EDITORIAL - Screening for pulmonary hypertension in scleroderma: how and when to look?

[Guest guest]

Journal of Rheumatology

February 2006

Editorial

--------------------------------------------------------------------------------

Screening for Pulmonary Hypertension in Scleroderma: How and When to Look?

PULMONARY HYPERTENSION

Pulmonary hypertension (PH) is a clinical-physiologic syndrome characterized

by elevated pulmonary artery pressure (PAP), as defined by mean PAP > 25 mm

Hg, or a systolic PAP > 35 mm Hg. PH most commonly arises due to underlying

cardiopulmonary disease, but may also be due to pulmonary thromboembolic

disease, or to intrinsic disease of the pulmonary microcirculation, which is

termed pulmonary arterial hypertension (PAH)1. Regardless of the clinical

setting, PH is often a severe illness that manifests symptoms of dyspnea,

fatigue, and peripheral edema; progresses to right heart failure; and is

associated with a high risk of mortality. Indeed, in many types of PAH,

including idiopathic (IPAH, formerly known as primary PH) and PAH associated

with connective tissue disease (CTD) such as scleroderma, average survival

in the absence of therapy is only 2 to 3 years.

Pulmonary complications of scleroderma contribute importantly to the

morbidity and mortality of scleroderma. Indeed, pulmonary disease has become

the major cause of mortality in patients with scleroderma2,3. Among

pulmonary complications, scleroderma-associated PAH is the most common.

Although PAH may be present pathologically in perhaps half of scleroderma

patients, PAH clinically affects 10-20%4-7. Most studies7, including the

report by Chang and colleagues in the current issue of The Journal8, suggest

PAH is more common in limited versus systemic scleroderma. PAH most commonly

arises in patients with longstanding, established scleroderma, the clinical

onset of PAH typically being delayed 10-15 years after onset of the more

common clinical features of Raynaud's phenomenon and esophageal dysmotility.

Most importantly, PAH in scleroderma is often associated with significant

and disabling dyspnea, as well as significant mortality9,10. Besides

isolated PAH, patients with scleroderma can also develop PH due to other

conditions, including pulmonary fibrosis, pulmonary thromboembolic disease,

and heart disease.

THERAPY OF PAH

Over the past 10 years, an increasing number of novel therapies for PAH have

been studied in randomized clinical trials, and many are available for

clinical use in the treatment of patients with PAH, including IPAH and

scleroderma-associated PAH. Current therapeutic options for PAH include

prostacyclin derivatives, such as intravenous epoprostenol, subcutaneous and

intravenous treprostinil, and inhaled iloprost, as well as oral therapies,

such as the nonselective endothelin-receptor antagonist, bosentan, and the

phosphodiesterase V inhibitor, sildenafil11,12. Therapy with many of these

agents is associated with improvements in pulmonary hemodynamics, symptoms,

and exercise capacity11,12. Moreover, therapy with intravenous epoprostenol

and oral bosentan is associated with improved survival in patients with

IPAH13, although a survival benefit has not been shown for other patients

with PAH, including scleroderma-associated PAH.

DIAGNOSIS OF PH IN SCLERODERMA

Given the availability of safe, effective therapeutic options for patients

with PAH, the accurate and timely diagnosis of PAH in patients with

scleroderma has assumed greater importance. However, it remains uncertain

how best to identify these patients. Can patients with scleroderma depend on

their physicians to recognize the clinical manifestations of PH and to make

a clinical diagnosis of PH? Unfortunately, the answer appears to be " No. " A

clinical diagnosis of PH is often delayed 12-18 months because of the

nonspecific nature of the symptoms. As well, physical examination findings

suggestive of PH, such as increased intensity of the pulmonic component (P2)

of the 2nd heart sound, a left parasternal right-ventricular heave, and

elevated jugular venous pressure, can be subtle and easily overlooked. In

addition, scleroderma patients are often limited on exertion by other

manifestations, including pulmonary fibrosis and arthritis, and other common

conditions, e.g., ischemic heart disease and asthma. Indeed, many patients

with PAH have historically been diagnosed at more advanced, World Health

Organization functional class III and IV stages of their disease.

As a result, screening for the PH in patients with scleroderma has been

advocated in clinical practice guidelines1. The definitive diagnostic test

for PH is right heart catheterization and invasive measurement of PAP.

However, this is neither practical nor cost-effective as a screening test.

The pulmonary diffusing capacity for carbon monoxide (DLCO) is a

reproducible test of pulmonary gas exchange that is cheap, simple to

perform, and widely available. In patients with scleroderma, a markedly

reduced DLCO is common at the time of the diagnosis of isolated PAH5,14.

Moreover, reduced DLCO on serial testing in scleroderma patients may

anticipate the onset of clinical PAH. For example, the incidence of PAH was

20% within 5 years in patients with limited scleroderma and reduced DLCO,

and increased to 35% in patients with DLCO < 55% of the predicted level15.

In another study, scleroderma patients with PAH at 5 years prior to

diagnosis of PAH had DLCO (mean 52% of predicted) lower than scleroderma

patients who did not subsequently develop PAH (mean DLCO > 80% of

predicted)16. Moreover, in some scleroderma-PAH patients followed for 15

years prior to diagnosis of PAH, DLCO declined progressively from 80% of

predicted 15 years before PAH to 45% of predicted at the time of diagnosis

of PAH, while remaining stable at > 80% in scleroderma patients not

developing PAH. As a result, serial DLCO testing in scleroderma patients has

been recommended for early detection of PAH1. It should be noted that a

reduced DLCO is not specific for significant PH, as parenchymal disease,

e.g., pulmonary fibrosis or emphysema, can also be associated with reduced

DLCO.

Doppler echocardiography has been proposed as a noninvasive screening test

for PH in scleroderma. Indirect signs of hemodynamically significant PH

include right ventricular (RV) hypertrophy and enlargement, right atrial

enlargement, paradoxical motion of the interventricular septum, and

diastolic left ventricular compression. PAP cannot be directly measured by

echocardiography, but RV systolic pressure (RVSP), a surrogate for systolic

PAP, can be estimated by echo. A moderate-high correlation (0.57-0.93) has

been reported between transthoracic echo estimation of RVSP and systolic PAP

measured via right heart catheterization14. RVSP is calculated using the

formula: RVSP = 4V2 + RAP, based on measurement of velocity (V) of the

systolic tricuspid regurgitation (TR) jet. The right atrial pressure (RAP)

can be clinically assessed from jugular venous distension, or estimated

based on respiratory variation of the inferior vena cava during

echocardiography, or a standardized value can be used. Unfortunately,

estimated RAP can vary widely, from 5 to 25 mm Hg. In addition, whereas a TR

jet can be detected in the majority (74%) of patients with PH, absence of a

detectable Doppler TR jet did not rule out significant PH17.

Among a broad population of healthy male and female control subjects aged

from 1 to 89 years, average RVSP was 28 ± 5 mm Hg, but values ranged from 15

to 57 mm Hg, being higher in older subjects with higher body mass index18.

The European Society of Cardiology has published guidelines for the

definition and classification of PH severity on echocardiographic

criteria19. Based on their definition of normal RVSP (< 35 mm Hg, or TR

velocity < 2.7 m/s), a number of patients may be falsely diagnosed with PH.

Moreover, the definitions of mild PH (RVSP 36-50 mm Hg, TR velocity 2.8-3.4

m/s), and moderate-severe PH (RVSP > 50 mm Hg, TR velocity > 3.4 m/s) remain

poorly validated against clinical features or prognosis. As well, there are

few data on intraobserver and interobserver variability and reproducibility

of RVSP assessment over time. This limitation is significant, as brought out

in the report by Chang, et al, in which 17% of patients with " mild-moderate "

PH (defined by the authors as RVSP 36-55 mm Hg) progressed to " severe " PH

(RVSP > 55 mm Hg), but 16% showed " improvement " with either normal RVSP or

undetectable TR on repeat echocardiography. Although these findings may

indicate worsening or improvement over time, they more likely highlight the

lack of data on (1) reliable echocardiographic criteria defining the

presence of hemodynamically significant PH, (2) the clinical correlates of

echocardiographically determined PH, and (3) the natural history of PH over

time.

As a final caveat, echocardiography may indicate the presence of PH, but

does not diagnose PAH, which requires a systematic clinical and laboratory

assessment for underlying causes of PH. As such, echocardiographic studies

of the prevalence of PH in patients with scleroderma20 should not be

mistakenly used as indications of the number of patients who will benefit

from pharmacologic therapy for PAH.

In summary, isolated PAH is an important complication of scleroderma, for

which safe and effective, novel therapies are available. Recent clinical

practice guidelines suggest both serial DLCO measurement and routine

echocardiography in order to screen for PH in scleroderma. However, such a

strategy remains poorly validated and subject to many limitations. New

echocardiographic methods are emerging that will likely facilitate the

future noninvasive assessment of patients with PH. For example, novel

contrast agents may improve the accuracy and reproducibility of the TR

Doppler signal. Real-time 3-dimensional echocardiography, tissue Doppler

assessment, and strain rate imaging may increase the sensitivity for

detection of RV dysfunction. As experience with newer imaging modalities

increases and they are rigorously assessed in future clinical studies, novel

noninvasive technologies for the assessment of PH and RV function will help

clinicians determine when and how scleroderma patients should be screened

for PH, and how that information should be used in therapeutic

decision-making.

http://www.jrheum.com/subscribers/06/02/204.html

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org