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Editorial
 
Dyspnea Due to Pulmonary Hypertension and Interstitial Lung Disease in Scleroderma: Room for Improvement in Diagnosis and Management
HEATHER RACZ, MD;
SM has received consulting and speaking fees (Actelion, Encysive, Pfizer, United Therapeutics) and clinical investigator fees (Actelion, Encysive, Pfizer, United Therapeutics). Address reprint requests to Dr. S. Mehta, Division of Respirology, London Health Sciences Center—Victoria Hospital, Room E2.623, Professional Building, 800 Commissioner's Road East, London, Ontario N6A 5W9, Canada. E-mail: sanjay.mehta@lhsc.on.ca Among the protean systemic manifestations of scleroderma, pulmonary involvement is frequent and contributes to significant clinical illness and mortality. Pulmonary disease is now the leading cause of death in patients with scleroderma 1,2 , accounting for up to half of scleroderma-related deaths 3,4 . Respiratory symptoms such as dyspnea in patients with scleroderma can be due to pulmonary hypertension (PH), interstitial lung disease (ILD), gastroesophageal reflux or recurrent aspiration related to esophageal dysmotility, airway disease such as bronchiectasis, or due to less common syndromes, such as cryptogenic organizing pneumonia or alveolar hemorrhage 4 . The most frequent and serious pulmonary complications of scleroderma are PH and ILD. Both are present in the vast majority of patients with scleroderma at autopsy. Clinically significant PH affects 15–20% of scleroderma patients, and results in dyspnea, impaired exercise tolerance, and a high risk of death 5,6 . For example, median survival of patients with scleroderma with some types of PH is only 1.5 to 2 years after diagnosis 7 , and few patients survive 5 years 8 . Similarly, ILD is a common cause of dyspnea, which can be detected on pulmonary function tests (PFT) in up to half of patients with scleroderma 9,10 . Longterm survival of scleroderma patients with ILD is also poor, with median survival of less than 5 years 11 . Given the frequency, significant morbidity, and high risk of mortality of PH and ILD in scleroderma, many clinical trials have assessed the effects of novel therapies for PH and ILD in scleroderma patients 12 . Specifically with regard to PH, many new therapies have shown significant benefit in scleroderma patients, including reduced severity of PH, improved dyspnea, greater exercise capacity, and better quality of life 13-16 . There is also some evidence to suggest survival in scleroderma patients with PH is improved 17 . Many of these novel PH therapies are widely available, recommended in clinical practice guidelines, and are increasingly being prescribed 18 . In contrast, treatment for ILD in scleroderma remains largely futile, although several new biologic directions are being pursued in clinical research. DIAGNOSIS OF PULMONARY HYPERTENSION AND INTERSTITIAL LUNG DISEASE Despite recognition of the prevalence and clinical significance of PH and ILD, and the availability of effective new PH therapies, both PH and ILD remain undiagnosed in many patients with scleroderma until disease is far advanced and therapeutic options are limited. Delayed or missed diagnosis of PH and ILD in scleroderma may be due to lack of awareness of their frequency and clinical impact, lack of familiarity with diagnostic approaches to PH and ILD, and lack of experience with novel PH therapies. Delayed diagnosis is likely also related to difficulty making a clinical diagnosis of PH and ILD. Dyspnea, fatigue, and exercise intolerance are recognized as common features of both PH and ILD, although patients are asymptomatic early in the course of both conditions. In addition, scleroderma patients frequently have fatigue and exercise intolerance due to other features of scleroderma, such as arthritis and fibromyalgia, as well as other conditions, such as obesity, cardiovascular disease, and anemia. As well, deconditioning due to inactivity is widespread in our society and contributes importantly to dyspnea and exercise intolerance. Indeed, the prevalence of respiratory symptoms is similar in scleroderma patients with and without PH 6 . Thus, although symptoms of dyspnea, fatigue, and exercise intolerance should raise suspicion of significant pulmonary involvement and the presence of PH or ILD, these symptoms are nonspecific and almost universal in patients with scleroderma, making clinical diagnosis of PH and ILD challenging. Physical examination can reveal findings suggestive of PH and ILD. For PH, findings include a right-ventricular (RV) heave, an accentuated pulmonic component (P2) of the second heart sound, and a systolic murmur of tricuspid insufficiency 19 . However, these findings can be subtle, especially in mild to moderate PH. Similarly, crackles on chest auscultation are infrequently present early in ILD, despite symptoms and physiologic and radiographic disease. Moreover, crackles are not specific for ILD, but are characteristic also of pneumonia and pulmonary edema. As evidenced in the article by Launay, et al in this issue of The Journal, radiographic pulmonary imaging is an important modality in the diagnosis of PH and ILD, although standard chest radiographs are insensitive for the detection of early disease. Characteristic chest radiographic features of PH include enlarged RV and hilar pulmonary arteries. ILD in scleroderma appears radiographically as symmetric, lower-lobe predominant, reticular or reticulonodular opacities. High resolution computer tomographic scanning (HRCT) can reveal abnormalities not visible on chest radiographs, such as septal and subpleural linear opacities, ground-glass opacities, and subpleural cysts. In advanced ILD, areas of isolated ground-glass opacities are replaced by architectural deformities, including honeycombing and traction bronchiectasis 20 . PFT are central to the assessment of dyspnea and to the diagnosis of PH and ILD. Impaired diffusing capacity of the lung for carbon monoxide (DLCO) is common when symptomatic PH is diagnosed in scleroderma patients, and is correlated with the severity of PH 21 . Moreover, DLCO is often reduced several years prior to the diagnosis of PH in patients with scleroderma 22 . Impaired DLCO is also an early functional marker of ILD, and appears to reflect HRCT extent of ILD 23 . Other PFT are also useful in the assessment of PH and ILD. For example, oxygen desaturation at rest or on exercise can indicate greater severity of both PH and ILD 24 . The measurement of reduced lung volumes is essential to defining the severity of the restrictive physiology of ILD. Echocardiography is one of the most useful tools in the assessment of patients with dyspnea and possible PH. Although limitations are well recognized, echocardiography can noninvasively assess the presence and severity of PH. Doppler estimation of RV systolic pressure, from the velocity of the tricuspid regurgitant jet of blood, has excellent sensitivity and specificity as compared to direct measurement of systolic pulmonary artery pressure during right heart catheterization 25 . Other echocardiographic findings of PH include hypertrophy and/or enlargement of the RV, right atrial enlargement, leftward shift or paradoxical motion of the interventricular septum, tricuspid valve insufficiency, and pericardial effusion 19 . Echocardiography can also detect significant underlying heart disease, including valvular disease, heart failure, and congenital heart disease. SUGGESTED APPROACH TO A SCLERODERMA PATIENT WITH DYSPNEA In the clinical assessment of patients with scleroderma, the presence of dyspnea, fatigue, or exercise intolerance should routinely be assessed. Careful clinical examination should seek out evidence of ILD (crackles, cyanosis, respiratory distress), as well as signs of other pulmonary conditions. Cardiac examination should assess for evidence of congestive heart failure, mitral or aortic valvular disease, and specifically PH (loud P2, RV heave, tricuspid insufficiency). Even in the absence of symptoms or abnormal findings, regular screening of patients with scleroderma for PH and ILD using PFT and Doppler echo has been suggested. However, there is currently no evidence of improved clinical outcomes to support such a strategy. Importantly, in patients who are not physically active, the lack of symptoms does not reliably exclude significant cardiopulmonary disease. Moreover, because of the subtlety of the physical signs, a "normal" cardiopulmonary physical examination does not rule out significant PH or ILD. In patients with symptoms, or abnormal cardiopulmonary examination findings, specific diagnostic testing for PH and ILD is strongly recommended. Initial studies include chest radiography and PFT with measurement of DLCO. An isolated reduction in DLCO is consistent with both PH and ILD. Reduced lung volumes are only apparent in advanced ILD. For detection of PH specifically, the recommended examination is by Doppler echocardiography. However, echocardiogram-documented PH needs to be confirmed and further assessed with right heart catheterization. Moreover, a rigorous and detailed evaluation should be pursued for common causes of PH, including underlying cardiac or pulmonary disease and recurrent pulmonary thromboembolic disease. For systematic evaluation including invasive assessment it is highly recommended to refer to a center with expertise in the diagnosis and management of patients with PH. In the presence of either decreased DLCO or restrictive disease on PFT, HRCT is indicated for better characterization of the presence and severity of ILD 20 . If initial PFT and Doppler echo examinations are normal, PH and ILD are unlikely. Noncardiopulmonary causes of symptoms and exercise intolerance should be considered, such as unfitness. Repeated or serial screening (e.g., repeat HRCT in possible ILD) may be indicated in some patients, based on initial clinical assessment (e.g., crackles on lung auscultation) or on laboratory studies. However, further clinical studies are needed to better define the approach to such patients. SUMMARY Rigorous assessment for pulmonary disease in patients with scleroderma, such as the algorithm described above, will reliably define the cause of dyspnea and exercise intolerance in the majority of patients. Moreover, the clinically important conditions of PH and ILD are unlikely to be missed, and indeed, are likely to be diagnosed at earlier, milder, and possibly more treatable stages. For some scleroderma patients with PH, several novel, effective, and safe therapies are available that can significantly enhance quality of life and possibly survival. In scleroderma patients with ILD, the prognosis is poor overall, given a lack of effective therapeutic options and progression of disease in the majority of patients. However, more rigorous diagnosis of ILD will facilitate better understanding of this serious complication of scleroderma, increase enrolment of patients in clinical trials, and accelerate development of future therapies.
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