrexate in patients with primary
biliary cirrhosis should be limited to the clinical
trials setting, Dr. Hendrickse and colleagues conclude.
They point out that higher doses of the drug may have enhanced efficacy in
this population, but this was not tested in the current study.
Elsewhere in the journal, Drs. Paul
Angulo and E. Rolland Dickson of the Mayo Clinic
and Foundation in
The editorialists note that several
promising drugs are currently in development for the treatment of primary
biliary cirrhosis, but that
ursodeoxycholic acid should remain the initial
treatment for this disease until further data are available.
Date:
As you can see, this is a controversial
area. The British investigators used approximately one half of the dose that
I and others have found to be the minimally effective dose. A colleague and
I have published a paper in the same issue of Gastroenterology that indicates
that methotrexate improves blood tests and liver
biopsy findings in patients who respond incompletely or not at all to
ursodiol. I am in the tenth year of a double-blind
trial comparing methotrexate plus
ursodiol to colchine
plus ursodiol but, because of the nature of the
study, do not have any survival results yet. All that I can say is that
methotrexate appears to be effective in my patients,
but that I only use it in patients who have not responded fully to
ursodioal or
colchicine.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
Question
25
This may be a radical thought, or
maybe one already considered and dismissed for good reason: Since many of
us have autoimmune diseases other than just PBC, I was wondering if the drugs
used to suppress the immune system after transplant (which probably decreases
the chance of PBC recurring) could be used as therapy years before transplant
in order to control the symptoms of many of our autoimmune diseases.
Answer
Many medical investigators are considering
your thought and it is neither "radical" nor has it been "dismissed for good
reason." Some of the same drugs used to prevent transplant rejection such
as tacrolimus,
cyclosporin A and
mycophenolate mofetil
are being investigated in the treatment of various autoimmune disorders.
More studies are necessary at this time.
Howard J.
Worman, M. D.
Associate Professor of Medicine and Anatomy and
July
2003
Question 2
Why is CellCept being
used in non-transplant, non-renal patients? What are the Benefits?
Side Effects? Do you know of studies done?
Answer 2
Mycophenolate mofetil
(CellCept) is an immunosuppressive agents used
to prevent allograft (transplanted organ) rejection. As PBC is likely an
autoimmune disease, some investigators have hypothesized that
mycophenolate mofetil
may be useful as a treatment. Nobody knows yet if it will work in PBC.
Mycophenolate mofetil
is not approved for the treatment of PBC and a patient should not take this
medication unless it is part of an IBR-approved clinical trial. I am aware
of at least one trial of mycophenolate
mofetil in patients with PBC.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
February 2000
13. I suffer fatigue on an ongoing
daily basis. I have been told that since I am on
Urso and my blood work is good that my PBC is not
the cause of the fatigue. Yet here I am and so are many other PBCers I have
listened too. Please explain fatigue and PBC.
Answer
Some patients with chronic liver diseases,
including PBC, suffer from fatigue. I am not aware of any study that correlates
fatigue with "blood work" (presumably you are referring to laboratory tests
such as alkaline phosphatase activity, etc.). To
my knowledge, there is no direct association between fatigue in liver disease
and any laboratory test results. The cause of fatigue in chronic liver disease
is not clear. And it is often difficult or impossible to determine if "fatigue"
is a result of the underlying liver disease or something else (e.g. depression).
But fatigue can result from chronic liver disease.
There is no single activity that can
relieve fatigue. Medications are probably not helpful. In part, maintaining
a positive attitude may help ("I know I'm tired but I'm not going to let
it get to me."). This is not always possible for individuals with severe
fatigue. Arranging your daily schedule so that you have time to rest may
also help. Similarly, doing most of your activities when you feel the best
(e.g. early morning) may also be beneficial.
Finally, a regular exercise program
may help overcome fatigue. In the near future, my colleague at Columbia Dr.
Nora Bergasa plans to start a study of regular
exercise for fatigue associated with liver disease. Before starting an exercise
program, individuals with PBC should consult their
doctors.
Alfred L. Baker, M.D.
Division
of Gastroenterology & Hepatology
Northwestern
2000-2001
4.) In reading many of the digest
notes from other PBCers, I see that often their
LFTs go down into the normal range after starting
Actigal or Urso. My
LFTs, after 10 1/2 years of
Actigal have never been in the normal range although
my bilirubin continues to be in the normal range
and my only symptoms are Sjorgen's and mild itching
and arthritis. Is this what is considered normal for those with PBC?
Answer
Ursodeoxycholic acid has been shown to delay the need for transplantation and
perhaps to improve survival in several controlled trials. The beneficial
effect is probably the greatest in individuals whose liver chemistry tests
show the most improvement. However, several studies suggest that a patient
with a normal serum bilirubin has a rather good
prognosis, although perhaps not so good as an individual whose liver chemistry
tests are entirely normal after treatment. For patients who do not have an
optimal response to ursodeoxycholic acid, additional
treatments may be available, particularly by way of ongoing clinical trials.
Patients who have continuing symptoms and abnormal liver chemistry tests
related to PBC should consult their physician about the need for additional
evaluation and the possibility of further treatment.
Dr. Melissa Palmer Answers Our
Questions
Specialty: Gastroenterology and
Hepatology
Medical advisory board of the ALF
New York Chapter
ALF National Chapter Nutrition Education
Subcommittee
November 1999
2.) How often should liver biopsies
be done on a patient already diagnosed with PBC?
Answer
There is no agreed upon, standardized
"correct" time for patients with PBC to undergo repeat liver biopsies, (if
ever). Patients on a study protocol often are required to have a biopsy performed
at the beginning and at the end of the study. However, patients not on a
study, need never have a biopsy repeated (so long
as at least one biopsy was done in order to correctly diagnose and stage
the disease).
Howard J.
Worman, M. D.
Associate Professor of Medicine and Anatomy and
July
2003
Question 5
Have there been any studies done on post-TX medications like
Prograf and Rapamune
causing Joint and Muscle Pain? Or leading to osteoporosis?
Answer 5
I am not aware of any studies that have specifically looked at
tacrolimus (Prograf)
or sirolimus (Rapamune)
causing joint and muscle pain. However, in clinical trials of these drugs,
patients have reported these symptoms. Osteoporosis is known to occur at
an increased frequency after organ transplantation and is probably aggravated
by anti-rejection medications. A few studies in laboratory animals suggest
that bone loss may be faster with cyclosporine A, somewhat less with
tacrolimus and even less with
sirolimus. I am not aware of similar studies in
human subjects but it is possible that they have been done. If you are interested
in published studies, you may want to know about the National Library of
Medicine resource Pub Med. You can search the medical literature using Pub
Med on the Internet. The URL is:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
Andrew Mason, MBBS MRCPI
Associate Professor of Medicine
Division of Gastroenterology, Department of Medicine,
University of Alberta, Edmonton, Canada
August 2000
Question 10
Have you found a transmissible agent in PBC? Could
we have contracted this or could we possibly be
contagious?
Are all viruses human
viruses? Just what is a retrovirus? Could this possibly be another form of
hepatitis or a
variation?
When do you expect the results of your research to be published? I personally
am glad to see someone
looking for possible
causal agents.
Answer
We have found a transmissible agent in PBC and
submitted a paper documenting infection of biliary
epithelial cells
with PBC patients'
tissues. In this paper we show that the transmissible factor is produced
by the infected biliary
epithelium and can be
passaged to other normal
biliary epithelium cells, it is particulate, and
we can kill it with gamma irradiation. In further studies, we have found
that the agent has the structural and chemical properties of a retrovirus.
We have not yet studied how the virus is transmitted
to patients. I suspect that the virus does not cause PBC in all patients
that are infected as very few people get PBC. It is thought that you need
to have specific genes to get PBC in the first place.
Not all viruses are human viruses. In fact, most
of our viruses appear to have evolved from animal viruses in the first place.
The name retrovirus is derived from the reverse transcriptase gene that the
virus uses to replicate. Other viruses, such as hepatitis B virus, also use
a reverse transcriptase gene and although this is not considered to be part
of the retrovirus family, it appears to be descended from this group of viruses.
The hepatitis virus group is just a collection of different viruses that
are associated with hepatitis and they are not a distinct family. I think
the PBC virus may turn out to cause hepatitis as well but we will have to
perform further studies to prove this. We hope to publish all the viral discovery
data soon.
Dr. Hugo
E. Vargas
Medical Director,
Transplantation
University of
Pittsburgh Medical Center
Pittsburgh,
PA
November 1999
2.) Fatigue plagues most everyone
with PBC. It is debilitating -- really interfering with life and daily plans.
Please explain what causes the fatigue. Is any research being done to solve
this issue? Should one push to continue exercising during a fatigue episode?
Answer
Fatigue is not unique to PBC and is
one of the more common problems in the setting of chronic liver disease.
Despite efforts to figure out why it develops, it has been hard. It is
particularly difficult to study because it is a complaint that although real
is difficult to measure. I recommend to my patients to exercise as
tolerated.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
September l999
1. Those with PBC have positive or
elevated AMA indicating the presence of
antimitochondrial antibodies. Are these antibodies
what causes the damage to our bile ducts and resulting cirrhosis. If not,
do doctors know what actually causes the damage to the bile ducts.
Answer
Nobody knows what causes the bile
duct damage in PBC. Some studies have suggested that a protein similar or
identical to the one recognized by the
antimitochondrial antibodies is present on the
bile ducts of individuals with PBC. However, it is still not clear if this
is the target responsible for bile duct damage. Furthermore, some individuals
with PBC do not have detectable antimitochondrial
antibodies. In summary, much more research is needed to determine what actually
causes the damage to the bile ducts in PBC.
Thomas
Shaw-Stiffel, MD,
Medical Director,
Living Donor Liver
Transplantation
Univ of Pittsburgh
Medical Center - Presbyterian Hospital
Center for Liver Diseases
March 2003
Question 1
Have there been any studies done for
post-TX depression? Why does depression seem to be common in
PBC?
Answer 1
Not aware of any such studies but
they need to be done. PBC causes fatigue and other nasty symptoms such as
itchy skin, keeping many patients up all night (or at least altering their
sleep). The need for sleep to prevent depression is currently under study
(which is the main problem, depression and poor sleep, or as some suspect,
the reverse may be the cause).
Howard J.
Worman, M. D.
Associate Professor of Medicine and Anatomy and Cell Biology
College of Physicians and Surgeons Columbia University
July 2003
Question 6
What progress has been made with the development of an extracorporeal liver
aid device? Is such a device currently available and would it be of benefit
to anyone who is not eligible for a liver transplant?
Answer 6
Extracorporeal liver assist devices are currently being studied in humans
in clinical trials. They are being studied at several medical centers as
a "bridge" to liver transplantation; that is, to support someone with liver
failure in need of a transplant for a few days until a donor liver becomes
available. A lot of work still needs to be done. There are no such devices
yet for "long-term" use, such as for an individual with an end-stage chronic
liver disease who needs a transplant but is not
eligible.
Dr. Ira M. Jacobson
Weill Medical College of Cornell University
Chief, Division of Gastroenterology
& Hepatology
New York Presbyterian Hospital-Cornell
Campus
Director, Gastrointestinal & Liver
Service
New York, NY
April
2001
3. What are the chances of reversing
the PBC Disease with the use of Methotrexate and
Ursodol? I have been in a Research Study for 5
years, it is a blind study. So I don't know whether I am getting the
Methotrexate or not. My Doctor says that I am doing
wonderful and the condition, has not progressed, any further. My blood tests
are good and stable. Has there been any studies in the past, that have proven
this drug (Methotrexate) to reverse the disease.
Answer
The use of
methotrexate is controversial. To my knowledge,
there are still no published, rigorously done studies that show the drug
is effective in this disease.
Dr. Marshall
Kaplan
Chief, Division of Gastroenterology
New England Medical Center
Boston, MA
September 9, 1999
10. What are the side effects of low
dose methatrexate when used in conjunction with
Actigall to treat PBC. What are the risks? Has
it been clinically proven to slow down progression of the disease?
Answer
It's well tolerated by most pts. Less
than 5% note nausea or loss of appetite the day they take it. Some complain
of hair loss, but hair loss is very common in PBC and pts on
ursodiol also complain about this. When I began
to use methotrexate, I was worried that it might
damage the liver but this does not happen. Likewise, in low dose it has no
bad effect on the bone marrow. I reported a 15% incidence of
methotrexate induced pneumonia 6 years ago in a
group of PBC patients who were in a research study with MTX.
I have not seen a case since. Dr.
Munoz who is conducting a multicenter study of
methotrexate in PBC presented a paper last year
at the AASLD meeting entitled "Absence of pulmonary toxicity in primary
biliary cirrhosis treated with
methotrexate and
ursodiol". It was based on 266 patients followed
for 4 years. (Hepatology 1998;28:392A.) The use
of methotrexate is controversial and not accepted
by many liver specialists. I introduced MTX to the treatment of liver disease
20 years ago, wrote the first paper about it 13 years ago and probably have
more experience with it than all other physicians, even if their experiences
are combined. In my experience it has not only slowed down the rate of
progression of disease, but has reversed it.(Kaplan et al, Ann
Int Med 1997;126:682).I am quite comfortable that
my positive experience with methotrexate will
eventually be reproduced by others.
Dr. Andrew Mason
Medical Director of Liver Transplantation
Ochsner Clinic
Assistant Professor of Medicine, Tulane
University Medical Center
Assistant Professor of Microbiology,
Immunology, and Parasitology, Louisiana State
University Medical Center
New Orleans, La
May 2000
3.) Can you recommend or suggest other
treatments for PBC besides Actigall &
Urso medications?
Answer
This is the only recommended treatment
for PBC at present but several groups are trying alternative immune based
and other therapies. We have conducted a pilot study using anti-viral treatment
for PBC patients and found that the treatment was well tolerated. Although
no one had a complete biochemical response, several patients with early disease
had marked improvements in their liver biopsies after a year’s treatment.
We will soon be commencing a second pilot study to assess efficacy and safety
of a more potent anti-viral regimen for PBC patients.
Dr. Andrew Mason
Medical Director of Liver Transplantation
Ochsner Clinic
Assistant Professor of Medicine, Tulane
University Medical Center
Assistant Professor of Microbiology,
Immunology, and Parasitology, Louisiana State
University Medical Center
New Orleans, La
August 2000
Question 8
A
metaanlysis published in the Lancet, Volume 354,
Page 1053, 25th September 1999, "Randomized controlled trials of
ursodeoxycholic acid therapy for primary
biliary cirrhoses, concludes that using UDCA as
a standard therapy has to be checked again as the trials did prove a lack
of effectiveness. What is your opinion?
Answer
Most
Hepatologists believe that UDCA has some benefit
for PBC patients but it is no panacea and will not cure the disease. The
Lancet Meta-analysis merely confirmed what most physicians already know.
It is clear that UDCA can contribute to an improvement in liver biopsy and
liver function tests. However, it may not impact that much on delaying the
onset of liver failure. I do not think that we will have to perform any further
studies on UDCA as a single agent as we have a good idea about its utility.
However, there are ongoing studies to assess UDCA as a combination therapy
with other drugs such as methotrexate, I personally
think that UDCA will be a good adjunct therapy with anti-viral treatment.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
December 1999
10. What are the side effects of low-does
methatrexate? Can
methatrexate harm the liver? If so, how and when?
Can methatrexate harm other organs or hurt the
immune system? How long can PBC patients stay on
Methatrexate? At what stage in PBC, or what
indications, should a patient begin treatment with this drug?
Answer
Methotrexate is NOT an approved drug for the treatment of PBC.
Studies so far have shown conflicting
results regarding it efficacy. The results of a large,
multicenter US trial are not yet available. I refer
you to two different studies published in the same issue of the same journal
that show conflicting results:
Bonis, P. A. L., and Kaplan, M. 1999.
Methotrexate improves biochemical tests in patients
with primary biliary cirrhosis who respond incompletely
to ursodiol. Gastroenterology. 117:395-399.
Hendrickse, M. T., Rigney, E.,
Giaffer, M. H., Soomro,
I., Triger, D. R., Underwood, J. C. E., and Gleeson,
D. 1999. Low-dose methotrexate is ineffective in
primary biliary cirrhosis: long-term results of
a placebo-controlled trial. Gastroenterology. 117:400-497.
Can
methotrexate harm the liver? The answer is yes.
It is associated with liver fibrosis.
Can
methotrexate harm other organs or the immune system.
The answer is yes (I refer you to the Physicians Desk Reference to read about
all of its potential adverse effects).
How long can PBC patients stay on
methotrexate: there are insufficient data to answer
this question.
At what stage in PBC, or what indications,
should a patient begin treatment with this drug
[methotrexate]? Patients with PBC should ONLY take
methotrexate as part of approved, clinical trials.
The results of well-controlled, large clinical trials will help establish
if methotrexate is or isn't a safe and effective
treatment for PBC
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
February 2000
15. What approaches, medications,
techniques are being investigated for PBC? Recently, several articles have
appeared in newspapers & on the PBC site on bone marrow treatment for
lowering the immune system activity. Has this technique been explored in
connection with PBC?
Answer
There are not that many different
experimental treatments for PBC currently under investigation. Most of you
are probably aware of trials of methotrexate. Some
trials are being planned for cytokines, which are naturally occurring compounds
in the body that modulate the immune system in various ways. Bone marrow
ablation followed by transplantation is being examined in a few experimental
trials of various autoimmune disorders. I am not aware of such trials for
individuals with PBC. As such treatment is very intense and even
life-threatening, it may not be suitable for PBC, a disease that is only
slowly progressive and can be "cured" by liver transplantation if and when
its necessary.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
February 2000
18. Use of cortisone. I am participating
a study in our university hospital where PBC patients are given either
Urso or Urso+cortisone
(a new kind of product called budesonide,
Entocort in Europe). What is your opinion on using
cortisone in treating PBC?
Answer
The use of
budesonide for PBC should only be examined in approved,
controlled, clinical trials. Until such trials are completed and the results
examined, nobody knows if budesonide treatment
is helpful (or even harmful for that matter). Any individual considering
taking budesonide for PBC should only do so in
an approved, clinical trial. I will only be able to formulate an "opinion"
on its use when I see the results of the studies.
Dr. Howard
Worman
Division of Digestive and Liver
Diseases
Departments of Medicine and of Anatomy and Cell Biology
College of Physicians & Surgeons
Columbia University
New York, NY 10032
April 2000
Question 32
I am Stage 2 on Actigall & either
Methytrexate or placebo & am in clinical Trials
at MCV. Now they want to try Rifampin - as a nurse
practitioner, I know the reasons for general prescribing and the side effects,
etc. but do not know why this can help with PBC itching. Comments? Any other
suggestions?
Answer
Itching secondary to liver diseases, including primary
biliary cirrhosis, is a very difficult symptom
for patients to endure and for physicians to manage. The reason why patients
with liver disease itch is not known. It has been thought that some substances
accumulate in the blood as a result of liver disease, causing itch. It is
not know how many of the drugs that may help itching in some cases actually
work. At our own center (Columbia-Presbyterian), we have several clinical
trials underway to figure out why some people with liver diseases itch and
what drugs may help. For more information on itching liver diseases, I refer
the readers to the following website:
http://cpmcnet.columbia.edu/dept/gi/itching.html
Dr. Hugo E. Vargas
Medical Director,
Transplantation
University of
Pittsburgh Medical Center
Pittsburgh, PA
February 2000
10. Is any research being conducted
in the specific area of itching in order to provide the badly needed relief?
Many of us have no symptoms other than the relentless itching, and could
deal with the illness much better if there was relief other than cold showers,
antihistamines, Questran,
Sarna lotion, etc. that only bring very short term
relief, if any.
Answer
The answer is yes. One researcher
that has notably specialized in this area and whose work I like to follow
is Dr N. Bergasa in Beth Israel Medical Center
in New York. In her work she gives very interesting insights to the problem.
Dr. Nathan Bass
Professor of Medicine, Medical Director,
Liver
Transplantation
Program,
University of
California
San Francisco
14.) Question
I am in a study at Einstein Medical
Center in Philadelphia, PA. It is a blind study, which includes taking
Actigal every night and taking
Methotrexate once a week, (5 tiny pills). Have
there been any new discoveries made lately, on how
Methotrexate helps put the disease of PBC into
remission. Do you have any facts or statistics?
Answer
Methotrexate has been used in a number of
diseases for its anti-inflammatory and immune modulating effects. These include
psoriasis (a skin disease) and rheumatoid arthritis. Some earlier observations
made by experienced physicians in patients with PBC who were treated with
methotrexate for other disease suggested that
methotrexate could improve blood tests and liver
biopsy findings. In order to determine whether this is a real or significant
effect, with a benefit in terms of quality of life as well as life expectancy,
a large, randomized study is currently underway. You are probably participating
in this study which is a national, multicenter
study currently being conducted at a number of medical centers. Some small
studies have reported that with short periods of treatment, a clear benefit
of methotrexate is not evident. However, the current
large multicenter study will have the advantage
of including a large number of patients followed for up to 10 years. When
the results of this study are published, I believe we will know whether there
is any real benefit or not from methotrexate in
PBC patients.
The Mount Sinai
Medical Center
New York, New York 10029
February 2000
23.) Question
My itching is severe - tried
Questran/ Benadryl/
Atarax without success. I am Stage 2/ on
Actigall & either
Methytrexate or placebo & am in clinical Trials
at MCV. Now they want to try Rifampin - as a nurse
practitioner, I know the reasons for general prescribing and the side effects,
etc. but do not know why this can help with PBC itching. Comments? Any other
suggestions?
Answer
I can't tell you "why"
rifampin helps, and I'm not sure anyone really
understands the reason. Several papers have found
rifampin beneficial in treating itching associated
with liver diseases such as PBC. Other experimental therapies that have met
some success include opiod antagonists (ex.
naloxone) and ultraviolet light.