Vallerie McLaughlin, MD |
Pulmonary Hypertension
Roundtable
Screening for
PAH in Scleroderma: Identifying Hallmarks of the
Disease and Optimal Treatment Strategies
Vallerie McLaughlin, MD, Associate Professor
of Medicine, Rush Presbyterian-St. Luke’s Medical
Center, Chicago, Illinois, conducted this roundtable
discussion. The panel included James R. Seibold,
MD, Professor and Director, UMDNJ Scleroderma
Program. New Brunswick New Jersey; David B. Badesch,
MD, Professor of Medicine and Clinical Director,
Pulmonary Hypertension Center, University of Colorado
Health Sciences Center, Denver, Colorado; and
Virginia Steen, MD, Professor of Medicine, Georgetown
University Medical Center, Washington, DC.
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James R. Seibold, MD |
David B. Badesch, MD |
Virginia Steen, MD |
Dr McLaughlin: What do we
think is the true inci-dence of pulmonary arterial hypertension
in the scleroderma population?
Dr Steen: We first have
to separate the different kinds of pulmonary hypertension
that occur in scle-roderma. Patients with limited scleroderma,
or the CREST syndrome, as it is referred to, get primarily
what we call vasculopathy or an isolated pulmonary hypertension
unrelated to interstitial fibrosis, and it can occur in
the very serious deadly form in up to as many as 20% of
patients. Other patients, and it’s anywhere from 10% to
30%, will have some evidence of either potential pulmonary
hypertension or mild pulmonary hypertension as evidenced
by abnormal findings on pulmonary function tests (PFTs)
or echocardiograms. Another patient population, those
with diffuse scleroderma, is more likely to have the interstitial
fibrosis and they can have pulmonary hypertension related
to that. And then there is the group of patients sort
of in between, those who have a little bit of pulmonary
fibrosis and a little bit of pulmonary hypertension, and
depending on the nuances of their disease, one seems to
predominate.
Dr Seibold: Scleroderma
generally segregates into a rapidly evolving widespread
form called diffuse scle-roderma. These patients have
a fairly high risk of having an inflammatory pulmonary
process that looks a lot like nonspecific interstitial
pneumonitis and the early onset of interstitial fibrosis.
These patients develop dyspnea and impaired exercise capacity
that is a mixture of their established inter-stitial lung
disease but is clinically exacerbated by the evolution
of the pulmonary vascular lesion. At the other end of
the spectrum, you have limited scleroderma patients who
seem to be relatively spared, although not completely,
from this whole dynamic of interstitial inflammation and
fibrosis but who develop an isolated vasculopathy that
really starts to become clinically relevant somewhere
around the 10th year or so of disease. The educated guess
here is that the pulmonary vascular or arterio-lar lesion
is universal, and it can progress slowly and show up as
pulmonary arterial hypertension alone at later stages
of limited scleroderma, but it is a cofactor in the morbidity
of patients with interstitial lung disease, including
diffuse scleroderma.
Dr McLaughlin: David, do
you have any pearls on how one might differentiate pulmonary
fibrosis from pulmonary arterial hypertension, recognizing
that in some patients they do occur simultaneously?
Dr Badesch: I would suggest
looking for physical exam find-ings that suggest pulmonary
hypertension or pulmonary fibrosis, and then using echocardiography
to support or refine the diagnosis of pulmonary hypertension.
A right-heart catheteri-zation can be done to confirm
the presence of pulmonary hypertension. The diffusing
capacity can fall in either pul-monary fibrosis or pulmonary
hypertension, but if it falls in isolation, meaning that
the lung volumes are normal, it may suggest the presence
of pulmonary hypertension.
Dr McLaughlin: Would the
pulmonary function test then be an appropriate screening
tool to perform on an annual basis in the scleroderma
population? Dr Badesch: I think it is very reasonable
to follow the PFTs regularly. If you see an isolated fall
in the diffusing capacity this should raise the possibility
and lead to further evaluation, perhaps with an echocardiogram.
Dr Seibold: The pearls are
that virtually all scleroderma patients who have pulmonary
arterial hypertension have a dif-fusing capacity less
than 55% of predicted. There are a couple of data sets
that argue that when the percent of forced vital capacity
(FVC) is compared with the percent of DLCO, if that ratio
is elevated, it also enriches for the diagnosis of pulmonary
arterial hypertension. One published series sug-gests
a ratio of greater than 1.4. Our own data at our center
suggest that that ratio might be 1.8.
Dr McLaughlin: Is there
a population that should have echocardiography on a regular
basis?
Dr Seibold: Yes. We might
want to step back a step. Before I said that pulmonary
arterial hypertension patients are typi-cally dyspneic
and sometimes clinical dyspnea on exertion is missed in
rheumatologic practice. Scleroderma patients have a chronic
catabolic disease; they tend to have ambulation difficulties,
they tend to become very sedentary for orthopedic and
musculoskeletal and peripheral vascular reasons, complicating
their scleroderma. So they don’t typically present com-plaining
of dyspnea on exertion. And I think that rheumatolo-gists
probably as a rule tend to back into this diagnosis through
regular performance of pulmonary function testing. And
it seems quite reasonable to recommend annual pul-monary
function testing as a minimum interval, across the board
for all scleroderma patients, probably more frequently,
if you were following someone early with active inflammatory
fibrotic disease. It also follows that if the best screening
test for pulmonary arterial hypertension is a Doppler
echocardio-gram, it is appropriate to obtain a baseline
study in all patients with scleroderma, and that this
test might also be repeated at some minimum interval.
I don’t think that we have the trial data that exactly
validate what the standard of clinical practice should
be. One argument should be that if you are doing pulmonary
function testing and you see changes in the diffusing
capacity, that might trigger repeat of the Doppler echocardiogram.
Another argument might be that repeat Doppler echocardiograms
might be done at about the same interval as repeat pulmonary
function tests.
Dr McLaughlin: What do you
do in your practice, Jim? Dr Seibold: I look at the pulmonary
function test as the out-come and turn to the Doppler
echo as a measure of process. We get baseline echoes on
as many patients as we can, but the decision to repeat
is usually not triggered by time interval but by some
index of suspicion, either clinical dyspnea or a change
in the pulmonary function test. Dr McLaughlin: And Ginny,
what do you do in your practice?
Dr Steen: I think that is
exactly what I do. I probably do not repeat the PFT yearly
in everyone if they have normal diffusing capacity or
only mildly decreased DLCO. On the other hand, if they
already have a diffusing capacity of 60 to 65% and they
have had 10 years of disease, then following PFT’s on
a yearly basis would be helpful at least to detect changes
that would precipitate doing an echocardiogram. Many patients
have echocardiograms that show mild pulmonary hypertension,
which is in the range where the echo is difficult to interpret.
Since we don’t know how many of those are real pulmonary
hypertension versus false positives, I think it is important
to keep that in mind and to proceed to catheterization
when you find mild pulmonary hypertension rather than
jumping ahead and making a diagnosis of this deadly disease.
I know we all have had experiences where we have an echo
that says that the pulmonary artery pressures are 40 and
you get all worried and nervous and you do a cath and
the results are totally normal.
Dr Badesch: My impression
is that follow-up and screening for pulmonary hypertension
in the rheumatology and internal medicine community are
probably not as stringent as what we have heard from Jim
and Ginny. My sense is that by the time patients get referred
to us for the evaluation and treatment of pulmonary hypertension
they often have relatively advanced disease.
Dr Seibold: I agree. I think
there is a disconnect between the way the true scleroderma
expert approaches this and the way the community rheumatologist/internist
approaches this. Lacking a pharmacoeconomic or costs of
care study to actual-ly validate it, I tend to come down
in favor of a recommenda-tion of a minimum annual interval.
I agree that there are sub-sets of patients who don’t
change much over time. But if we are looking at a rate
of transition from nonpulmonary hyper-tension to pulmonary
hypertension of any level that may approach 5% of patients
per year, that is a rather high inci-dence and I think
that would justify a blanket recommenda-tion for annual
pulmonary function testing.
Dr McLaughlin: And I think
this is all more an issue now that we have effective therapies.
Perhaps 10 or 15 years ago rheumatologists were not screening
because frankly there was not much to do, but I think
all of that has changed in the current era.
Dr Seibold: From a recent
questionnaire that the Scleroderma Clinical Trials Consortium
circulated to the broad community of United States and
Canadian rheumatologists, it looked like echocar-diography
was being performed in the assessment of dyspnea only
about 25% of the time.
Dr McLaughlin: I’d like
to talk about proceeding with a heart catheterization
to further evaluate patients who have pulmonary hypertension
on an echocardio-gram. One thing that is always important
in looking at pul-monary hypertension patients is testing
for vasoreactivity. And the scleroderma population, at
least in my experience, is very rarely vasoreactive and
so I am frequently asked by rheumatol-ogists “Why do we
have to cath in the first place?” Dave, do you want to
comment on that?
Dr Badesch: That’s a good
question. Our experience mimics yours somewhat in that
I think the likelihood of acute vasore-activity is lower
in the population with scleroderma than in primary pulmonary
hypertension. I still think that cardiac  catheterization
plays an important role in evaluation of these patients.
I think that establishing their baseline hemodynamics,
or ruling out the rare patient with an intercardiac shunt
or some other lesion that is contributing to their development
of pulmonary hypertension, is important. Furthermore,
in patients who are failing despite the best available
medical therapy, it may be important to repeat the cardiac
catheterization to confirm that it is worsening of their
pulmonary hyper-tension that is accounting for their symptoms.
In that situa-tion, comparing the current hemodynamics
to their baseline results can be very helpful. So, I still
feel that right-heart catheterization plays a role in
these patients, but it may not be so much in terms of
evaluating vasoreactivity as in estab-lishing a baseline,
ruling out other contributing factors, and then having
that information available for future comparison.
Dr McLaughlin: The other
important measurement on the right-heart cath, particularly
in this patient population, is wedge pressure or left
ventricular end-diastolic pressure. This patient population
tends to be older than the primary pul-monary hypertension
population, they tend to have more con-comitant illnesses,
such as hypertension, and they may in fact have mild pulmonary
hypertension on an echocardiogram that is really the result
of systemic hypertension and left ventricu-lar hypertrophy
and elevation of LVEDP causing their pul-monary hypertension.
So it is also crucial in securing the cor-rect diagnosis
and subsequently the correct treatment for these patients.
Dr Seibold: If I had to
make a quick list about why one should be willing to do
right- heart catheterization in scleroderma it would be
1) to confirm and to precisely quantify the diagno-sis;
2) to exclude the possibility of occult left ventricular
diastolic failure; and 3) to exclude a component of concomi-tant
cardiac problems. In around 20% of the caths that we do
here, we frequently find that the aortic valvular lesions
are a little bit worse than was suspected, or we find
mitral valve pathology, or something along those lines
that truly influences our approach to therapy. Fourth
on the list would be that the echo is not a perfect test.
It is relatively imprecise in those that have estimated
pulmonary artery systolic pressures less than 40. And
there is a relatively substantial group of patients, maybe
as many as 20%, who lack a tricuspid jet and one cannot
get a reliable estimate of pulmonary artery systolic pressure
by Doppler. So, that would be the complete list. There
is no question that rheumatologists are not requesting
right-heart catheterizations by their consultants frequently
enough.
Dr McLaughlin: Why don’t
we move along to those therapies? David, you were the
principal investigator of the first trial of Pulmonary
Arterial Hypertension in the Scleroderma Spectrum of Diseases
with Flolan. Do you want to summarize the very impressive
results of that trial for the group?
Dr Badesch: As you know,
prostacyclin was initially developed for patients with
primary pulmonary hypertension and we saw an improvement
in exercise capacity, cardiopulmonary hemo-dynamics, and
survival in a 12-week study. We attempted to replicate
that study in the scleroderma population and what we found
was that prostacyclin did in fact improve the exercise
capacity and cardiopulmonary hemodynamics similarly to
the way that it had in the population with primary pulmonary
hypertension. We did not see a survival benefit over the
three-month course of that study, but the study was not
powered to detect a survival benefit. I believe that the
study of prostacyclin in patients with scleroderma-associated
pulmonary hypertension has led to the inclusion of such
patients in the subsequent trials of therapeutic agents
for pulmonary hypertension.
Dr McLaughlin: It is important
to point out what the prognosis is of scleroderma complicated
by pulmonary hypertension in the absence of any treatment
at all. It is a horrific survival curve.
Dr Badesch: In looking at
several studies done prior to the use of prostacyclin
in these patients, it appears as though the two-year survival
rate was in the range of 40 to 55% or so, in patients
who developed pulmonary hypertension as a compli-cation
of scleroderma disease.
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