Systemic sclerosis-associated pulmonary arterial hypertension is characterized by a distinct peripheral T helper cell profile.

OBJECTIVES: Systemic sclerosis (SSc) is characterized by multiple clinical manifestations. Vasculopathy is a main disease hallmark and ranges in severity from an exacerbated Raynaud phenomenon to pulmonary arterial hypertension (PAH). The potential involvement of immune system in SSc associated vascular abnormalities is not clear. Here, we set out to study SSc-related immune parameters and determine whether and which peripheral T cell subsets associate with vascular severity in SSc patients. METHODS: Peripheral blood and clinical data were collected from 30 SSc patients, 5 patients with idiopathic pulmonary arterial hypertension (IPAH) and 15 age and sex-matched healthy donors (HD). In this cross-sectional cohort SSc patients with PAH (n = 15) were matched for their age, sex and medication with SSc patients with no signs of PAH (n = 15). Lymphocyte subsets were quantified by multi-colour flow cytometry. RESULTS: SSc patients exhibited elevated percentages of T peripheral helper cells (Tph), CD4+GZMB+ T cells and decreased levels of Th1 cells compared with HD. Increased presence of both CD4+ and CD8+ exhausted-like (CD28-) T cells, characterized by raised cytokine and cytotoxic signature, was also observed in SSc compared with HD blood. Furthermore, IL-4 expressing CD4+CD8+ T cells were significantly increased in SSc peripheral blood. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and Tph cells. CONCLUSION: SSc patients with severe vasculopathy (presence of PAH) exhibited a distinct T cell profile, suggesting for a potential role of auto-immune inflammation in SSc vascular complications.

Efficacy of methylprednisolone in very early systemic sclerosis: results of the "Hit hard and early'' randomized controlled trial.

OBJECTIVE: We hypothesized that glucocorticoids would induce remission in very early Systemic Sclerosis patients by inhibition of inflammation driving the disease. We examined the efficacy and safety of methylprednisolone in very early Systemic Sclerosis. METHODS: In this trial adults with puffy fingers for less than three years, specific auto-antibodies and meeting the Very Early Diagnosis of Systemic Sclerosis criteria were randomly assigned (2:1) to methylprednisolone 1000 mg intravenously or placebo for 3 consecutive days 3 times with monthly intervals. The primary end point was nailfold capillary density at week 12. Capillary density at 52 weeks, number of megacapillaries, and patient-reported outcomes were secondary outcomes. In addition, we assessed disease progression and lung function decline over 52 weeks. We used linear regression analyses adjusted for baseline values and stratification variables to estimate differences between groups. RESULTS: Between February 2017 and February 2021, 87 patients were screened, of whom 30 (70% female, median (IQR) age 52·9 (40·8-60·8) years, median (IQR) disease duration 11.4 (4.6-18.6) months) were randomly assigned to methylprednisolone (n = 21) or placebo (n = 9). We found no difference in nailfold capillary density at 12 weeks: -0.5 (95% CI 1.1, 0.2) nor in any of the secondary outcomes. Eleven (37%) patients showed disease progression during 1 year follow up, 7 (23%) patients had a relevant pulmonary function decline. No serious adverse events were reported. CONCLUSIONS: No clinically relevant effect of short-term methylprednisolone in patients with very early Systemic Sclerosis was observed. A substantial proportion of patients showed disease progression.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

AIMS: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). METHODS AND RESULTS: Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). CONCLUSION: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

Patient-reported outcomes to assess dyspnoea in interstitial lung disease and pulmonary hypertension: a systematic literature review of measurement properties.

OBJECTIVE: This COnsensus-based Standards for the selection of health measurement INstruments (COSMIN)-based systematic review aims to identify and summarise the quality of measurement properties of dyspnoea-specific patient-reported outcome measures (PROMs) for patients with interstitial lung disease (ILD), pulmonary hypertension (PH) or connective tissue diseases (CTDs). METHODS AND RESULTS: Relevant articles in PubMed and Embase were screened. Based on COSMIN analysis and the Grading of Recommendations, Assessment, Development and Evaluation approach, overall rating and level of evidence were assessed to formulate recommendations. We identified 26 publications on 10 PROMs. For patients with ILD, including CTD-associated ILD, nine PROMs were evaluated, of which the Dyspnea-12 (D12), EXACT-Respiratory Symptoms Idiopathic Pulmonary Fibrosis Breathlessness subscale (ERS-IPF-B), King's Brief Interstitial Lung Disease Health Status Questionnaire breathlessness and activities subscale (KBILD-B) and the University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) had high-quality evidence for sufficient internal consistency, without high-quality evidence of insufficient measurement properties. We reached this same conclusion regarding the D12 for use in patients with PH, including CTD-associated PH. Most PROMs in this systematic review have moderate- or low-quality evidence on construct validity and responsiveness. CONCLUSION: Four dyspnoea-specific PROMs, D12, ERS-IPF-B, KBILD-B and UCSD-SOBQ, can be recommended for use in patients with ILD, including CTD-associated ILD. Of these four, the D12, despite the limited evidence and the lack of evidence on several important domains, is also suitable for use in patients with PH, including CTD-associated PH.