A 60-year-old Caucasian female with a history of smoking and chronic obstructive pulmonary disease, and diffuse cutaneous systemic sclerosis (SSc) diagnosed nine years ago, was referred to a pulmonary hypertension (PH) clinic due to progressive dyspnea (WHO functional class III), pre-syncope and high probability of PH by transthoracic echocardiogram (TTE). Physical examination revealed loud second heart sound, tricuspid systolic murmur, basal lung crepitations, bilateral peripheral edema and findings associated with SSc – proximal limb and trunk involvement with skin sclerosis, sclerodactyly, Raynaud’s phenomenon and digital ulceration. She walked 337 meters on six-minute walk test (6MWT) with significant desaturation (nadir 77%). The TTE revealed dilated right heart cavities and right ventricular systolic dysfunction, severe secondary tricuspid regurgitation, elevated trans-tricuspid pressure gradient (64 mmHg) and moderate pericardial effusion (Figure 1A), with no left heart disease. NT-proBNP level was 5118 pg/mL, anti-topoisomerase I (anti-Scl-70) antibodies were present and anti-centromere antibodies were absent. A lung ventilation/perfusion scan excluded pulmonary embolism. Pulmonary function tests showed a moderate restrictive pattern [forced expiratory volume in one second of 84% predicted, forced vital capacity (FVC) of 77% predicted, total lung capacity of 69% predicted] and a severe reduction in pulmonary diffusing capacity for carbon monoxide (DLCO) of 26% predicted, with an FVC/DLCO ratio of 2.96.

Chest computed tomography (CT) demonstrated centrilobular emphysema, especially in the upper lobes, ground-glass opacities, subpleural sparing, honeycombing in basilar and peripheral predominant distribution, and reticular pattern with traction bronchiectasis (Figure 1B). Therapy with diuretics was started, and after optimization, the patient was referred for right heart catheterization (RHC). Hemodynamic evaluation showed a pre-capillary PH, with a mean pulmonary arterial pressure (mPAP) of 45 mmHg, pulmonary capillary wedge pressure of 9 mmHg and pulmonary vascular resistance (PVR) of 12 WU. The right atrial pressure (RAP) was 9 mmHg, cardiac index (CI) was 2 L/min/m², systolic volume index (SVI) was 19 mL/m² and mixed venous oxygen saturation (SvO₂) was 64%.

At first glance, differential diagnosis between pulmonary arterial hypertension (PAH) associated with connective tissue disease versus PH associated with combined pulmonary fibrosis and emphysema was considered. Nevertheless, an FVC/DLCO ratio > 2 pointed to the first hypothesis. Additionally, following an unforeseen conversation with a relative, later confirmed by the patient, it was found a history of cocaine and amphetamine abuse (for eight years, five years ago) and clobenzorex consumption for weight loss (for three years, discontinued six months ago). Accordingly, drug-associated PAH (DPAH) diagnosis was suspected, and initial monotherapy with an endothelin receptor antagonist (ambrisentan) was started, given the presence of pulmonary comorbidities – emphysema and fibrosis. Three months later, the patient was at intermediate-high risk of one-year mortality, according to the simplified four-strata risk-assessment tool^1,2 and additional PAH medication with a phosphodiesterase-5 inhibitor (tadalafil) was initiated. After six months, the patient was at low risk of one-year mortality. Clinical and laboratory parameters significantly improved: WHO functional class II, 426 meters in the 6MWT and NT-proBNP of 197 pg/mL. RHC with vasoreactivity test, depicting a low-risk hemodynamic profile (RAP of 4 mmHg, CI of 4 L/min/m², SVI of 48 mL/m² and SvO₂ of 78%) with a mPAP of 31 mmHg, PVR of 5 WU and no acute response to inhaled nitric oxide.

PH is a pathophysiological disorder that may be associated with multiple clinical conditions. The management of PH is complex and requires a multifaceted, holistic, and multidisciplinary approach, considering all potential risk factors for the development of intrinsic pulmonary vascular disease along with other mechanisms that lead to PAH, such as parenchymal-interstitial lung disease.³

We report the case of a patient with symptomatic PH associated with SSc whose initial assessment indicated group 3 (clinical classification) PH.³The patient had a history of drugs/toxins ( appetite suppressant, cocaine and methamphetamines) consumption as a contributing factor for intrinsic pulmonary vascular disease, which changed the panorama of the diagnosis of PAH, with important therapeutic and prognostic implications. In fact, the excellent clinical, laboratory and hemodynamic response to therapy confirmed the hypothesis of a case of DPAH in a patient with diffuse SSc and lung disease.⁴

Considering the presence of DPAH, it was deemed necessary to assess acute vasoreactivity during RHC.⁵If criteria were met,⁶ the clinical scenario may change towards a favorable and sustained clinical and hemodynamic response with oral calcium channel blockers. However, the response to inhaled nitric oxide was negative in our patient and the therapeutic strategy with dual pulmonary vasodilator therapy remained unchanged.

The etiology of PAH is often challenging, in which a detailed clinical history is of upmost importance. The integration of all possible contributing factors for the development of PH with the global clinical picture, highlights the complexity of intrinsic pulmonary vascular disease, the true target of pulmonary vasodilator therapy.

Figure 1