AZATHIOPRINE & 6-MP
THERAPY FOR CROHN'S DISEASE
Azathioprine (Imuran®) and 6-mercaptopurine (6-MP,
Purinethol®) suppress the immune system. They are chemically similar and
were developed in the 1950s. 6-MP was first used in high doses to treat
leukemia. Azathioprine was used as an immune system suppressor for people
who had received kidney transplants. These drugs have been used to treat
Crohn's disease since the late 1960s.
Many clinicians and patients continue to avoid using these agents because
of the slow response time (3-12 months) and concern about side effects.
Yet, numerous studies have been done over the past 25 years that have shown
6-MP and azathioprine to be safe and effective for Crohn's disease
patients.
Goals of a Meta-Analysis
The most effective drug trials are controlled (the drug under study
is compared to another treatment or to placebo-- a pill that contains no
drug); randomized (participants are selected at random to receive a
treatment or placebo); and double-blind (neither the researchers nor
the patients know who is receiving the study drug). But large trials of this
type are expensive and difficult to organize. Combining the results of
previously published smaller trials and analyzing the combined data is
called meta-analysis. This enables researchers to learn more about
the effectiveness of a drug without having to recruit and test hundreds of
patients. The results of a 1995 meta-analysis, which included all of the
published, randomized, double-blind, placebo-controlled trials using
azathioprine and 6-MP in Crohn's disease, were reported in the July 15,
1995 issue of Annals of Internal Medicine.
The researchers reviewed the literature for all studies performed between
1966 and 1994 that used either agent to treat Crohn's disease. To be
included in the meta-analysis, the studies had to pass strict scientific
and statistical criteria. They had to be double-blind, and some of the
patients had to receive placebo. The studies were independently reviewed by
at least three authors. The authors reviewed 221 studies; nine trials met
their criteria.
Results
Seven of the studies included people who suffered from active disease. Of a
total of 367 patients, 177 received 6- MP or azathioprine, and 190 received
placebo. Fifty-six percent of those who received the medicines responded to
treatment, compared to 32 percent who received placebo. Furthermore, the
longer that patients received the medication, the more likely they were to
respond.
Six studies examined a total of 319 patients with inactive disease: 136
received azathioprine and 183, placebo. Sixty- seven percent of those
taking azathioprine responded to the drug, compared to 53 percent of the
those who received placebo.
The meta-analysis revealed that giving the medication for more than 17
weeks increased the likelihood of a response for active and inactive
disease. When people with fistulas (abnormal channels) took these drugs,
they were more likely to heal than patients on placebo. Finally,
steroid-dependent patients were more likely to reduce or stop taking
steroids.
The most common side effects that required withdrawal from a trial were
allergic reaction (2 percent), leukopenia, or low white blood cell count
(l.7 percent), and pancreatitis (1.3 percent). No cancers were reported.
One patient died of infection after a long history of taking azathioprine.
The incidence of side effects increased the longer the medicines were
taken.
Conclusion
This meta-analysis further demonstrates the safety and effectiveness of
these medicines for Crohn's disease. People with active disease, disease in
remission, and those who are rely on steroids can benefit. The analysis
also highlights one of the major disadvantages of these agents, namely, the
slow onset of action. Side effects were few and generally reversible.
Recent uncontrolled trials using the intravenous form of azathioprine have
demonstrated a shortened response time and have prompted controlled trials,
which are now taking place. We already have learned that, by testing
patients for the enzyme thiopurine methyltransferasse, which metabolizes 6-
MP, we can avoid leukopenia in some patients. Recent uncontrolled reports
also have shown these agents to be effective in ulcerative colitis, and
controlled trials are planned.
Ongoing studies will allow clinicians to individualize therapy to speed
response to the drugs, and to minimize the chance of side effects.
--James F. Marion, M.D.
Clinical Instructor of Medicine
Mount Sinai School of Medicine, New York, NY
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