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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE - Viewpoint based on presentations from the First Systemic Sclerosis World Congress

Florence, Italy / February 11-13, 2010

Reviewed and edited by

Janet Pope, MD, FRCPC

Chair, Division of Rheumatology St. Joseph’s Health Centre London, Ontario

In 2008, systemic sclerosis (SSc) experts from EUSTAR (EULAR Scleroderma Trial and Research Group) were asked to contribute a list of up to 20 criteria they considered to be the most important items by which to reach a very early diagnosis of SSc. After multiple stages of selection, results from the Delphi Consensus study identified eight overall criteria as being key features of very early SSc (Table 1):

Table 1

For rheumatologists who see SSc infrequently, these items should help trigger further investigations to confirm the diagnosis of SSc.

Once diagnosed, symptomatic SSc patients should always be screened for early signs of pulmonary arterial hypertension (PAH). Indeed, data from the French national registry indicate that without screening, the majority of patients with SSc-PAH are diagnosed as having New York Heart Association/World Health Organization (NYHA/WHO) functional class (FC) III or IV. Diagnosis of PAH before patients reach FC III is all the more compelling given that evidence now clearly indicates that patients derive significantly more benefit when treated at an earlier stage of disease than with more progressive disease. In other words, when treated earlier, there is more improvement and less clinical worsening than treating PAH later.

As discussed by Prof. Gerry Coghlan, Royal Free and University College Medical School, London, UK, recently updated guidelines for the diagnosis and treatment of pulmonary hypertension (PH) from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) provide a framework that should help aid in the timely identification of PAH-SSc. These guidelines recommended that symptomatic patients who present with dyspnea or fatigue should undergo echocardiographic screening. Guidelines also suggest that for patients with shortness of breath, specific questions such as, “Do you get short of breath when you carry in your groceries?” or “If you hurry to answer the phone, are you short of breath when you answer it?” are more likely to elicit the presence of dyspnea than simply asking them if they are short of breath.

The guidelines also state that echocardiographic screening may be considered in asymptomatic patients although physicians need to be mindful that the false positive rate in this setting can be fairly substantial. Following is an echocardiographic evaluation categorizing the likelihood of PH based on tricuspid regurgitation velocity (TRV) with or witho
ble 2).

Table 2.

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Because PAH always has elevated pulmonary vascular resistance (PVR), it is necessary to ascertain the PVR; the wedge pressure (which is normal in PAH) and cardiac output by right heart catheterization.

The guidelines clearly emphasize that right heart catheterization must be carried out in all patients with suspected PAH to confirm the diagnosis.

HIGHLIGHTING THE IMPORTANCE OF EARLY TREATEMENT IN PAH-SSC

Intervening early with approved therapies will optimize the prognosis for PAH-SSc patients cannot be overstated. In fact, the benefit of treatment is most pronounced in NYHA/WHO FC II patients, so much so that maintenance of or reversal to FC II status is now considered one of the most important treatment goals in the management of PAH.

The value of early therapeutic intervention was first demonstrated definitively in the EARLY (Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients) trial (Lancet 2008;371:2093-100). As detailed by Prof. Eric Hachulla, Claude Huriez Hospital, Lille, France, the EARLY study was a placebo-controlled trial dedicated to FC II patients, including those with PAH-SSc, who were randomized to either the dual endothelin receptor antagonist (ERA) bosentan or placebo. The primary end points of the EARLY trial were changes in PVR and exercise capacity as measured by the 6-minute walk distance. Disease progression was assessed by the secondary end points of time to clinical worsening and change in FC (Figure 1).

At the end of six months, investigators observed a significant reduction in PVR (P<0.001) and a delay in PAH progression in the active treatment arm compared to placebo (P=0.0114). Importantly as well, 14% of patients in the placebo arm experienced a clinical worsening event by study end compared with only 3% of those treated with bosentan, a relative risk reduction of 77% in favour of bosentan. As Prof. Hachulla noted, all patients who survived the first clinical worsening event showed subsequent signs of deterioration, supporting the reliability of this end point. Also notable was the observation that 97% of patients treated with bosentan either stabilized or improved their FC status over the six-month treatment interval. Improvements in the 6-minute walk test were modest with bosentan therapy but researchers suggested this might reflect the fact that patients in this study had relatively well-preserved
h might be difficult to improve (a ceiling effect).

Figure 1.

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EARLY findings clearly demonstrated that timely intervention with an ERA delays progression of PAH in FC II patients. It also demonstrated that the absence of treatment leads to rapid progression of PAH even among patients with relatively mild symptoms, as 13% of placebo patients in the EARLY study evolved into FC III within a span of six months. Approximately 20% of the patients in this study had connective tissue disease, mostly SSc.

Speakers here at the congress also emphasized the importance of other markers in addition to FC which also signify a better prognosis such as improved brain natriuretic peptide (BNP). The aim of rheumatologists is to identify SSc patients as soon as possible who may have PAH and refer for right heart catheterization if PAH is suspected.

As developed by Galiè et al. (Eur Heart J 2009; 30:2493-537), determinants of prognosis for PAH-SSc patients should include assessment of certain factors, with every effort made to keep patients in the “better prognosis” category. Should treatment not lead to a satisfactory clinical response within three to four months of treatment, combination therapy should be introduce
ective, as speakers here emphasized, is to maintain all patients in NYHA/WHO FC I/II (Table 3).

Table 3.

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The new ESC/ERS guidelines also support a more aggressive approach for patients in FC III and IV who fail to improve with first-line therapy as well as for patients in FC II who deteriorate on first-line therapy. For patients with severe PAH, combination therapy should be considered “up-front.” According to the guidelines, an inadequate clinical response for patients in FC II or III is defined as a stable but not satisfactory clinical status or as an unstable and deteriorating clinical status. For those who are initially in FC IV, an inadequate clinical response is defined as no rapid improvement to FC III or better; or as a stable but not satisfactory clinical status.

Dr. Nazzareno Galiè, University of Bologna, Italy, discussed how new aggressive treatment goals can be better achieved through the use of combination therapy, ideally by using drugs that target several different pathways affecting endothelial function. Although most of the combination studies have involved only a small sample size and have not always shown a treatment effect, STEP-1 (Safety and Pilot Efficacy Trial in Combination with Bosentan for Evaluation in Pulmonary Arterial Hypertension) (Am J Resp Crit Care Med 2006;174:1257-03) for example, demonstrated that time to clinical worsening in patients treated with concurrent bosentan plus inhaled iloprost was longer by day 84 compared to patients who remained on bosentan treatment alone (P=0.02).

In the PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) trial (Circulation 2009;119:2894-903), the addition of tadalafil 40 mg increased the 6-minute walk distance by 23 m compared to placebo in 206 patients on established first-line bosentan therapy. Time to clinical worsening, exercise capacity and mean pulmonary arterial pressure also improved with the addition of sildenafil 80 mg t.i.d. in PAH patients already stabilized on epoprostenol in the PACES (Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil) study (Simoneau et al. Ann Intern Med 2008;149(8):521-30). Dr. Galiè similarly emphasized how important monitoring patients’ progress is to limit PAH progression as well as treating to “target” prognostic indicators.

The new ESC/ERS guidelines recommend that all PAH patients should be frequently assessed to determine FC status at: baseline; prior to initiation of treatment; three to four months after initiation of therapy; after any change in therapy; or in the case of clinical worsening. Patients should also be subjected to either the 6-minute walk test or undergo cardiopulmonary exercise testing at all time points and levels of BNP/NT-proBNP should be monitored as well. Echocardiography and right heart catheterization are both indicated at all time points as well, while additional clinical assessment, exercise testing and BNP/NT-proBNP testing should be carried every three to six months.

Prognosis for patients with PAH-SSc remains poor and certainly worse than for patients with idiopathic PAH with no underlying scleroderma. Nevertheless, following the introduction of PAH treatments (ERAs, PDE-5 inhibitors and prostaglandins) as well as experience with combination strategies, targeting improvement and FC, the prognosis may well continue to improve.

A subgroup analysis of patients with PAH associated with connective tissue diseases (CTDs) (most of who had scleroderma) from randomized trials, Study 351 and BREATHE-1 (Bosentan Randomized Trial of Endothelin Receptor Antagonists Therapy for Pulmonary Hypertension) and their open-label extensions, it can be shown that bosentan improves FC and walk time similarly to PAH.

Prof. Christopher Denton, Royal Free and University College Medical School, presented Kaplan-Meier estimates of survival where 86% of this subgroup of patients was still alive after receiving bosentan for one year, and 73% after two years. These estimates are better than previously published historical controls, where two-year survival was approximately 40% for PAH-SSc. Further evidence supporting the long-term benefits of bosentan was demonstrated in a six-year longitudinal study of 92 PAH-SSc patients treated at the Royal Free Hospital in London. Survival with bosentan was compared to previous controls (half of the controls received epoprostenol and the rest received no treatment as few treatments were available in the past). Survival was 81% for those receiving bosentan at one year and 71% were alive at two years. Comparable survival estimates for the matched historical control group were 68% and 47% at one and two years, respectively.

The TRUST study (Tracleer Use in PAH Associated with Scleroderma and Connective Tissue Disease) was a prospective trial designed to examine long-term outcomes and quality of life in patients with PAH-CTD in NYHA/WHO FC III on initial treatment, where two-year survival was 83%. Bosentan was well tolerated, and FC status either improved or remained stable in the majority of patients enrolled in the TRUST study.

CANADIAN SCLERODERMA RESEARCH GROUP (CSRG)

Increased disease awareness and the introduction of annual screening programs allow for earlier detection of PAH-SSc, including the use of annual echocardiograms to estimate the PA pressure and pulmonary function tests where a low diffusing capacity may be related to pulmonary vascular disease. Here in Canada, the CSRG prospectively collect data on patients with scleroderma (now approximately 1000 SSc patients are included in the database) to facilitate both research directives and improve clinical outcomes. Regarding site-to-site variability in the treatment of scleroderma, results indicate that those sites who manage at least 50 patients with scleroderma a year are generally meeting the European guidelines for investigations and treatment of SSc, with virtually all sites performing annual echocardiography by their second visit in the database.

The sites assessed also appear to be relatively consistent in their management of SSc-related complications, although there was some inter-site variability in terms of application of recommended treatment such as for GERD and Raynaud’s phenomenon and no longer recommended therapeutic options such as D-penicillamine. These represent practices among the most experienced of practitioners, however, and for many rheumatologists, screening, treatment and monitoring of patients with SSc is far from routine. Thus, it is likely that SSc guidelines such as annual echocardiograms are not performed as often in the community SSc patients.

In an effort to help community-based rheumatologists adhere to rigorous guidelines, the CSRG is in the process of developing a simple office tool to help prompt timely screening for PAH and to encourage more thorough monitoring of SSc patients. A simple and practical dyspnea questionnaire for SSc will be validated. It is hoped that more focused efforts on the management of this challenging patient group will improve their prognosis and quality of life. Thus the early identification of organ involvement such as ILD and PAH is necessary.