Impact of targeted pulmonary arterial hypertension therapy in patients with combined post- and precapillary pulmonary hypertension.

BACKGROUND: Combined post- and precapillary pulmonary hypertension (CpcPH) portends poor outcomes in pulmonary hypertension related to left heart disease (PH-LHD). While recent evidence does not support the use of targeted pulmonary arterial hypertension (PAH) therapy in PH-LHD, there is a lack of clinical data on their use in CpcPH. We evaluated the outcomes in patients with CpcPH treated with PAH therapies. METHODS: Retrospectively, 50 patients meeting hemodynamic criteria of CpcPH and started on PAH-targeted drugs were identified. Fifty age- and gender-matched PAH patients were chosen as controls. We evaluated the change in 6-minute walk distance, World Health Organization functional class (FC), tricuspid annular plane systolic excursion, BNP or NT-proBNP, and pulmonary artery systolic pressure at 3, 6, 12, and 24 months of follow-up. RESULTS: After adjusting for age and gender, there was no improvement in World Health Organization FC in CpcPH over 2 years (odds ratio of change to FC I/II 1.01, 95% CI: 0.98-1.04). There was no significant improvement in 6-minute walk distance (ß coefficient 0.21, 95% CI: -0.98 to 1.4), reduction in BNP/NT-proBNP (ß coefficient -12.16, 95% CI: -30.68 to 6.37), increase in tricuspid annular plane systolic excursion (ß coefficient 0.074, 95% CI: 0.010-0.139), or decrease in pulmonary artery systolic pressure (0.996, 95% CI: 0.991-1.011) in CpcPH with therapy. There was higher mortality in CpcPH compared to PAH on treatment (24% vs 4%, P = .003). CONCLUSIONS: There were no improvements in symptoms, exercise capacity, or echocardiographic parameters with PAH-targeted therapy in CpcPH. Further studies into potential treatments benefiting this population are needed.

A Clinical Classification Scheme for Tracheobronchomegaly (Mounier-Kuhn Syndrome).

INTRODUCTION: Tracheobronchomegaly (Mounier-Kuhn Syndrome) is a rare disease characterized by tracheal enlargement and associated loss of elastic fibers in the trachea and main bronchi. MATERIALS: MEDLINE, Index Medicus, and other databases were searched with pre-defined criteria to identify cases of tracheobronchomegaly (TBM). Two new cases of TBM were also identified from the Provincial Medical Genetics Program of British Columbia. RESULTS: We identified 166 publications describing 365 occurrences of TBM. We observed that affected individuals could be grouped into subgroups according to clinical features. Type 1A (105 individuals) consists of infants who developed TBM after having undergone fetoscopic tracheal occlusion, and Type 1B patients (24 individuals) are infants and children who developed TBM after prolonged intubation. Type 2 individuals developed TBM following recurrent pulmonary infections (2A) (14 individuals) or pulmonary fibrosis (2B) (10 individuals). Type 3 represents TBM with evidence of extra-pulmonary elastolysis (18 individuals), and Type 4 denotes the development of TBM with no clear predisposing factors (196 individuals). Both of our patients had TBM and evidence of extra-pulmonary elastolysis. As well, one patient had a mildly dilated aortic root, which is a previously unreported co-occurrence. CONCLUSION: We introduce a novel classification scheme, which may sort patients into etiologically distinct groups, furthering our understanding of its pathogenesis and potentially, prevention or therapy. We also hypothesize that TBM and generalized elastolysis may have etiological commonalities, suggesting a need for further study.

Association Between the Pulmonary Artery Pulsatility Index and Prognosis in Pulmonary Arterial Hypertension: A Multicentre Study.

Background: Risk stratification is fundamental in the management of pulmonary arterial hypertension (PAH). Pulmonary artery pulsatility index (PAPi), defined as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), is a hemodynamic index shown to predict acute right ventricular (RV) dysfunction in several settings. Our objective was to test the prognostic utility of PAPi in a diverse multicentre cohort of patients with PAH. Methods: A multicentre retrospective cohort study of consecutive adult patients with a new diagnosis of PAH on right heart catheterization between January 2016 and December 2020 was undertaken across 4 major centres in Canada. Hemodynamic data, clinical data, and outcomes were collected. The association of PAPi and other hemodynamic variables with mortality was assessed by receiver-operating characteristic curves and Cox proportional hazards modeling. Results: We identified 590 patients with a mean age of 61.4 ± 15.5 years, with 66.3% being female. A low PAPi (defined as < 5.3) was associated with higher mortality at 1 year: 10.2% vs 5.2% (P = 0.02). In a multivariable model including age, sex, body mass index, and functional class, a low PAPi was associated with mortality at 1 year (area under the curveof 0.64 (95% confidence interval 0.55-0.74). However, high RAP (> 8 mm Hg) was similarly predictive of mortality, with an area under the curve of 0.65. Conclusion: PAPi was associated with mortality in a large incident PAH cohort. However, the discriminative value of PAPi was not higher than that of RAP alone.

Contexte: La stratification des risques est fondamentale dans la prise en charge de l'hypertension artérielle pulmonaire (HTAP). L'indice de pulsatilité des artères pulmonaires (iPAP), défini comme la pression différentielle dans les artères pulmonaires divisée par la pression auriculaire droite (PAD), est un indice hémodynamique qui s'est révélé prédictif d'une dysfonction ventriculaire droite (VD) aiguë dans plusieurs situations. Notre objectif était d'évaluer l'utilité pronostique de l'iPAP dans une cohorte multicentrique diversifiée de patients atteints d'HTAP. Méthodologie: Une étude de cohorte multicentrique rétrospective de patients adultes consécutifs atteints d'une HTAP nouvellement diagnostiquée par cathétérisme cardiaque droit entre janvier 2016 et décembre 2020 a été effectuée dans quatre grands centres au Canada. Les données hémodynamiques, les données cliniques et les résultats ont été recueillis. La corrélation de l'iPAP et d'autres va-riables hémodynamiques avec la mortalité a été évaluée par les courbes caractéristiques opérationnelles du receveur et des modèles à risques proportionnels de Cox. Résultats: Nous avons recensé 590 patients dont l'âge moyen était de 61,4 ± 15,5 ans; la proportion de femmes était de 66,3 %. Un faible iPAP (défini comme une valeur < 5,3) a été associé à une hausse de la mortalité à 1 an : 10,2 % contre 5,2 % (p= 0,02). Dans un modèle multivarié comprenant l'âge, le sexe, l'indice de masse corporelle et la classe fonctionnelle, un faible iPAP a été associé à la mortalité à 1 an (aire sous la courbe de 0,64 [intervalle de confiance à 95 %; de 0,55 à 0,74]). Cependant, une PAD élevée (> 8 mmHg) a aussi été un facteur prédictif de mortalité, l'aire sous la courbe étant de 0,65. Conclusions: L'iPAP a été associé à la mortalité dans une vaste cohorte de patients atteints d'une HTAP. Toutefois, la valeur discriminante de l'iPAP n'a pas été supérieure à celle de la PAD seule.

Chronic Lung Allograft Dysfunction: Review of CT and Pathologic Findings.

Chronic lung allograft dysfunction (CLAD) is the most common cause of mortality in lung transplant recipients after the 1st year of transplantation. CLAD has traditionally been classified into two distinct obstructive and restrictive forms: bronchiolitis obliterans syndrome and restrictive allograft syndrome. However, CLAD may manifest with a spectrum of imaging and pathologic findings and a combination of obstructive and restrictive physiologic abnormalities. Although the initial CT manifestations of CLAD may be nonspecific, the progression of findings at follow-up should signal the possibility of CLAD and may be present on imaging studies prior to the development of functional abnormalities of the lung allograft. This review encompasses the evolution of CT findings in CLAD, with emphasis on the underlying pathogenesis and pathologic condition, to enhance understanding of imaging findings. The purpose of this article is to familiarize the radiologist with the initial and follow-up CT findings of the obstructive, restrictive, and mixed forms of CLAD, for which early diagnosis and treatment may result in improved survival. Supplemental material is available for this article. © RSNA, 2021.

Does community size or commute time affect severity of illness at diagnosis or quality of care in a centralized care model of pulmonary hypertension?

BACKGROUND: Centralized care models are often used for rare diseases like pulmonary hypertension (PH). It is unknown how living in a rural or remote area influences outcomes. METHODS: We identified all patients from our PH database who carried a diagnosis of WHO Group 1 or WHO Group 4 PH. Using Canadian postal code data, patients were classified as living in a rural area; or a small, medium or large community size. The commute time from patient residence to our clinic was determined using mapping software. We compared baseline catheterization data according to community size and commute time. At follow up, we evaluated the association between community size and commute time with prognostic parameters of functional class, walk distance and echocardiography. RESULTS: Of the 342 patients identified, 72(21%) patients lived in rural areas, while 26(8%), 49(14%) and 195(57%) resided in small, medium and large population centres, respectively. The commute time was <1 h for 160(47%), 1-3 h for 62(18%), and >3 h for 120(35%). There was no association seen for any catheterization parameter by either community size or commute time. At last follow up, there was no association between any prognostic parameter and community size or commute time. CONCLUSIONS: We found no association between community size or commute time with severity of illness at diagnosis, or markers of prognosis at follow up. This suggests that patients who reside in rural or remote environments are not experiencing deficiencies in care compared to urban patients.

Pharmacotherapy in pulmonary arterial hypertension: a systematic review and meta-analysis.

BACKGROUND: Previous meta-analyses of treatments for pulmonary arterial hypertension (PAH) have not shown mortality benefit from any individual class of medication. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through November 2009 for randomized trials that evaluated any pharmacotherapy in the treatment of PAH. Reference lists from included articles and recent review articles were also searched. Analysis included randomized placebo controlled trials of at least eight weeks duration and studies comparing intravenous medication to an unblinded control group. RESULTS: 1541 unique studies were identified and twenty-four articles with 3758 patients were included in the meta-analysis. Studies were reviewed and data extracted regarding study characteristics and outcomes. Data was pooled for three classes of medication: prostanoids, endothelin-receptor antagonists (ERAs), and phosphodiesterase type 5 (PDE5) inhibitors. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated for mortality, 6-minute walk distance, dyspnea scores, hemodynamic parameters, and adverse effects. Mortality in the control arms was a combined 4.2% over the mean study length of 14.9 weeks. There was significant mortality benefit with prostanoid treatment (RR 0.49, CI 0.29 to 0.82), particularly comparing intravenous agents to control (RR 0.30, CI 0.14 to 0.63). Mortality benefit was not observed for ERAs (RR 0.58, CI 0.21 to 1.60) or PDE5 inhibitors (RR 0.30, CI 0.08 to 1.08). All three classes of medication improved other clinical and hemodynamic endpoints. Adverse effects that were increased in treatment arms include jaw pain, diarrhea, peripheral edema, headache, and nausea in prostanoids; and visual disturbance, dyspepsia, flushing, headache, and limb pain in PDE5 inhibitors. No adverse events were significantly associated with ERA treatment. CONCLUSIONS: Treatment of PAH with prostanoids reduces mortality and improves multiple other clinical and hemodynamic outcomes. ERAs and PDE5 inhibitors improve clinical and hemodynamic outcomes, but have no proven effect on mortality. The long-term effects of all PAH treatment requires further study.

Impact of saline loading at cardiac catheterization on the classification and management of patients evaluated for pulmonary hypertension.

BACKGROUND: The extent to which saline loading (SL) during cardiac catheterization influences clinical practice in pulmonary hypertension (PH) is unknown. We surveyed a national cohort of PH specialists to determine how SL affected diagnosis and management. METHODS: Relevant clinical and hemodynamic data pre-SL for patients with a baseline pulmonary arterial wedge pressure (PAWP) ≤15 mm Hg were presented as surveys to 7 PH specialists. The specialists were asked to classify patients according to the WHO classification scheme, rate their confidence, and state their treatment plans. Hemodynamic data following 500 mL of SL was then presented, and specialists answered the same questions. A positive fluid challenge (PFC) was defined as PAWP >18 mm Hg after SL. RESULTS: Seven specialists evaluated 48 cases, for a total of 336 surveys. SL influenced PH classification with 19.6% of cases reclassified as having a component of Group 2 PH. SL increased confidence in PH classification (mean difference 0.25; 95% CI 0.15-0.35). With a PFC, physicians were more likely to classify patients as PH due to left heart disease (OR 6.1; 95% CI 2.8-13.1), extend time to follow-up (OR 3.2; 95% CI 1.6-6.7), and discharge patients from PH clinic (OR 5.0; 95% CI 1.9-13.1). SL changed the treatment plan in 6.5% of cases, mostly with a PFC causing reconsideration in treatment initiation. CONCLUSION: The addition of SL to hemodynamic assessment of PH can impact physicians' classification and management decisions. However, decisions are not solely based on the SL results, but rather the entirety of the clinical data available.

Clinical and hemodynamic factors in predicting response to fluid challenge during right heart catheterization.

Fluid challenge during right heart catheterization has been used for unmasking pulmonary hypertension (PH) related to left-sided heart disease. We evaluated the clinical and hemodynamic factors affecting the response to fluid challenge and investigated the role of fluid challenge in the classification and management of PH patients. We reviewed the charts of 67 patients who underwent fluid challenge with a baseline pulmonary arterial wedge pressure (PAWP) of ≤ 18 mmHg. A positive fluid challenge (PFC) was defined as an increase in PAWP to > 18 mmHg after 500 mL saline infusion. Clinical characteristics and echocardiographic and hemodynamic parameters were compared between PFC and negative fluid challenge (NFC). PFC was associated with female sex, increased BMI, and hypertension. A greater rise in PAWP was observed in PFC (6.8 ± 2.3 vs. 3.8 ± 2.7 mmHg, P = 0.001). A larger increase in PAWP correlated with a lower transpulmonary gradient (r = -0.42, P < 0.001), diastolic pulmonary gradient (r = -0.42, P < 0.001), and pulmonary vascular resistance (r = -0.38, P < 0.001). We found 100% of the patients with PFC were classified as WHO group 2 PH compared to 49% of the NFC patients ( P < 0.001). Fewer patients with PFC were started on advanced PH therapies and more were discharged from PH clinic. A PFC and the magnitude of PAWP increase after saline loading are associated with parameters related to left heart disease. In our population, fluid challenge appeared to influence the classification of PH and whether patients are started on therapy or discharged from clinic.

Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.

BACKGROUND: Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants. CASE PRESENTATION: We report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation. CONCLUSIONS: This is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.

Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension.

BACKGROUND: The accurate measurement of cardiac output (CO) is required in patients with pulmonary hypertension (PH).While both the thermodilution (TDCO) and indirect Fick (IFCO) methods are commonly used, there is little data comparing them in patients with PH. METHODS: We performed a retrospective analysis of patients evaluated at our center. All patients who had right heart catheterization (RHC) within 3 months of an echocardiogram, and CO assessment by both TDCO and IFCO methods were included. Bland-Altman analysis was used to assess agreement between the two methods. We further evaluated their agreement in each sex, and within tertiles of age, BMI and TR severity. We investigated the correlation between each method of CO and objective parameters of right ventricular function on echocardiography. RESULTS: In a cohort of 168 patients, the correlation between IFCO and TDCO was modest at (r = 0.61). On average, values for CO were lower with IFCO than with TDCO, by 0.62 L/min (95% CI -0.82, -0.40). This difference was greater for females: 0.86 L/min (95% CI -1.08, -0.63) and in the highest tertile of BMI: 0.97 L/min (95% CI -1.4, -0.55). Moderate and severe TR did not in general result in lower TDCO values. Echocardiographic parameters of right ventricular function were correlated more strongly with TDCO than with IFCO. CONCLUSION: In PH patients, IFCO was substantially lower than TDCO on average, suggesting that these two techniques cannot be used interchangeably. TDCO correlated more strongly with echocardiographic measures of RV function, suggesting that it may be preferred over IFCO.

Validity of algorithm for estimating left sided filling pressures on echocardiography in a population referred for pulmonary arterial hypertension.

The determination of LV filling pressure is integral to the diagnosis of pulmonary arterial hypertension (PAH). The American Society of Echocardiography (ASE) has devised algorithms for their estimation. We aimed to test these algorithms in a population referred for suspected PAH. In our retrospective study, we evaluated the accuracy of the ASE Algorithms compared to right heart catheterization done within three months, in patients seen during 2006-2014. All echocardiograms were classified as showing normal, elevated or indeterminate filling pressures. Those with indeterminate pressures were excluded. We evaluated the diagnostic properties of this algorithm to predict a pulmonary artery wedge pressure (PAWP) and left ventricular end diastolic pressure (LVEDP) >15 mmHg. A total of 94 patients were included. The ASE algorithms yielded indeterminate results in 50 (53.2%) patients. This occurred more commonly in older patients and patients with cardiovascular comorbidities. The algorithm had a high sensitivity for predicting an elevated PAWP at 89.5% (95% confidence interval [CI] = 66.9-98.7) and an elevated LVEDP at 100% (95% CI = 76.8-100). The algorithm had a negative predictive value of 81.8% and 100% for predicting an elevated PAWP (95% CI = 52.4-94.8) and LVEDP, respectively, but a poor positive predictive value. The ASE algorithm for predicting LV filling pressures often cannot be applied in populations with suspected PAH. When they are interpretable, they have a high negative predictive value for elevated PAWP and LVEDP. We recommend caution when using these algorithms in populations with suspected PAH.

Prognostic utility of right atrial emptying fractions in pulmonary arterial hypertension.

Although left atrial function has been extensively studied in patients with heart failure, the determinants and clinical correlates of impaired right atrial (RA) function have been poorly studied. We investigated measures of RA function in pulmonary arterial hypertension (PAH). We identified all treatment-naive patients with World Health Organization category 1 PAH seen at our center during 2000-2011 who had right heart catheterization and 6-minute walk test (6MWT) within 1 month of initial echocardiographic examination. Atrial size was measured using the monoplane area-length method, and atrial function was quantified using total, passive, and active RA emptying fractions (RAEFs). We compared measures of RAEF with known prognostic clinical, echocardiographic, and hemodynamic parameters. For the subset of patients with follow-up echocardiographic examination/6MWT within 6-18 months, we investigated the change in RAEF. In an exploratory analysis, we investigated the association between RAEF and mortality. Our population consisted of 39 patients with treatment-naive (incident) PAH, 30 of whom had follow-up testing. The mean total, passive, and active RAEFs were 24.4% ± 15.1%, 8.5% ± 6.9%, and 17.6% ± 13.9%, respectively. Total and active RAEFs correlated with tricuspid annular plane systolic excursion (P = 0.004 and P = 0.005) and cardiac output (P = 0.02 and P = 0.01). The change in active RAEF correlated with change in 6-minute walk distance (P = 0.02). In our Cox regression analysis, low active and total RAEF were associated with mortality, with hazard ratios of 5.6 (95% confidence interval [CI], 1.2-26.2; P = 0.03) and 4.2 (95% CI, 1.1-15.5; P = 0.03), respectively. Passive RAEF was poorly reproducible and not associated with outcome. Measures of RAEF appear to have prognostic importance in PAH and warrant further study.

Riociguat: a novel therapeutic option for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious and often fatal diseases. The pathophysiology of both diseases is complex and in part is attributed to alterations in the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate pathway. Riociguat, a novel sGC stimulator, acts on this pathway through a dual mechanism of action by directly stimulating sGC in a NO-independent manner and also increasing the sensitivity of sGC to NO. Based on benefits from clinical trials for both PAH and CTEPH, riociguat was approved by Health Canada and the US Food and Drug Administration as the first medical therapy for patients with CTEPH who are deemed inoperable or have residual/recurrent PH after pulmonary endarterectomy (PEA), and as a novel treatment option for patients with PAH. This article reviews the key findings from the phase III trials for riociguat that led to these approvals and the implications this has for the treatment of patients with PAH and CTEPH.

Assessing response to therapy in idiopathic pulmonary arterial hypertension: a consensus survey of Canadian pulmonary hypertension physicians.

BACKGROUND: Many treatment options are now available for patients with idiopathic pulmonary arterial hypertension (IPAH). Data regarding the optimal combination of therapies are lacking, as is consensus on how to assess response to therapy and when to change therapeutic regimens. OBJECTIVES: To gather the opinions of Canadian pulmonary hypertension (PH) experts regarding standard practice in the care of IPAH patients after therapy is initiated. METHODS: Canadian PH physicians were surveyed using short questionnaires to assess their opinions and practices in the care of IPAH patients. A Delphi forecasting approach was used to gain consensus among Canadian physicians on the most important clinical parameters to consider when assessing patients after the initiation of therapy. RESULTS: Twenty-six of 37 Canadian PH experts who were invited to participate completed the study. All endorsed the use of combination therapy for IPAH patients despite the lack of universal provincial coverage for this approach. By consensus, WHO functional class, 6 min walk distance and hospitalization for right heart failure were the most important clinical parameters. The most highly rated physical examination parameters were jugular venous pressure, peripheral edema, the presence of ascites and body weight. CONCLUSIONS: The overall approach to care of IPAH patients is similar across PH centres in Canada. A limited number of clinical and physical examination parameters were considered to be most important to reassess patients after therapy is initiated. These parameters, along with definition of threshold values, will facilitate the development of standard practice guidelines for IPAH patients in Canada.

Prognostic factors for survival in scleroderma associated pulmonary arterial hypertension.

OBJECTIVE: Identification of prognostic factors for survival in systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is necessary for appropriate monitoring, interventions, and timely referral for lung transplantation. Our objectives were (1) to identify factors associated with survival in SSc-PAH and (2) to evaluate the methodologic quality of prognostic studies against current standards. METHODS: A systematic review was performed to identify studies evaluating factors associated with survival in SSc-PAH. The methodologic quality of each study was evaluated using a methodologic quality index. RESULTS: HLA-DRw6 (RR 54.52, p = 0.01), HLA-DRw52 (RR not reported, p = 0.02), initial systolic pulmonary artery pressure (sPAP) > 60 mmHg (HR 3.60, 95% CI 1.42, 9.15), elevated mean right atrial pressure (mRAP) (HR 20.7, p = 0.0001), and shorter time between SSc onset and observed PAH (5.24 vs 9.93 yrs, p < 0.01) were associated with decreased survival. Age > 50 years (HR 2.34, 95% CI 0.54, 10.2), male sex (HR 2.02, 95% CI 0.65, 6.20), limited subtype (HR 2.37, 95% CI 0.68, 8.20), pulmonary fibrosis [Kaplan-Meier (KM) curves, p = 0.3], change in pulmonary vascular resistance (KM curves, p = 0.8), anti-centromere (HR 1.67, 95% CI 0.66, 4.26) and anti-ScL-70 (HR 0.28, 95% CI 0.03, 1.99) antibodies were not definitively associated with survival. Attributes of participants, prognostic factors, and outcome measures were well reported. Study attrition, confounding, and analysis were not well reported. CONCLUSION: HLA-DRw52 and -DRw6, initial sPAP > 60 mmHg, mRAP, and shorter time between SSc onset and observed PAH were associated with decreased survival; however, methodologic quality of study reporting was variable. Prognostic factor research is needed using current methodologic standards.