Clinical Rheumatology (2019) 38:1117–1124 https://doi.org/10.1007/s10067-018-4390-x ORIGINAL ARTICLE Pulmonary hypertension in Spanish patients with systemic sclerosis. Data from the RESCLE registry Francisco J. García-Hernández1 & María J. Castillo-Palma1 & Carles Tolosa-Vilella2 & Alfredo Guillén-del Castillo3 & Manuel Rubio-Rivas4 & Mayka Freire5 & José A. Vargas-Hitos6 & José A. Todolí-Parra7 & Mónica Rodríguez-Carballeira8 & Gerard Espinosa-Garriga9 & Dolores Colunga-Argüelles10 & Norberto Ortego-Centeno11 & Luis Trapiella-Martínez12 & María M. Rodero-Roldán13 & Xavier Pla-Salas14 & Isabel Perales-Fraile15 & Isaac Pons-Martín del Campo16 & Antonio J. Chamorro17 & Rafael A. Fernández-de la Puebla Giménez18 & Ana B. Madroñero-Vuelta19 & Manuel Ruíz-Muñoz20 & Vicent Fonollosa-Pla3 & Carmen P. Simeón-Aznar3 & on behalf of the Spanish Scleroderma Study Group (SSSG) & Autoimmune Diseases Study Group (GEAS) & Spanish Society of Internal Medicine (SEMI) Received: 10 June 2018 /Revised: 12 November 2018 /Accepted: 30 November 2018 /Published online: 7 December 2018 # International League of Associations for Rheumatology (ILAR) 2018 Abstract Introduction Our objective was to evaluate the pulmonary hypertension (PH) data for Spanish patients with systemic sclerosis (SSc), define the PH types and determine the associated factors. Method Descriptive study of PH-related data from the multicentre RESCLE registry. Estimated systolic pulmonary artery pressure (esPAP), measured via echocardiogram was considered elevated if ≥ 35 mmHg. Left heart disease (LHD) and interstitial lung disease (ILD) were identified. When performed, data from right heart catheterisation (RHC) were collected. Results esPAP was elevated in 350 of 808 patients (43.3%). One hundred and forty-four patients (17.8%) were considered to have PH (88 via RHC and the rest due to elevated esPAP along with evidence of significant LHD or ILD): PAH 3.7%, secondary to ILD 8.3%, secondary to LHD 2.8% and unclassified 3%. Prevalence of elevated esPAP was greater in diffuse SSc (dSSc) than in limited scleroderma (lSSc) (50.5 vs. 42.2%, p 0.046). In the group with elevated esPAP, a lower prevalence of anti-centromere antibodies (41.9% vs. 52.3%, p 0.006) and a greater prevalence of anti-topoisomerase-1 antibodies (ATA) (25.1% vs. 18.6%, p 0.04) were observed compared to the group with normal esPAP. Patients with elevated esPAP had a lower rate of digital ulcers (50.6% vs. 60.2%, p 0.007) and esophageal involvement (83.6% vs. 88.7%, p 0.07) and higher rate of renal crisis (4.6% vs. 1.8%, p 0.066). Conclusions Prevalence of PAH was lower than expected (3.7%). Probability of having elevated esPAP was higher among patients with dSSc and among those with ATA. Keywords Anti-centromere antibodies . Pulmonary hypertension . Systemic sclerosis Introduction and objective treatment differences [1]. Pulmonary arterial hypertension (PAH) is a variant of PH caused by an obstructive proliferation Pulmonary hypertension (PH) is defined by a mean pulmonary of pulmonary arterioles. It may be idiopathic or associated with artery pressure (mPAP) ≥ 25 mmHg measured via right heart various processes. These include connective tissue diseases, catheterisation (RHC) at rest. The different processes with especially systemic sclerosis (SSc). Patients with SSc consti- which it is associated are classified in groups that share path- tute a population at risk of suffering PAH, which is a serious ogenic and haemodynamic characteristics, conditioning and relatively frequent complication. SSc-associated PAH (SSC-PAH) has worse evolution and response to treatment than those observed in idiopathic PAH (IPAH) [2–4]. For all of these reasons, clinical practice guidelines recommend an * Francisco J. García-Hernández [email protected] annual screening for PAH via an echocardiogram to ease early detection and treatment, aiming to improve its prognosis [1, 5]. Extended author information available on the last page of the article Suspected PH in SSc patients requires a careful differential 1118 Clin Rheumatol (2019) 38:1117–1124 diagnosis to distinguish PAH from PH secondary to left heart as an ejection fraction ≤ 45%. The existence of left ventricular disease (LHD), interstitial lung disease (ILD) and chronic diastolic dysfunction was estimated using the measurement of thromboembolic disease (especially in patients with anti- the ratio between the early maximal ventricular filling velocity phospholipid antibodies) since their treatments are different. and the late filling velocity (E/A ratio). From the respiratory This differentiation may be very difficult in SSc, in light of perspective, the existence of radiological alterations (via chest the possible coexistence of pulmonary vasculopathy with dif- X-ray and/or computed tomography [CT]) and alterations in ferent degrees of ILD and LHD. the functional tests (forced vital capacity [FVC] and the forced In Spain, only one single-centre study has been published expiratory volume in the first second [FEV1]) were to date evaluating the frequency of PAH and other forms of considered. PH in patients with SSc [6]. The RESCLE registry gathers an The definitions of PH (precapillary, postcapillary and PAH) extensive and multicentre series of Spanish patients with SSc. and their classification followed international consensus [1]. Our objective was to evaluate the PH data among patients PH was defined as an mPAP ≥ 25 mmHg measured via RHC included in the registry, define their HP types and determine at rest. Precapillary PH was characterised by a pulmonary which factors are associated with PAH. capillary wedge pressure (PCWP) ≤ 15 mmHg and postcapillary PH by a PCWP > 15 mmHg. Precapillary PH was considered to be secondary to an ILD if the FVC was < Patients and methods 60% of the theoretical value, and the extent of radiological alterations exceeded 20%. The term PAH refers to a group Descriptive transversal study of PH-related data collected in of patients with precapillary PH with pulmonary vascular re- the multicentre RESCLE registry. The RESCLE registry was sistance > 3 WU in the absence of other causes of precapillary created by the Spanish Internal Medicine Society in 2006 with PH (such as pulmonary diseases or pulmonary thromboembo- the aim of compiling a large series of Spanish SSc patients. lism). Patients with an mPAP between 21 and 24 mmHg were Thirty Spanish hospitals are participating in the patient recruit- considered to have borderline PAH. ment, with the approval of their respective ethics committees. Epidemiological, clinical, laboratory and immunological data Statistical analysis The mean and standard deviation of the are collected according to a standard protocol. A diagnosis of continuous quantitative variables were determined. The chi- SSc is considered when the patients met the ACR/EULAR square test (or Fisher’s exact test when necessary) was used 2013 criteria [7] and/or the modified classification criteria for qualitative variables, and Student’s t test for quantitative proposed by LeRoy and Medsger [8]. Thus, four groups of variables. All analyses were performed using the SPSS 15.0 patients with SSc were established according to the extension software for windows (SPSS, Chicago, IL). Statistical signif- of their cutaneous sclerosis [8]: icance was set at p <0.05. 1. Pre-SSc, defined by the presence of Raynaud’sphenom- enon (RP), characteristic SSc nailfold capillaroscopic Results changes and/or disease-specific autoantibodies but no skin thickening. A total of 1463 patients included in the registry were collected 2. Limited SSc (lSSc), when skin thickening was confined (1302 women, 89%): 860 with lSSc (58.8%), 348 with dSSc distally to the elbows and knees or the face. (23.8%), 142 with ssSSc (9.7%), 97 with pre-SSc (6.6%) and 3. Diffuse SSc (dSSc), when skin thickening extended prox- 16 cases in which the subtype was not available (1.1%). Their imally to the elbows and knees or included the trunk. mean (standard deviation (SD)) age at diagnosis was 51.8 ± 4. Sine scleroderma SSc (ssSSc), defined by the presence of 15.4 years, and the mean time of evolution from diagnosis to RP, scleroderma clinical features, and disease-specific au- their inclusion in the registry was 8.2 ± 7.7 years. toantibodies but no cutaneous sclerosis. At least one echocardiogram had been performed in 1307 patients (89.3%), and the esPAP value was available in 808 The visceral involvement data, capillaroscopy patterns and (55.2%), of which 350 had an esPAP ≥ 35 mmHg (43.3%). immunological changes were considered in the same way in The mean time of evolution from diagnosis was similar for which they were defined in prior works by RESCLE Group [9]. patients with esPASP within normal ranges or elevated (9.2 ± Via an echocardiogram, the estimated systolic pulmonary 7.3 and 9.3 ± 8.1 years, p 0.758). artery pressure (esPAP) was calculated and left ventricular A RHC was performed in 114 patients with esPAP ≥ systolic or diastolic dysfunction data were identified. In order 35 mmHg with the following result: PH confirmed in 79, to establish an adequate cutoff point, and consistent with pre- absence of PH in 14 and borderline PH in 9; the mPAP value vious studies [5, 10], the esPASP was deemed elevated if ≥ was not present in the other 12 patients (6 with echocardio- 35 mmHg. Left ventricular systolic dysfunction was defined graphic data of left ventricular diastolic dysfunction and 2 Clin Rheumatol (2019) 38:1117–1124 1119 with ILD with FVC ≤ 60%). The RHC was also performed in positive in 83/331 patients with esPAP ≥ 35 mmHg (25.1%) 20 patients with esPAP < 35 mmHg, detecting PH in 9 and compared to 80/429 with normal esPAP (18.6%). The preva- borderline PH in 2. lence of ACA was significantly lower (41.9% vs. 52.3%, p Of the 88 patients with PH confirmed via RHC (10.9% of 0.006), and the prevalence of ATA was significantly higher patients with available esPAP values), 36 had a precapillary PH (25.1% vs. 18.6%, p 0.04) in patients with esPAP ≥ pattern(26withILD,6ofthemwithFVC≤ 60%)and16hada 35 mmHg than in patients with esPAP < 35 mmHg.