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From ACCP Guidelines to Pharmacogenomics
of PH, Lewis Rubin, MD, Stands Tall as a Prime Mover
 Lewis
J. Rubin, MD, is one of a select group of physicians who
have seen pulmonary hypertension from many different perspectives,
one of a handful of clinicians worldwide
whose experience spans more than 20 years in this clinical
setting. Their experience covers a dramatic time in the
evolution of therapy—from the years when virtually
no treatments were available to the current state-of-the
art therapies. Only Dr Rubin, however, was looked to by
the American College of Chest Physicians (ACCP) as the
physician who should lead the initiative to update its
guidelines on the disease in 2004.
Serving as Chair of the ACCP Consensus Panel on Pulmonary
Hypertension, Dr Rubin headed a multidisciplinary team
to revise the guidelines for the first time in 10 years
as the panel produced a landmark document in evidence-
based medicine. That document is expected to influence
treatment strategies for years to come. In those years
ahead, however, new directions pursued by Dr Rubin and
his colleagues are also likely to determine the direction
of management in pulmonary hypertension. The area he and
his research team will be concentrating on is how therapeutic
interventions are likely to flow from genomics, how treatment
will be based on the genomic profiles of individual patients.
Looking ahead to this next career challenge, Dr Rubin
is involved in the study of the pharmacogenomics of pulmonary
hypertension, the genetic basis for pharmacologic responses.
“Why do some people take diet drugs and develop pulmonary
hypertension, why do some people respond to prostacyclin
and others don’t? Why do others do best with an endothelin
blocker or with combination treatment? As part of that
direction we’re exploring new genetic mechanisms responsible
for pulmonary hypertension and trying to identify novel
targets that we can go after therapeutically. We’ve already
identified that there are some novel regulatory genes
that are abnormal in pulmonary hypertension and that may
be targets. This will become an important direction.”
These
future therapies will be a quantum leap from the early
days of his career when he first saw patients with pulmonary
hypertension. Every physician on the ACCP panel and other
physicians as well surely remember their first patient
who died of pulmonary hypertension, but for Dr Rubin the
experience was even more unforgettable because of the
bizarre circumstances surrounding the patient’s death.
At the time of his residency at Duke University Medical
Center, Dr Rubin treated a patient with hydralazine; vasodilators
were one of the only therapies available. “He did well
for about 2 years but then became sick, developed severe
anemia and kidney failure, and he died. We assumed that
because he had severe pulmonary hypertension that his
death was the final consequence of that.”
About 2 months later, however, Dr Rubin received a call
from the North Carolina State Board of Investigations.
“They said they had reason to believe the cause of death
was not natural and were exhuming the body. They wanted
some additional information from me. It turned out that
this rural North Carolina farmer owned a piece of land
in the path of a planned federal highway, and the government
wanted to buy it from him. His wife had visions of a big
profit but he did not want to sell. His wife had poisoned
him with arsenic. So that was my first patient who we
thought had died as a result of pulmonary hypertension,
but actually of arsenic poisoning.”
Coincidentally, Burroughs Wellcome, which had begun
developing epoprostenol, had its US offices not far from
Duke University and before long, Dr Rubin was immersed
in the first clinical trials exploring the role of prostacyclin,
an agent that would transform treatment strategies in
pulmonary hypertension. Representatives of the company
had heard Dr Rubin lecture about pulmonary hypertension
and recruited him for their protocol with prostacyclin.
Soon afterward, Dr Rubin and colleagues published their
first paper on intravenous epoprostenol in pulmonary hypertension.
From there numerous other investigations followed as Dr
Rubin pursued his research interest for more than 20 years,
continuing with work now being done at the University
of California, San Diego, where he is Professor of Medicine
and Director of the Pulmonary Vascular Center. Prior to
that he served as Director of the Division of Pulmonary
and Critical Care Medicine.
During the last 10 years, the ACCP has twice turned to
him for leadership in establishing guidelines for pulmonary
hypertension. Recognizing the dramatic expansion in therapy
within the last 10 years, the College issued the new guidelines
in a supplement to Chest this year. The 20-member panel
received the imprimatur from the ACCP, the American Heart
Association, the American College of Cardiology, the American
College of Rheumatology, and the Pulmonary Hypertension
Association. The charge was to revise guidelines for the
diagnosis and treatment of pulmonary hypertension by applying
rigorous, evidence-based criteria and Dr Rubin led the
effort to assemble international experts whose work is
addressed in this issue. Dr Rubin thinks it may be another
5 years before the ACCP considers yet another revision
of the guidelines on pulmonary hypertension. When that
happens, he will no doubt remain in the forefront of the
creation of new evidence-based criteria for treating the
disease.
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