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Birzniece
76 van der Gronde T, de Hon O, Haisma HJ, Pieters T. Gene doping: an overview and current implications for athletes. Br J Sports Med 2013; 47: 670–8. 77 Rabinovsky ED, Gelir E, Gelir S, Lui H, Kattash M, DeMayo FJ et al. Targeted expression of IGF-1 transgene to skeletal muscle accelerates muscle and motor neuron regeneration. FASEB J 2003; 17: 53–5. 78 Kostek MC, Delmonico MJ, Reichel JB, Roth SM, Douglass L, Ferrell RE et al. Muscle strength response to strength
training is influenced by insulin-like growth factor 1 genotype in older adults. J Appl Physiol (1985) 2005; 98: 2147–54. 79 Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004; 350: 2682–8. 80 Muona K, Makinen K, Hedman M, Manninen H, Yla-Herttuala S. 10-year safety follow-up in patients with local
VEGF gene transfer to ischemic lower limb. Gene Ther 2012; 19: 392–5. 81 Lippin Y, Dranitzki-Elhalel M, Brill-Almon E, Mei-Zahav C, Mizrachi S, Liberman Y et al. Human erythropoietin gene therapy for patients with chronic renal failure. Blood 2005; 106: 2280–6. 82 Chenuaud P, Larcher T, Rabinowitz JE, Provost N, Cherel Y, Casadevall N et al. Autoimmune anemia in macaques following erythropoietin gene therapy. Blood 2004; 103: 3303–4.
C L I N I C A L P E R S P E CT I V E S
Prospects for improving outcomes in systemic sclerosis-related pulmonary hypertension V. Thakkar,1,2 M. Nikpour,3,4 W. M. Stevens3 and S. M. Proudman5,6 1 Department of Rheumatology, Liverpool Hospital, 2School of Medicine, University of Western Sydney, Sydney, New South Wales, 3Department of Rheumatology, St Vincent’s Hospital Melbourne, 4Department of Medicine, The University of Melbourne, Melbourne, Victoria, 5Rheumatology Unit,
Royal Adelaide Hospital and 6Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
Key words systemic sclerosis, pulmonary hypertension, screening, PAH-specific therapy, anticoagulation. Correspondence Susanna Proudman, Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. Email: [email protected] Received 3 November 2014; accepted 27 November 2014. doi:10.1111/imj.12691
Abstract Pulmonary arterial hypertension (PAH) is a leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Approximately one in 10 will develop PAH during their lifetime. These patients have a worse prognosis than those with PAH due to other causes. The most common clinical feature of SSc-PAH in the early stages is non-specific exercise intolerance that can be erroneously attributed to other manifestations of SSc. Screening provides an opportunity for early identification of SSc-PAH and prompt initiation of therapies with the potential to improve quality of life and survival. International guidelines recommend annual transthoracic Doppler echocardiography (TTE), but TTE has limitations. The tricuspid regurgitant jet required for estimating the systolic pulmonary artery pressure is absent in up to 39% of patients, including a proportion with PAH. This has prompted a move to new screening algorithms that are less dependent on TTE. Not all pulmonary hypertension (PH) in patients with SSc is PAH. Other causes include PH secondary to left heart disease, interstitial lung disease-related PH, chronic thromboembolic PH and pulmonary veno-occlusive disease. With the advent of evidence-based therapies, including newer agents such as macitentan, riociguat and selexipag, the establishment of centres with expertise in PAH and the focus on early detection, there has been considerable improvement in survival. The role of anticoagulation for SSc-PAH has been the subject of a recent meta-analysis of nine observational studies that suggests it may confer a survival benefit, but to date, there have been no randomised controlled trials to confirm this.
© 2015 Royal Australasian College of Physicians
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Pulmonary hypertension in scleroderma
Introduction Systemic sclerosis (SSc) is a complex multisystem connective tissue disease characterised by auto-antibodies, endothelial dysfunction and extensive fibrosis affecting the skin and internal organs. Pulmonary arterial hypertension (PAH), a disorder of increased pulmonary vascular resistance that can lead to right heart failure, is a leading cause of morbidity and mortality. While PAH is the most common cause of pulmonary hypertension (PH) in SSc, and the focus of this review, SSc patients are at risk of multiple potential causes of PH, posing diagnostic and management challenges. The goal of this article is to review this interesting and evolving area.
What is PAH? PAH is a clinical syndrome characterised by restricted flow through the pulmonary arterial circulation. It is diagnosed by finding precapillary PH at right heart catheterisation (RHC) (mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest with a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) of >3 Wood units) in the absence of significant lung disease and chronic thromboembolic pathology. The pathophysiology of PAH is characterised by progressive loss of the usually high-capacitance, lowresistance pulmonary microcirculation at the level of the distal pulmonary vasculature (40 mmHg and/or diffusing capacity for carbon monoxide (DLCO) < 55% predicted and/or forced vital capacity (FVC)/DLCO ratio >1.6), with a recent study showing the frequency of PH in this population being 10% at 2 years, 13% at 3 years and 25% at 5 years.3
The mortality of SSc-PAH In most patients, SSc-PAH is a progressive disease associated with an extremely poor prognosis. A recent large systematic review, which included 22 studies representing 2244 SSc patients with all types of PH, reported 1-, 2- and 3-year survival rates of 81%, 64% and 52% respectively.4 These figures highlight the seriousness of PH in SSc, with a mortality rate similar to that observed in advanced malignancy. SSc-PAH patients consistently demonstrate a worse prognosis than other CTD-PAH subgroups and a worse prognosis than iPAH patients. However, with the emergence of evidence-based therapies, the establishment of centres with expertise in SSc and PAH and the focus on early detection, there have been considerable improvements in the survival of patients with SSc-PAH. The Australian Scleroderma Cohort Study (ASCS), which is a prospective, multicentre study of risk and prognostic factors for cardiopulmonary outcomes in SSc in which an early detection algorithm is applied, reported 1- and 3-year survival rates in CTD-PAH of 94% and 73% respectively.5 Similarly, the 1- and 3-year survival rates in a large US cohort of SSc patients utilising a screening programme were 93% and 75%, respectively, illustrating the significant progress that is being made in reducing mortality from this serious disease.6 Several important poor prognostic factors have been identified. These include a worse haemodynamic profile at diagnosis (increased mPAP, mean right atrial pressure PVR and reduced cardiac index (CI)), older age, male sex, advanced functional class of impairment, a pericardial effusion at diagnosis and severely impaired DLCO.6 These factors highlight the imperative to reduce the time to diagnosis and the commencement of effective therapies. They also provide a rationale for closer monitoring in this poor prognostic group, including repeated haemodynamic assessments, rapid escalation of therapies (including dual and triple therapy combinations) and enrolment in clinical trials of novel therapies.
Drug treatment in SSc-PAH Double blind, placebo controlled trials have demonstrated efficacy in PAH for each of the following classes of
advanced pulmonary vasodilator therapy currently available on the Australian Pharmaceutical Benefits Scheme (PBS): (i) endothelin receptor antagonists (ERA, ambrisentan, bosentan and most recently, macitentan); (ii) phosphodiesterase inhibitors (sildenafil and tadalafil) and (iii) prostanoids (epoprostenol and iloprost). While generally these studies have not been powered to show independent efficacy for the SSc-PAH subgroup, the direction of the results has been consistent with that seen in iPAH, where significant improvements in exercise capacity and secondary end-points, such as reduction in mortality of 39% (P < 0.041) have been demonstrated.7 Importantly, there have been no head-to-head, blinded RCT comparing these therapies, so there is no firm evidence upon which to recommend one therapy ahead of another in SSc-PAH. Newer therapies have recently met primary outcome measures in phase 3 studies. In the Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) study, macitentan, an oral dual ERA, decreased the risk of a first occurrence morbidity/mortality event by 45% over placebo.8 The rate of elevated liver transaminases greater than three times the upper limit of normal (3.5%) was similar to that of placebo and although a decrease in haemoglobin was observed more frequently in macitentan treated patients, there was no difference in treatment discontinuation rates between groups at the 10 mg/day dose that is now PBS listed. Aside from being one of the largest, prospective, controlled PAH studies to date with 742 patients, the SERAPHIN study represents a major shift in PAH trial design towards more clinically relevant end-points, with event-driven morbidity/ mortality as the primary outcome measure over a longer term follow-up period (up to 3.5 years) as compared with many previous RCT in which change in exercise capacity (for example, as measured by 6-min walk distance (6MWD) over a relatively short trial period (12–18 weeks)) was the primary end-point. Riociguat is a Therapeutic Goods Administration approved therapy that acts by stimulating guanylate cyclase and increasing the sensitivity to endogenously produced nitric oxide. In the Pulmonary Arterial Hypertension sGC-Stimulator Trial (PATENT-1) study, riociguat was compared with placebo in 443 patients, and the 2.5 mg three times daily dose resulted in a 36-m increase in 6MWD over placebo over the 12-week study period.9 Significant improvements were also seen in the secondary end-points of pulmonary vascular resistance, N-terminal pro–B-type natriuretic peptide (NT-proBNP), World Health Organization functional class, time to clinical worsening and the Borg Dyspnoea score. Selexipag is an orally bioavailable, selective prostacyclin agonist that was developed as an alternative to © 2015 Royal Australasian College of Physicians
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Pulmonary hypertension in scleroderma
the currently available prostanoids, which are often effective, but limited by their complex administration and side-effects. Preliminary reports from the large, phase 3 Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial HypertensiON (GRIPHON) study indicate that selexipag reduces the risk of morbidity/mortality compared with placebo by 39%, with a tolerability profile similar to other prostanoids. The full report is anticipated in the first half of 2015, but selexipag may be an effective oral prostanoid option in PAH management.
The combination treatment era More recently, attention has turned to the use of combination therapies in PAH. The rationale for this approach stems from the fact that despite improved survival in the modern treatment era, PAH remains a debilitating disease associated with high mortality, and disease progression is inevitable for the majority of patients receiving monotherapy. Furthermore, abnormalities in multiple signalling pathways are characteristic. Combination strategies may better target these pathways and optimise use of existing therapies. Perhaps, the most compelling evidence to date for combination therapy was seen in the recently reported AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION (AMBITION) study.10 Preliminary results suggest a 50% reduction in the number of clinical failure events at 24 weeks with upfront combination ambrisentan and tadalafil compared with monotherapy, mostly driven by a reduction in hospitalisations in the combination therapy arm (4% in combination vs 12% in monotherapy). The clinically relevant issue of early add-on therapy for deteriorating patients or patients with poor prognosis was not specifically addressed in this study. A systematic review of dual therapy in PAH, that included 26 observational studies and six RCT, concluded that there was a beneficial effect with dual therapy in iPAH and SSc-PAH, particularly in patients deteriorating despite monotherapy.11 However, there were no uniform criteria by which to increase therapy, nor consensus on the optimal choice of combination strategy. Recently, two important Australian studies have been published reporting the potential benefit of combination therapy in PAH. In a cohort of 117 CTD-PAH patients, the majority of whom had SSc-PAH (94.9%), combination therapy reduced mortality by 45%.5 Similarly, in an observational study of 112 patients deteriorating on monotherapy (inclusive of 40 patients with CTD-PAH, 29 of whom had SSc-PAH), Keogh et al. reported 1-,2-, 3-year survival rates, after the addition of a second PAH therapy, of 88%, 71% and 61% respectively.12 Overall, it appears likely that combination therapy confers morbidity and mortality
benefits in deteriorating SSc-PAH patients. However, further research is necessary into the optimal dual combination strategy, the timing of initiation and criteria for patient selection.
Anti-coagulation in SSc-PAH In the absence of any RCT, the role of anticoagulation in all forms of PAH is currently being defined.13 While thrombotic arteriopathy is one of the key pathogenic events in SSc-PAH, the results from observational studies of anticoagulation have been conflicting. In a recent Australian multicentre cohort study of 117 patients with CTDPAH (95% of whom had SSc-PAH), anticoagulation with warfarin conferred an estimated fivefold reduction in mortality compared with patients who were not anticoagulated over a mean 2.6 years of follow up.5 In contrast, Canadian investigators reported a low probability of a survival benefit with 6 months or more of anticoagulation.14 However, the minimum dose and duration of exposure to warfarin in this single-centre study was not specified, and a substantial proportion of patients were not on concomitant advanced PAH therapy. A recent meta-analysis of nine observational studies in 1730 patients with PAH reported a hazard ratio for death of 0.69 (95% confidence interval 0.57–0.82) with oral anticoagulation.15 The potential utility of anti-coagulation will be the focus of the Scleroderma-Pulmonary arterial Hypertension Intervention with ApiXaban (SPHInX) study, an National Health and Medical Research Councilfunded multi-centre randomised double blind placebo controlled study of apixaban in SSc-PAH. Recruitment for this study will commence in the latter part of 2014, with results anticipated in 2019.
Screening for SSc-PAH Screening for PAH has become a cornerstone of SSc management. The rationale behind screening for SSc-PAH is based on the early identification of an aggressive, but treatable complication in an at-risk population, allowing prompt initiation of therapies that offer significant clinical benefit. Major pulmonary hypertension guidelines from the American College of Cardiology Foundation/ American Heart Association, European Society of Cardiology (ESC)/European Respiratory Society (ERS) and the National Pulmonary Hypertension Centres of the UK and Ireland recommend annual transthoracic Doppler echocardiography (TTE), with the latter also recommending regular DLCO corrected for haemoglobin (DLCOcorr) assessment. The impressive 8-year survival rate of 64% in a group of SSc-PAH patients in whom PAH was detected as a result of screening, compared with 17% for
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patients diagnosed with PAH in the course of routine care, published by Humbert et al., suggests the improved survival in patients detected though screening is more than just due to lead time bias.16 Guidelines published by the Australian Scleroderma Interest Group (ASIG) recommend that all SSc patients undergo an annual clinical assessment, TTE and pulmonary function tests (PFT). Any patient identified as having possible PAH (sPAPTTE ≥40 mmHg and/or DLCOcorr ≤50% predicted with FVC > 85%, and/or fall in DLCOcorr ≥20% compared with the previous year), especially in the presence of symptoms and without adequate explanation on high-resolution CT (HRCT) lung and/or V/Q scanning, should undergo RHC that offers the only means of making a definitive diagnosis of PH.17 Recently, there have been concerted efforts to improve screening and rationalise the use of limited resources, such as TTE. Furthermore, while TTE is the single most important non-invasive assessment tool for PH (offering direct and indirect signs of PH, right and left ventricular systolic and diastolic function, valvular heart disease and shunts, together with poor prognostic features of PH, including right ventricular enlargement/ dysfunction and pericardial effusion), high-quality studies in centres with specific echocardiographic expertise for the detection of PH have variously estimated that the tricuspid regurgitant jet is absent and/or images are of insufficient quality in 20–39% of SSc patients, including studies where up to one-third of patients with PAH had unobtainable pressures on TTE.18 This highlights the need for multimodal strategies in screening for SSc-PAH. ASIG recently derived and validated a two-component screening algorithm comprising PFT and serum NT-proBNP level (Fig. 2).19,20 In this algorithm, patients with DLCOcorr 1.6 were followed, demonstrated 2-, 3- and 5-year rates of developing PH of 10%, 13% and 25% respectively.3 Similarly, a mPAP of 20–24 mmHg in SSc patients does not appear to be as benign as once thought, being associated with an increased risk of PAH in the future.23 © 2015 Royal Australasian College of Physicians
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The differential diagnosis of PH in SSc While PAH is probably the most common cause of PH among SSc patients, several other causes of PH can be important in the individual SSc patient. PH secondary to left heart disease affects up to 12% of SSc patients, and is diagnosed by the finding of postcapillary PH at RHC (PAWP > 15 mmHg). The underlying pathogenesis often reflects primary myocardial fibrosis, which is a common, but usually occult process. Alternatively, left heart disease can be related to the presence of traditional risk factors for left heart dysfunction, such as older age, hypertension, smoking or renal disease. Lung disease associated pulmonary hypertension, which is usually due to ILD in SSc, refers to the RHC finding of precapillary PH coupled with significant ILD, usually defined according to the extent of involvement on HRCT coupled with PFT abnormalities. Importantly, only a small proportion of patients with severe ILD will actually develop clinically significant PH. As the pathogenesis of ILD-PH includes parenchymal destruction of the pulmonary capillary bed and hypoxiainduced vascular remodelling, the rationale for specific PAH vasodilator therapies in ILD-PH is uncertain. Observational studies have failed to show a clear survival benefit with specific PAH therapies and confirmed the grim prognosis of patients with this disease.24 Nonetheless, in a disease like SSc, where a true pulmonary vasculopathy is regularly observed, more
References 1 Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 2010; 138: 1383–94. 2 Hachulla E, de Groote P, Gressin V, Sibilia J, Diot E, Carpentier P et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum 2009; 60: 1831–9. 3 Hsu VM, Chung L, Hummers LK, Wigley F, Simms R, Bolster M et al. Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma
research is needed to define the role of PAH therapies in ILD-PH. PH due to pulmonary veno-occlusive disease (PVOD) is probably under-recognised in SSc.25 Features of PVOD can be detected by HRCT (lymph node enlargement, centrilobular ground glass opacities and septal lines), and the importance of identifying this as the cause for precapillary PH rests on the fact that pulmonary vasodilator therapy can actually precipitate pulmonary oedema. PH due to chronic thromboembolic disease (CTEPH) is rare in SSc, but can occur. Here, organised thrombi result in luminal occlusion. It is important to identify this condition as it can be surgically curable. Without appropriate recognition and therapy, it is associated with a very poor prognosis. Recently, favourable results in the CHronic thromboEmbolic pulmonary hypertension Soluble guanylate cyclase–Stimulator Trial 1 (CHEST-1) study would suggest that riociguat may have a role in inoperable CTEPH.26
Conclusion There have been several advances in pulmonary vascular medicine over the past 15 years that have turned PAH, once an invariably fatal disease, into one with improved outcomes. SSc features as a particular prototype disease for PH, and showcases some of the victories and challenges that remain in reducing morbidity and mortality from this serious disease.
(PHAROS) cohort study. Semin Arthritis Rheum 2014; 44: 55–62. 4 Lefevre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M et al. Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Arthritis Rheum 2013; 65: 2412–23. 5 Ngian GS, Stevens W, Prior D, Gabbay E, Roddy J, Tran A et al. Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2012; 14: R213. 6 Chung L, Domsic RT, Lingala B, Alkassab F, Bolster M, Csuka ME et al. Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken) 2014; 66: 489–95.
7 Galie N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J 2010; 31: 2080–6. 8 Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809–18. 9 Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330–40. 10 Galie N, Barbera JA, Frost A, Ghofrani A, Hoeper MM, McLaughlin V et al. AMBITION: a randomised, multicenter study of first-line ambrisentan and tadalafil combination therapy in subjects with pulmonary arterial hypertension (PAH). Eur Respir J 2014; 44: 2916. 11 Johnson SR, Brode SK, Mielniczuk LM, Granton JT. Dual therapy in IPAH and
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12
13
14
15
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SSc-PAH. A qualitative systematic review. Respir Med 2012; 106: 730–9. Keogh A, Strange G, Kotlyar E, Williams T, Kilpatrick D, Macdonald P et al. Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: an Australian collaborative report. Intern Med J 2011; 41: 235–44. Nikpour M, Stevens W, Proudman SM, Buchbinder R, Prior D, Zochling J et al. Should patients with systemic sclerosis-related pulmonary arterial hypertension be anticoagulated? Intern Med J 2013; 43: 599–603. Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Le T, Lee P et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol 2012; 39: 276–85. Caldeira D, Loureiro MJ, Costa J, Pinto FJ, Ferreira JJ. Oral anticoagulation for pulmonary arterial hypertension: systematic review and meta-analysis. Can J Cardiol 2014; 30: 879–87. Humbert M, Yaici A, de Groote P, Montani D, Sitbon O, Launay D et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum 2011; 63: 3522–30.
17 Thakkar V, Stevens W, Moore O, Nikpour M. Managing Scleroderma: challenges in primary care. Med Today 2012; 13: 35–42. 18 Kowal-Bielecka O, Avouac J, Pittrow D, Huscher D, Behrens F, Denton CP et al. Echocardiography as an outcome measure in scleroderma-related pulmonary arterial hypertension: a systematic literature analysis by the EPOSS Group. J Rheumatol 2009; 37: 105–15. 19 Thakkar V, Stevens WM, Prior D, Moore OA, Byron J, Liew D et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther 2012; 14: R143. 20 Thakkar V, Stevens W, Prior D, Youssef P, Liew D, Gabbay E et al. The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2013; 15: R193. 21 Coghlan JG, Denton CP, Grunig E, Bonderman D, Distler O, Khanna D et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 2014; 73: 1340–9. 22 Hao YJ, Thakkar V, Stevens W, Prior D, Rabusa C, Youssef P et al. A comparison of the predictive accuracy of three
23
24
25
26
screening models (DETECT v. ESC/ERS v. ASIG) for pulmonary arterial hypertension in systemic sclerosis. Clin Exp Rheumatol 2014; 32(Suppl 81): 19. Valerio CJ, Schreiber BE, Handler CE, Denton CP, Coghlan JG. Borderline mean pulmonary artery pressure in patients with systemic sclerosis: transpulmonary gradient predicts risk of developing pulmonary hypertension. Arthritis Rheum 2013; 65: 1074–84. Le Pavec J, Girgis RE, Lechtzin N, Mathai SC, Launay D, Hummers LK et al. Systemic sclerosis related pulmonary hypertension associated with interstitial lung disease: impact of pulmonary arterial hypertension therapies. Arthritis Rheum 2011; 63: 2456–64. Gunther S, Jais X, Maitre S, Berezne A, Dorfmuller P, Seferian A et al. Computed tomography findings of pulmonary venoocclusive disease in scleroderma patients presenting with precapillary pulmonary hypertension. Arthritis Rheum 2012; 64: 2995–3005. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369: 319–29.
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76 van der Gronde T, de Hon O, Haisma HJ, Pieters T. Gene doping: an overview and current implications for athletes. Br J Sports Med 2013; 47: 670–8. 77 Rabinovsky ED, Gelir E, Gelir S, Lui H, Kattash M, DeMayo FJ et al. Targeted expression of IGF-1 transgene to skeletal muscle accelerates muscle and motor neuron regeneration. FASEB J 2003; 17: 53–5. 78 Kostek MC, Delmonico MJ, Reichel JB, Roth SM, Douglass L, Ferrell RE et al. Muscle strength response to strength
training is influenced by insulin-like growth factor 1 genotype in older adults. J Appl Physiol (1985) 2005; 98: 2147–54. 79 Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T, Komen W et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 2004; 350: 2682–8. 80 Muona K, Makinen K, Hedman M, Manninen H, Yla-Herttuala S. 10-year safety follow-up in patients with local
VEGF gene transfer to ischemic lower limb. Gene Ther 2012; 19: 392–5. 81 Lippin Y, Dranitzki-Elhalel M, Brill-Almon E, Mei-Zahav C, Mizrachi S, Liberman Y et al. Human erythropoietin gene therapy for patients with chronic renal failure. Blood 2005; 106: 2280–6. 82 Chenuaud P, Larcher T, Rabinowitz JE, Provost N, Cherel Y, Casadevall N et al. Autoimmune anemia in macaques following erythropoietin gene therapy. Blood 2004; 103: 3303–4.
C L I N I C A L P E R S P E CT I V E S
Prospects for improving outcomes in systemic sclerosis-related pulmonary hypertension V. Thakkar,1,2 M. Nikpour,3,4 W. M. Stevens3 and S. M. Proudman5,6 1 Department of Rheumatology, Liverpool Hospital, 2School of Medicine, University of Western Sydney, Sydney, New South Wales, 3Department of Rheumatology, St Vincent’s Hospital Melbourne, 4Department of Medicine, The University of Melbourne, Melbourne, Victoria, 5Rheumatology Unit,
Royal Adelaide Hospital and 6Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
Key words systemic sclerosis, pulmonary hypertension, screening, PAH-specific therapy, anticoagulation. Correspondence Susanna Proudman, Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. Email: [email protected] Received 3 November 2014; accepted 27 November 2014. doi:10.1111/imj.12691
Abstract Pulmonary arterial hypertension (PAH) is a leading cause of morbidity and mortality in patients with systemic sclerosis (SSc). Approximately one in 10 will develop PAH during their lifetime. These patients have a worse prognosis than those with PAH due to other causes. The most common clinical feature of SSc-PAH in the early stages is non-specific exercise intolerance that can be erroneously attributed to other manifestations of SSc. Screening provides an opportunity for early identification of SSc-PAH and prompt initiation of therapies with the potential to improve quality of life and survival. International guidelines recommend annual transthoracic Doppler echocardiography (TTE), but TTE has limitations. The tricuspid regurgitant jet required for estimating the systolic pulmonary artery pressure is absent in up to 39% of patients, including a proportion with PAH. This has prompted a move to new screening algorithms that are less dependent on TTE. Not all pulmonary hypertension (PH) in patients with SSc is PAH. Other causes include PH secondary to left heart disease, interstitial lung disease-related PH, chronic thromboembolic PH and pulmonary veno-occlusive disease. With the advent of evidence-based therapies, including newer agents such as macitentan, riociguat and selexipag, the establishment of centres with expertise in PAH and the focus on early detection, there has been considerable improvement in survival. The role of anticoagulation for SSc-PAH has been the subject of a recent meta-analysis of nine observational studies that suggests it may confer a survival benefit, but to date, there have been no randomised controlled trials to confirm this.
© 2015 Royal Australasian College of Physicians
248
Pulmonary hypertension in scleroderma
Introduction Systemic sclerosis (SSc) is a complex multisystem connective tissue disease characterised by auto-antibodies, endothelial dysfunction and extensive fibrosis affecting the skin and internal organs. Pulmonary arterial hypertension (PAH), a disorder of increased pulmonary vascular resistance that can lead to right heart failure, is a leading cause of morbidity and mortality. While PAH is the most common cause of pulmonary hypertension (PH) in SSc, and the focus of this review, SSc patients are at risk of multiple potential causes of PH, posing diagnostic and management challenges. The goal of this article is to review this interesting and evolving area.
What is PAH? PAH is a clinical syndrome characterised by restricted flow through the pulmonary arterial circulation. It is diagnosed by finding precapillary PH at right heart catheterisation (RHC) (mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg at rest with a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and pulmonary vascular resistance (PVR) of >3 Wood units) in the absence of significant lung disease and chronic thromboembolic pathology. The pathophysiology of PAH is characterised by progressive loss of the usually high-capacitance, lowresistance pulmonary microcirculation at the level of the distal pulmonary vasculature (40 mmHg and/or diffusing capacity for carbon monoxide (DLCO) < 55% predicted and/or forced vital capacity (FVC)/DLCO ratio >1.6), with a recent study showing the frequency of PH in this population being 10% at 2 years, 13% at 3 years and 25% at 5 years.3
The mortality of SSc-PAH In most patients, SSc-PAH is a progressive disease associated with an extremely poor prognosis. A recent large systematic review, which included 22 studies representing 2244 SSc patients with all types of PH, reported 1-, 2- and 3-year survival rates of 81%, 64% and 52% respectively.4 These figures highlight the seriousness of PH in SSc, with a mortality rate similar to that observed in advanced malignancy. SSc-PAH patients consistently demonstrate a worse prognosis than other CTD-PAH subgroups and a worse prognosis than iPAH patients. However, with the emergence of evidence-based therapies, the establishment of centres with expertise in SSc and PAH and the focus on early detection, there have been considerable improvements in the survival of patients with SSc-PAH. The Australian Scleroderma Cohort Study (ASCS), which is a prospective, multicentre study of risk and prognostic factors for cardiopulmonary outcomes in SSc in which an early detection algorithm is applied, reported 1- and 3-year survival rates in CTD-PAH of 94% and 73% respectively.5 Similarly, the 1- and 3-year survival rates in a large US cohort of SSc patients utilising a screening programme were 93% and 75%, respectively, illustrating the significant progress that is being made in reducing mortality from this serious disease.6 Several important poor prognostic factors have been identified. These include a worse haemodynamic profile at diagnosis (increased mPAP, mean right atrial pressure PVR and reduced cardiac index (CI)), older age, male sex, advanced functional class of impairment, a pericardial effusion at diagnosis and severely impaired DLCO.6 These factors highlight the imperative to reduce the time to diagnosis and the commencement of effective therapies. They also provide a rationale for closer monitoring in this poor prognostic group, including repeated haemodynamic assessments, rapid escalation of therapies (including dual and triple therapy combinations) and enrolment in clinical trials of novel therapies.
Drug treatment in SSc-PAH Double blind, placebo controlled trials have demonstrated efficacy in PAH for each of the following classes of
advanced pulmonary vasodilator therapy currently available on the Australian Pharmaceutical Benefits Scheme (PBS): (i) endothelin receptor antagonists (ERA, ambrisentan, bosentan and most recently, macitentan); (ii) phosphodiesterase inhibitors (sildenafil and tadalafil) and (iii) prostanoids (epoprostenol and iloprost). While generally these studies have not been powered to show independent efficacy for the SSc-PAH subgroup, the direction of the results has been consistent with that seen in iPAH, where significant improvements in exercise capacity and secondary end-points, such as reduction in mortality of 39% (P < 0.041) have been demonstrated.7 Importantly, there have been no head-to-head, blinded RCT comparing these therapies, so there is no firm evidence upon which to recommend one therapy ahead of another in SSc-PAH. Newer therapies have recently met primary outcome measures in phase 3 studies. In the Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) study, macitentan, an oral dual ERA, decreased the risk of a first occurrence morbidity/mortality event by 45% over placebo.8 The rate of elevated liver transaminases greater than three times the upper limit of normal (3.5%) was similar to that of placebo and although a decrease in haemoglobin was observed more frequently in macitentan treated patients, there was no difference in treatment discontinuation rates between groups at the 10 mg/day dose that is now PBS listed. Aside from being one of the largest, prospective, controlled PAH studies to date with 742 patients, the SERAPHIN study represents a major shift in PAH trial design towards more clinically relevant end-points, with event-driven morbidity/ mortality as the primary outcome measure over a longer term follow-up period (up to 3.5 years) as compared with many previous RCT in which change in exercise capacity (for example, as measured by 6-min walk distance (6MWD) over a relatively short trial period (12–18 weeks)) was the primary end-point. Riociguat is a Therapeutic Goods Administration approved therapy that acts by stimulating guanylate cyclase and increasing the sensitivity to endogenously produced nitric oxide. In the Pulmonary Arterial Hypertension sGC-Stimulator Trial (PATENT-1) study, riociguat was compared with placebo in 443 patients, and the 2.5 mg three times daily dose resulted in a 36-m increase in 6MWD over placebo over the 12-week study period.9 Significant improvements were also seen in the secondary end-points of pulmonary vascular resistance, N-terminal pro–B-type natriuretic peptide (NT-proBNP), World Health Organization functional class, time to clinical worsening and the Borg Dyspnoea score. Selexipag is an orally bioavailable, selective prostacyclin agonist that was developed as an alternative to © 2015 Royal Australasian College of Physicians
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the currently available prostanoids, which are often effective, but limited by their complex administration and side-effects. Preliminary reports from the large, phase 3 Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial HypertensiON (GRIPHON) study indicate that selexipag reduces the risk of morbidity/mortality compared with placebo by 39%, with a tolerability profile similar to other prostanoids. The full report is anticipated in the first half of 2015, but selexipag may be an effective oral prostanoid option in PAH management.
The combination treatment era More recently, attention has turned to the use of combination therapies in PAH. The rationale for this approach stems from the fact that despite improved survival in the modern treatment era, PAH remains a debilitating disease associated with high mortality, and disease progression is inevitable for the majority of patients receiving monotherapy. Furthermore, abnormalities in multiple signalling pathways are characteristic. Combination strategies may better target these pathways and optimise use of existing therapies. Perhaps, the most compelling evidence to date for combination therapy was seen in the recently reported AMBrIsentan and Tadalafil in patients with pulmonary arterial hypertensION (AMBITION) study.10 Preliminary results suggest a 50% reduction in the number of clinical failure events at 24 weeks with upfront combination ambrisentan and tadalafil compared with monotherapy, mostly driven by a reduction in hospitalisations in the combination therapy arm (4% in combination vs 12% in monotherapy). The clinically relevant issue of early add-on therapy for deteriorating patients or patients with poor prognosis was not specifically addressed in this study. A systematic review of dual therapy in PAH, that included 26 observational studies and six RCT, concluded that there was a beneficial effect with dual therapy in iPAH and SSc-PAH, particularly in patients deteriorating despite monotherapy.11 However, there were no uniform criteria by which to increase therapy, nor consensus on the optimal choice of combination strategy. Recently, two important Australian studies have been published reporting the potential benefit of combination therapy in PAH. In a cohort of 117 CTD-PAH patients, the majority of whom had SSc-PAH (94.9%), combination therapy reduced mortality by 45%.5 Similarly, in an observational study of 112 patients deteriorating on monotherapy (inclusive of 40 patients with CTD-PAH, 29 of whom had SSc-PAH), Keogh et al. reported 1-,2-, 3-year survival rates, after the addition of a second PAH therapy, of 88%, 71% and 61% respectively.12 Overall, it appears likely that combination therapy confers morbidity and mortality
benefits in deteriorating SSc-PAH patients. However, further research is necessary into the optimal dual combination strategy, the timing of initiation and criteria for patient selection.
Anti-coagulation in SSc-PAH In the absence of any RCT, the role of anticoagulation in all forms of PAH is currently being defined.13 While thrombotic arteriopathy is one of the key pathogenic events in SSc-PAH, the results from observational studies of anticoagulation have been conflicting. In a recent Australian multicentre cohort study of 117 patients with CTDPAH (95% of whom had SSc-PAH), anticoagulation with warfarin conferred an estimated fivefold reduction in mortality compared with patients who were not anticoagulated over a mean 2.6 years of follow up.5 In contrast, Canadian investigators reported a low probability of a survival benefit with 6 months or more of anticoagulation.14 However, the minimum dose and duration of exposure to warfarin in this single-centre study was not specified, and a substantial proportion of patients were not on concomitant advanced PAH therapy. A recent meta-analysis of nine observational studies in 1730 patients with PAH reported a hazard ratio for death of 0.69 (95% confidence interval 0.57–0.82) with oral anticoagulation.15 The potential utility of anti-coagulation will be the focus of the Scleroderma-Pulmonary arterial Hypertension Intervention with ApiXaban (SPHInX) study, an National Health and Medical Research Councilfunded multi-centre randomised double blind placebo controlled study of apixaban in SSc-PAH. Recruitment for this study will commence in the latter part of 2014, with results anticipated in 2019.
Screening for SSc-PAH Screening for PAH has become a cornerstone of SSc management. The rationale behind screening for SSc-PAH is based on the early identification of an aggressive, but treatable complication in an at-risk population, allowing prompt initiation of therapies that offer significant clinical benefit. Major pulmonary hypertension guidelines from the American College of Cardiology Foundation/ American Heart Association, European Society of Cardiology (ESC)/European Respiratory Society (ERS) and the National Pulmonary Hypertension Centres of the UK and Ireland recommend annual transthoracic Doppler echocardiography (TTE), with the latter also recommending regular DLCO corrected for haemoglobin (DLCOcorr) assessment. The impressive 8-year survival rate of 64% in a group of SSc-PAH patients in whom PAH was detected as a result of screening, compared with 17% for
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patients diagnosed with PAH in the course of routine care, published by Humbert et al., suggests the improved survival in patients detected though screening is more than just due to lead time bias.16 Guidelines published by the Australian Scleroderma Interest Group (ASIG) recommend that all SSc patients undergo an annual clinical assessment, TTE and pulmonary function tests (PFT). Any patient identified as having possible PAH (sPAPTTE ≥40 mmHg and/or DLCOcorr ≤50% predicted with FVC > 85%, and/or fall in DLCOcorr ≥20% compared with the previous year), especially in the presence of symptoms and without adequate explanation on high-resolution CT (HRCT) lung and/or V/Q scanning, should undergo RHC that offers the only means of making a definitive diagnosis of PH.17 Recently, there have been concerted efforts to improve screening and rationalise the use of limited resources, such as TTE. Furthermore, while TTE is the single most important non-invasive assessment tool for PH (offering direct and indirect signs of PH, right and left ventricular systolic and diastolic function, valvular heart disease and shunts, together with poor prognostic features of PH, including right ventricular enlargement/ dysfunction and pericardial effusion), high-quality studies in centres with specific echocardiographic expertise for the detection of PH have variously estimated that the tricuspid regurgitant jet is absent and/or images are of insufficient quality in 20–39% of SSc patients, including studies where up to one-third of patients with PAH had unobtainable pressures on TTE.18 This highlights the need for multimodal strategies in screening for SSc-PAH. ASIG recently derived and validated a two-component screening algorithm comprising PFT and serum NT-proBNP level (Fig. 2).19,20 In this algorithm, patients with DLCOcorr 1.6 were followed, demonstrated 2-, 3- and 5-year rates of developing PH of 10%, 13% and 25% respectively.3 Similarly, a mPAP of 20–24 mmHg in SSc patients does not appear to be as benign as once thought, being associated with an increased risk of PAH in the future.23 © 2015 Royal Australasian College of Physicians
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The differential diagnosis of PH in SSc While PAH is probably the most common cause of PH among SSc patients, several other causes of PH can be important in the individual SSc patient. PH secondary to left heart disease affects up to 12% of SSc patients, and is diagnosed by the finding of postcapillary PH at RHC (PAWP > 15 mmHg). The underlying pathogenesis often reflects primary myocardial fibrosis, which is a common, but usually occult process. Alternatively, left heart disease can be related to the presence of traditional risk factors for left heart dysfunction, such as older age, hypertension, smoking or renal disease. Lung disease associated pulmonary hypertension, which is usually due to ILD in SSc, refers to the RHC finding of precapillary PH coupled with significant ILD, usually defined according to the extent of involvement on HRCT coupled with PFT abnormalities. Importantly, only a small proportion of patients with severe ILD will actually develop clinically significant PH. As the pathogenesis of ILD-PH includes parenchymal destruction of the pulmonary capillary bed and hypoxiainduced vascular remodelling, the rationale for specific PAH vasodilator therapies in ILD-PH is uncertain. Observational studies have failed to show a clear survival benefit with specific PAH therapies and confirmed the grim prognosis of patients with this disease.24 Nonetheless, in a disease like SSc, where a true pulmonary vasculopathy is regularly observed, more
References 1 Chung L, Liu J, Parsons L, Hassoun PM, McGoon M, Badesch DB et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest 2010; 138: 1383–94. 2 Hachulla E, de Groote P, Gressin V, Sibilia J, Diot E, Carpentier P et al. The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France. Arthritis Rheum 2009; 60: 1831–9. 3 Hsu VM, Chung L, Hummers LK, Wigley F, Simms R, Bolster M et al. Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma
research is needed to define the role of PAH therapies in ILD-PH. PH due to pulmonary veno-occlusive disease (PVOD) is probably under-recognised in SSc.25 Features of PVOD can be detected by HRCT (lymph node enlargement, centrilobular ground glass opacities and septal lines), and the importance of identifying this as the cause for precapillary PH rests on the fact that pulmonary vasodilator therapy can actually precipitate pulmonary oedema. PH due to chronic thromboembolic disease (CTEPH) is rare in SSc, but can occur. Here, organised thrombi result in luminal occlusion. It is important to identify this condition as it can be surgically curable. Without appropriate recognition and therapy, it is associated with a very poor prognosis. Recently, favourable results in the CHronic thromboEmbolic pulmonary hypertension Soluble guanylate cyclase–Stimulator Trial 1 (CHEST-1) study would suggest that riociguat may have a role in inoperable CTEPH.26
Conclusion There have been several advances in pulmonary vascular medicine over the past 15 years that have turned PAH, once an invariably fatal disease, into one with improved outcomes. SSc features as a particular prototype disease for PH, and showcases some of the victories and challenges that remain in reducing morbidity and mortality from this serious disease.
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SSc-PAH. A qualitative systematic review. Respir Med 2012; 106: 730–9. Keogh A, Strange G, Kotlyar E, Williams T, Kilpatrick D, Macdonald P et al. Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: an Australian collaborative report. Intern Med J 2011; 41: 235–44. Nikpour M, Stevens W, Proudman SM, Buchbinder R, Prior D, Zochling J et al. Should patients with systemic sclerosis-related pulmonary arterial hypertension be anticoagulated? Intern Med J 2013; 43: 599–603. Johnson SR, Granton JT, Tomlinson GA, Grosbein HA, Le T, Lee P et al. Warfarin in systemic sclerosis-associated and idiopathic pulmonary arterial hypertension. A Bayesian approach to evaluating treatment for uncommon disease. J Rheumatol 2012; 39: 276–85. Caldeira D, Loureiro MJ, Costa J, Pinto FJ, Ferreira JJ. Oral anticoagulation for pulmonary arterial hypertension: systematic review and meta-analysis. Can J Cardiol 2014; 30: 879–87. Humbert M, Yaici A, de Groote P, Montani D, Sitbon O, Launay D et al. Screening for pulmonary arterial hypertension in patients with systemic sclerosis: clinical characteristics at diagnosis and long-term survival. Arthritis Rheum 2011; 63: 3522–30.
17 Thakkar V, Stevens W, Moore O, Nikpour M. Managing Scleroderma: challenges in primary care. Med Today 2012; 13: 35–42. 18 Kowal-Bielecka O, Avouac J, Pittrow D, Huscher D, Behrens F, Denton CP et al. Echocardiography as an outcome measure in scleroderma-related pulmonary arterial hypertension: a systematic literature analysis by the EPOSS Group. J Rheumatol 2009; 37: 105–15. 19 Thakkar V, Stevens WM, Prior D, Moore OA, Byron J, Liew D et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: a case-control study. Arthritis Res Ther 2012; 14: R143. 20 Thakkar V, Stevens W, Prior D, Youssef P, Liew D, Gabbay E et al. The inclusion of N-terminal pro-brain natriuretic peptide in a sensitive screening strategy for systemic sclerosis-related pulmonary arterial hypertension: a cohort study. Arthritis Res Ther 2013; 15: R193. 21 Coghlan JG, Denton CP, Grunig E, Bonderman D, Distler O, Khanna D et al. Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis 2014; 73: 1340–9. 22 Hao YJ, Thakkar V, Stevens W, Prior D, Rabusa C, Youssef P et al. A comparison of the predictive accuracy of three
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