Pulmonary arterial hypertension in systemic sclerosis-when criteria and pathobiology differ.

Haemodynamic definitions of SSc-associated pulmonary arterial hypertension are sometimes not reflected in histological examination of lung vasculature.

Dear Sir, At the 2018 World Symposium on Pulmonary Hypertension, it was suggested that the haemodynamic definitions of pulmonary hypertension be revised, but that the diagnosis of pulmonary arterial hypertension (PAH) should still rely purely on right heart catheterization (RHC) measurements, after excluding pulmonary and left heart disease with other diagnostic modalities. We here report on two cases illustrating discordant haemodynamic and microscopic characteristics, questioning the validity of the current criteria with regard to pathobiology [1].

A 69-year-old female smoker (case A) was diagnosed with adenocarcinoma of the lung and underwent left lower lobe resection. Six months later she was diagnosed with SSc with nucleolar antinuclear antibodies and limited skin involvement, with an estimated disease duration of 10 years. High-resolution CT showed subtle signs of emphysema and interstitial lung disease. She had dyspnoea and increased systolic pulmonary arterial pressure on echocardiography. RHC revealed a normal mean pulmonary artery pressure (MPAP, 18 mmHg), but increased pulmonary vascular resistance (PVR, 3.6 WU), thus not fulfilling the criteria for PAH. Histology of the resected left lower lobe, explanted 6 months earlier, showed severe arteriolar abnormalities with medial/intimal thickening and small-vessel fibrosis, no plexiform lesions, but focal affection of venules with mild wall thickening (Fig. 1A–C). ‘Early’ SSc-associated PAH (SSc-APAH) was suspected and ambrisentan monotherapy was initiated. Renewed RHC, 7 months later, revealed elevated MPAP (26 mmHg) with reduced PVR (3.1 WU), now fulfilling the diagnostic criteria for SSc-APAH. She died of her malignancy 1 year and 8 months after SSc-APAH diagnosis.

. 1

Histopathology of lung not fulfilling and fulfilling criteria for PAH associated with SSc

Case A: severe arteriolar abnormalities in areas without (A) and with (B, C) fibrosis. Case B: very few thickened arterioles in areas with fibrosis with architectural distortion (D), but normal in most such areas (E), as well as in areas with fibrosis with preserved architecture (F), organizing pneumonia (G) and interstitial inflammation (H). Scale bars: 100 µm.

The second case was a 50-year-old woman, who had never smoked (case B), with 11 years of stable limited cutaneous Jo-1 positive SSc and overlap with severe arthritis, mild myositis and interstitial lung disease who presented with dyspnoea. Lung function testing revealed low diffusing capacity of the lung for carbon monoxide (28% of predicted) and she underwent RHC. She fulfilled the criteria for SSc-APAH (MPAP 33 mmHg, PVR 4.0 WU) and ambrisentan monotherapy was initiated. She continued immunosuppressive therapy with rituximab and azathioprine, and improved haemodynamically. Eight years after PAH diagnosis she was also diagnosed with adenocarcinoma of the lung and underwent a partial left lower lobe resection. Histological examination revealed very few altered arterioles with wall thickening and no plexiform lesions or pathological venules. These altered arterioles were only present in areas with dense fibrosis with architectural distortion and honeycombing. No signs of wall thickening or other alterations were observed in the arterioles in areas showing inflammation, interstitial fibrosis with preserved architecture or other non-fibrotic lung tissue (Fig. 1D–H).

The clinical characteristics of the patients are presented in Supplementary Table S1 and Figs S1–S3, available at Rheumatology online. Case A challenges the current European Society of Cardiology/European Respiratory Society 2015 definition of PAH [2], as histological examination showed the presence of typical SSc-APAH abnormalities before the haemodynamic criteria for PAH were fulfilled. It cannot be ruled out that the vasculopathy was secondary not only to SSc but also to the adenocarcinoma [3]. However, the histological examination was consistent with previous reports of SSc-APAH [4, 5].

In case B, no PAH-specific alterations were identified in the histological examination of the left lower lobe despite the fact that PAH had been diagnosed 8 years before lobectomy. Lung fibrosis, present already early in disease, might have aggravated pulmonary hypertension. However, repeated high-resolution CT examinations before and after initiation of ambrisentan and rituximab have consistently regarded the overall extent of lung fibrosis as mild [6].

SSc-APAH is another disease than idiopathic PAH. In contrast to idiopathic PAH, plexogenic arteriopathy is absent in SSc-APAH, while small-vessel fibrosis is common [4, 5]. Even after the advent of modern vascular therapy, the prognosis for patients with SSc-APAH remains poor, and earlier initiation of treatment has been suggested to improve survival [7].

We suggest that not only haemodynamics but also vascular pathobiology should be included in the future classification of SSc-APAH by the European Society of Cardiology/European Respiratory Society. Ultimately, a biomarker specific for the pathobiology of lung arterioles is warranted. In the absence of such a tool, we appreciate the recent proposal that pre-capillary PH may be defined in patients with PVR ⩾3 WU, pulmonary arterial wedge pressure ⩽15 mmHg and mPAP >20 mmHg [1]. These patients often have underlying right ventricular dysfunction and could benefit from a more thorough examination of the right ventricle during stress, including the assessment of pulmonary arterial compliance. At present, we agree with previous studies suggesting that exercise RHC offers an opportunity to correctly diagnose early SSc-APAH [8].

In conclusion, early and correct identification of SSc-APAH still poses a considerable challenge [1]. We suggest that the current definitions do not completely reflect the microscopic pathobiology of this disease, and that these classification criteria occasionally fail to identify early SSc-APAH. For future classification criteria, a biomarker specific for the SSc-APAH pathobiology is warranted.

Funding: This work was supported by grants from the Lund University Faculty of Medicine, the Swedish Rheumatism Association, King Gustaf V’s 80-Year Fund, the Österlund Foundation and the Koch Foundation.

Disclosure statement: The authors have declared no conflicts of interest.

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