Our aim is to assess the safety and potential efficacy of a novel treatment paradigm in pulmonary arterial hypertension (PAH), immunomodulation by blocking interleukin-6 (IL6) signaling with the IL6 receptor antagonist, tocilizumab. Inflammation and autoimmunity are established as important in PAH pathophysiology. One of the most robust observations across multiple cohorts in PAH has been an increase in IL6, both in the lung and systemically. Tocilizumab is an IL-6 receptor antagonist established as safe and effective, primarily in rheumatoid arthritis, and has shown promise in scleroderma. In case reports where the underlying cause of PAH is an inflammatory process such as systemic lupus erythematosus, mixed connective tissue disease (MCTD), and Castleman's disease, there have been case reports of regression of PAH with tocilizumab. TRANSFORM-UK is an open-label study of intravenous (IV) tocilizumab in patients with group 1 PAH. The co-primary outcome measures will be safety and the change in resting pulmonary vascular resistance (PVR). Clinically relevant secondary outcome measurements include 6-minute walk distance, WHO functional class, quality of life score, and N-terminal pro-brain natriuretic peptide (NT-proBNP). If the data support a potentially useful therapeutic effect with an acceptable risk profile, the study will be used to power a Phase III study to properly address efficacy.
Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg−1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
There is renewed interest in the haemodynamic definitions of pulmonary hypertension (PH), reigniting an old debate about diagnostic thresholds [1]. Recent prospective data support work dating back over 40 years demonstrating patients with "borderline" PH (mean pulmonary artery pressure (mPAP) <25 mmHg) can still have significant morbidity and mortality [2]. Therefore, lowering the mPAP threshold for the diagnosis of precapillary pulmonary arterial hypertension (PAH) has been discussed at World Symposium on Pulmonary Hypertension in Nice, France, in 2018. A potentially different approach has arisen in group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)), where the concept of chronic thromboembolic disease without PH (CTED) has gained traction. This describes a population of patients with mPAP <25 mmHg, with no lower limit, who have persistent vascular obstructions, impaired response to exercise, and a high impact of disease on symptoms and quality of life (QoL). The 25-mmHg threshold is important partly because it excludes patients who might benefit from treatment, and then precludes their participation in clinical trials, forming a cycle that prevents regulatory approved treatment in the future. In the CTED to CTEPH spectrum, it is unclear if reducing the threshold is the best way to address this inequity, as minimal data exists detailing outcomes <25 mmHg. In the UK, we have undertaken pulmonary endarterectomy (PEA) on a selected, symptomatic cohort of operable CTED patients with good results [3], which were recapitulated by others [4,5]. A valid criticism of our previous work [3] is the retrospective, selective nature of the subjects and a lack of understanding about the natural history of the disease without treatment. Here, we present the first prospective cohort of patients with operable CTED (institutional review board project reference S02297), and hypothesised that clinically meaningful symptoms, limitation and physiology would relate to haemodynamics. Royal Papworth Hospital (Cambridge, UK) is the national PEA referral centre and to minimise tertiary speciality referral bias, we have included only regional nonspecialist referrals. Regional incident cases referred in 2015-2017 with suspected CTED/CTEPH were prospectively assessed. All patients were reviewed at the national CTEPH multidisciplinary team (MDT) meeting. Patients with operable CTED underwent standard CTEPH investigations [6] with additional exercise right heart catheterisation (RHC) and incremental cardiopulmonary exercise testing (CPET) [7]. The zero reference was set at the midthoracic level. During exercise RHC, patients were asked to pedal for 5 min at 40% of the workload achieved during incremental CPET (load range 9-104 W, maximal supine exercise test could not been performed due to technical limitation of ergometer). The mPAP, pulmonary wedge pressure (measured over three breath cycles, when feasible), mixed venous saturation, heart rate and systemic blood pressure were measured, followed by cardiac output (CO) measurement us...
IntroductionPatients with chronic thromboembolic disease (CTED) without pulmonary hypertension commonly present with dyspnoea and fatigue. These symptoms limit physical function and impair quality of life. As resting haemodynamics in these patients are normal or near normal, stress testing may be a useful investigation to clarify mechanisms of functional impairment.MethodsWe prospectively evaluated baseline characteristics of patients with CTED in a single referral centre between January 2015 and June 2016. Newly referred patients with suspected CTED underwent a standard assessment as delineated in international guidelines1 with a minimum of 2 imaging modalities, resting and exercise right heart catheterisation (RHC) and additionally incremental cardiopulmonary exercise testing (CPET). All patients were assessed in a pulmonary endarterectomy MDT.ResultsOf 21 patients with confirmed CTED, 16 have completed the full assessment protocol (median age 53, 47–62). 14 (87%) were in functional class II/III. All patients had normal right ventricular function on echocardiography. Airway obstruction was present in 7 patients (44.5%). In majority of patients peak VO2 and oxygen pulse were decreased and VE/VCO2 at anaerobic threshold (AT) was increased (Table 1). CPET revealed 3 types of exercise limitation: combined cardiovascular and ventilatory limitation (n = 12), ventilatory limitation (n = 2) and limitation due to other reasons (n = 2). Peak oxygen consumption correlated with the symptoms domain of CAMPHOR (pulmonary hypertension specific quality of life measure) (p = 0.0242, R 0.56), cardiac output increase on exercise (p = 0.03, R 0.569) and VE/VCO2 at anaerobic threshold (p = 0.012, R 0.608). Resting mPAP and PVR did not correlate with peak VO2 or symptoms.ConclusionsWe confirm the limited utility of resting measurements, including RHC in CTED for understanding exercise and functional limitation. CPET identified alternative causes for breathlessness and clarifies that patients with CTED are limited on exertion because of inability to increase cardiac output and hyperventilation.ReferenceGalie N, et al. ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. EHJ 2015;58(1):e129–e152.Abstract P29 Table 1Exercise intolerance in chronic thromboembolic diseaseGender M/F number(%)11 (69)/5 (31)Age [years] Median, IQR53, 46.6–61.5Camphor score Median, IQR• Symptoms• Activity• QoL9.5, 5–12.33, 1.8–6.85, 0.8–12mPAP [mmHg] Median, IQR20.5, 18–23PVR [dyn·s·cm- 5] Median, IQR158, 112–195.7PAWP [mmHg] Median, IQR10.5, 8–12Cardiac Output [L/min] Median, IQR5.35, 4.1–5.8Cardiac Output fold increase on exercise*2.4 ± 0.5mPAP on exercise [mmHg]*30, 25.8–32.8TPR on exercise [WU]2.6, 2.1–3.9Peak VO2 [%pred.] Mean ± SD90 ± 19.5VE/VCO2 at AT Median, IQR36, 31–44.9Peak O2 pulse [% pred.] Median, IQR84.5, 71–107* Exercise at 40% of peak workload achieved during incremental CPET
2Corresponding author's email: noblel1@yahoo.co.uk Introduction A reduced gas transfer factor is frequently observed in patients with CTEPH. Transfer factor for Carbon monoxide (TLCO) is the most widely accepted measure of gas transfer. Previous work has indicated the value of using nitric oxide (NO) to allow the differentiation of diffusing membrane capacity (Dm) and capillary blood volume (Vc); the components of gas transfer. It has been suggested, that transfer factor for nitric oxide (TLNO) is a more accurate reflection of the true Dm than TLCO, due to its greater affinity for haemoglobin and independence from capillary blood volume. To date, many studies have derived Dm and Vc from the Roughton and Forster equation, using triplicate measurements of TLCO at high and low oxygen concentrations. This study uses new technology to measure Dm and Vc, using NO, in a cohort of post PEA CTEPH patients. The aim of the study is to compare the relative contribution of Dm and Vc to the reduction in gas transfer. Methods We studied 24 CTEPH patients (14 male, 10 female, mean age 60 13) post PEA as part of their routine follow up at either 3 months or 1 + year. Full lung function were performed and TLNO and Dm were measured directly using single breath for NO and carbon monoxide on a PFTpro system (Viasys). Vc was calculated using the equation 1/DLCO-1/DmCOxqCO=1/Vc. Patients with co-existing parenchymal lung disease were excluded from the study. Predicted values for Dm and Vc were calculated from the equations of Crapo and colleages. Correlations between variables were looked at using Pearsons. ResultsBoth Dm and Vc demonstrated a significant correlation with TLCO, however, Vc was reduced more than Dm (57.5%/86.8% respectively). No difference in Dm or Vc was found between smokers and non-smokers. Results are shown in table 1. Correlation Matrix Measured Mean ( Sd) + % Pred Mean (Sd) Dm Measured R (P)
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