Pathogenesis of rheumatoid arthritis: one year in review 2024.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by joint destruction and extra-articular manifestations. Different cells and soluble components of the innate as well as adaptive immune system actively contribute to the amplification and perpetuation of the inflammatory processes and structural changes. To date, the knowledge on the mechanisms involved in RA pathogenesis is increasingly precise, mainly due to the recent data obtained from studies on genetics and molecular and cellular biology. In this review article we summarised the new insights into RA pathogenesis from original research articles published in the last year.

Increased locomotor activity via regulation of GABAergic signalling in foxp2 mutant zebrafish-implications for neurodevelopmental disorders.

Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.

Distribution of transcripts of the GFOD gene family members gfod1 and gfod2 in the zebrafish central nervous system.

The glucose-fructose oxidoreductase domain containing gene family (GFOD) is small and contains only two members in human (GFOD1 and GFOD2). Information about its function is scarce. As the name implies the proteins contain an enzyme-defining domain, however, if this is functional and has enzymatic activity remains to be shown. A single nucleotide polymorphism situated in an intron of GFOD1 was found to be associated with inattentive symptomology in patients with attention-deficit/hyperactivity disorder. Further, in a large schizophrenia genome-wide association study the GFOD2 locus was found to be associated with the psychiatric condition. Until now, however, it is unclear what specific functions are associated with the two GFOD-family members, if they might be involved in neurodevelopment and how this may relate to the development of psychiatric disorders. In order to gain first insights into the hypothesis that GFOD-family members are involved in brain development and/or function we performed RNA in situ hybridization on zebrafish (Danio rerio) tissues at different developmental stages. We found that both family members are expressed in the central nervous system at embryonic, larvae and adult stages. We were able to define subtle differences of expression of the two gfod genes and we showed that a subset of GABAergic neurons express gfod1. Taken together, we conclude that both gfod gene family members are expressed in overlapping as well as in distinct regions in the zebrafish central nervous system. Our data suggest that gfod1 and gfod2 are relevant both for the developing and adult zebrafish brain. This study paves the way for further functional analyses of this yet unexplored gene family.

Evaluation of the Educational Needs in Argentine Patients with Rheumatoid Arthritis Using the SpENAT Questionnaire. / Evaluación de las necesidades educacionales de los pacientes con artritis reumatoide mediante el cuestionario SpENAT.

BACKGROUND: The SpENAT, a Spanish version of the Educational Needs Assessment Tool, is a self-completed questionnaire that assesses educational needs (ENs) with the purpose of providing tailored and patient-centered information. It consists of 39 questions grouped into the 7 following domains: Pain management, Movement, Feelings, Arthritic process, Treatments, Self-help measures and Support system. OBJECTIVES: The objective of the study was to describe the ENs of rheumatoid arthritis (RA) patients using the SpENAT and to determine the main sources of information consulted by these patients. MATERIAL AND METHODS: Multicenter, observational, cross-sectional study. We included consecutive patients≥18 years with diagnosis of RA (ACR 87/ACR-EULAR 2010). Sociodemographic data, disease characteristics and clinimetric properties were recorded. All patients completed the SpENAT and were asked about the sources employed to obtain information about their disease. STATISTICAL ANALYSIS: Population characteristics were described. ENs were determined as percentages of the highest possible score for each domain. Needs for each domain according to sex, years of education, disease duration, use of biologicals and functional capacity were analyzed by means of ANOVA, and bivariate comparisons were made with Student's t-test and the Bonferroni correction. Correlation between domains was determined with the Spearman correlation coefficient. We compared patients' age by source of information with Student's t-test. RESULTS: We included 496 patients from 20 centers across the country. More ENs were observed in the domains of Movement, Feelings and the Arthritic process. Patients with higher educational level (>7 years) reported more ENs in the Arthritic process and Self-help measure domains. A higher functional impairment (HAQ-A≥0.87) was associated with more ENs in every domain. Patients with high activity showed more ENs than those in remission in the domains of Pain management, Movement, Feelings, Treatments and Support system, as well as those with low activity in Self-help measures and Support system domains. All SpENAT domains showed positive correlations among each other (P<.0001), the most important being Pain management/Movement and Treatments/Arthritic process (r≥0.7). The source of information most frequently consulted was the rheumatologist (93.95%); those who made use of Internet were on average younger (P=.0004). CONCLUSION: RA patients were very interested about knowing more about their disease. High functional impairment was associated with more ENs. Patients with high disease activity had higher EN levels in almost every domain. The rheumatologist was the main source of information for the patient with RA.

Indicación de terapia biológica en pacientes con enfermedades reumáticas de la consulta ambulatoria / Biologic treatment in patients with Rheumatic Diseases from the clinic

Introducción y objetivo: Determinar la proporción de pacientes que presentan indicación de tratamiento con terapia biológica y comparar las características demográficas y clínicas de los pacientes con y sin indicación y entre aquellos que reciben o no dicho tratamiento. Material y métodos: Se incluyeron pacientes consecutivos con diagnóstico de AR (ACR`87) y EASN (criterios europeos). Se recolectaron datos demográficos, socioeconómicos, clínicos, laboratorio. Se evaluó si los pacientes presentaban indicación de tratamiento con agentes anti-TNF, de acuerdo a guías de tratamiento (ASAS 2003 y SAR 2004) y/u opinión del evaluador. En pacientes con indicación y que no reciben actualmente se consignaron las causas de la misma. Resultados: Se incluyeron 200 pacientes, 182 AR y 18 EASN. De los 182 pacientes, el 44,5% presentan indicación de terapia biológica por guías de tratamiento y el 44% por opinión del evaluador. El 11% recibe actualmente tratamiento anti-TNF. El 16,5% de los pacientes que tenían indicación y no recibían tratamiento se encontraban entrámite y el 17% no tenía indicación por parte del profesional. En el análisis de regresión logística, la presencia de mayor HAQ y DAS 28 fueron las variables con mayor fuerza de asociación entre los que reciben tratamiento biológico. Los 3 grupos que no recibían biológicos difirieron significativamente en la actividad de la enfermedad. Conclusiones: El 44% tiene indicación de terapia biológica, pero sólo el 11% la recibe; las 2 principales causas son la falta de indicación por el médico y que se encuentra tramitando el mismo.

Terapia biológica en Espondiloartropatías seronegativas: experiencia en 21 pacientes / Biological therapy on seronegative Spondyloarthropathies: experience in 21 patients

Introducción: Actualmente numerosos estudios demuestran la efectividad de los agentes anti-TNF¦Á para mejorar la actividad y la capacidad funcional en pacientes con espondiloartropatías seronegativas (EASN). Objetivos: Evaluar eficacia y seguridad de la terapia biológica con agentes anti-TNF en pacientes con EASN del Instituto de Rehabilitación Psicofísica (IREP). Materiales y m todos: Se incluyeron pacientes con diagnóstico de EASN (criterios Europeos) en tratamiento con terapia biológica de la consulta ambulatoria del IREP. Se consignaron datos demográficos, clínicos, de laboratorio, e índices de la actividad de la enfermedad (BASDAI), capacidad funcional (BASFI), calidad de vida (ASQoL) previo y posterior al inicio de la terapia biológica. También se consignó efectos adversos y discontinuación del tratamiento. Resultados: Se incluyeron 21 pacientes; 13 pacientes recibían Etanercept, 5 Infliximab y 2 Adalimumab. Se observó una mejoría significativa de la actividad de la enfermedad (p=0,008), capacidad funcional (p=0,021) y calidad de vida (p=0,027). Con respecto a la clinimetría sólo se observó una diferencia significativa en la distancia dedo-piso (p=0,008). Conclusión: Observamos que el tratamiento con agentes Anti-TNF es efectivo para mejorar la capacidad funcional, controlar la actividad de la enfermedad y mejorar la calidad de vida de los pacientes con EASN con buena tolerancia y seguridad