Pulmonary Arterial Hypertension-A Deadly Complicationof Systemic Sclerosis

Edward A Pankey1, Matthew Epps1, Bobby D Nossaman1,2, Albert L Hyman1 and Philip J Kadowitz1

Affiliations: 1Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA and 2Department of Anesthesiology, Ochsner ClinicFoundation, New Orleans, LA, USA

A B S T R A C T

Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Moreover, when PAH occurs in patientsdiagnosed with systemic sclerosis, worse outcomes are observed. The purpose of this review is to discuss the etiologies of PAH found in thesystemic sclerosis patient, limitations of current medical therapies, and, finally, potential therapies for patients with this combination.

Keywords: connective tissue disease, pulmonary arterial hypertension, pulmonary hypertension, systemic sclerosis

Correspondence: Philip J Kadowitz, Department of Pharmacology SL-83, Tulane University School of Medicine, 1430 Tulane Avenue, NewOrleans, LA, 70112-2699, USA. Tel: 504-988-5444; Fax: 504-988-5283; e-mail: pkadowi@tulane.edu

INTRODUCTIONPulmonary complications of systemic sclerosis (SSc) are a

life threatening and commonly observed outcome. Pulmonaryarterial hypertension (PAH) and pulmonary fibrosis are majorcontributors to mortality in the SSc patient, responsible for61% of SSc-related deaths (PAH 26% and fibrosis 35%).1 Thediagnosis of SSc alone carries an estimated 50% 10-yearmortality.2�4 When PAH develops in the SSc patient, themedian survival rate falls, with reports as low as 1 year.4

While recent novel pharmacologic developments for theisolated PAH (IPAH) patient have shown improved outcomes,these improvements are not paralleled in the SSc-PAHpatient.5

The goal of this review is to provide updated information onSSc-PAH burden, etiology, diagnostic criteria, and geneticetiologic factors. We also provide an update on currentresearch into novel therapeutic targets.

EPIDEMIOLOGY

In the United States, the prevalence of SSc is estimated at 240per million and that of SSc-PAH at 24 per million, which issignificantly higher than the prevalence of Idiopathic PAH(IPAH) in this country.6 Recent reports from the EuropeanEULAR (European Union League Against Rheumatism) Scler-oderma Trials and Research (EUSTAR) cohort estimated SScprevalence at 5 per 100 000.1 The incidence of PAH in the SScpatient has been estimated at 0.61 cases per 100 patient yearsbased on data from the French itinerair-sclerodermie study.7

RISK FACTORS

A diagnosis of SSc-PAH without accompanying fibrosisoccurs more often in the limited cutaneous form (lcSSc) when

compared to the diffuse cutaneous form (dcSSc) (60 vs 27.7%respsectively).8 Other reported associations with increasedrisk of developing PAH in the SSc patient are onset of SSc at alater age9 duration of SSc greater than 10 years,10 increasedduration and severity of associated Raynaud phenomenon,11,12

and decreased nailfold capillary density.13

VASCULAR DYSFUNCTION

The normally functioning EC is a key regulator of vascularsmooth muscle tone, blood flow, cell migration growth anddifferentiation, coagulation, vessel growth, and repair.14

Although a comprehensive description of its full functionalityis beyond the scope of this review, two mediators produced bythe EC of particular note are nitric oxide (NO)15�17 andendothelin (ET-1).18

It is the source of several modulators of vascular tone(Nitric Oxide, Endothelin -1),as well as profibrotic regulators(transforming growth factor beta (TGF-b), interleukins (IL)4,12,17), cell recruitment and differentiation (TGF-b, plateletderived growth factor (PDGF)), and plays a key role ininflammation (IL-1, monocyte chemo attractant protein-1(MCP-1)).19�21 The dysfunction of the endothelium has beenimplicated in the pathology of SSc and PAH19,22

The inciting event leading to endothelial dysfunction in theSSc patient remains unkown. When endothelial damageoccurs, the dysfunction manifests as an inability to repairthe endothelium which ultimately leads to apoptosis andcapillary breakdown.19 In the SSc patient, the angiogenicresponse to resultant hypoxemia is the unbalanced produc-tion of angiogenic and angiostatic factors leading to vasculo-pathy. Despite the consistent upregulation of pro-agniogenicfactors (ET-1, TGF-b, vascular endothelial growth factor(VEGF), PDGF,MCP- 1) there is a paucity of angiogenesis in

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the SSc patient.19 Additionally, alterations in the productionof other factors that have a role in the vasconstriction ofpulmonary arteries such as NO, Prostacyclin, ET-1, andserotonin.14

PAH develops as a consequence of restricted flow throughthe pulmonary arterial circulation and subsequent increasedresistance and eventual deleterious effects on right-heartfunction.23 PAH has many established causes and associa-tions, including HIV and schistosomiasis, congenital heartdisease, and portal hypertension.22 We direct the curiousreader to the American College of Cardiology Foundation/American Heart Association 2009 expert consensus documenton pulmonary hypertension for an extensive review of thisdisease.23

NO is an important regulator of vascular SMC tone. NO isproduced in the EC via the conversion of L-arginine by theendothelial nitric oxide synthase eNOS (NOS3) in response tosheer stress; activation by cytokines (tumor necrosis factor-alpha, vascular endothelial growth factor [VEGF], transform-ing growth factor-beta [TGF-b]);24 and the agonistsacetylcholine, bradykinin, and serotonin.16,25 Once produced,NO diffuses to neighboring smooth muscle cells (SMCs),binds to soluble guanylate cyclase leading to an increase incyclic-GMP formation, a net decrease in intracellular calcium,SMC relaxation, and resulting vasodilatation.17,26

NO inhibits SMC growth and proliferation and elicitsantithrombotic effects, which contribute to its role as animportant regulator of vascular function.27 In addition, NOpossesses immune modulating effects via the inhibition ofleukocyte attachment25 and the regulation of chemokineexpression, such as MCP-1.28

ET-1 is also produced by ECs and is an importantvasocontrictor and SMC mitogen that exerts its effects viatwo receptors, ETA and ETB.29�31 Endothelin may also play animportant role in fibrosis and modulation of the immuneresponse via cytokine and adhesion molecule upregulation,leukocyte activation, and modulation of vascular permeabil-ity.27 The ETA receptor, located on pulmonary vascular SMCsand fibroblasts, binds ET-1 and this results in SMC prolifera-tion and growth, fibroblast recruitment and differentiation,and a vasoconstriction.32 Activation of the ETB receptor,located primarily on pulmonary ECs and present in smallerquantities on pulmonary vascular SMCs, results in vasodila-tion via the clearance of excess ET-1,33 inhibition ofendothelin-converting enzyme,34,35 release of NO and pros-tacyclin,36 attenuation of SMC proliferation,34,37 and de-creased cell differentiation and migration to the pulmonaryvascular bed.38

PAHPAH is defined as an elevation in mean pulmonary arterial

pressure, ]25 mmHg at rest or ]30 mmHg with exercise.39

Idiopathic PAH (IPAH) is thought to develop after an initialinsult and/or injury to pulmonary ECs.40,41 The initialendothelial insult leads to dysfunctional repair, decreased

production of vasodilators NO and prostaglandin I2 (PGI2),coupled with paradoxically increased levels of the vasocon-strictors ET-1 and thromboxane A2. This results in a shifttoward vasoconstriction and platelet aggregation in thepulmonary vascular bed,42 and vascular SMC differentiation,migration, and hyperplasia.41 Chronic pathologic changes arecharacterized by a predominant homogenous plexiformarteriopathy43,44 in the pulmonary vascular bed that appearto involve reactive inflammatory changes, antiapoptoticevents, smooth muscle hypertrophy, intimal hyperplasia,and eventual fibrosis and distal venoocclusion,42 ultimatelyresulting in tissue fibrosis, right-heart (RH) failure, anddeath.4

Elevated levels of plasma ET-1 and its endothelial receptorsare found in IPAH patients and have been shown to correlatewith disease severity.45,46 IPAH patients exhale less measuredNO,47 despite a prevalence of distinctive plexiform arterio-pathy containing elevated levels of eNOS.48 The importanceof this contradiction has yet to be elucidated.

SScSSc vasculopathy results from the culmination of events

including activation of lymphocytes, inflammation, produc-tion of autoantibodies, fibrosis, and disrupted cell signalingbetween endothelial cells, epithelial cells, and fibroblasts.19,49

The end result is the replacement of normal organ parench-ymal tissue architecture with extracellular matrix elementsleading to fibrosis and ultimate organ failure.19

Overexpression of ET-1 and its receptors in SSc are welldescribed.29 Elevated ET-1 expression has been found in theskin50 and lungs51,52 of SSc patients, and this correlates withthe degree of fibrosis and mortality.51 Of particular clinicalvalue in the dcSSc patient is the increased ET-1 expressionobserved in SSc-related ILD populations prior to the onset ofclinical PAH,53 despite a lack of further ET-1 elevation in SScpatients with documented PAH.54

The end result of alterations in most of these mechanismsis vasculopathy, cell proliferation, loss of apoptosis, andultimately fibrotic changes in the vascular wall and surround-ing tissue.55

GENETICS

Abundant evidence has linked hPAH and some cases offormally diagnosed IPAH to mutations in the super family oftransforming growth factor beta (TGFb) and their receptors,specifically BMPR2.56 The history of genomic investigation iswell described by Austin and colleagues.57 Investigationsfocus on the link between BMPR2 and activin-like kinase 1(ALK1), endoglin (ENG), and their common downstreamSMAD transcription factors.56,58,59

The genetic mutations associated with SSc are numerous, asdocumented in a recent review:60 Mutations in BMPR2 anddownstream signals were found to be at increased levels insuch patients.61�64 A recently identified imatinib susceptibilitygene pattern for dcSSc shows promise as a genetic marker for

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targeted therapy.65 Transcription factor Fli1 mutations in-volved in endothelial cell regulatoin and angiogenesis66 haverecently been proposed as a cell-specific potential target inSSc.67 Moreover, a new susceptibility locus CD247 and theconfirmation of MHC, IRF5, and STAT4 as regions for SScgenetic risk have been reported.68

In comparison, the study of genetic susceptibility of SSc-PAH has been limited to lack of cohorts and power.69 UnlikeIPAH, BMPR2 mutations were not identified in CTD-PAHpatients.70,71 A six base insertion in intron 7 of the endoglingene was found in differing amounts between SSc pathitens,SSc-PAH patients, and controls.72

Variations in ET-1 levels have recently stimulated investiga-tion. Studies have shown no difference between levels of ET-1in SSc and SSc-PAH groups.73 A later study discovered anincrease in the KCNA5 gene mutation for the Kv1.5 potassiumchannel in IPAH patients;74 ET-1 is a modulator of theexpression of Kv1.5.69 Kawaguchi and colleagues reported adecreased NO:ET-1 ratio in SSc-PAH patients compared tothose in SSc patients as well as to three unique single-nucleotide polymorphisms in the nitric oxide synthase 2(NOS2) gene associated with SSC-PAH patients.75,76 Poly-morphisms in NOS275,76 and the identification of upregu-lated genes for matrix metalloproteinase 9 and VEGF beyondthe levels seen in the IPAH patients77 further supportinvestigation into the unique genetic characteristics of SSc-PAH. A recently reported difference in expression of a 6-baseinsertion of intron 7 of ENG*a member of the TGF-breceptor complex found in the human vascular en-dothelium*and SSc-PAH but not in controls or SSc patientswithout PAH.72 The role of the ENG polymorphism in thepathogenesis of SSc-PAH is still being examined.78

SSC-PAH SYMPTOMS AND CLINICAL

MEASURES

The early stages of PAH are often asymptomatic orcharacterized by nonspecific manifestations such as dyspnea,cough, shortness of breath, chest pain, decreased exercisecapacity, and near-syncope to syncope.41 Physical findings ofbilateral inspiratory crackles on lung bases, jugular venousdistention, and right ventricular (RV) heave indicate RHcompromise and progression of the disease.79�81 If theclinician is not acutely aware of these subtle signs of PAHin the SSc population, they misled to investigate morecommon causes of these nonspecific symptoms, such asexercise-induced angina or congestive heart failure (CHF). Asa result, the diagnosis of PAH is delayed an average of 2 ormore years, at which time conventional treatments may notprove successful.4

PATHOLOGY OF PAH

Several pathologic changes occur in PAH depending onetiology.43 IPAH lesions exhibit a homogenous plexogenicarteriopathy (plexiform lesions with nearby concentric ob-literative lesions) with variable intimal remodeling andmucoid changes.43 Acquired PAH, such as seen in SSc,

exhibits a more heterogeneous picture characterized by ahigher concentration of obliterative lesions than with inter-stitial inflammation and a pneumonitis pattern, accompany-ing a more prominent muscularization. Of particular note isthe absence of the plexiform lesions found in IPAH. Thisdifference in pathology provides a source for further inves-tigation into why the therapies for the SSc-PAH patient arenot as beneficial when compared to those for the IPAHpatient.

Evaluating the SSc Patient for PAH

Despite having good New York Heart Association (NYHA)functional capacity and mild symptoms at diagnosis, out-comes in the SSc-PAH patient are poor.82 Therefore earlydetection and initiation of treatment are paramount.

Exercise capacity by the World Health Organization func-tional classes should be determined, chest x-ray taken andelectrocardiogram measured for clinical investigation andbaseline comparisons for evaluating treatments. Less invasiveprocedures, such as echocardiography for tricuspid valveregurgitation velocity83 and the combined myocardial perfor-mance measured by the Tei index, should also be under-taken.84 An elevated velocity greater than 2.8m/s, or RHdilation are both suggestive of SSc-PAH.5

Lung function tests can detect the presence PAH: thresholdsof concern include lung carbon monoxide diffusing capacity(DLCO) B60% of the predicted score, functional vitalcapacity (FVC) B70%, FVC/DLCO �1.6, or RV systolicpressure �35 mmHg.11,85 A decreasing DLCO may be aharbinger of SSc-PAH. One group of lcSSc patients with PAHdisplayed drastically lower mean DLCO roughly 5 years priorto being diagnosed with PAH.11,86,87

Despite ongoing efforts, noninvasive techniques of HRCTand echocardiography have yet to replace right-heart cathe-terization (RHC) for definitive diagnosis of PAH.22 RHCremains the gold standard for confirming PAH.88�91 Thecorrelation between RHC hemodynamic data and clinicalpresentation of the SSc-PAH patient has come into ques-tion.78 RHC evaluations recently showed that patients withSSc-PAH had lower mean pulmonary artery pressure andpulmonary vascular resistances despite a cardiac index thatwas depressed to a similar level as compared to that inIPAH.92 It has been suggested that in the SSc-PAH patient,the right ventricle’s ability to adapt to changes in pulmonaryvascular resistance is depressed.78

The criteria to evaluate SSc patients for the presence ofpulmonary complications have recently been reviewed, andthe concerned reader is directed to those algorithms.4,5,22

Indicators of worse prognosis at time of diagnosis have beenreported,78 and include later age of onset,93 degree of NYHAimpairment,93 RH dysfunction,81 pericardial effusion,92 lowserum sodium,94 and male gender.93

The use of N-terminal brain naturietic peptide (NT-proBNP)as a biomarker for SSc-PAH is encouraging. NT-proBNP inthe SSc-PAH patient is elevated to a greater degree than in theIPAH patient,95 and have been shown to predict survival

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rates.95,96 It is interesting to note that these elevations werepresent despite less-severe RHC hemodynamic measure-ments.95,97

CURRENT THERAPIES

Research on novel PAH therapies continues to improve ourunderstanding of the mechanisms regulating endothelialfunction and smooth muscle tone. However, when estab-lished therapies for isolated PAH are used to treat SSc-PAHpatients, poor outcomes are observed.5 Even more proble-matic are the etiologies of these poor outcomes; althoughseveral factors may be involved, such as the severity of PAH atpresentation and dysfunctional levels of the RV and pulmon-ary vasculature, more research into these differences isneeded.5

Prostacyclin Therapy

Prostacyclin is a well-described powerful pulmonary vaso-dilator.98,99 A continuous infusion of epoprostenol hasshown to be an effective therapy for PAH, by increasingexercise capacity, improving cardiopulmonary function, in-hibiting platelet aggregation, and SMC hyperplasia. It has avasodilator effect on the pulmonary vasculature, leading toimprovements in survival and morbidity.5,100�102 In contrast,although SSc-PAH patients treated with intravenous (IV)prostacyclin show improvement in hemodynamic parametersand exercise capacity,102 improved survival benefits have yet tobe demonstrated.5,103 Intavenous epoprostenol has producedpulmonary edema during treatment, raising concern about itsuse as a therapeutic option.104,105 It has been recommendedthat this intravenous treatment be reserved for serious cases:NYHA class IV and class III patients who have not respondedto conventional oral prostacyclin therapy.5 A subcutaneousprostacyclin preparation, treprostinil, is less cumbersome touse, but demands an increased dosing schedule.106 Inhalediloprost has been used in combination with oral therapies;however, the full utility of this route of administration has yetto be evaluated in a formal study and therefore has no formalrecommendation.107

Endothelin Receptor Antagonists

Bosentan, a nonselective endothelin receptor antagonist,has been a staple of isolated PAH treatment, showingconsistent improvement in clinical measures, lung functionalcapacity (FC),6MWD, hemodynamics, and quality oflife.108�110 However, the results in the SSc-PAH populationare less encouraging. In a recent study, 1-, 2-, and 3-yearsurvival rates with firstline bosentan were 92%, 89%, and79% for IPAH and the corresponding rates for SSc-PAH were80%, 56%, and 51%.111 Moreover, long-term outcome studieshave also shown that SSc-PAH patients have attenuatedbenefit in terms of clinical measures when compared toother CTDs associated with PAH. SSc-PAH patients onbosentan monotherapy show a modest effect on preventingfurther deterioration.112 A recent long-term outcome analysisof bosentan along with a prostanoid or sildenafil in SSc-PAHpatients showed improved or stable effects in both NYHA

functional class and 6MWD at 4 months, but these benefitswere attenuated by 1 year.111 Elevated liver function tests(LFTs) prompted cessation of bosentan in 10% of partici-pants.111 Despite these limitations, randomized controlledtrials have shown bosentan to improve mortality in SSc-PAHpatients,113�115 and it has been formally recommended forWorld Health Organization class III/IV severe PAH by theAmerican College of Chest Physicians.89

Sitaxsentan

Targeting ETA, the novel antagonist sitaxsentan inhibits thevasoconstrictive effects of ET-1 without upsetting the bene-ficial vasodilator component that is associated with ETB

activation.116 A 12-week study by Barst and colleagues showedimprovement in exercise capacity; however, a 10% incidenceof elevated LFTs was also observed.117 In one report of CTD-PAH treated with sitaxsentan or bosentan, the sitaxsentangroup had significantly better 1-year survival rate compared tobosentan (96 vs 88%).118

Ambriesentan

In the US, the Ambriesentan in Pulmonary Arterial Hyper-tension, Randomized, Double Blind, Placebo Controlled,Multicenter, Efficacy Study 1 and 2 (ARIES 1 and ARIES 2)of the selective ETA antagonist ambriesentan showedimprovement in 6 minute walk distance (6MWD) in theSSc-PAH CTD sub-group; however, the results were attenu-ated compared to the IPAH group (15�23 meter improvementvs 50�66 meters, respectively).119 Although elevations inaminotransferases were less likely when compared to bosen-tan, side effects of peripheral edema and CHF werereported.119 A recently published long-term study of ambrie-sentan combination therapy for IPAH showed persistentimprovement in cardiac hemodynamics of mean pulmonaryarterial pressure, cardiac output, 6MWD, and RV ejectionfraction after 2 years.120

Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors decrease the breakdown ofcyclic guanosine monophosphate. This enhances the effectsof cellular mechanisms regulated by NO, leading to pro-longed vasodilation.

Sildenafil

Sildenafil use results in increased exercise tolerance and hasbeen found to be an effective treatment for PAH.121 A recentdose-related trial showed that an oral sildenafil dose of 20 mgthree times a day improved 6MWD, but higher doses createdno significant difference.122 Data from the Sildenafil Use inPulmonary Arterial Hypertension (SUPER) study showedimprovements in 6MWDand FC after 12 weeks in the CTD-PAH patient (45% with SSc-PAH).123 This dose regimen hasbecome the first line therapy for SSc-PAH in NYHA classes IIand III at Johns Hopkins University Hospital.5 An additionalphosphodiesterase inhibitor, tadalafil, was evaluated in thePulmonary Arterial Hypertension and Response to Tadalafiltrial.124 Twenty patients had PAH associated with various

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CTDs showed an improvement in 6MWD and time to clinicalworsening with an optimum dose of 40 mg;124 long-termSSc-PAH data are unavailable.125

Combination Therapies

In order to find more efficacious treatments for theirpatients, clinicians combine therapies after failed monother-apy.5 Several combinations have been studied in the SSc-PAHpopulation: Inhaled iloprost plus bosentan have proveneffective in a small patient group, and inhaled iloprost plussildenafil suggest synergistic potential.126,127 The combina-tion of sildenafil and bosentan has been recently evaluatedand shown to have improved 6MWD and functional (FC),128

yet these effects are attenuated when compared to IPAHpatients, with the addition of increased frequency of sideeffects, such as hepatotoxicity.128,129 The Pulmonary ArterialHypertension Combination Study of Epoprostenol and Silde-nafil (11% of study participants have SSc-PAH) showed thatthe addition of sildenafil at 80 mg three times per day tointravenous epoprostenol results in significant improvementsin exercise capacity, quality of life, hemodynamic parameters,and time to clinical worsening,129 which would be beneficialin SScPAH patients.107 Sabnani and colleagues recently foundin a small study that the combination of imatinib andcyclophosphamide is effective in mild-to-moderate pulmon-ary disease, but further trials are needed.130

Anticoagulation Therapies

The impetus to anticoagulate SSC-PAH patients is largelydue to increased thrombogenesis seen with IPAH.5 Antic-oagulation in the IPAH population has been recentlyreviewed.131 Some institutions routinely treat their SSc-PAHpatients with anticoagulants, only to stop the therapy becauseof occult gastrointestional bleeding.5 There are sparse data onanticoagulation specifically for the SSc-PAH population.

Lung Transplant

Usually a treatment of last resort for IPAH patients is lungtransplant and it may have a role in treating SScPAH patientswho are properly screened for potential morbidities. Thesepatients share similar 2-year survival rates compared to thosewith IPAH or pulmonary fibrosis who undergo lung trans-plantation.132,133 It has been stressed that lung transplant beconsidered a viable option for consideration in SSc-PAHpatients.5

Novel Investigations

Rho-Kinase Inhibition

The RhoA/Rho-kinase pathway has been implicated in manycardiovascular diseases, and it has recently been reviewed inthe context of PH.134 As evidence for the activation of thispathway in patients with PAH continues to bedescribed,135�137 the emergence of Rho-kinase inhibitors asa therapeutic target may lead to a novel treatment forSScPAH. Our laboratory has already shown that the use ofthe Rho-kinase inhibitor fasudil can attenuate pulmonaryvasoconstrictor response via multiple mechanisms in the rat

model.138,139 Although more research is needed, it is clearthat the inhibition of Rho-kinase shows promise as atherapeutic target for PAH and SSc-PAH.138,139

Soluble Guanylate Cyclase Stimulators and Activators

Riociguat is a new, first-in-class oral drug that stimulatessoluble guanylate cyclase in NO independent and synergisticmanner.140,141 Single oral doses of riociguat were welltolerated by patients in a Phase I study for IPAH.141,142

Riociguat had a favorable safety profile, and the patientsexperienced improved hemodynamics and cardiac indices.141

Riociguat was more effective than inhaled NP in a proof-of-concept study for patients with moderate-to-severe PH.141,142

Patients with chronic thromboembolic PH or PAH showedimproved pulmonary hemodynamics and exercise capacityfollowing a 12- week Phase II trial of oral riociguat followingindividual dose titration.142,143

Inhibition of Serotonin Signaling

Serotonin has been show to participate in the pathogenesisof PAH via the vasoconstrictive and proliferative effects ofSMC. Microvascular cells from the pulmonary vascular bed ofPAH patients produce elevated serotonin in vitro.67,144

Although not statistically significant, a recent retrospectivestudy showed that 15% of PAH patients on a selectiveserotonin reuptake inhibitor had a lower risk of PAH-relatedmortality.145

Stem Cell Transplantation

Research into autologous hematopoietic stem cell trans-plantation (HSCT) and high immunosuppressive therapy haveshown promise in the treatment of autoimmune dis-eases.146,147 Longterm studies of HSCT and high-doseimmunosuppressive therapy in SSc patients show stabiliza-tion/improvement of pulmonary disease, dermal sclerosis,and functioning147,148 as well as normalization of micro-vasculature changes.149,150 Farge and colleagues recentlyreported results of a 12-year observational study of HSCT inCTD patients who were refractory to firstline treatment.151 OfSSc patients, 55% were progression free for 5 years; however,the SSc patients were more susceptible to morbidity second-ary to immunosuppression than the other CTD groups.152

Several studies are currently underway to further evaluate theefficacy of HSCT in the SSc population,eg, the Europeanmulticenter prospective randomized Autologous Stem cellTransplantation International Scleroderma (ASTIS) trial153

and 4 active studies found on http://ClinicalTrials.gov as ofApril 2010.

Alternative Approaches

Efforts to target antifibroblast antibodies in SSc patientsresulted in the identification of alpha-enolase as a main targetantigen; however, no significant difference was foundbetween the SSc-PAH population and the SSc-PAH populationwith concurrent pulmonary fibrosis.154 This may serve as afuture target for both evaluation and treatment.

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Tyrosine Kinase Inhibitors

By inhibiting both the TGF-b and PDGF pathways, thetyrosine kinase inhibitor works to prevent inflammatorydriven fibrosis. The tyrosine kinase inhibitor, imatinib, hasbeen successfully used to treat IPAH in both isolated casesand experimental models.155�158 Imatinib targets the SMAD-1159 early growth response protein 1160 and inhibits the c-Abl, PDGF receptor, and c-Kit receptors.67 One case reporthas shown improvement in RV function in a SSc-PAHpatient.161

Imatinib has been shown to prevent new fibrosis, regresspreexisting dermal fibrosis, and prevent the differentiation offibroblasts into myofibroblasts in the Tsk-1 mouse model ofSSc.162 Extensive trials for imatinib in SSc patients areongoing. Two groups of SSc patients in the above trial haveshown significant improvement in the extremity-relatedsymptoms of SSc (Raynaud’s phenomenon and sclero-sis).65,163 However, no patients with SSc-PAH in the absenceof ILD have presented to investigators. The potential impacton SSc-PAH is theoretical, based on the shared upregulationof VEGF pathways between ILD and PAH.

Two newly developed tyrosine kinase inhibitors, dasatiniband nilotinib, are oral agents that might prove beneficial forpatients whose tolerance of imatinib is an issue, but theyrequire further investigation.164 At present, the use of tyrosinekinase inhibitors for the treatment of SSC-PAH has no formalrecommendation.

Statins

Atorvastatin has recently been used in the treatment ofdigital ulcerative vasculopathy in SSc patients.165,166 Treat-ment with atorvastatin has been associated with decreasedlevels of ET-1 and intracellular adhesion molecule 1 (ICAM-1).166 The effects of atorvastatin on SSc-PAHare not known,but its impact on ET- 1 and ICAM-1 levels are reason enoughto warrant exploration.

Simvastatin has been shown to be effective in inhibiting theeffects of platelet derived growth factor (PDGF) in IPAHpatients.167 Western blot analysis showed the p27 cyclin-dependant kinase inhibitor in the pulmonary artery SMCs ofIPAH patients to be significantly increased in a simvastatinplus PDGF treatment group compared to those exposed toPDGF.127 Simvastatintreated pulmonary artery SMCs of IPAHpatients also expressed signifigantly less bone morphogeneticprotein receptor 2 (BMPR2) mRNA than in controls.127

Evaulating Treatment

Pulmonary function tests (PFTs)*including DLCO, 6MWD,and total lung capacity11,168*are under constant evaluationfor efficacy as screening tools and measures of diseaseprogression. These measures should be paired with serialevaluations of heart function via echocardiography.22 Oncethought to be a necessity, bronchio-alveolar lavage (BAL) andbiopsy have lost favor due to limited therapeutic or diagnosticvalue.169 While large-scale studies are still needed, it isevident that BAL may have a place in evaluating SSc-PAH

patients for progression to interstitial lung disease (ILD) ornew pulmonary infection.170

CONCLUSIONS

Given the number of biomarkers, heterogenicity of thedisease process and clinical manifestations, variety of riskfactors, and unusual familial patterns, it is well within therealm of reason to pursue a mechanism that is dependent on‘‘multiple hits’’.46,171

Patients with SSc-PAH have poor prognosis and survival.The vasculitis that occurs in SSc-PAH is complex, withunderlying pathogenic mechanisms that include fibrosis,vascular SMC and EC dysfunction, and activation of theimmune system and inflammation. ET-1 is an importantmediator of vasculopathy and represents an important targetfor intervention in SSc patients. Progress is being made inunderstanding the vasculopathy in SSc-PAH. Although cur-rent therapies for SSc-PAH offer benefits, conventionaltherapies have had no major impact on the disease courseand have not prolonged survival. Based on recent studies ofmolecular mechanisms and various animal models, potentialtherapeutic targets need to be investigated. The clinicalmanagement of patients with SSc-PAH remains a challenge,and the disease poses numerous difficulties in determiningideal clinical outcome. Although there have been advances inthe treatments available for SSc-PAH, this syndrome con-tinues to be associated with high morbidity and mortality andpoor prognosis.

Disclosure: Dr Phillip J. Kadowitz is the principal investigator forthis study. This work was supported by National Heart, Lung, andBlood Institute Grants HL-62000 and HL-77421.

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