Pulmonary Arterial Hypertension-A Deadly Complication of Systemic Sclerosis

Abstract

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

INTRODUCTION

Pulmonary complications of systemic sclerosis (SSc) are a life threatening and commonly observed outcome. Pulmonary arterial hypertension (PAH) and pulmonary fibrosis are major contributors to mortality in the SSc patient, responsible for 61% of SSc-related deaths (PAH 26% and fibrosis 35%).¹ The diagnosis of SSc alone carries an estimated 50% 10-year mortality.^2–4 When PAH develops in the SSc patient, the median survival rate falls, with reports as low as 1 year.⁴

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

The goal of this review is to provide updated information on SSc-PAH burden, etiology, diagnostic criteria, and genetic etiologic factors. We also provide an update on current research into novel therapeutic targets.

EPIDEMIOLOGY

In the United States, the prevalence of SSc is estimated at 240 per million and that of SSc-PAH at 24 per million, which is significantly higher than the prevalence of Idiopathic PAH (IPAH) in this country.⁶ Recent reports from the European EULAR (European Union League Against Rheumatism) Scleroderma Trials and Research (EUSTAR) cohort estimated SSc prevalence at 5 per 100 000.¹ The incidence of PAH in the SSc patient has been estimated at 0.61 cases per 100 patient years based on data from the French itinérair-sclérodermie study.⁷

RISK FACTORS

A diagnosis of SSc-PAH without accompanying fibrosis occurs 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 increased risk of developing PAH in the SSc patient are onset of SSc at a later age 9 duration of SSc greater than 10 years,¹⁰ increased duration 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 vascular smooth muscle tone, blood flow, cell migration growth and differentiation, coagulation, vessel growth, and repair.¹⁴ Although a comprehensive description of its full functionality is beyond the scope of this review, two mediators produced by the EC of particular note are nitric oxide (NO)^15–17 and endothelin (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-β), interleukins (IL) 4,12,17), cell recruitment and differentiation (TGF-β, platelet derived growth factor (PDGF)), and plays a key role in inflammation (IL-1, monocyte chemo attractant protein-1 (MCP-1)).^19–21 The dysfunction of the endothelium has been implicated in the pathology of SSc and PAH^19,22

The inciting event leading to endothelial dysfunction in the SSc patient remains unkown. When endothelial damage occurs, the dysfunction manifests as an inability to repair the endothelium which ultimately leads to apoptosis and capillary breakdown.¹⁹ In the SSc patient, the angiogenic response to resultant hypoxemia is the unbalanced production of angiogenic and angiostatic factors leading to vasculopathy. Despite the consistent upregulation of pro-agniogenic factors (ET-1, TGF-β, vascular endothelial growth factor (VEGF), PDGF,MCP-1) there is a paucity of angiogenesis in the SSc patient.¹⁹ Additionally, alterations in the production of other factors that have a role in the vasconstriction of pulmonary arteries such as NO, Prostacyclin, ET-1, and serotonin.¹⁴

PAH develops as a consequence of restricted flow through the pulmonary arterial circulation and subsequent increased resistance and eventual deleterious effects on right-heart function.²³ PAH has many established causes and associations, including HIV and schistosomiasis, congenital heart disease, and portal hypertension.²² We direct the curious reader to the American College of Cardiology Foundation/American Heart Association 2009 expert consensus document on pulmonary hypertension for an extensive review of this disease.²³

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

NO inhibits SMC growth and proliferation and elicits antithrombotic effects, which contribute to its role as an important regulator of vascular function.²⁷ In addition, NO possesses immune modulating effects via the inhibition of leukocyte attachment²⁵ and the regulation of chemokine expression, such as MCP-1.²⁸

ET-1 is also produced by ECs and is an important vasocontrictor and SMC mitogen that exerts its effects via two receptors, ET_A and ET_B. ^29–31 Endothelin may also play an important role in fibrosis and modulation of the immune response via cytokine and adhesion molecule upregulation, leukocyte activation, and modulation of vascular permeability.²⁷ The ET_A receptor, located on pulmonary vascular SMCs and fibroblasts, binds ET-1 and this results in SMC proliferation and growth, fibroblast recruitment and differentiation, and a vasoconstriction.³² Activation of the ET_B receptor, located primarily on pulmonary ECs and present in smaller quantities on pulmonary vascular SMCs, results in vasodilation via the clearance of excess ET-1,³³ inhibition of endothelin-converting enzyme,^34,35 release of NO and prostacyclin,³⁶ attenuation of SMC proliferation,^34,37 and decreased cell differentiation and migration to the pulmonary vascular bed.³⁸

PAH

PAH 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 initial insult and/or injury to pulmonary ECs.^40,41 The initial endothelial insult leads to dysfunctional repair, decreased production of vasodilators NO and prostaglandin I2 (PGI2), coupled with paradoxically increased levels of the vasoconstrictors ET-1 and thromboxane A2. This results in a shift toward vasoconstriction and platelet aggregation in the pulmonary vascular bed,⁴² and vascular SMC differentiation, migration, and hyperplasia.⁴¹ Chronic pathologic changes are characterized by a predominant homogenous plexiform arteriopathy^43,44 in the pulmonary vascular bed that appear to involve reactive inflammatory changes, antiapoptotic events, smooth muscle hypertrophy, intimal hyperplasia, and eventual fibrosis and distal venoocclusion,⁴² ultimately resulting in tissue fibrosis, right-heart (RH) failure, and death.⁴

Elevated levels of plasma ET-1 and its endothelial receptors are found in IPAH patients and have been shown to correlate with disease severity.^45,46 IPAH patients exhale less measured NO,⁴⁷ despite a prevalence of distinctive plexiform arteriopathy containing elevated levels of eNOS.⁴⁸ The importance of this contradiction has yet to be elucidated.

SSc

SSc vasculopathy results from the culmination of events including activation of lymphocytes, inflammation, production of autoantibodies, fibrosis, and disrupted cell signaling between endothelial cells, epithelial cells, and fibroblasts.^19,49 The end result is the replacement of normal organ parenchymal tissue architecture with extracellular matrix elements leading to fibrosis and ultimate organ failure.¹⁹

Overexpression of ET-1 and its receptors in SSc are well described.²⁹ Elevated ET-1 expression has been found in the skin⁵⁰ and lungs^51,52 of SSc patients, and this correlates with the degree of fibrosis and mortality.⁵¹ Of particular clinical value in the dcSSc patient is the increased ET-1 expression observed in SSc-related ILD populations prior to the onset of clinical PAH,⁵³ despite a lack of further ET-1 elevation in SSc patients with documented PAH.⁵⁴

The end result of alterations in most of these mechanisms is vasculopathy, cell proliferation, loss of apoptosis, and ultimately fibrotic changes in the vascular wall and surrounding tissue.⁵⁵

GENETICS

Abundant evidence has linked hPAH and some cases of formally diagnosed IPAH to mutations in the super family of transforming growth factor beta (TGFβ) and their receptors, specifically BMPR2.⁵⁶ The history of genomic investigation is well described by Austin and colleagues.⁵⁷ Investigations focus on the link between BMPR2 and activin-like kinase 1 (ALK1), endoglin (ENG), and their common downstream SMAD transcription factors.^56,58,59

The genetic mutations associated with SSc are numerous, as documented in a recent review:⁶⁰ Mutations in BMPR2 and downstream signals were found to be at increased levels in such patients.^61–64 A recently identified imatinib susceptibility gene pattern for dcSSc shows promise as a genetic marker for targeted therapy.⁶⁵ Transcription factor Fli1 mutations involved in endothelial cell regulatoin and angiogenesis⁶⁶ have recently been proposed as a cell-specific potential target in SSc.⁶⁷ Moreover, a new susceptibility locus CD247 and the confirmation of MHC, IRF5, and STAT4 as regions for SSc genetic 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 Unlike IPAH, BMPR2 mutations were not identified in CTD-PAH patients.^70,71 A six base insertion in intron 7 of the endoglin gene was found in differing amounts between SSc pathitens, SSc-PAH patients, and controls.⁷²

Variations in ET-1 levels have recently stimulated investigation. Studies have shown no difference between levels of ET-1 in SSc and SSc-PAH groups.⁷³ A later study discovered an increase in the KCNA5 gene mutation for the Kv1.5 potassium channel in IPAH patients;⁷⁴ ET-1 is a modulator of the expression of Kv1.5.⁶⁹ Kawaguchi and colleagues reported a decreased NO:ET-1 ratio in SSc-PAH patients compared to those 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 Polymorphisms in NOS2^75,76 and the identification of upregulated genes for matrix metalloproteinase 9 and VEGF beyond the levels seen in the IPAH patients⁷⁷ further support investigation into the unique genetic characteristics of SSc-PAH. A recently reported difference in expression of a 6-base insertion of intron 7 of ENG—a member of the TGF-β receptor complex found in the human vascular endothelium—and SSc-PAH but not in controls or SSc patients without PAH.⁷² The role of the ENG polymorphism in the pathogenesis of SSc-PAH is still being examined.⁷⁸

SSC-PAH SYMPTOMS AND CLINICAL MEASURES

The early stages of PAH are often asymptomatic or characterized by nonspecific manifestations such as dyspnea, cough, shortness of breath, chest pain, decreased exercise capacity, and near-syncope to syncope.⁴¹ Physical findings of bilateral inspiratory crackles on lung bases, jugular venous distention, and right ventricular (RV) heave indicate RH compromise and progression of the disease.^79–81 If the clinician is not acutely aware of these subtle signs of PAH in the SSc population, they misled to investigate more common causes of these nonspecific symptoms, such as exercise-induced angina or congestive heart failure (CHF). As a result, the diagnosis of PAH is delayed an average of 2 or more years, at which time conventional treatments may not prove successful.⁴

PATHOLOGY OF PAH

Several pathologic changes occur in PAH depending on etiology.⁴³ IPAH lesions exhibit a homogenous plexogenic arteriopathy (plexiform lesions with nearby concentric obliterative lesions) with variable intimal remodeling and mucoid changes.⁴³ Acquired PAH, such as seen in SSc, exhibits a more heterogeneous picture characterized by a higher concentration of obliterative lesions than with interstitial inflammation and a pneumonitis pattern, accompanying a more prominent muscularization. Of particular note is the absence of the plexiform lesions found in IPAH. This difference in pathology provides a source for further investigation into why the therapies for the SSc-PAH patient are not as beneficial when compared to those for the IPAH patient.

Evaluating the SSc Patient for PAH

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

Exercise capacity by the World Health Organization functional classes should be determined, chest x-ray taken and electrocardiogram measured for clinical investigation and baseline comparisons for evaluating treatments. Less invasive procedures, such as echocardiography for tricuspid valve regurgitation velocity⁸³ and the combined myocardial performance measured by the Tei index, should also be undertaken.⁸⁴ An elevated velocity greater than 2.8m/s, or RH dilation are both suggestive of SSc-PAH.5

Lung function tests can detect the presence PAH: thresholds of concern include lung carbon monoxide diffusing capacity (DLCO) <60% of the predicted score, functional vital capacity (FVC) <70%, FVC/DLCO >1.6, or RV systolic pressure >35 mmHg.^11,85 A decreasing DLCO may be a harbinger of SSc-PAH. One group of lcSSc patients with PAH displayed drastically lower mean DLCO roughly 5 years prior to being diagnosed with PAH.^11,86,87

Despite ongoing efforts, noninvasive techniques of HRCT and echocardiography have yet to replace right-heart catheterization (RHC) for definitive diagnosis of PAH.²² RHC remains the gold standard for confirming PAH.^88–91 The correlation between RHC hemodynamic data and clinical presentation of the SSc-PAH patient has come into question.⁷⁸ RHC evaluations recently showed that patients with SSc-PAH had lower mean pulmonary artery pressure and pulmonary vascular resistances despite a cardiac index that was depressed to a similar level as compared to that in IPAH.⁹² It has been suggested that in the SSc-PAH patient, the right ventricle’s ability to adapt to changes in pulmonary vascular resistance is depressed.⁷⁸

The criteria to evaluate SSc patients for the presence of pulmonary complications have recently been reviewed, and the concerned reader is directed to those algorithms.^4,5,22 Indicators of worse prognosis at time of diagnosis have been reported,⁷⁸ and include later age of onset,⁹³ degree of NYHA impairment,⁹³ RH dysfunction,⁸¹ pericardial effusion,⁹² low serum 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 in the SSc-PAH patient is elevated to a greater degree than in the IPAH patient,⁹⁵ and have been shown to predict survival rates.^95,96 It is interesting to note that these elevations were present despite less-severe RHC hemodynamic measurements.^95,97

CURRENT THERAPIES

Research on novel PAH therapies continues to improve our understanding of the mechanisms regulating endothelial function and smooth muscle tone. However, when established therapies for isolated PAH are used to treat SSc-PAH patients, poor outcomes are observed.⁵ Even more problematic are the etiologies of these poor outcomes; although several factors may be involved, such as the severity of PAH at presentation and dysfunctional levels of the RV and pulmonary vasculature, more research into these differences is needed.⁵

Prostacyclin Therapy

Prostacyclin is a well-described powerful pulmonary vasodilator.^98,99 A continuous infusion of epoprostenol has shown to be an effective therapy for PAH, by increasing exercise capacity, improving cardiopulmonary function, inhibiting platelet aggregation, and SMC hyperplasia. It has a vasodilator effect on the pulmonary vasculature, leading to improvements in survival and morbidity.^5,100–102 In contrast, although SSc-PAH patients treated with intravenous (IV) prostacyclin show improvement in hemodynamic parameters and exercise capacity,¹⁰² improved survival benefits have yet to be demonstrated.^5,103 Intavenous epoprostenol has produced pulmonary edema during treatment, raising concern about its use as a therapeutic option.^104,105 It has been recommended that this intravenous treatment be reserved for serious cases: NYHA class IV and class III patients who have not responded to conventional oral prostacyclin therapy.⁵ A subcutaneous prostacyclin preparation, treprostinil, is less cumbersome to use, but demands an increased dosing schedule.¹⁰⁶ Inhaled iloprost has been used in combination with oral therapies; however, the full utility of this route of administration has yet to be evaluated in a formal study and therefore has no formal recommendation.¹⁰⁷

Endothelin Receptor Antagonists

Bosentan, a nonselective endothelin receptor antagonist, has been a staple of isolated PAH treatment, showing consistent improvement in clinical measures, lung functional capacity (FC),6MWD, hemodynamics, and quality of life.^108–110 However, the results in the SSc-PAH population are less encouraging. In a recent study, 1-, 2-, and 3-year survival rates with firstline bosentan were 92%, 89%, and 79% for IPAH and the corresponding rates for SSc-PAH were 80%, 56%, and 51%.¹¹¹ Moreover, long-term outcome studies have also shown that SSc-PAH patients have attenuated benefit in terms of clinical measures when compared to other CTDs associated with PAH. SSc-PAH patients on bosentan monotherapy show a modest effect on preventing further deterioration.¹¹² A recent long-term outcome analysis of bosentan along with a prostanoid or sildenafil in SSc-PAH patients showed improved or stable effects in both NYHA functional class and 6MWD at 4 months, but these benefits were attenuated by 1 year.¹¹¹ Elevated liver function tests (LFTs) prompted cessation of bosentan in 10% of participants.¹¹¹ Despite these limitations, randomized controlled trials have shown bosentan to improve mortality in SSc-PAH patients,^113–115 and it has been formally recommended for World Health Organization class III/IV severe PAH by the American College of Chest Physicians.⁸⁹

Sitaxsentan

Targeting ET_A, the novel antagonist sitaxsentan inhibits the vasoconstrictive effects of ET-1 without upsetting the beneficial vasodilator component that is associated with ET_B activation.¹¹⁶ A 12-week study by Barst and colleagues showed improvement in exercise capacity; however, a 10% incidence of elevated LFTs was also observed.¹¹⁷ In one report of CTD-PAH treated with sitaxsentan or bosentan, the sitaxsentan group had significantly better 1-year survival rate compared to bosentan (96 vs 88%).¹¹⁸

Ambriesentan

In the US, the Ambriesentan in Pulmonary Arterial Hypertension, Randomized, Double Blind, Placebo Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES 1 and ARIES 2) of the selective ET_A antagonist ambriesentan showed improvement in 6 minute walk distance (6MWD) in the SSc-PAH CTD sub-group; however, the results were attenuated compared to the IPAH group (15–23 meter improvement vs 50–66 meters, respectively).¹¹⁹ Although elevations in aminotransferases were less likely when compared to bosentan, side effects of peripheral edema and CHF were reported.¹¹⁹ A recently published long-term study of ambriesentan combination therapy for IPAH showed persistent improvement in cardiac hemodynamics of mean pulmonary arterial pressure, cardiac output, 6MWD, and RV ejection fraction after 2 years.¹²⁰

Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors decrease the breakdown of cyclic guanosine monophosphate. This enhances the effects of cellular mechanisms regulated by NO, leading to prolonged vasodilation.

Sildenafil

Sildenafil use results in increased exercise tolerance and has been found to be an effective treatment for PAH.¹²¹ A recent dose-related trial showed that an oral sildenafil dose of 20 mg three times a day improved 6MWD, but higher doses created no significant difference.¹²² Data from the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) study showed improvements in 6 MWD and FC after 12 weeks in the CTD-PAH patient (45% with SSc-PAH).¹²³ This dose regimen has become the first line therapy for SSc-PAH in NYHA classes II and III at Johns Hopkins University Hospital.⁵ An additional phosphodiesterase inhibitor, tadalafil, was evaluated in the Pulmonary Arterial Hypertension and Response to Tadalafil trial.¹²⁴ Twenty patients had PAH associated with various CTDs showed an improvement in 6MWD and time to clinical worsening with an optimum dose of 40 mg;¹²⁴ long-term SSc-PAH data are unavailable.¹²⁵

Combination Therapies

In order to find more efficacious treatments for their patients, clinicians combine therapies after failed monotherapy.⁵ Several combinations have been studied in the SSc-PAH population: Inhaled iloprost plus bosentan have proven effective in a small patient group, and inhaled iloprost plus sildenafil suggest synergistic potential.^126,127 The combination of sildenafil and bosentan has been recently evaluated and shown to have improved 6MWD and functional (FC),¹²⁸ yet these effects are attenuated when compared to IPAH patients, with the addition of increased frequency of side effects, such as hepatotoxicity.^128,129 The Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil (11% of study participants have SSc-PAH) showed that the addition of sildenafil at 80 mg three times per day to intravenous epoprostenol results in significant improvements in exercise capacity, quality of life, hemodynamic parameters, and time to clinical worsening,¹²⁹ which would be beneficial in SScPAH patients.¹⁰⁷ Sabnani and colleagues recently found in a small study that the combination of imatinib and cyclophosphamide is effective in mild-to-moderate pulmonary disease, but further trials are needed.¹³⁰

Anticoagulation Therapies

The impetus to anticoagulate SSC-PAH patients is largely due to increased thrombogenesis seen with IPAH.⁵ Anticoagulation in the IPAH population has been recently reviewed.¹³¹ Some institutions routinely treat their SSc-PAH patients with anticoagulants, only to stop the therapy because of occult gastrointestional bleeding.⁵ There are sparse data on anticoagulation specifically for the SSc-PAH population.

Lung Transplant

Usually a treatment of last resort for IPAH patients is lung transplant and it may have a role in treating SScPAH patients who are properly screened for potential morbidities. These patients share similar 2-year survival rates compared to those with IPAH or pulmonary fibrosis who undergo lung transplantation.^132,133 It has been stressed that lung transplant be considered a viable option for consideration in SSc-PAH patients.⁵

Novel Investigations

Rho-Kinase Inhibition

The RhoA/Rho-kinase pathway has been implicated in many cardiovascular diseases, and it has recently been reviewed in the context of PH.¹³⁴ As evidence for the activation of this pathway in patients with PAH continues to be described,^135–137 the emergence of Rho-kinase inhibitors as a therapeutic target may lead to a novel treatment for SScPAH. Our laboratory has already shown that the use of the Rho-kinase inhibitor fasudil can attenuate pulmonary vasoconstrictor response via multiple mechanisms in the rat model.^138,139 Although more research is needed, it is clear that the inhibition of Rho-kinase shows promise as a therapeutic target for PAH and SSc-PAH.^138,139

Soluble Guanylate Cyclase Stimulators and Activators

Riociguat is a new, first-in-class oral drug that stimulates soluble guanylate cyclase in NO independent and synergistic manner.^140,141 Single oral doses of riociguat were well tolerated by patients in a Phase I study for IPAH.^141,142 Riociguat had a favorable safety profile, and the patients experienced 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 showed improved pulmonary hemodynamics and exercise capacity following a 12- week Phase II trial of oral riociguat following individual dose titration.^142,143

Inhibition of Serotonin Signaling

Serotonin has been show to participate in the pathogenesis of PAH via the vasoconstrictive and proliferative effects of SMC. Microvascular cells from the pulmonary vascular bed of PAH patients produce elevated serotonin in vitro.^67,144 Although not statistically significant, a recent retrospective study showed that 15% of PAH patients on a selective serotonin reuptake inhibitor had a lower risk of PAH-related mortality.¹⁴⁵

Stem Cell Transplantation

Research into autologous hematopoietic stem cell transplantation (HSCT) and high immunosuppressive therapy have shown promise in the treatment of autoimmune diseases.^146,147 Longterm studies of HSCT and high-dose immunosuppressive therapy in SSc patients show stabilization/improvement of pulmonary disease, dermal sclerosis, and functioning^147,148 as well as normalization of microvasculature changes.^149,150 Farge and colleagues recently reported results of a 12-year observational study of HSCT in CTD patients who were refractory to firstline treatment.¹⁵¹ Of SSc patients, 55% were progression free for 5 years; however, the SSc patients were more susceptible to morbidity secondary to immunosuppression than the other CTD groups.¹⁵² Several studies are currently underway to further evaluate the efficacy of HSCT in the SSc population, eg, the European multicenter prospective randomized Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial¹⁵³ and 4 active studies found on http://ClinicalTrials.gov as of April 2010.

Alternative Approaches

Efforts to target antifibroblast antibodies in SSc patients resulted in the identification of alpha-enolase as a main target antigen; however, no significant difference was found between the SSc-PAH population and the SSc-PAH population with concurrent pulmonary fibrosis.¹⁵⁴ This may serve as a future target for both evaluation and treatment.

Tyrosine Kinase Inhibitors

By inhibiting both the TGF-β and PDGF pathways, the tyrosine kinase inhibitor works to prevent inflammatory driven fibrosis. The tyrosine kinase inhibitor, imatinib, has been successfully used to treat IPAH in both isolated cases and experimental models.^155–158 Imatinib targets the SMAD-1159 early growth response protein 1160 and inhibits the cAbl, PDGF receptor, and c-Kit receptors.⁶⁷ One case report has shown improvement in RV function in a SSc-PAH patient.¹⁶¹

Imatinib has been shown to prevent new fibrosis, regress preexisting dermal fibrosis, and prevent the differentiation of fibroblasts into myofibroblasts in the Tsk-1 mouse model of SSc.¹⁶² Extensive trials for imatinib in SSc patients are ongoing. Two groups of SSc patients in the above trial have shown significant improvement in the extremity-related symptoms of SSc (Raynaud’s phenomenon and sclerosis).^65,163 However, no patients with SSc-PAH in the absence of ILD have presented to investigators. The potential impact on SSc-PAH is theoretical, based on the shared upregulation of VEGF pathways between ILD and PAH.

Two newly developed tyrosine kinase inhibitors, dasatinib and nilotinib, are oral agents that might prove beneficial for patients whose tolerance of imatinib is an issue, but they require further investigation.¹⁶⁴ At present, the use of tyrosine kinase inhibitors for the treatment of SSC-PAH has no formal recommendation.

Statins

Atorvastatin has recently been used in the treatment of digital ulcerative vasculopathy in SSc patients.^165,166 Treatment with atorvastatin has been associated with decreased levels 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 enough to warrant exploration.

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

Evaulating Treatment

Pulmonary function tests (PFTs)—including DLCO, 6MWD, and total lung capacity^11,168—are under constant evaluation for efficacy as screening tools and measures of disease progression. These measures should be paired with serial evaluations of heart function via echocardiography.²² Once thought to be a necessity, bronchio-alveolar lavage (BAL) and biopsy have lost favor due to limited therapeutic or diagnostic value.¹⁶⁹ While large-scale studies are still needed, it is evident that BAL may have a place in evaluating SSc-PAH patients for progression to interstitial lung disease (ILD) or new pulmonary infection.¹⁷⁰

CONCLUSIONS

Given the number of biomarkers, heterogenicity of the disease process and clinical manifestations, variety of risk factors, and unusual familial patterns, it is well within the realm 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, with underlying pathogenic mechanisms that include fibrosis, vascular SMC and EC dysfunction, and activation of the immune system and inflammation. ET-1 is an important mediator of vasculopathy and represents an important target for intervention in SSc patients. Progress is being made in understanding the vasculopathy in SSc-PAH. Although current therapies for SSc-PAH offer benefits, conventional therapies have had no major impact on the disease course and have not prolonged survival. Based on recent studies of molecular mechanisms and various animal models, potential therapeutic targets need to be investigated. The clinical management of patients with SSc-PAH remains a challenge, and the disease poses numerous difficulties in determining ideal clinical outcome. Although there have been advances in the treatments available for SSc-PAH, this syndrome continues to be associated with high morbidity and mortality and poor prognosis.