Prospects for improving outcomes in systemic sclerosis‐related pulmonary hypertension

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 anti‐coagulation 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.     

Cost savings with a novel algorithm for early detection of systemic sclerosis‐related pulmonary arterial hypertension: alternative scenario analyses

Pulmonary arterial hypertension is an important cause of death and disability in patients with systemic sclerosis (SSc). Yearly screening of all SSc patients with transthoracic echocardiography (TTE) is recommended in international guidelines and currently utilised by the Australian Scleroderma Interest Group (ASIG_STANDARD). Owing to the limitations of TTE, the ASIG developed a new screening algorithm (ASIG_PROPOSED) utilising a serum biomarker, NT‐proBNP, in place of TTE, which has been shown to be equally accurate as the current algorithm. The aim of this study was to compare the cost of these two algorithms using different scenarios. The new algorithm resulted in significant yearly cost savings of between AU$42 913.35 and AU$84 570 in screening and diagnosis of an Australian cohort which, if extrapolated to the Australian population, would result in a yearly cost saving of between AU$367 066 and AU$725 564. There was no scenario in which the proposed algorithm did not result in a cost saving.     

HIV and pulmonary arterial hypertension: a systematic review

Objectives

HIV‐related pulmonary arterial hypertension (PAH) is a rare entity but is associated with significant morbidity and mortality. The literature describing the outcomes of therapy for this disease is limited to case series and cohort studies. The objective of this study was to systematically review and synthesize the literature on HIV‐related PAH.

Methods

MEDLINE, EMBASE, PapersFirst, the Cochrane collaboration and the Cochrane Register of controlled trials were searched with pre‐defined search terms. Randomized controlled trials, observational cohort studies, case–control studies and case reports were considered for inclusion in the qualitative analysis.

Results

A total of 180 case reports of PAH in HIV‐infected patients were identified. Twenty‐six were excluded and thus 154 case reports were included in the qualitative analysis. Thirteen cohort, one case series and two case–control studies were also identified and included in the review. The average baseline CD4 count at the time of diagnosis of PAH was 352 ± 304 cells/μL. The average time from diagnosis of HIV infection to diagnosis of PAH was 4.3 ± 4.0 years. Predominant chest X‐ray findings included cardiomegaly (80%) and pulmonary arterial enlargement (75%). Highly active antiretroviral therapy, bosentan, and prostaglandin therapy have all been reported to be beneficial in improving haemodynamic and functional status in HIV‐related PAH.

Conclusion

HIV‐related PAH is a rare entity with clinical, laboratory, imaging and pathological manifestations similar to those of idiopathic PAH. The evidence for various treatments is limited to cohort, case series and case–control studies. Randomized controlled trials are needed to properly assess the utility of these therapies in the treatment of HIV‐related PAH.     

Prevalence of pulmonary arterial hypertension in an Australian scleroderma population: screening allows for earlier diagnosis

Background:  We sought to determine the prevalence of pulmonary complications and especially pulmonary arterial hypertension (PAH) in an Australian scleroderma population.
Methods:  Between July 2005 and June 2007, physicians in Western Australia were asked to refer patients with scleroderma specifically for pulmonary hypertension screening. All patients were assessed for PAH and other respiratory conditions using echocardiography, lung function testing and clinical assessments. Right heart catheterization was carried out in patients with evidence of increased right ventricular systolic pressure.
Results:  Of the 184 patients analysed, 44 had possible PAH on echocardiography. Right heart catheterization confirmed the diagnosis in 24 (13%). Diffuse interstitial lung disease was found in 32 patients representing a point prevalence of 17.4%. The severity of PAH at diagnosis varied according to whether the patients were referred for screening (group A) or for diagnostic (group B) purposes. The 6-min-walk test distance and median pulmonary vascular resistance were significantly worse in group B versus group A (324 vs 402 m; P = 0.02 and 884 dynes/s per cm⁻⁵ vs 486 dynes/s per cm⁻⁵; P < 0.01, respectively).
Conclusion:  Screening may result in earlier diagnosis of PAH with, in general more mild disease. This is important, given that early treatment for PAH while patients are less symptomatic is associated with improved exercise tolerance and pulmonary haemodynamics: indices indicative of disease progression and clinical worsening.     

系统性硬化症相关性肺动脉高压的临床特点

目的 探讨系统性硬化症（SSc）合并肺动脉高压（PAH）的发病率、临床特点及评估指标.方法 分析本院确诊的18例系统性硬化症合并肺动脉高压的患者临床资料和诊治过程,并以同期确诊的系统性硬化症（未合并肺动脉高压）患者作为对照.结果 两组患者在性别比和年龄上并无统计学差异.但SSc合并PAH组（SSc-PAH）患者在肺动脉收缩压（sPAP）、雷诺现象发生率、肺间质性改变发生率等方面明显高于SSc组.此外,SSc-PAH组患者的RNP抗体阳性率、IgG水平显著高于对照组.结论 雷诺现象、肺间质性改变、RNP抗体、血清IgG水平与SSc患者合并PAH密切相关.这类患者应及早行心超检查,以求早期诊治,改善预后.     

Prognostic factors of mortality and 2-year survival analysis of systemic sclerosis with pulmonary arterial hypertension in Thailand

Aims: Pulmonary arterial hypertension (PAH) is a major complication and cause of death in systemic sclerosis (SSc). Our objective was to identify the predictive factors of mortality and the 2‐year survival rate among Thai sufferers of PAH‐SSc. Methods: An historical cohort study was performed among PAH‐SSc patients followed up at Srinagarind Hospital, Thailand, between January 2005 and December 2008. Kaplan‐Meier and Cox regression analyses were used to estimate the probability of survival and to assess the significant factors associated with death. Results: Pulmonary arterial hypertension was recognized in 60 patients using ECHO criteria, right ventricular systolic pressure (RVSP) > 35 mmHg. Two‐thirds of the patients were female, > 50 years of age, with the dSSc subtype. Twenty patients (33.3%) died: the mortality rate was 15.6% per 100 person‐years. The respective 1‐, 2‐, 3‐ and 4‐year survival rate was 86.1%, 71.3%, 64.6% and 53.9%. The majority (85%) died without any specific treatment for PAH. Using univariate analysis, the mortality risk was associated with: the WHO functional class (FC) III (HR = 27.82), visceral organ involvement (HR = 5.14), myositis (HR = 3.14), esophageal dysmotility (HR = 3.08) and pericarditis (HR = 2.84). Using Cox regression, the only predictor of death was FCIII. The causes of death in PAH‐SSc were related to PAH (60%), infection (30%) and acute renal failure (10%). Conclusion: Up to one‐third of Thai sufferers of PAH‐SSc died within 2 years of PAH diagnosis, without any specific treatment being given. Increased mortality risk was found in SSc patients who had FCIII and visceral organ involvement.     

Determinants of pulmonary arterial hypertension in scleroderma

OBJECTIVE: To define risk factors associated with pulmonary arterial hypertension (PAH) in a large cohort of patients with systemic sclerosis (SSc). METHODS: SSc patients undergoing screening for PAH by means of Doppler echocardiography were identified and their charts were retrospectively reviewed. In all patients, we recorded systolic pulmonary artery pressure along with pulmonary function testing, clinical, and laboratory data. PAH was defined as right ventricular systolic pressure equal or greater than 40 mm Hg. RESULTS: Of 114 SSc patients with echocardiographic measurements, PAH was found in 33 (29%) patients. In a multiple logistic regression analysis, the presence of pulmonary fibrosis on thoracic computed tomography (OR 6.78, CI 1.54 to 29.9), forced vital capacity less than 80% predicted (OR 3.03, CI 1.1 to 8.35), and duration of Raynaud's phenomenon preceding the onset of skin changes for at least 3 years (OR 5.75, CI 1.9 to 17.41) were found to be independent predictors of PAH. Age, disease duration, disease subtype, or autoantibodies were not associated with PAH in our patients. CONCLUSIONS: The present analysis identified pulmonary fibrosis and Raynaud's phenomenon preceding SSc skin manifestations by at least 3 years as risk factors for PAH in our scleroderma cohort. Screening for PAH in these high-risk patients may detect PAH at an earlier stage and guide decisions on therapeutic interventions.     

Isolated pulmonary hypertension in scleroderma

BACKGROUND: Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival. AIM: To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients. METHODS: Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma. RESULTS: Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that >11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT. CONCLUSION: Isolated PHT occurs as a late-stage complication in > or =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.     

Determinants of exercise-induced pulmonary arterial hypertension in systemic sclerosis

Background

Exercise-induced pulmonary arterial hypertension (EIPH) in systemic sclerosis (SSc) has already been observed but its determinants remain unclear. The aim of this study was to determine the incidence and the determinants of EIPH in SSc.

Methods and results

We prospectively enrolled 63 patients with SSc (age 54 ± 3 years, 76% female) followed in CHU Sart-Tilman in Liège. All patients underwent graded semi-supine exercise echocardiography. Systolic pulmonary arterial pressure (sPAP) was derived from the peak velocity of the tricuspid regurgitation jet and adding the estimation of right atrial pressure, both at rest and during exercise. Resting pulmonary arterial hypertension (PH) was defined as sPAP > 35 mm Hg and EIPH as sPAP > 50 mm Hg during exercise. The following formulas were used: mean PAP (mPAP) = 0.61 × sPAP + 2, left atrial pressure (LAP) = 1.9 + 1.24 × left ventricular (LV) E/e′ and pulmonary vascular resistance (PVR) = (mPAP–LAP) / LV cardiac output (CO) and slope of mPAP–LVCO relationship = changes in mPAP / changes in LVCO. Resting PH was present in 3 patients (7%) and 21 patients developed EIPH (47%). Patients with EIPH had higher resting LAP (10.3 ± 2.2 versus 8.8 ± 2.3 mm Hg; p = 0.03), resting PVR (2.6 ± 0.8 vs. 1.4 ± 1.1 Woods units; p = 0.004), exercise LAP (13.3 ± 2.3 vs. 9 ± 1.7 mm Hg; p < 0.0001), exercise PVR (3.6 ± 0.7 vs. 2.1 ± 0.9 Woods units; p = 0.02) and slope of mPAP–LVCO (5.8 ± 2.4 vs. 2.9 ± 2.1 mm Hg/L/min; p < 0.0001). After adjustment for age and gender, exercise LAP (β = 3.1 ± 0.8; p = 0.001) and exercise PVR (β = 7.9 ± 1.7; p = 0.0001) were independent determinants of exercise sPAP.

Conclusion

EIPH is frequent in SSc patients and is mainly related to both increased exercise LV filling pressure and exercise PVR.