Prevalence, risk factors and echocardiographic predictors of pulmonary hypertension in systemic lupus erythematosus: towards a screening protocol.

BACKGROUND: Systemic lupus erythematosus (SLE) significantly affects the lungs and heart, and pulmonary hypertension (PH) is a severe manifestation that leads to considerable morbidity and mortality. OBJECTIVES: We aimed to determine the prevalence and risk factors of probable SLE-PH, assess the main echocardiographic predictors and develop a potential screening strategy. METHODS: A prospective single-centre study was conducted on 201 patients with SLE who underwent transthoracic echocardiography. Patients meeting PH criteria were referred for right heart catheterisation (RHC). RESULTS: Among patients, 88.56% were women, 85.57% were of Spanish origin and 43.78% had structural heart disease. Out of these, 16 (7.96%) had intermediate or high probability criteria for PH according to European Society of Cardiology (ESC) 2022. Six RHCs confirmed PH with a prevalence of 2.99% for SLE-PH and 1.99% for SLE-pulmonary arterial hypertension (PAH). KEY RISK FACTORS: Key risk factors included age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered pulmonary function tests (PFTs). PH was linked to a higher Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index (SDI) (mean SDI 4.75 vs 2.05, p<0.001) and increased mortality risk in a 2-year follow-up (12.50% vs 1.08%, p=0.002). CONCLUSION: In our cohort, 7.96% of patients with SLE had an intermediate or high PH probability. By RHC, six patients (2.99%) met the ESC/European Respiratory Society criteria for PH and four (1.99%) for PAH. The main risk factors were older age, cardiorespiratory symptoms, serositis, anti-Ro, cardiac biomarkers and altered PFTs. PH was a severe SLE complication, suggesting the need for earlier diagnosis through data-driven screening to reduce associated morbidity and mortality.

Macitentan for the Treatment of Refractory Digital Ulcers in Patients With Connective Tissue Diseases.

Systemic sclerosis (SSc) is a chronic autoimmune disease with complex pathogenesis, characterized by vascular dysfunction and fibrosis. Digital ulcers (DUs) are a common and severe complication in SSc patients, negatively impacting their quality of life. This retrospective study evaluates the use of macitentan, an endothelin receptor antagonist, in six female patients with connective tissue disease (CTD) and sclerodermiform features (five SSc and one mixed connective tissue disease) for the treatment of refractory DUs. Macitentan demonstrated a safe and effective alternative to bosentan, reducing DU relapses, hospitalizations, and the use of systemic prostaglandin therapy. The findings suggest that macitentan may be a valuable therapeutic option in specific cases of recurrent or refractory DUs and warrant further investigation in larger, long-term studies.

Cardiac involvement in a Spanish unicentric prospective cohort of patients with systemic lupus erythematosus.

BACKGROUND: Cardiac involvement is one of the most frequent manifestations of Systemic Lupus Erythematosus (SLE). Transthoracic echocardiogram (TTE) may be valuable for the early detection of cardiac abnormalities in SLE. Few studies analyze both TTE findings in SLE and the risk factors that predispose to different cardiac manifestations in a long follow-up cohort. We aimed to investigate cardiac involvement's prevalence, risk factors, and outcomes in a Spanish Lupus Clinic. METHODS: Spanish single-center prospective study of cardiac involvement in SLE. Two hundred and one patients met the 2019 EULAR/ACR classification criteria, performed TTE, and were eligible for the study. RESULTS: Cardiac involvement was present in 43.8%. Patients with older age, hypertension, hyperlipidemia, higher body mass index, peripheral arterial disease, thrombosis, and major cardiovascular events had significantly more cardiac involvement. Neurological, hematological, and serosal involvement (pleuritis and/or pericarditis) were clinical risk factors for abnormal TTE. The combination of the four clinical variables (dyspnea, chest pain, cough, and/or syncope) was present in 40.9% of the patients with abnormal TTE in the follow-up and was superior to each of the manifestations separately. Troponin I (TnI) ≥ 0.2 ng/mL and NTproBNP ≥ 300 pg/mL were excellent biomarkers with a good correlation with cardiac abnormalities. Anti-B2GP1 was the only autoantibody associated with cardiac involvement in our cohort. Presenting cardiac involvement was correlated with higher SLICC Damage Index and increased mortality risk in the 2-year follow-up period. CONCLUSIONS: Cardiac involvement in SLE is diverse, heterogeneous, and highly prevalent. Presenting a pathological TTE was associated with greater damage accrual and greater mortality. Based on our results, we consider that echocardiographic screening of patients with SLE is essential, especially those symptomatic and/or with risk factors, to diagnose and treat cardiac involvement earlier.

Directrices para la realización de la tesis doctoral en ciencias de la salud / Guidelines for the completion of a doctoral thesis in health sciences

La realización de una tesis doctoral en Ciencias de la Salud es un proceso largo en el tiempo y laborioso en su ejecución. Como técnica de aprendizaje para llevarla a cabo se ha utilizado una herramienta lúdica representada por el juego de la oca, en el que cada casilla contiene una etiqueta informativa de todos los pasos del proceso, así como los enlaces a los recursos necesarios para alcanzar con éxito la meta final: la lectura del trabajo de investigación para acceder al grado de Doctor. (AU)

Developing a doctoral thesis in Health Sciences is a long-term, laborious process. As a learning technique for carrying it out a playful tool represented by the goose game has been used, in which each box contains an informative label on every step of the process, as well as links to the resources needed to successfully achieve the final goal: present a research-based oral dissertation to obtain a PhD degree. (AU)

The challenge of comprehensive nailfold videocapillaroscopy practice: a further contribution.

OBJECTIVES: Although classification systems and scores for capillaroscopy interpretation have been published, there is a lack of homogenization for the procedure, especially in the way and place the images are taken, the counting of the capillaries and the measuring of their size. Our objective is to provide a deep learning-based software to obtain objective and exhaustive data for the whole nailfold without increasing the time or effort needed to do the examination, or requiring expensive equipment. METHODS: An automated software to count nailfold capillaries has been designed, through an exploratory image dataset of 2,713 images with 18,000 measurements of 3 different types. Subsequently, application rules have been created to detect the morphology of nailfold videocapillaroscopy images, through a training set of images. The software reliability has been evaluated with standard metrics used in the machine learning field for object detection tasks, comparing automatic and manual counting on the same NVC images. RESULTS: A mean average precision (mAP) of 0.473 is achieved for detecting and classifying capillaries and haemorrhages by their shape, and a mAP of 0.515 is achieved for detecting and classifying capillaries by their size. A precision of 83.84% and a recall of 92.44% in the identification of capillaries was estimated. CONCLUSIONS: Deep learning is a useful tool in nailfold videocapillaroscopy that allows to analyse objectively and homogeneously images taken with multiple devices. It should make the assessment of the capillary morphology in nailfold video capillaroscopy easier, quicker, more complete and accessible to everyone.

Anti-Polymyositis/Scl Antibodies in Systemic Sclerosis: Clinical Associations in a Multicentric Spanish Cohort and Review of the Literature.

OBJECTIVES: To assess the clinical profile of patients with anti-polymyositis/Scl (PM/Scl) antibodies in a cohort of Spanish patients with systemic sclerosis. METHODS: From the Spanish Scleroderma Study Group database, we selected patients in whom PM/Scl antibodies had been tested. We compared demographic, clinical, laboratory, and survival data between patients with and without PM/Scl antibodies. RESULTS: Seventy-two of 947 patients (7.6%) tested positive for PM/Scl antibodies. Patients with PM/Scl antibodies presented initially with more puffy fingers and arthralgias but less Raynaud phenomenon. Regarding cumulative manifestations, myositis and arthritis were more prevalent in patients with PM/Scl antibodies, as well as pulmonary fibrosis. On the contrary, patients with PM/Scl antibodies had less pulmonary hypertension. No difference in terms of survival at 5 and 10 years was noticed between the 2 groups. CONCLUSIONS: In systemic sclerosis patients from Spain, PM/Scl antibodies are associated with a distinct clinical profile. However, PM/Scl antibodies did not influence survival.

Spanish scleroderma risk score (RESCLESCORE) to predict 15-year all-cause mortality in scleroderma patients at the time of diagnosis based on the RESCLE cohort: Derivation and internal validation.

A few scores predicting the short-term risk of mortality in Systemic sclerosis (SSc) have been reported to date. Our study aimed to create a predictive 15-year all-cause mortality score at the time of the diagnosis of SSc. The study was based on the Spanish Scleroderma Registry (RESCLE). The cohort was split up in derivation (DC) and validation cohort (VC). A multivariate analysis to detect variables related to all-cause mortality within the first 15 years from SSc diagnosis was performed, assigning points to the rounded beta values to create the score (RESCLESCORE). 1935 SSc patients were included. The variables in the final model were as follows: age at diagnosis (+2 points > 65 years-old), male gender (+1 point), lcSSc subset (-1 point), mode of onset other than Raynaud's (+1 point), cancer (+1 point) and visceral involvement, such as ILD (+1 point), PAH (+1 point), heart (+1 point) and renal involvement (+2 points). Autoantibodies did not achieve statistical significance in the multivariate analysis. The 3 categories of risk to predict 15-year all-cause mortality at the time of diagnosis were as follows: low risk (5% vs. 7%, p = .189), intermediate risk (26.5% vs. 25.5%, p = .911) and high risk (47.8% vs. 59%, p = .316). The AUC was 0.799 (DC) vs. 0.778 (VC) (p = .530). In conclusion, the RESCLESCORE demonstrated an excellent ability to categorize SSc patients at the time of diagnosis in separate 15-year all-cause mortality risk strata at the time of diagnosis.

Comparison of the Birmingham Vasculitis Activity Score and the Five-Factor Score to Assess Survival in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Study of 550 Patients From Spain (REVAS Registry).

OBJECTIVE: To compare the accuracy of the Birmingham Vasculitis Activity Score (BVAS), version 3, and the Five Factor Score (FFS), version 1996 and version 2009, to assess survival in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: A total of 550 patients with AAV (41.1% with granulomatosis with polyangiitis, 37.3% with microscopic polyangiitis, and 21.6% with eosinophilic granulomatosis with polyangiitis), diagnosed between 1990 and 2016, were analyzed. Receiver operating characteristic (ROC) curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores. RESULTS: Overall mortality was 33.1%. The mean ± SD BVAS at diagnosis was 17.96 ± 7.82 and was significantly higher in nonsurvivors than in survivors (mean ± SD 20.0 ± 8.14 versus 16.95 ± 7.47, respectively; P < 0.001). The mean ± SD 1996 FFS and 2009 FFS were 0.81 ± 0.94 and 1.47 ± 1.16, respectively, and were significantly higher in nonsurvivors than in survivors (mean ± SD 1996 FFS 1.17 ± 1.07 versus 0.63 ± 0.81 [P < 0.001] and 2009 FFS 2.13 ± 1.09 versus 1.15 ± 1.05 [P < 0.001], respectively). Mortality rates increased according to the different 1996 FFS and 2009 FFS categories. In multivariate analysis, BVAS, 1996 FFS, and 2009 FFS were significantly related to death (P = 0.007, P = 0.020, P < 0.001, respectively), but the stronger predictor was the 2009 FFS (hazard ratio 2.9 [95% confidence interval 2.4-3.6]). When the accuracy of BVAS, 1996 FFS, and 2009 FFS to predict survival was compared in the global cohort, ROC analysis yielded area under the curve values of 0.60, 0.65, and 0.74, respectively, indicating that 2009 FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001 and when assessing the 1-year, 5-year, and long-term mortality. Correlation among BVAS and 1996 FFS was modest (r = 0.49; P < 0.001) but higher than between BVAS and the 2009 FFS (r = 0.28; P < 0.001). CONCLUSION: BVAS and FFS are useful to predict survival in AAV, but the 2009 FFS has the best prognostic accuracy at any point of the disease course.

Correction to: First clinical symptom as a prognostic factor in systemic sclerosis: results of a retrospective nationwide cohort study.

When first published, this article inadvertently listed the RESCLE investigators individually within the author list. The names should instead have been listed within the Acknowledgements section only. The corrected author list and the updated Acknowledgements section are presented in this Correction.

First clinical symptom as a prognostic factor in systemic sclerosis: results of a retrospective nationwide cohort study.

The objective of the study is to determine the importance of the mode of onset as prognostic factor in systemic sclerosis (SSc). Data were collected from the Spanish Scleroderma Registry (RESCLE), a nationwide retrospective multicenter database created in 2006. As first symptom, we included Raynaud's phenomenon (RP), cutaneous sclerosis, arthralgia/arthritis, puffy hands, interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and digestive hypomotility. A total of 1625 patients were recruited. One thousand three hundred forty-two patients (83%) presented with RP as first symptom and 283 patients (17%) did not. Survival from first symptom in those patients with RP mode of onset was higher at any time than those with onset as non-Raynaud's phenomenon: 97 vs. 90% at 5 years, 93 vs. 82% at 10 years, 83 vs. 62% at 20 years, and 71 vs. 50% at 30 years (p < 0.001). In multivariate analysis, factors related to mortality were older age at onset, male gender, dcSSc subset, ILD, PAH, scleroderma renal crisis (SRC), heart involvement, and the mode of onset with non-Raynaud's phenomenon, especially in the form of puffy hands or pulmonary involvement. The mode of onset should be considered an independent prognostic factor in systemic sclerosis and, in particular, patients who initially present with non-Raynaud's phenomenon may be considered of poor prognosis.

Clinical and epidemiological differences between men and women with systemic sclerosis: a study in a Spanish systemic sclerosis cohort and literature review.

OBJECTIVES: The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in Ssc patients, and contradictory results have often been show among those studies that have been performed. METHODS: A prospective study was conducted with the Spanish RESCLE register to analyse the influence of gender on survival of SSc patients. RESULTS: In total, 1506 SSc patients (1341 women, 165 men) were recruited from 21 centres. Older age at onset (OR 1.02), shorter time from onset to diagnosis (OR 0.96), smoking (OR 2.57), interstitial lung disease (ILD) (OR 1.58), less predisposition to sicca syndrome and to antinuclear antibody positivity (OR 0.29 and 0.43, respectively), and higher compliance with the ACR 1980 criteria (OR 1.79) were independently associated with the male sex. During follow-up, 30.4% of men versus 14.6% of women died (p<0.001). Survival at 10 years from the onset of symptoms was 75.3% for men and 92.9% for women (p<0.001), and the difference remained after selecting only SSc-related deaths (85.6% vs. 96.1%, p<0.001). The mortality predictive factors were diffuse SSc (OR 2.26), ILD (OR 1.82), digital ulcers (OR 1.38), tendon friction rubs (OR 1.74), male sex (OR 1.53), increased age at onset (OR 1.13) and isolated PH (considering only deaths from diagnosis), both in the overall (OR 3.63) and female cohorts (OR 3.97). The same risk factors were observed in the male cohort, except for isolated PH and ILD. CONCLUSIONS: The present study confirms the existence of epidemiological, clinical, laboratory and prognostic gender differences in systemic sclerosis patients.

Influence of antibody profile in clinical features and prognosis in a cohort of Spanish patients with systemic sclerosis.

OBJECTIVES: To assess the clinical manifestations and prognosis of Spanish patients with systemic sclerosis (SSc) according to their immunological profile. METHODS: From the Spanish Scleroderma Study Group or RESCLE (Registro de ESCLErodermia as Spanish nomenclature) Registry we selected those patients in which anti-centromere (ACA), anti-topoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies had been determined, and a single positivity for each SSc specific antibody was detected. Demographic, clinical, laboratory, and survival data were compared according to the serologic status of these antibodies. RESULTS: Overall, 209 SSc patients were included. In 128 (61%) patients ACA was the only positive antibody, 46 (22%) were only positive for ATA, and 35 (17%) for ARA. Of note, the three groups were mutually exclusive. In univariate analysis, patients with ACA presented more frequently limited cutaneous SSc (lcSSc) (p<0.001), whereas diffuse cutaneous SSc (dcSSc) was the most frequent subtype in patients with ATA (54%) and ARA (62%) (both p<0.001). Positive patients for ARA showed the highest prevalence of joint involvement (p<0.001) and those from ATA group had a higher prevalence of interstitial lung disease (ILD) (p<0.001). Scleroderma renal crisis was more frequent in the ARA group (p<0.001). In multivariate analysis, ACA were associated with female gender and were protective for dcSSc and ILD. ATA were found to be protective for lcSSc and they were independently associated with interstitial reticular pattern. ARA positivity was independently associated with dcSSc. We did not find differences in mortality between the three groups. CONCLUSIONS: In Spanish SSc patients, the presence of SSc specific antibodies conferred a distinctive clinical profile.

Very early and early systemic sclerosis in the Spanish scleroderma Registry (RESCLE) cohort.

OBJECTIVES: According to the existence of subclinical organ involvement pre-scleroderma should be divided into two subsets: very early and early disease. Pre-scleroderma patients included in the Spanish Scleroderma Registry (RESCLE) Cohort were reclassified into subsets. Differences were evaluated and the risk of progression to definite systemic sclerosis was estimated. METHODS: The characteristics of very early and early SSc patients were compared. A logistic regression model was used to determine the risk factors of progression. RESULTS: 1632 patients were included, 36 (2.2%) in the very early subset and 111 (6.8%) in the early subset. There were no differences in sex, age at disease onset, duration of Raynaud's phenomenon, antinuclear antibodies or capillaroscopic findings. Three (8.3%) very early SSc patients evolved to definite SSc, 2 (5.6%) of them meeting the ACR/EULAR 2013 criteria, unlike 31 (28%) early SSc patients, 20 (24%) of them meeting the criteria (p=0.034). Digestive involvement was an independent risk factor of progression (OR 17; 95% CI, 6.1-47.2). CONCLUSIONS: The classification of early forms of scleroderma identifies patients with different prognostic risk of progression. The evolution to definite SSc is more frequent in early than in very early SSc patients. Digestive involvement is a risk factor of progression. An active assessment of organ damage in preclinical stages allows a correct classification and risk stratification, with implications for monitoring and treatment.

Changes in the pattern of death of 987 patients with systemic sclerosis from 1990 to 2009 from the nationwide Spanish Scleroderma Registry (RESCLE).

OBJECTIVES: To determine the changes in the pattern of death of patients with systemic sclerosis (SSc) throughout 20 years. METHODS: Data were collected from the Spanish Scleroderma Registry (RESCLE), retrospective multicentre database from 1990 to 2009. SSc-related and SSc-non related causes of death were assessed. RESULTS: 987 patients were recruited. Overall standardised mortality ratio (SMR) was 2.34 (2.24-2.44). SSc-related causes of death were responsible of 72% of all deaths of those patients diagnosed within 1990-99 vs. 48% within 2000-09 (p=0.006). Relative pulmonary death rate was stable over time (68.1% within 1990-99 vs. 63.9% within 2000-09, p=0.815). Relative renal death rate was decreasing over time (17% within 1990-99 vs. 5.5% within 2000-09, p=0.175). Heart distribution tripled its ratio (12.8% within 1990-99 vs. 30.6% within 2000-09, p=0.058). CONCLUSIONS: SSc-related causes of death were decreasing over time and, among them, pulmonary involvement was the leading cause of death in both decades. The ratio of renal causes decreased since 1990 at the time that the ratio of cardiac causes increased.

Digital ulcers and cutaneous subsets of systemic sclerosis: Clinical, immunological, nailfold capillaroscopy, and survival differences in the Spanish RESCLE Registry.

OBJECTIVE: Digital ulcers (DU) are the most common vascular complication of systemic sclerosis (SSc). We compared the characteristics between patients with prior or current DU with those never affected and evaluated whether a history of DU may be a predictor of vascular, organ involvement, and/or death in patients with SSc. METHODS: Data from SSc patients with or without prior or current DU were collected by 19 referral centers in an ongoing registry of Spanish SSc patients, named Registro de ESCLErodermia (RESCLE). Demographics, organ involvement, autoimmunity features, nailfold capillary pattern, survival time, and causes of death were analyzed to identify DU related characteristics and survival of the entire series and according to the following cutaneous subsets-diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). RESULTS: Out of 1326, 552 patients enrolled in the RESCLE registry had prior or current DU, 88% were women, the mean age was 50 ± 16 years, and the mean disease duration from first SSc symptom was 7.6 ± 9.6 years. Many significant differences were observed in the univariate analysis between patients with and without prior/current DU. Multivariate analysis identified that history of prior/current DU in patients with SSc was independently associated to younger age at SSc diagnosis, diffuse cutaneous SSc, peripheral vascular manifestations such Raynaud's phenomenon, telangiectasia, and acro-osteolysis but no other vascular features such as pulmonary arterial hypertension or scleroderma renal crisis. DU was also associated to calcinosis cutis, interstitial lung disease, as well as worse survival. Multivariate analysis performed in the cutaneous subsets showed that prior/current DU were independently associated: (1) in dcSSc, to younger age at SSc diagnosis, presence of telangiectasia and calcinosis and rarely a non-SSc pattern on nailfold capillaroscopy; (2) in lcSSc, to younger age at SSc diagnosis, presence of Raynaud's phenomenon as well as calcinosis cutis, interstitial lung disease, and higher incidence of death from all causes; and (3) in ssSSc, to younger age at first SSc symptom and greater incidence of death from all causes. CONCLUSIONS: Digital ulcers develop in patients with SSc younger at diagnosis, mainly in patients with dcSSc and lcSSc, and they are associated to other peripheral vascular manifestations such as Raynaud's phenomenon, telangiectasia, and acro-osteolysis but also to calcinosis, and interstitial lung disease. History of DU in SSc leads to worse survival, also noticeable for lcSSc and ssSSc subsets but not for dcSSc patients.

Brain Microvasculature Involvement in ANCA Positive Vasculitis.

OBJECTIVE: Endothelial dysfunction is associated with arterial stiffness, a factor that is increasingly recognised as an important determinant of cardiovascular risk. High-flow organs such as the brain and kidneys are particularly sensitive to excessive pressure and flow pulsatility. High, local blood flow is associated with low microvascular impedance, which facilitates the penetration of excessive pulsatile energy into the microvascular bed leading to tissue damage. Systemic endothelial dysfunction and arterial stiffness have been demonstrated in peripheral vessels in associated vasculitis (AAV). Although, the brain involvement is not infrequent in AAV, it has not been evaluated previously. Our aim is to evaluate the involvement of the brain microvasculature in AAV. METHODS: Twenty-three patients with inactive AAV were studied. Brain blood flow was assessed by transcranial Doppler (TCD) and single-photon positron emission tomography (SPECT), structural brain involvement by brain MRI and cognitive scores by Montreal Cognitive Assessment (MoCA) test. RESULTS: Lower mean flow velocity (MFV) was associated to altered SPECT perfusion, higher white matter changes (WMC), lower MoCA scores and younger age (p < 0.05). Middle cerebral artery pulsatility index (MCA-PI) was related to hypertension, diabetes, lower scores on MoCA, increased vasculitis damage index (VDI) and perfusion impairment in SPECT (p < 0.05). These data were reproduced for all intracranial arteries. Up to 88.9% of patients had WMC on MRI. A higher lesion load was associated with age, decreased MoCA and fewer MFV with higher PI. The multivariable linear regression analysis showed that the greater the lesion loads, greater the bifrontal atrophy, MCA-PI and lower MoCA scores. Up to 60.9% of patients presented a decreased MoCA score (p = 0.012). It appeared to be related to VDI (p = 0.04), WMC (p = 0.004) and altered SPECT (p = 0.05). CONCLUSIONS: The alterations in brain perfusion SPECT, the presence of white matter lesions on MRI, as well as increased PI and RI with lower MFV of the cerebral vessels in TCD suggest the presence of microangiopathy in asymptomatic AAV that could lead to cognitive impairment.