Corrigendum to Relationship between structural damage with loss of strength and functional disability in psoriatic arthritis patients [Clin. Biomech. volume 68 (2019) Pages 169–174/Article Number JCLB 4795]

Erratu

Prevalence and clinical characteristics of patients with rheumatoid arthritis with interstitial lung disease using unstructured healthcare data and machine learning

Artritis reumatoide; Epidemiologia; Fibrosi pulmonarRheumatoid arthritis; Epidemiology; Pulmonary fibrosisArtritis reumatoide; Epidemiología; Fibrosis pulmonarObjectives Real-world data regarding rheumatoid arthritis (RA) and its association with interstitial lung disease (ILD) is still scarce. This study aimed to estimate the prevalence of RA and ILD in patients with RA (RAILD) in Spain, and to compare clinical characteristics of patients with RA with and without ILD using natural language processing (NLP) on electronic health records (EHR). Methods Observational case–control, retrospective and multicentre study based on the secondary use of unstructured clinical data from patients with adult RA and RAILD from nine hospitals between 2014 and 2019. NLP was used to extract unstructured clinical information from EHR and standardise it into a SNOMED-CT terminology. Prevalence of RA and RAILD were calculated, and a descriptive analysis was performed. Characteristics between patients with RAILD and RA patients without ILD (RAnonILD) were compared. Results From a source population of 3 176 165 patients and 64 241 683 EHRs, 13 958 patients with RA were identified. Of those, 5.1% patients additionally had ILD (RAILD). The overall age-adjusted prevalence of RA and RAILD were 0.53% and 0.02%, respectively. The most common ILD subtype was usual interstitial pneumonia (29.3%). When comparing RAILD versus RAnonILD patients, RAILD patients were older and had more comorbidities, notably concerning infections (33.6% vs 16.5%, p<0.001), malignancies (15.9% vs 8.5%, p<0.001) and cardiovascular disease (25.8% vs 13.9%, p<0.001) than RAnonILD. RAILD patients also had higher inflammatory burden reflected in more pharmacological prescriptions and higher inflammatory parameters and presented a higher in-hospital mortality with a higher risk of death (HR 2.32; 95% CI 1.59 to 2.81, p<0.001). Conclusions We found an estimated age-adjusted prevalence of RA and RAILD by analysing real-world data through NLP. RAILD patients were more vulnerable at the time of inclusion with higher comorbidity and inflammatory burden than RAnonILD, which correlated with higher mortality.The RA-WILD study was fully supported by Bristol-Myers Squibb Company. Award/grant number not applicable

Recomendaciones de experto sobre el bloqueo de la interleucina 6 en pacientes con artritis reumatoide

[Abstract] Objective: To draft recommendations on interleukin 6 (IL-6) blockade in rheumatoid arthritis (RA), based on best evidence and experience. Methods: A group of 10 experts on IL-6 blockade in RA was selected. The 2 coordinators formulated 23 questions about IL-6 blockade (indications, efficacy, safety, etc.). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (Medline, EMBASE and the Cochrane Library were searched). Two different reviewers selected the articles. Evidence tables were created. At the same time, European League Against Rheumatism and American College of Rheumatology abstracts were evaluated. Based on this evidence, the coordinators proposed preliminary recommendations that the experts discussed and voted on in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Centre for Evidence Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). Results: The 8 preliminary recommendations were accepted after the Delphi process. They covered aspects such as the use of these therapies in monotherapy, in combination, in patients with refractory disease or intolerant patients, response evaluation, optimization and risk management. Conclusions: The manuscript aims to solve frequently asked questions and aid in decision making strategies when treating RA patients with IL-6 blockade.[Resumen] Objetivo. Generar recomendaciones sobre el bloqueo de la interleucina 6 (IL-6) en pacientes con artritis reumatoide (AR), basadas en la mejor evidencia y experiencia. Métodos. Se seleccionó a 10 expertos reumatólogos en el manejo de los inhibidores de la IL-6. Los 2 coordinadores generaron 23 preguntas sobre el bloqueo de la IL-6 en la AR (perfiles de indicación, eficacia, seguridad, etc.) para ser contestadas mediante una revisión sistemática de la literatura. Con base en las preguntas se definieron los criterios de inclusión y exclusión, y las estrategias de búsqueda (para interrogar Medline, Embase y la Cochrane Library). Dos revisores seleccionaron los artículos resultantes de la búsqueda. Se generaron tablas de evidencia. Paralelamente, se evaluaron abstracts de congresos de EULAR y ACR. Con toda esta evidencia los coordinadores propusieron 8 recomendaciones preliminares que se evaluaron, discutieron y votaron en una reunión de grupo nominal con el resto de los expertos. Para cada recomendación se estableció el nivel de evidencia y grado de recomendación, y el grado de acuerdo mediante un Delphi. Se definió acuerdo si al menos el 80% de los participantes contestaban sí a la recomendación (sí o no). Resultados. Las 8 recomendaciones preliminares se aceptaron tras el Delphi. Abarcan aspectos como su uso en monoterapia, en combinación, en pacientes refractarios o intolerantes, la evaluación de su respuesta, la optimización o la gestión del riesgo. Conclusiones. Este documento pretende resolver algunos interrogantes clínicos habituales y facilitar la toma de decisiones con el bloqueo de la IL-6 en el manejo de la AR

El género Orobanche L. (Orobanchaceae) en Andalucía

RESUMEN. El género Orobanche L. (Orobanchaceae) en Andalucía. Se actualiza el conocimiento del género Orobanche L. para la Flora de Andalucía, sur de la Península Ibérica. La revisión se ha hecho mediante el análisis crítico de la información bibliográfica y de los principales herbarios relacionados con el territorio. Para facilitar la identificación de las diferentes especies aportamos una clave de determinación. Para los 31 taxones presentes aportamos su distribución detallada en unidades geográficas así como su categoría UICN. Resaltamos la presencia de taxones de marcado interés corológico, poco citados en todo el territorio, como O. ramosa, O. olbiensis, O. mariana, O. lavandulacea, O. schultzii, O. mutelii subsp. georgii-reuteri, O. purpurea, O. clausonis, O. rapumgenistae, O. gracilis subsp. deludens, O. haenseleri, O. alba, O. icterica, O. amethystea subsp. castellana, O. almeriensis, O. santolinae. Consideramos que especies como O. sanguinea, O. crinita, O. variegata, O. caryophyllaceae, O. lutea, O. reticulata y O. artemisiae-campestris no se encuentran en Andalucía y a O. calendulae como especie conflictiva a buscar.Palabras clave. Orobanche, Orobanchaceae, jopo, parásita, corología, Andalucía.ABSTRACT. The genus Orobanche (Orobanchaceae) in Andalusia. A botanical survey has been carried out in order to improve the knowledge of the genus Orobanche L. of the Flora of Andalusia, South of the Iberian Peninsula. With this aim, a critical review of the concerning bibliographical information and of the main territorial herbaria was accomplished. An identification key is provided. For each of the 31 taxa considered its detailed distribution in geographical units as well as its category UICN are given. The presence of taxa of important chorological interest such as O. ramosa, O. olbiensis, O. mariana, O. lavandulacea, O. schultzii, O. mutelii subsp. georgii-reuteri, O. purpurea, O. clausonis, O. rapum-genistae, O. gracilis subsp. deludens, O. haenseleri, O. alba, O. icterica, O. amethystea subsp. castellana, O. almerienses, O. santolinae is pointed out. Moreover, we consider that O. sanguinea, O. crinita, O. variegata, O. caryophyllaceae, O. lutea, O. reticulata and O. artemisiaecampestris are species not found in Andalusia and O. calendulae is a conflictive taxon to investigate.Key words. Orobanche, Orobanchaceae, broomrape, parasite, chorology, Andalusia

A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort

&lt;p&gt;&lt;b&gt;Objectives&lt;/b&gt; The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods&lt;/b&gt; A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results&lt;/b&gt; A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively).&lt;/p&gt; &lt;p&gt;&lt;b&gt;Conclusions&lt;/b&gt; The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.&lt;/p&gt

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.&lt;p&gt;&lt;/p&gt; Methods: Sixty-six non-HLA SNPs showing a P value &#60;10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.&lt;p&gt;&lt;/p&gt; Conclusion: Our results suggest a role of PPARG gene in the development of SSc

New structural insights into the role of TROVE2 complexes in the on-set and pathogenesis of systemic lupus eythematosus determined by a combiantion of QCM-D and DPI

The final publication is available at link.springer.com.[EN] The mechanism of self-recognition of the autoantigen TROVE2, a common biomarker in autoimmune diseases, has been studied with a quartz crystal microbalance with dissipation monitoring (QCM-D) and dual polarization interferometry (DPI). The complementarity and remarkable analytical features of both techniques has allowed new insights into the onset of systemic lupus erythematosus (SLE) to be achieved at the molecular level. The in vitro study for SLE patients and healthy subjects suggests that anti-TROVE2 autoantibodies may undergo an antibody bipolar bridging. An epitope-paratope-specific binding initially occurs to activate a hidden Fc receptor in the TROVE2 tertiary structure. This bipolar mechanism may contribute to the pathogenic accumulation of anti-TROVE2 autoantibody immune complex in autoimmune disease. Furthermore, the specific calcium-dependent protein-protein bridges point out at how the TRIM21/TROVE2 association might occur, suggesting that the TROVE2 protein could stimulate the intracellular immune signaling via the TRIM21 PRY-SPRY domain. These findings may help to better understand the origins of the specificity and affinity of TROVE2 interactions, which might play a key role in the SLE pathogenesis. This manuscript gives one of the first practical applications of two novel functions (-df/dD and Delta h/molec) for the analysis of the data provided by QCM-D and DPI. In addition, it is the first time that QCM-D has been used for mapping hidden Fc receptors as well as linear epitopes in a protein tertiary structure.We would like to thank Sylvia Daunert for her invaluable help with the discussion of the paper. Furthermore, we acknowledge financial support from the Generalitat Valenciana (GVA-PROMETEOII/2014/040) as well as the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund under award numbers CTQ2013-45875-R and CTQ2013-42914-RJuste-Dolz, AM.; Do Nascimento, NM.; Monzó, IS.; Grau-García, E.; Roman-Ivorra, JA.; López-Paz, JL.; Escorihuela Fuentes, J.... (2019). New structural insights into the role of TROVE2 complexes in the on-set and pathogenesis of systemic lupus eythematosus determined by a combiantion of QCM-D and DPI. Analytical and Bioanalytical Chemistry. 411(19):4709-4720. https://doi.org/10.1007/s00216-018-1407-xS4709472041119Kakatia S, Teronpia R, Barmanb B. Frequency, pattern and determinants of flare in systemic lupus erythematosus: a study from North East India. Egypt Rheumatol. 2015;37:S55–9.Kuhn A, Wenzel J, Weyd H. Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: a critical review. Clinic Rev Allerg Immunol. 2014;47:148–62.American Lupus Foundation. 2016. http://www.lupus.org .World Health Organization. Environmental health criteria 236. Geneva: WHO Press; 2006.Li W, Titov AA, Morel L. An update on lupus animal models. Curr Opin Rheumatol. 2017;29:1040–8711.Routsias JG, Tzioufas AG, Moutsopoulos HM. The clinical value of intracellular autoantigens B-cell epitopes in systemic rheumatic diseases. Clin Chim Acta. 2004;340:1–25.Franceschini F, Cavazzana I. Anti-Ro/SSA and La/SSB antibodies. Autoimmunity. 2005;38:55–63.Kelekar A, Saitta MR, Keene JD. Molecular composition of Ro small ribonucleoprotein complexes in human cells. Intracellular localization of the 60- and 52-kD proteins. J Clin Ivest. 1994;93:1637–44.Slobbe RL, Pluk W, van Venrooij WJ, Prujin GJM. Ro ribonucleoprotein assembly in vitro: identification of RNA-protein and protein-protein interactions. J Mol Biol. 1992;2:361–6.Chen X, Taylor DW, Fowler CC, Galan JE, Wang HW, Wolin SL. An RNA degradation machine sculpted by Ro autoantigen and noncoding RNA. Cell. 2013;153:166–77.Stein AJ, Fuchs G, Fu C, Wolin SL, Reinisch KM. Structural insights into RNA quality control: the Ro autoantigen binds misfolded RNAs via its central cavity. Cell. 2005;121:529–39.Reed JH, Gordon TP. Autoimmunity: Ro60-associated RNA takes its toll on disease pathogenesis. Nat Rev Rheumatol. 2016;12:136–8.Sim S, Weinberg DE, Fuchs G, Choi K, Chung J, Wolin SL. The subcellular distribution of an RNA quality control protein, the Ro autoantigen, is regulated by noncoding Y RNA binding. Mol Biol Cell. 2009;20:1555–64.Reed JH, Jackson MW, Gordon TP. A B cell apotope of Ro 60 in systemic lupus erythematosus. Arthritis Rheum. 2008;58:1125–9.Wolin SL, Reinisch KM. The Ro 60 kDa autoantigen comes into focus: interpreting epitope mapping experiments on the basis of structure. Autoimmun Rev. 2006;5:367–72.Routsias JG, Tzioufas AG. B-cell epitopes of the intracellular autoantigens Ro/SSA and La/SSB: tools to study the regulation of the autoimmune response. J Autoimmun. 2010;35:256–64.Whittaker CA, Hynes RO. Distribution and evolution of von Willebrand/integrin a domains: widely dispersed domains with roles in cell adhesion and elsewere. Mol Bio Cell. 2002;13:3369–87.Lacy DB, Wigelsworth DJ, Scobie HM, Young JA, Collier RJ. Crystal structure of the von Willebrand factor a domain of human capillary morphogenesis protein 2: an anthrax toxin receptor. Proc Natl Acad Sci U S A. 2004;101:6367–72.O’Brien CA, Wolin SL. A possible role for the 60-kD Ro autoantigen in a discard pathway for defective 5S rRNA precursors. Genes Dev. 1994;8:2891–903.Chen X, Wolin SL. The Ro 60 autoantigen : insights into cellular function and role in autoimmunity. J Mol Med (Berl). 2004;82:232–9.Escorihuela J, González-Martínez MA, López-Paz JL, Puchades R, Maquieira A, Gimenez-Romero D. Dual-polarization interferometry: a novel technique to light up the nanomolecular world. Chem Rev. 2014;115:265–94.do Nascimento NM, Juste-Dolz A, Bueno PR, Monzó I, Tejero R, Lopez-Paz JL, et al. Mapping molecular binding by means of conformational dynamics measurements. RSC Adv. 2018;8:867–76.do Nascimento NM, Juste-Dolz A, Grau-García E, Román-Ivorra J, Puchades R, Maquieira A, et al. Label-free piezoelectric biosensor for prognosis and diagnosis of systemic lupus erythematosus. Biosens. Bioelectron. 2016;90:166–73.Seo MH, Park J, Kim E, Hohng S, Kim HS. Protein conformational dynamics dictate the binding affinity for a ligand. Nat Commun. 2014;5:3724.Lakshmanan RS, Efremov V, O’Donnell JS, Killard AJ. Measurement of the viscoelastic properties of blood plasma clot formation in response to tissue factor concentration-dependent activation. Anal Bioanal Chem. 2016;408:6581–8.Fakhrullin RF, Vinter VG, Zamaleeva AI, Matveeva MV, Kourbanov RA, Temesgen BK, et al. Quartz crystal microbalance immunosensor for the detection of antibodies to double-stranded DNA. Anal Bioanl Chem. 2007;388:367–75.Shen F, Rojas OJ, Genzer J, Gurgel PV, Carbonell RG. Affinity interactions of human immunoglobulin G with short peptides: role of ligand spacer on binding, kinetics, and mass transfer. Anal Bioanl Chem. 2015;408:1829–41.Fogarty AC, Laage D. Water dynamics in protein hydration shells: the molecular origins of the dynamical perturbation. J Phys Chem B. 2014;118:7715–29.Born B, Kim SJ, Ebbinghaus S, Gruebelebc M, Havenith M. The terahertz dance of water with the proteins: the effect of protein flexibility on the dynamical hydration shell of ubiquitin. Faraday Discuss. 2009;141:161–73.Yoshimi R, Ueda A, Ozato K, Ishigatsubo Y. Clinical and pathological roles of Ro/SSA autoantibody system. Clin Dev Immunol. 2012;2012:606195.Boire G, Gendron M, Monast N, Bastin B, Ménard HA. Purification of antigenically intact Ro ribonucleoproteins; biochemical and immunological evidence that the 52-kD protein is not a Ro protein. Clin Exp Immunol. 1995;100:489–98.Gazzaruso C, Montecucco CM, Geroldi D, Garzaniti A, Finardi G. Severe hypercalcemia and systemic lupus erythematosus. Joint Bone Spine. 2000;67:485–8.Hassan AB, Lundberg IE, Isenberg D, Wahren-Herlenius M. Serial analysis of Ro/SSA and La/SSB antibody levels and correlation with clinical disease activity in patients with systemic lupus erythematosus. Scand J Rheumatol. 2002;31:133–9.Huang RY, Chen G. Higher order structure characterization of protein therapeutics by hydrogen/deuterium exchange mass spectrometry. Anal Bioanal Chem. 2014;406:6541–58.Yu F, Roy S, Arevalo E, Schaeck J, Wang J, Holte K, et al. Characterization of heparin-protein interaction by saturation transfer difference (STD) NMR. Anal Bioanal Chem. 2014;406:3079–89.Rizzuto R, Pozzan T. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev. 2006;86:369–408.Gaipl US, Kuhn A, Sheriff A, Munoz LE, Franz S, Voll RE, et al. Clearance of apoptotic cells in human SLE. Curr Dir Autoimmun. 2006;9:173–87.Falati S, Edmead CE, Poole AW. Glycoprotein Ib-V-IX, a receptor for Von Willebrand factor, couples physically and functionally to the Fc receptor gamma-chain, Fyn, and Lyn to activate human platelets. Blood. 1999;94:1648–56.Muñoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol. 2010;6:280–9

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice