Características del empleo y la remuneración económica en el ejercicio de la Reumatología en diferentes distritos de Argentina / Characteristics of employment and economic remuneration in the practice of Rheumatology in different districts of Argentina

Introducción: la Reumatología es una especialidad clínica con elevada de-manda y gran desigualdad en su ejercicio en Latinoamérica y el país. Objetivos: describir el estado del ejercicio de la Reumatología en nuestro país. Materiales y métodos: estudio observacional de corte transversal que recabó información a través de una encuesta online difundida por e-mail y de un código QR en el 54º Congreso Argentino de Reumatología. Resultados: se recibieron 127 respuestas; 86 (67,7%) fueron del sexo femenino, con una mediana de edad de 45 años. Ciento trece (113; 89%) encuestados eran especialistas en Reumatología, con 20 años (RIC 14-28) de ejercicio de la medicina y 13 años (RIC 6,5-20) de la especialidad. El 55,5% ejercía tanto en el ámbito público como privado, el 38,6% solo en el privado y el 7,6% únicamente en el público. Del total, el 84,3% trabajaba en dos o más lugares y el 21,2% en cuatro o más. Sesenta de los encuestados (60; 59,8%) recibía una remuneración mensual de entre 100.000 a 249.000 pesos (U$S: 501,68-1249,18) y 27 (23,1%) de menos de 100.000 pesos (U$S 501,68). Conclusiones: nuestro estudio muestra un alto porcentaje de profesionales que se desempeña en múltiples lugares de trabajo. Una quinta parte de ellos tenía remuneración baja.

Introduction: Rheumatology is a clinical specialty with high demand and great inequality in its practice throughout Latin America and our country. Objectives: to describe the state of the practice of Rheumatology in our country. Materials and methods: cross-sectional observational study that collected information through an online survey distributed by email and through a QR code in the 54thArgentine Congress of Rheumatology. Results: 127 responses were received. Eighty-six (67.7%) were women, with a median age of 45 years. One hundred thirteen (89%) were specialists in Rheumatology, with 20 years (IQR 14-28) in the practice of medicine and 13 years (IQR 6.5-20) in the specialty.The 55.5% worked in both the public and private spheres, 38.6% only in the private sphere and 7.6% only in the public sphere. Of the total, 84.3% worked in 2 or more locations, with 21.2% working in 4 or more. In 60 (59.8%), the monthly remuneration was between 100,000 to 249,000 pesos (U$S: 501.68-1249.18) and in 27 (23.1%) it was less than 100,000 pesos (US$ 501.68). Conclusions: Our study shows that a high percentage of professionals who work in multiple places. One-fifth of respondents had low pay

Características del empleo y la remuneración económica en el ejercicio de la Reumatología en diferentes distritos de Argentina / Characteristics of employment and economic remuneration in the practice of Rheumatology in different districts of Argentina

Resumen Introducción: la Reumatología es una especialidad clínica con elevada demanda y gran desigualdad en su ejercicio en Latinoamérica y el país. Objetivos: describir el estado del ejercicio de la Reumatología en nuestro país. Materiales y métodos: estudio observacional de corte transversal que recabó información a través de una encuesta online difundida por e-mail y de un código QR en el 54º Congreso Argentino de Reumatología. Resultados: se recibieron 127 respuestas; 86 (67,7%) fueron del sexo femenino, con una mediana de edad de 45 años. Ciento trece (113; 89%) encuestados eran especialistas en Reumatología, con 20 años (RIC 14-28) de ejercicio de la medicina y 13 años (RIC 6,5-20) de la especialidad. El 55,5% ejercía tanto en el ámbito público como privado, el 38,6% solo en el privado y el 7,6% únicamente en el público. Del total, el 84,3% trabajaba en dos o más lugares y el 21,2% en cuatro o más. Sesenta de los encuestados (60; 59,8%) recibía una remuneración mensual de entre 100.000 a 249.000 pesos (U$S: 501,68-1249,18) y 27 (23,1%) de menos de 100.000 pesos (U$S 501,68). Conclusiones: nuestro estudio muestra un alto porcentaje de profesionales que se desempeña en múltiples lugares de trabajo. Una quinta parte de ellos tenía remuneración baja.

Abstract Introduction: Rheumatology is a clinical specialty with high demand and great inequality in its practice throughout Latin America and our country. Objectives: to describe the state of the practice of Rheumatology in our country. Materials and methods: cross-sectional observational study that collected information through an online survey distributed by e-mail and through a QR code in the 54th Argentine Congress of Rheumatology. Results: 127 responses were received. Eighty-six (67.7%) were women, with a median age of 45 years. One hundred thirteen (89%) were specialists in Rheumatology, with 20 years (IQR 14-28) in the practice of medicine and 13 years (IQR 6.5-20) in the specialty. The 55.5% worked in both the public and private spheres, 38.6% only in the private sphere and 7.6% only in the public sphere. Of the total, 84.3% worked in 2 or more locations, with 21.2% working in 4 or more. In 60 (59.8%), the monthly remuneration was between 100,000 to 249,000 pesos (U$S: 501.68-1249.18) and in 27 (23.1%) it was less than 100,000 pesos (US$ 501.68). Conclusions: Our study shows that a high percentage of professionals who work in multiple places. One-fifth of respondents had low pay.

Humoral and T Cell Response to SARS-CoV-2 Vaccination in Patients With Rheumatoid Arthritis.

OBJECTIVE: The objective of this study was to assess the SARS-CoV-2-specific humoral and T cell response after a two-dose regimen of SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA). METHODS: In this observational study, patients with RA who are ≥18 years of age and vaccinated for SARS-CoV-2 according to the Argentine National Health Ministry's vaccination strategy were included. Anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies (ELISA-COVIDAR test), neutralizing activity (cytotoxicity in VERO cells), and specific T cell response (IFN-γ ELISpot Assay) were assessed after the first and second dose. RESULTS: A total of 120 patients with RA were included. Mostly, homologous regimens were used, including Gam-COVID-Vac (27.5%), ChAdOx1 (24.2%), and BBIBP-CorV (22.5%). The most frequent combination was Gam-COVID-Vac/mRNA-1273 (21.7%). After the second dose, 81.7% presented with anti-SARS-CoV-2 antibodies, 70.0% presented with neutralizing activity, and 65.3% presented with specific T cell response. The use of BBIBP-CorV and treatment with abatacept (ABA) and rituximab (RTX) were associated with undetectable antibodies and no neutralizing activity after two doses. BBIBP-CorV was also associated with the absence of T cell response. The total incidence of adverse events was 357.1 events per 1,000 doses, significantly lower with BBIBP-CorV (166.7 events per 1,000 doses, P < 0.02). CONCLUSION: In this RA cohort vaccinated with homologous and heterologous regimens against COVID-19, 2 out of 10 patients did not develop anti-SARS-CoV-2 IgG, 70% presented with neutralizing activity, and 65% presented with specific T cell response. The use of BBIBP-CorV was associated with deficient humoral and cellular response, whereas treatment with ABA and RTX resulted in an impaired anti-SARS-CoV-2 IgG formation and neutralizing activity.

Active lupus in Argentina: Results of a multicenter and national registry.

OBJECTIVE: To evaluate the association between patients' characteristics and disease activity in an Argentine lupus registry. METHODS: Cross-sectional study. Disease activity was stratified into: Remission off-treatment: SLEDAI = 0, without prednisone and immunosuppressive drugs. Low disease activity Toronto Cohort (LDA-TC): SLEDAI ≤2, without prednisone or immunosuppressive drugs. Modified lupus low disease activity (mLLDAS): SLEDAI score of ≤4, with no activity in major organ systems and no new features, prednisone of ≤10 mg/day and/or immunosuppressive drugs (maintenance dose) and Active disease: SLEDAI score of >4 and prednisone >10 mg/day and immunosuppressive drugs. A descriptive analysis and logistic regression model were performed. RESULTS: A total of 1346 patients were included. Of them, 1.6% achieved remission off steroids, 0.8% LDA-TC, 12.1% mLLDAS and the remaining 85.4% had active disease. Active disease was associated with younger age (p ≤ 0.001), a shorter time to diagnosis (p ≤ 0.001), higher frequency of hospitalizations (p ≤ 0.001), seizures (p = 0.022), serosal disease (p ≤ 0.001), nephritis (p ≤ 0.001), higher SDI (p ≤ 0.001), greater use of immunosuppressive therapies and higher doses of prednisone compared to those on mLLDAS. In the multivariable analysis, the variables associated with active disease were the presence of pleuritis (OR 2.1, 95% CI 1.2-3.9; p = 0.007), persistent proteinuria (OR 2.5, 95% CI 1.2-5.5; p ≤ 0.011), nephritis (OR 2.5, 95% CI 1.2-5.6; p = .018) and hospitalizations (OR 8.9, 95% CI 5.3-16.0; p ≤ 0.001) whereas age at entry into the registry was negatively associated with it (OR 0.9, 95% CI 0.9-1.0; p = 0.029). CONCLUSION: Active disease was associated with shorter time to diagnosis, worse outcomes (SDI and hospitalizations) and renal, neurological and serosal disease.

Bone effects of epidural and intra-articular glucocorticoids: a systematic literature review / Efectos óseos de los glucocorticoides epidurales e intraarticulares: revisión sistemática de la literatura

Osteoporosis and vertebral and non-vertebral fractures are common in glucocorticoids (GC) treated patients. Oral GC treatment leads to bone loss, particularly of trabecular bone. The benefits of GC used in rheumatological and traumatological disorders are known but they would have possible negative effects on bone. This systematic review aimed to evaluate the effects of epidural steroid injections (ESI), and intra-articular and intramuscular GC administration on bone mineral density (BMD) and fragility fractures. A systematic review of Medline/PubMed, Cochrane, and LILACS up to November 2020 was conducted. Meta-analyses, systematic reviews, randomized and non-randomized controlled trials, and prospective and retrospective studies comparing the effect of ESI, intra-articular or intramuscular GC used compared to a control group or baseline measurements were included. Results: A total of 8272 individuals were included among the 13 selected articles (10 about ESI and 3 about intra-articular GC; no article was found evaluating intramuscular GC). Only a few studies showed a negative effect of ESI on bone in the qualitative analysis considering osteopenia and osteoporosis in lumbar spine, femoral neck and total hip and BMD as surrogate outcomes. On the other hand, the qualitative analysis showed that most studies found an increased risk of fragility fracture. However, only two studies could be included in the quantitative analysis, in which there were no differences between patients exposed to ESI versus controls in all evaluated regions. In conclusion, there was insufficient evidence to suggest that ESI and intra-articular GC, unlike oral GC, negatively affect bone mass. Longitudinal studies are needed to obtain more knowledge regarding the effect of ESI or intra-articular GC on BMD and fragility fractures. (AU)

La osteoporosis y las fracturas vertebrales y no vertebrales son comunes en pacientes tratados con glucocorticoides (GC). El tratamiento oral con GC conduce a la pérdida ósea, particularmente del hueso trabecular. Los beneficios de los GC utilizados en patologías reumatológicas y traumatológicas son conocidos, pero tendrían posibles efectos negativos sobre el hueso. Esta revisión sistemática tuvo como objetivo evaluar los efectos de las inyecciones epidurales de esteroides (ESI), GC intraarticulares e intramusculares sobre la densidad mineral ósea (DMO) y las fracturas por fragilidad. Se realizó una revisión sistemática de Medline/PubMed, Cochrane y LILACS hasta noviembre de 2020. Se incluyeron metanálisis, revisiones sistemáticas, ensayos controlados aleatorizados y no aleatorizados, estudios prospectivos y retrospectivos que compararon el efecto de ESI, GC intraarticular o intramuscular utilizado en comparación con un grupo de control o mediciones iniciales. Resultados: Se incluyeron un total de 8272 individuos entre los 13 artículos seleccionados (10 sobre ESI y 3 sobre GC intraarticular; no se encontró ningún artículo que evaluara GC intramuscular). Solo unos pocos estudios mostraron un efecto negativo del ESI sobre el hueso en el análisis cualitativo considerando la osteopenia y la osteoporosis en la columna lumbar, el cuello femoral y la cadera total y la DMO como un resultado indirecto. Por otro lado, el análisis cualitativo mostró que la mayoría de los estudios encontraron un mayor riesgo de fractura por fragilidad. Sin embargo, solo dos estudios pudieron incluirse en el análisis cuantitativo, en los que no hubo diferencias entre los pacientes expuestos a ESI versus los controles en todas las regiones evaluadas. En conclusión, no hallamos datos suficientes para sugerir que la ESI y los GC intraarticulares, a diferencia de los GC orales, afectan negativamente a la pérdida ósea. Se necesitan estudios longitudinales para obtener más conocimiento sobre el efecto de ESI o GC intraarticular en la DMO y las fracturas por fragilidad. (AU)

Argentine Guidelines for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis in Postmenopausal Women and Men Aged 50 Years and Older.

OBJECTIVE: The aim of this study was to provide an evidence-based framework to guide health care professionals treating patients under glucocorticoid (GC) therapy and develop guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis (GIO) in postmenopausal women and men aged ≥50 years. METHODS: An expert panel on bone diseases designed a series of clinically meaningful questions following the PICO (Population, Intervention, Comparator, and Outcome) structure. Using GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology, we made a systematic literature review, extracted and summarized the effect estimates, and graded the quality of the evidence. The expert panel voted each PICO question and made recommendations after reaching an agreement of at least 70%. RESULTS: Seventeen recommendations (9 strong and 8 conditional) and 8 general principles were developed for postmenopausal women and men aged ≥50 years under GC treatment. Bone mineral density (BMD), occurrence of fragility fractures, probability of fracture at 10 years by Fracture Risk Assessment Tool, and other screening factors for low BMD are recommended for patient evaluation and stratification according to fragility fracture risk. The treatment of patients under GC therapy should include counseling on lifestyle habits and strict control of comorbidities. The goal of GIO treatment is the nonoccurrence of new fragility fractures as well as to increase or maintain BMD in certain clinical situations. This was considered for the therapeutic approach in different clinical scenarios. CONCLUSIONS: This GIO guideline provides evidence-based guidance for health care providers treating patients.

Polymerase iota (Pol ι) prevents PrimPol-mediated nascent DNA synthesis and chromosome instability.

Recent studies have described a DNA damage tolerance pathway choice that involves a competition between PrimPol-mediated repriming and fork reversal. Screening different translesion DNA synthesis (TLS) polymerases by the use of tools for their depletion, we identified a unique role of Pol ι in regulating such a pathway choice. Pol ι deficiency unleashes PrimPol-dependent repriming, which accelerates DNA replication in a pathway that is epistatic with ZRANB3 knockdown. In Pol ι-depleted cells, the excess participation of PrimPol in nascent DNA elongation reduces replication stress signals, but thereby also checkpoint activation in S phase, triggering chromosome instability in M phase. This TLS-independent function of Pol ι requires its PCNA-interacting but not its polymerase domain. Our findings unravel an unanticipated role of Pol ι in protecting the genome stability of cells from detrimental changes in DNA replication dynamics caused by PrimPol.

A Surgical and Clinical Approach to Persistent Müllerian Duct Syndrome: Laparoscopic, Histological, and Molecular Findings.

BACKGROUND: Persistent müllerian duct syndrome (PMDS) is characterized by the persistence of müllerian duct derivatives in otherwise normally virilized 46,XY males. Biallelic mutations of the anti-müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes lead to PMDS type 1 and 2, respectively. AIM: The aims of the study were to report the clinical, hormonal, and genetic findings in a patient with PMDS and discuss surgical strategies to achieve successful orchidopexy. RESULTS: A 4-year-old boy was evaluated after the incidental finding of müllerian derivates during laparoscopy for nonpalpable gonads. Karyotype was 46,XY and laboratory tests revealed normal serum gonadotropin and androgen levels but undetectable serum AMH levels. PMDS was suspected. Molecular analysis revealed a novel variant c.902_929del in exon 5 and a previously reported mutation (c.367C>T) in exon 1 of the AMH gene. Successful orchidopexy was performed in two sequential surgeries in which the müllerian duct structure was preserved and divided to protect the vascular supply to the gonads. Histological evaluation of the testicular biopsy showed mild signs of dysgenesis. Doppler ultrasound showed blood flow in both testes positioned in the scrotum 1.5 years after surgery. CONCLUSION: PMDS is a rare entity that requires a high index of suspicion (from surgeons) when evaluating a patient with bilateral cryptorchidism. Surgical treatment is challenging and long-term follow-up is essential. Histological evaluation of the testis deserves further investigation.

Seguridad de las drogas biológicas y sintéticas dirigidas utilizadas en pacientes con enfermedades reumáticas inmunomediadas. Datos del registro BIOBADASAR 3.0 / Safety of biological and targeted synthetic drugs in patients with immune-mediated rheumatic diseases. Data from the BIOBADASAR 3.0 registry

Introducción: conocer la seguridad de las drogas actualmente disponibles para el tratamiento de las enfermedades reumáticas es muy importante al momento de tomar decisiones terapéuticas objetivas e individualizadas en la consulta médica diaria. Asimismo, datos de la vida real amplían el conocimiento revelado por los ensayos clínicos. Objetivos: describir los eventos adversos (EA) reportados, estimar su frecuencia e identificar los factores relacionados con su desarrollo. Materiales y métodos: se utilizaron datos BIOBADASAR, un registro voluntario y prospectivo de seguimiento de EA de tratamientos biológicos y sintéticos dirigidos en pacientes con enfermedades reumáticas inmunomediadas. Los pacientes son seguidos hasta la muerte, pérdida de seguimiento o retiro del consentimiento informado. Para este análisis se extrajeron datos recopilados hasta el 31 de enero de 2023. Resultados: se incluyó un total de 6253 pacientes, los cuales aportaron 9533 ciclos de tratamiento, incluyendo 3647 (38,3%) ciclos sin drogas modificadoras de la enfermedad biológicas y sintéticas dirigidas (DME-b/sd) y 5886 (61,7%) con DME-b/sd. Dentro de estos últimos, los más utilizados fueron los inhibidores de TNF y abatacept. Se reportaron 5890 EA en un total de 2701 tratamientos (844 y 1857 sin y con DME-b/sd, respectivamente), con una incidencia de 53,9 eventos cada 1000 pacientes/año (IC 95% 51,9-55,9). La misma fue mayor en los ciclos con DME-b/sd (71,1 eventos cada 1000 pacientes/año, IC 95% 70,7-77,5 versus 33,7, IC 95% 31,5-36,1; p<0,001). Las infecciones, particularmente las de la vía aérea superior, fueron los EA más frecuentes en ambos grupos. El 10,9% fue serio y el 1,1% provocó la muerte del paciente. El 18,7% de los ciclos con DME-b/sd fue discontinuado a causa de un EA significativamente mayor a lo reportado en el otro grupo (11,5%; p<0,001). En el análisis ajustado, las DME-b/sd se asociaron a mayor riesgo de presentar al menos un EA (HR 1,82, IC 95% 1,64-1,96). De igual manera, la mayor edad, el mayor tiempo de evolución, el antecedente de enfermedad pulmonar obstructiva crónica, el diagnóstico de lupus eritematoso sistémico y el uso de corticoides se asociaron a mayor riesgo de EA. Conclusiones: la incidencia de EA fue significativamente superior durante los ciclos de tratamientos que incluían DME-b/sd.

Introduction: knowing the efficacy and safety of the drugs currently available for the treatment of rheumatic diseases is very important when making objective and individualized therapeutic decisions in daily medical consultation. Likewise, real-life data extends the knowledge revealed by clinical trials. Objectives: to describe the reported adverse events (AEs), estimate their frequency and identify factors associated to them. Materials and methods: BIOBADASAR data were used, which is a voluntary, prospective follow-up registry of AEs of biological and synthetic treatments in patients with immune-mediated rheumatic diseases. Patients are followed until death, loss of followup, or withdrawal of informed consent. To carry out this analysis, the data collected up to January 31, 2023 was extracted. Results: a total of 6253 patients were included, who contributed with 9533 treatment periods, including 3647 (38.3%) periods without b/ts-DMARDs and 5886 (61.7%) with b/ts-DMARDs. Among the latter, the most used were TNF inhibitors and abatacept. A total of 5890 AEs were reported in a total of 2701 treatments (844 and 1857 without and with b/ts-DMARDs, respectively), with an incidence of 53.9 events per 1000 patients/ year (95% CI 51.9-55.9). It was higher during the periods with b/ts-DMARDs (71.1 events per 1000 patients/year, 95% CI 70.7-77.5 vs 33.7, 95% CI 31.5-36.1, p<0.001). Infections, particularly those of the upper respiratory tract, were the most frequent AEs in both groups. 10.9% were severe and 1.1% were associated with the death of the patient. 18.7% of the periods with b/ts-DMARDs were discontinued due to an AE, significantly higher than that reported in the other group (11.5%; p<0.001). In the adjusted analysis, b/ts-DMARDs were associated with a higher risk of presenting at least one AE (HR 1.82, 95% CI 1.64-1.96). Similarly, older age, longer evolution time, history of chronic obstructive pulmonary disease, diagnosis of systemic lupus erythematosus, and use of corticosteroids were associated with a higher risk of AE. Conclusions: the incidence of AEs was significantly higher during those treatment periods that included DME-b/sd.

Características de los pacientes con artritis reumatoidea que impactan en la satisfacción y la adherencia al tratamiento: subanálisis de los datos de Argentina, Chile y Uruguay del estudio SENSE / Characteristics of patients with rheumatoid arthritis that impact treatment satisfaction and adherence: subanalysis of data from Argentina, Chile and Uruguay from the SENSE study

Introducción: las necesidades y perspectivas de los pacientes son determinantes para tratar la artritis reumatoidea (AR). Objetivos: evaluar el impacto de la respuesta inadecuada a los fármacos antirreumáticos modificadores de la enfermedad (DMARD) sobre la satisfacción con el tratamiento, los resultados y las perspectivas de pacientes adultos con control inadecuado de la AR de actividad moderada/alta. Materiales y métodos: se evaluó la satisfacción mediante el cuestionario Treatment Satisfaction Questionnaire for Medication (TSQM) v1.4. Se recolectaron datos sobre la calidad de vida, la adherencia y las estrategias de manejo. Se presentan los resultados para Argentina, Chile y Uruguay (n=202). Resultados: el promedio de la escala de satisfacción global TSQM fue de 62,3±21,8. El 83% informó buena adherencia. Las principales expectativas del tratamiento fueron "alivio duradero de los síntomas" y "menos dolor articular". El 53,47% prefirió tratamiento oral y el 75,74% eligió un rápido inicio de acción. El efecto secundario menos aceptado fue "mayor riesgo de neoplasias". Se planificó rotar el DMARD en el 55% de los casos. De estos, el 84,7% se consideraron terapias avanzadas. La mayoría estaba abierto a un esquema combinado, pero el 25,2% prefirió no utilizarlo. Conclusiones: los resultados reafirman el compromiso con las estrategias treat-to-target, considerando la individualización de las decisiones terapéuticas en el contexto regional.

Introduction: patients' needs and perspectives are determinants for the treatment of rheumatoid arthritis (RA). Objectives: to evaluate the impact of inadequate response to disease-modifying antirheumatic drugs (DMARDs) on treatment satisfaction, outcomes and perspectives of adult patients with inadequate control of moderate/high activity RA. Materials and methods: satisfaction was assessed using the TSQM v1.4 questionnaire. Data on quality of life, adherence and management strategies were collected. Results are presented for Argentina, Chile and Uruguay (n=202). Results: the mean of the TSQM global satisfaction score was 62.3±21.8. Eighty-three percent reported good adherence. The main expectations of treatment were "lasting relief of symptoms" and "less joint pain". The 53.47% of patients preferred an oral treatment; 75.74% chose a rapid onset of action. The least accepted side effect was "increased risk of malignant neoplasms". Fifty-five percent planned to rotate DMARD. Of these, advanced therapies were considered in only 84.7%. Most were open to a combination treatment, but 25.2% preferred not to use it. Conclusions: the results reaffirm the commitment to treat-to-target strategies, considering the individualization of therapeutic decisions in the regional context.

An Argentinean cohort of patients with rheumatic and immune-mediated diseases vaccinated for SARS-CoV-2: the SAR-CoVAC Registry-protocol and preliminary data.

BACKGROUND/OBJECTIVE: To evaluate the efficacy and safety of SARS-CoV-2 vaccine in patients with rheumatic and immune-mediated inflammatory diseases (IMIDs) in Argentina: the SAR-CoVAC registry. METHODS: SAR-CoVAC is a national, multicenter, and observational registry. Adult patients with rheumatic or IMIDs vaccinated for SARS-CoV-2 were consecutively included between June 1 and September 17, 2021. Sociodemographic data, comorbidities, underlying rheumatic or IMIDs, treatments received, their modification prior to vaccination, and history of SARS-CoV-2 infection were recorded. In addition, date and place of vaccination, type of vaccine applied, scheme, adverse events (AE), disease flares, and new immune-mediated manifestations related to the vaccine were analyzed. RESULTS: A total of 1234 patients were included, 79% were female, with a mean age of 57.8 (SD 14.1) years. The most frequent diseases were rheumatoid arthritis (41.2%), osteoarthritis (14.5%), psoriasis (12.7%), and spondyloarthritis (12.3%). Most of them were in remission (28.5%) or low disease activity (41.4%). At the time of vaccination, 21% were receiving glucocorticoid treatment, 35.7% methotrexate, 29.7% biological (b) disease modifying anti-rheumatic drugs (DMARD), and 5.4% JAK inhibitors. In total, 16.9% had SARS-CoV-2 infection before the first vaccine dose. Most patients (51.1%) received Gam-COVID-Vac as the first vaccine dose, followed by ChAdOx1 nCoV-19 (32.8%) and BBIBP-CorV (14.5%). Half of them (48.8%) were fully vaccinated with 2 doses; 12.5% received combined schemes, being the most frequent Gam-COVID-Vac/mRAN-1273. The median time between doses was 51 days (IQR 53). After the first dose, 25.9% of the patients reported at least one AE and 15.9% after the second, being flu-like syndrome and local hypersensitivity the most frequent manifestations. There was one case of anaphylaxis. Regarding efficacy, 63 events of SARS-CoV-2 infection were reported after vaccination, 19% occurred during the first 14 days post-vaccination, 57.1% after the first dose, and 23.8% after the second. Most cases (85.9%) were asymptomatic or mild and 2 died due to COVID-19. CONCLUSIONS: In this national cohort of patients, the most common vaccines used were Gam-COVID-Vac and ChAdOx1 nCoV-19. A quarter of the patients presented an AE and 5.1% presented SARS-CoV-2 infection after vaccination, in most cases mild. STUDY REGISTRATION: This study has been registered in ClinicalTrials.gov under the number: NCT04845997. Key Points • This study shows real-world data about efficacy and safety of SARS-CoV-2 vaccination in patients with rheumatic and immune-mediated inflammatory diseases. Interestingly, different types of vaccines were used including vector-based, mRNA, and inactivated vaccines, and mixed regimens were enabled. • A quarter of the patients presented an adverse event. The incidence of adverse events was significantly higher in those receiving mRAN-1273 and ChAdOx1 nCoV-19. • In this cohort, 5.1% presented SARS-CoV-2 infection after vaccination, in most cases mild.

Multicenter lupus register from Argentina, the RELESSAR database: Influence of ethnicity on disease phenotype.

OBJECTIVE: The objective is to describe the main characteristics of patients with systemic lupus erythematosus (SLE) in Argentina and to examine the influence of ethnicity on the expression of the disease. PATIENTS AND METHODS: RELESSAR is a multicentre register carried out by 106 researchers from 67 rheumatologic Argentine centres. It is a cross-sectional study of SLE (1982/1997 ACR) patients. RELESSAR electronic database includes demographic, cumulative SLE manifestations, SELENA-SLEDAI, SLICC-SDI, Katz's severity and Charlson's comorbidity indexes and treatment patterns. RESULTS: We included 1,610 patients, 91.7% were female with a median age at diagnosis of 28.1 ± 12.8; 96.2% met ≥4 ACR 1982/97 criteria. Frequent manifestations were arthritis (83.5%), malar rash (79.5%), photosensitivity (75.3%), haematological (63.8%) and renal disease (47.4%), antinuclear antibodies (96%), anti-dsDNA (66.5%) and anti-Smith antibodies (29%). The mean Selena-SLEDAI score at last visit was 3.18 (SD 4.3) and mean SDI was 1 (SD 1.3). The accumulated treatments most frequently used were antimalarials (90.4%), corticosteroids (90%), azathioprine (31.8%), intravenous cyclophosphamide (30.2%), mycophenolate mofetil or mycophenolic acid (24.5%), methotrexate (19.3%), belimumab 5.3% and rituximab 5.1%. Refractory lupus was diagnosed in 9.3% of the cases. The main causes of death were lupus activity (25.0%), activity and concomitant infections (25.0%), infections (18.2%), vascular disease (13.6%) and cancer (4.5%). Mortality was associated with higher SLEDAI, Katz, damage indexes and comorbidities. Of the 1610 patients included, 44.6% were Caucasian, 44.5% Mestizo, 8.1% Amerindian and 1.2% Afro-Latin American. Mestizo patients had higher male representation, low socioeconomic status, more inadequate medical coverage, fewer formal years of education and shorter disease duration. Polyadenopathies and Raynaud's phenomenon were more frequent in Caucasians. In the logistic regression analysis higher damage index (OR 1.28, CI 95% 1.02-1.61, p = 0.03) remained associated to mestizo ethnicity. CONCLUSIONS: This study represents the largest number of adult patients with SLE studied in Argentina. Caucasian patients were differentiated by having Raynaud's phenomenon and polyadenopathy more frequently, while patients of Mestizo origin had higher damage indexes.

Lupus en Argentina. Pacientes no respondedores al tratamiento estándar y belimumab como posible opción. Datos del registro RELESSAR / Lupus in Argentina. Non-responders to standard treatment and belimumab as a possible option. RELESSAR record data

Introducción: el lupus es una enfermedad compleja y varias veces de difícil abordaje. Alcanzar la remisión es uno de los objetivos, incorporando opciones terapéuticas. Objetivos: describir las características generales de los pacientes según el estado de la enfermedad y el uso de belimumab. Materiales y métodos: estudio de corte transversal, registro RELESSAR. Se definió el estado de la enfermedad como: remisión: SLEDAI=0 y sin corticoides; baja actividad de la enfermedad: SLEDAI >0 y ≤4 y sin corticoides; control no óptimo: SLEDAI >4 y cualquier dosis de corticoides. Resultados: se incluyeron 1.277 pacientes, 23,4% en remisión, 12,6% en baja actividad y 63,8% con control no óptimo. En este último grupo eran más jóvenes y con menor duración de la enfermedad; presentaban mayores índices de actividad y cronicidad, y mayor empleo de inmunosupresores. Solo el 22,3% de los pacientes con criterio potencial de uso de belimumab (lupus eritematoso sistémico activo a pesar del tratamiento estándar) lo recibía en ese momento. Las variables asociadas a hospitalizaciones fueron: terapia con corticoides, ciclofosfamida y mayor SLICC. Conclusiones: se refleja la complejidad del manejo de estos pacientes y se visualizan aspectos estructurales como la desigualdad. El uso del belimumab resultaría beneficioso en los pacientes seleccionados.

Introduction: lupus is a complex disease and often difficult to approach. Achieving remission is one of the objectives, incorporating therapeutic options. Objectives: to describe the characteristics of the patients and the use of belimumab, according to the status of the disease. Materials and methods: cross-sectional study. Patients of the RELESSAR registry. Stratification: Remission: SLEDAI=0 and without corticosteroids. Low disease activity SLEDAI> 0 and ≤4 and without corticosteroids and non-optimal control: SLEDAI> 4 and any dose of corticosteroids. Results: a total of 1,277 patients were included, 23.4% in remission, 12.6% in low disease activity and 63.8% in non-optimal control. The last group was younger and had a shorter duration of the disease. They had higher activity and chronicity indices and greater use of immunosuppressants. Only 22.3% of the patients with potential criteria for the use of belimumab (activity disease despite standard treatment) were receiving it. The variables associated with hospitalizations were: corticosteroids, cyclophosphamide and higher SLICC. Those associated with severe infection: mycophenolate mofetil, azathioprine, corticosteroids, and higher SLICC. Conclusions: the complexity of the management of these patients is reflected, visualizing structural aspects such as inequality. The use of belimumab could be beneficial in selected patients.

Respuesta immune humoral asociada a las vacunas contra SARS-CoV-2 en pacientes con artritis reumatoidea: datos del registro SAR-CoVAC / Humoral immune response associated to the vaccines against SARS-CoV-2 in patients with rheumatic arthritis: data from the SAR-CoVAC registry

Introducción: la artritis reumatoidea (AR) y los tratamientos indicados para su manejo pueden afectar la respuesta a la vacuna para SARS-CoV-2. Sin embargo, aún no se cuenta con datos locales. Objetivos: evaluar la respuesta humoral de la vacuna para SARS-CoV-2 y su seguridad en esta población. Materiales y métodos: estudio observacional. Se incluyeron pacientes ≥18 años, con AR ACR/EULAR 2010 que recibieron la vacunación para SARS-CoV-2. Detección de IgG anti-proteína S (kit COVIDAR). Resultados: se incluyeron 120 pacientes con AR. El 24,4% recibió tratamiento con glucocorticoides, 50,9% drogas biológicas y 13,3% inhibidores de JAK (janus kinases). El 6% había tenido infección por SARS-CoV-2 previamente. La vacuna más utilizada en la primera dosis fue Sputnik V (52,9%). El 25% recibió esquemas heterólogos. Luego de la primera dosis, el 59% presentó una prueba no reactiva o indeterminada, y un 18% luego de la segunda dosis. La aplicación de esquemas homólogos de vacuna Sinopharm (63,6% vs 13,3%, p<0,0001), y el uso de abatacept (27,3% vs 5,1%, p=0,005) y rituximab (18,2% vs 0%, p=0,001) al momento de la vacunación se asociaron a un resultado no reactivo o indeterminado. Conclusiones: similar a lo reportado en otras poblaciones internacionales, en esta cohorte, dos de cada 10 pacientes no desarrollaron anticuerpos. Una menor respuesta se asoció con la vacuna Sinopharm y al tratamiento con abatacept y rituximab.

Introduction: rheumatoid arthritis (RA) and its treatments can affect the response to the SARS-CoV-2 vaccine. However, we still do not have local data. Objectives: to evaluate the humoral response of the SARS-CoV-2 vaccine and its safety in this population. Materials and methods: observational study. Patients ≥18 years of age, with RA ACR/EULAR 2010 who had received vaccination for SARS-CoV-2 were included. Detection of anti-protein S IgG (COVIDAR Kit). Results: a total of 120 patients with RA were included. A quarter was receiving glucocorticoids, 50.9% biological drugs and 13.3% JAK inhibitors (janus kinases). Only 6% had a history SARS-CoV-2 infection. The most used vaccine was Sputnik V (52.9%) and 25% received mixed regimenes. After the first dose, 59% had a non-reactive or indeterminate test, and after the second, 18% were still having this result. The application of homologous Sinopharm vaccine regimen (63.6% vs 13.3%, p<0.0001) and the use of abatacept (27.3% vs 5.1%, p=0.005) and rituximab (18.2% vs 0%, p=0.001) at vaccination was associated with a non-reactive or indeterminate result. Conclusions: similar to other international populations, in this cohort, two out of 10 patients did not develop antibodies. A lower response was associated with the Sinopharm vaccine and treatment with abatacept and rituximab.

Predictors of response to etanercept-methotrexate treatment: a post hoc logistic regression analysis of a randomized, open-label study in Latin American patients with rheumatoid arthritis.

BACKGROUND: Determining potential predictors of clinical response would allow a more personalized rheumatoid arthritis (RA) treatment approach in heterogeneous populations such as Latin American (LA) patients. METHODS: Post hoc analysis to identify baseline characteristics predictive of clinical remission in response to treatment with etanercept (ETN) plus methotrexate (MTX) in LA patients with moderate to severe MTX-resistant RA. We report data from the group of patients who received ETN 50 mg/week plus MTX (ETN + MTX, n = 281) in a clinical trial consisting of an initial 24-week open-label phase, followed by a 104-week extension. Remission was defined as 28-joint Disease Activity Score with erythrocyte sedimentation rate (DAS28-ESR) score < 2.6. Cutoff values to dichotomize baseline variables maximizing the detection of remission were obtained from Receiver Operator Curve analyses. Baseline dichotomized and categorical variables were analyzed altogether in a stepwise logistic regression model. Odds of attaining response at Weeks 24 and 128 were estimated for each significant predictor. RESULTS: At Week 24 and Week 128, 27% (66/241) and 42% (91/219) of patients in the ETN + MTX group achieved remission. On average, patients achieving remission were younger and had lower baseline ESR, lower Physician Global Assessment (PGA) scores, lower total Health Assessment Questionnaire (HAQ) scores, and lower visual analog scale (VAS) Pain scores compared with patients who did not achieve remission. The best subset of baseline variables predicting Week 24 remission in the stepwise regression model were age ≤ 49 years (odds ratio [OR] 2.93), body mass index (BMI) > 28.5 kg/m2 (OR 3.24), disease duration > 3.7 years (OR 2.22), ESR ≤ 42 mm/h (OR 2.72), PGA ≤ 6 (OR 3.21), tender joint count ≤ 14 (OR 2.25), and total HAQ score ≤ 1.6 (OR 2.86). At Week 128, age ≤ 42 years (OR 2.21), SF-36 Mental Health Scale score > 39.6 (OR 2.16), White race (OR 4.07), > 18 swollen joints (OR 2.11), and VAS Pain ≤ 41 (OR 6.05) at baseline were the best subset of significant predictors of remission. CONCLUSIONS: In LA patients with RA, younger age, higher BMI, longer disease duration, higher SF-36 Mental Health Scale score, higher swollen joint count, and overall lower disease activity predicted clinical response to ETN + MTX therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00848354.

Lung involvement prevalence in patients with early rheumatoid arthritis without known pulmonary disease: a multicentric cross sectional study.

BACKGROUND: Clinically evident interstitial lung disease (ILD) affects between 10 and 42% of the patients with rheumatoid arthritis (RA). Airway involvement seems to be even more common. Most of the available evidence comes from studies performed in established RA patients. The aim of our study was to know the prevalence of non-diagnosed lung disease (airway and interstitial involvement) in patients with early RA and look for associated factors. METHODS: We designed an observational, multicenter, cross-sectional study, and included patients with RA of less than two years since diagnosis. We performed a structured questionnaire, HRCT and lung functional tests looking for lung disease, together with joint disease evaluation. We analyzed which variables were associated with the presence of lung disease on HRCT. RESULTS: We included 83 patients, 83% females. The median (IQR) of time since RA diagnosis was 3 (1-6) months. In the HRCT, 57 patients had airway compromisea (72%), and 6 had interstitial abnormalities (7.5%). The most common altertion found in lung functional tests was a reduced DLCO (14%). The presence of at least one abnormality in the physical exam was associated with lung involvement on HRCT [13 (21.6%) vs 0 (0%); p = 0.026]. Also, patients with lung involvement presented significantly lower values of FVC% and DLCO%, and higher values of RV/TLC. No variable related to joint involvement was found associated with alterations in HRCT. CONCLUSION: Our study shows that a large proportion of early RA patients has abnormal findings in HRCT. Further studies are required to confirm these findings.

Performance of the RABBIT infection risk score in an Argentinian rheumatoid arthritis cohort.

Patients with rheumatic autoimmune diseases have a higher risk of infections compared with age-and sex-matched controls. In Latin America, there are no validated tools to assess the risk of serious infection. The objectives were to estimate the incidence of serious infections in a cohort of rheumatoid arthritis (RA) patients followed for 12 months and to validate the RABBIT risk score for serious infections. Patients with RA were included and followed for 12 months. Baseline sociodemographic data, comorbidities, RA characteristics, and vaccination status were recorded. The baseline RABBIT risk score was calculated. Serious infections were documented, describing site and time since enrollment. Six hundred five patients were included (13 centers). The incidence of serious infection was 5% (95% CI 3-7). The most frequent sites were respiratory and urinary (90%). Performance of RABBIT risk score: patients with no infection during follow-up had a median score of 1.2 (IQR 0.8-2.1) and patients with infection 5.1 (IQR 2.15-12.6) p 0.00001. ROC curve analysis: AUC 0.86 (95% CI 0.8-0.94), best cut-off 2.85 (sensibility 75%, specificity 85%). The incidence of serious infections was 5% during the follow-up. The RABBIT score performed excellently in our patients. Key Points • The RABBIT risk score for serious infections showed an excellent performance in a population different (Latin America) from the original one included in the German registry. • This may assist rheumatologists in selecting drugs for patients according to the individual risk of infection, in a fast and simple way.

CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication.

p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.

Unscheduled MRE11 activity triggers cell death but not chromosome instability in polymerase eta-depleted cells subjected to UV irradiation.

The elimination of DNA polymerase eta (pol η) causes discontinuous DNA elongation and fork stalling in UV-irradiated cells. Such alterations in DNA replication are followed by S-phase arrest, DNA double-strand break (DSB) accumulation, and cell death. However, their molecular triggers and the relative timing of these events have not been fully elucidated. Here, we report that DSBs accumulate relatively early after UV irradiation in pol η-depleted cells. Despite the availability of repair pathways, DSBs persist and chromosome instability (CIN) is not detectable. Later on cells with pan-nuclear γH2AX and massive exposure of template single-stranded DNA (ssDNA), which indicate severe replication stress, accumulate and such events are followed by cell death. Reinforcing the causal link between the accumulation of pan-nuclear ssDNA/γH2AX signals and cell death, downregulation of RPA increased both replication stress and the cell death of pol η-deficient cells. Remarkably, DSBs, pan-nuclear ssDNA/γH2AX, S-phase arrest, and cell death are all attenuated by MRE11 nuclease knockdown. Such results suggest that unscheduled MRE11-dependent activities at replicating DNA selectively trigger cell death, but not CIN. Together these results show that pol η-depletion promotes a type of cell death that may be attractive as a therapeutic tool because of the lack of CIN.