Short communication: Differences in clinical outcomes according to the healthcare regime in Colombian patients with rheumatoid arthritis / Comunicación corta: diferencias en los desenlaces clínicos según el régimen de salud en pacientes colombianos con artritis reumatoide

ABSTRACT Introduction/Objectives: Rheumatoid arthritis (RA) is a burdensome disease from both individual and societal perspectives, in which access to a rheumatologist plays a pivotal role in disease activity and reduction of its impact. We describe preliminary results of our study aimed at exploring whether healthcare regime affiliation influences disease outcomes of Colombian patients with RA. Materials and methods: We performed a retrospective observational study of RA patients (2010 ACR/EULAR classification criteria) with at least 3 assessments in rheumatology clinics from different healthcare regimes: Contributory (CR), Subsidized (SR), a centre of clinical excellence (C3) that follows CR patients. We retrieved data from clinical charts including a follow-up period of 2 years. Results: We included one hundred and sixty patients (C3: 79 [49.4%], CR: 26 [16.2%], SR: 55 [34.2%]). Median initial age was 54 years (IQR 48-62) and most patients were women (77.8%). Of the patients, 79% had established RA and 70% had high disease activity at the beginning of the follow-up. We observed statistical differences between groups with regards to (1) median time to scheduled visits, (2) percentage of visits accomplished in scheduled time, (3) median time to real visit, (4) adherence, (5) median percentage of time in high disease activity, and (6) percentage of patients in high disease activity at the end of follow-up. The best outcomes were observed in the C3 cohort. Conclusions: Access opportunity and clinical outcomes of Colombian patients with RA appear to differ between healthcare regimes. Although systematic bias may be present due to sample size, these data imply the healthcare regime is a major determinant of disease outcomes.

RESUMEN Introducción/Objetivos: La artritis reumatoide (AR) presenta una alta carga de enfermedad tanto desde una perspectiva individual como social. La posibilidad de acceder a un reumatólogo desempeña un papel fundamental en la actividad de la enfermedad y la reducción de su impacto. Se describen los resultados preliminares de un estudio que tiene por objetivo explorar la influencia del régimen de afiliación en salud en los desenlaces de la enfermedad en pacientes colombianos con AR. Materiales y métodos: Se realizó un estudio observacional retrospectivo en pacientes colombianos con AR (criterios de clasificación ACR/EULAR 2010), con al menos 3 consultas por reumatología, en 3 servicios ambulatorios de diferentes regímenes de atención: contributivo (RC), subsidiado (RS) y un centro de cuidado clínico de excelencia (C3). Se recogieron datos de las historias clínicas, incluyendo un periodo de seguimiento de 2 años. Resultados: Se incluyó un total de 160 pacientes (C3: 79 [49,4%], RC: 26 [16,2%], RS: 55 [34,2%]). La mediana de la edad inicial fue de 54 años (RIC 48-62) y la mayoría fueron mujeres (77,8%). El 79% de los pacientes tenía AR establecida y el 70% presentaba una alta actividad de la enfermedad al inicio del seguimiento. Se encontraron diferencias estadísticas entre los grupos en: 1) la mediana del tiempo programado para la siguiente consulta; 2) el porcentaje de las consultas cumplidas en el tiempo previsto; 3) la mediana del tiempo real en consulta; 4) la mediana de la adherencia a la toma de laboratorios; 5) la mediana del porcentaje de tiempo durante el seguimiento en alta actividad, y 6) el porcentaje de pacientes con alta actividad al final del seguimiento. Los mejores desenlaces se observaron en el grupo C3. Conclusiones: La oportunidad de acceso y los desenlaces clínicos de pacientes colombianos con AR parecen diferir según el régimen de afiliación en salud. Aunque puede existir un sesgo sistemático debido al tamaño de la muestra, estos datos apuntan a que el régimen de afiliación en salud es un determinante mayor en los desenlaces de la enfermedad.

Cost-effectiveness analysis of treatments for the first episode of catastrophic antiphospholipid syndrome: A study based on the catastrophic antiphospholipid syndrome registry.

BACKGROUND: Treatments for catastrophic antiphospholipid syndrome (CAPS) rose from recommendations and consensus of international experts based on case series or case reports. We aimed to evaluate the treatment scheme with the best cost-effectiveness ratio associated with lower mortality as a high-impact clinical benefit. METHODS: The CAPS Registry was used as our source of structured data on the different therapeutic strategies, their frequency, and their effectiveness (survival). Starting from around 50 different schemes, we identified those with a mortality of less than 33% within the 18 most frequently utilized. After applying the efficiency frontier method, we included two schemes to conduct a cost-effectiveness analysis from the Colombian healthcare sector perspective. Scheme 1 (Glucocorticoids + Anticoagulation + Anti-aggregation + Intravenous IgG immunoglobulin) and scheme 2 (Glucocorticoids + Anticoagulation + Anti-aggregation + Plasma exchange) were compared in terms of costs and survival. Deterministic and probabilistic sensitivity analyses (Monte Carlo simulation) were conducted to evaluate model robustness and uncertainty. RESULTS: Our analysis uses the information corresponding to 427 cases from the CAPS registry, the majority being women (68.8%), with a mean age of 45.7 years and bearing general mortality of 38.17% (female: 38.4%, male: 37.5%). Scheme 2 was the cost-effective strategy over scheme 1. The results were robust on discrete sensitivity analysis and probability sensitivity analysis (Monte Carlo simulation). CONCLUSION: To our knowledge, this is the first economic evaluation focused on the treatment of CAPS. For the Colombian health system, schemes 1 and 2 have similar behavior; nevertheless, scheme 2 represents the best cost-effectiveness ratio. This treatment approach is highly susceptible to the allocation of resources by the system and beneficial in terms of health outcomes.

Correlation and agreement between physical and ultrasound examination after a training session dedicated to the standardization of synovitis assessment in rheumatoid arthritis patients.

OBJECTIVES: Assessing disease activity in rheumatoid arthritis (RA) patients requires comprehensive quantification of tender and swollen joints. We aimed to evaluate the correlation and agreement between rheumatologists after a training session dedicated to the standardization of synovitis assessment and compare its performance with a reference imaging modality such as musculoskeletal ultrasonography (MSUS). METHODS: In this cross-sectional study, a total of 28 and 10 joints in RA patients were evaluated by physical examination and ultrasound (US), respectively. After participating in a training session, individual joint assessment for tenderness and swelling was performed by three rheumatologists. MSUS examination was performed separately by an experimented radiologist in a standardized manner, evaluating findings according to the Outcome Measures in Rheumatology Clinical Trial (OMERACT) guidelines. RESULTS: A total of 80 RA patients were included, with a mean Disease Activity Score based on 28 joints (DAS28)-ESR of 4.02. The interobserver overall agreement and concordance rate in a total of 2240 joints assessed was 81.7% (k = 0.449, p < 0.0001) for tender joints and 66% (k = 0.227, p < 0.0001) for swollen joints. The overall concordance rate was fair (Fleiss' kappa = 0.21, p = 0.027) with an overall agreement of 67.18% yet, more joints were found to be swollen by the US assessment, compared to the physical examination (43% vs 39%). CONCLUSION: In our study population, joint tenderness showed better interobserver agreement, correlation, and concordance rate than joint swelling. When comparing the US assessment to the physical examination, a fair overall concordance rate supports the need for the implementation of training sessions dedicated to standardization in rheumatology clinics.

A longitudinal multiethnic study of biomarkers in systemic lupus erythematosus: Launching the GLADEL 2.0 Study Group.

Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of "Lupus Investigators" in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.

Does healthcare regime affiliation influence the clinical outcomes of patients with rheumatoid arthritis?

BACKGROUND/PURPOSE: Adequate control of disease activity in rheumatoid arthritis (RA) depends, to a great extent, on the access to a rheumatologist. This study aimed to compare the disease outcomes of patients with RA, based on their healthcare regime affiliation. METHODS: A retrospective observational study of Colombian patients with RA in three outpatient services of different regimes: Contributory (CR, workers and their families with a monthly income above a yearly defined threshold, approximately US$ 220, who allocate a percentage of their income to financing the national health fund and to get access to healthcare services), subsidized (SR, a vulnerable population with a monthly income below the threshold, who have access to healthcare through the national health fund; comparable to the USA Medicaid population), and an excellence clinical care center (C3, access to specialized care, regardless of their healthcare affiliation regime). Data were collected from clinical records for 2 years of follow-up and included demographics, lag times between appointments, and time in high disease activity. We used the Mantel-Cox test for the analysis of time to remission/low disease activity. RESULTS: A total of 240 patients were included (80 patients per regime). At the start of follow-up, mean age was 53.7 years; 21.6% of patients were men; 79.6% of patients had established RA; 72.9% of patients had high disease activity. Patients in the CR had longer lag times between scheduled appointments (p < 0.0001). During follow-up, SR had the highest proportion of patients with high disease activity. Survival curve analysis showed no significant difference between SR and CR groups (p = 0.2903), but was significantly different compared with the C3 group (p < 0.0001). Median survival in high disease activity was greater in the SR group (293 days), followed by CR (254 days), and finally by C3 (64 days). CONCLUSION: Patients that were treated in the excellence clinical care center had better outcomes when compared with other regimes. These data support that healthcare regime may influence disease outcome in patients with RA. Key Points • Prompt access to healthcare in patients with rheumatoid arthritis is pivotal for an adequate control of the disease, for timely adjustment of treatment, and to reduce both the societal burden of the disease and its impact on individual well-being. • As an example of "structural iatrogenesis," healthcare regime affiliation appears to influence disease outcomes in patients with rheumatoid arthritis, in whom differences between regimes are observed. The most vulnerable patients appear to experience the worst outcomes. • Excellence clinical care centers for patients with rheumatoid arthritis should be implemented as an alternative to counteract structural healthcare barriers and as an approach to improve clinical outcomes through a tighter disease control.

Association of Obesity With Lower Rates of Remission in a Colombian Cohort of Patients With Rheumatoid Arthritis.

OBJECTIVES: Modifiable risk factors associated with the severity of rheumatoid arthritis have been studied, including the body mass index (BMI). The aim was to compare the evolution of disease activity during 24 months of follow-up in different initial BMI groups of patients with rheumatoid arthritis. METHOD: Patients were classified based on their initial BMI (normal weight, overweight, and obese). Data were collected during 24 months of follow-up. At 24 months, they were reclassified based on their BMI. The proportion of patients in each BMI category was calculated. The mean differences between the initial and final DAS-28 (Disease Activity Score 28) were calculated using the Kruskal-Wallis test. Results were stratified based on sex and age. Survival analysis and Mantel-Cox test for the achievement of sustained remission during follow-up were calculated. RESULTS: A total of 269 patients were included. Most patients were at the normal weight category (n = 111). Normal weight group had the highest initial score (DAS-28, 4.01). Women present higher variability in BMI and greater disease activity compared with men. Based on age group, patients between the ages 31 and 50 years are more stable in their BMI, whereas those older than 50 years had lower BMI with time. Sustained remission was achieved by 58% of patients from the normal weight group, by 57% of patients from the overweight group, and by 42% of patients from the obese group. Survival curves of the initial normal and obese groups were significantly different (p = 0.0209). CONCLUSIONS: Patients with initial obesity were less likely to achieve remission compared with patients with initial overweight or normal weight. Sex and age affects disease activity and BMI variation.

Correlation and agreement between physical and ultrasound examination after a training session dedicated to the standardization of synovitis assessment in rheumatoid arthritis patients

Abstract Objectives: Assessing disease activity in rheumatoid arthritis (RA) patients requires comprehensive quantification of tender and swollen joints. We aimed to evaluate the correlation and agreement between rheumatologists after a training session dedicated to the standardization of synovitis assessment and compare its performance with a reference imaging modality such as musculoskeletal ultrasonography (MSUS). Methods: In this cross-sectional study, a total of 28 and 10 joints in RA patients were evaluated by physical examination and ultrasound (US), respectively. After participating in a training session, individual joint assessment for tenderness and swelling was performed by three rheumatologists. MSUS examination was performed separately by an experimented radiologist in a standardized manner, evaluating findings according to the Outcome Measures in Rheumatology Clinical Trial (OMERACT) guidelines. Results: A total of 80 RA patients were included, with a mean Disease Activity Score based on 28 joints (DAS28)-ESR of 4.02. The interobserver overall agreement and concordance rate in a total of 2240 joints assessed was 81.7% (k = 0.449, p < 0.0001) for tender joints and 66% (k = 0.227, p < 0.0001) for swollen joints. The overall concordance rate was fair (Fleiss' kappa = 0.21, p = 0.027) with an overall agreement of 67.18% yet, more joints were found to be swollen by the US assessment, compared to the physical examination (43% vs 39%). Conclusion: In our study population, joint tenderness showed better interobserver agreement, correlation, and concordance rate than joint swelling. When comparing the US assessment to the physical examination, a fair overall concordance rate supports the need for the implementation of training sessions dedicated to standardization in rheumatology clinics.

Prognostic value of capillaroscopy in organ involvement and identification of subtypes in systemic sclerosis (SS): A systematic literature review / Valor pronóstico de la capilaroscopia en el compromiso de órganos e identificación de subtipos en la esclerosis sistémica (ES): una revisión sistemática de la literatura

ABSTRACT Background: Capillaroscopy is an essential tool for the diagnosis of systemic sclerosis. Using this exam as a prognostic factor will allow earlier intervention and probably, delay on disease progression. We aimed to evaluate the prognostic value of capillaroscopy for the prediction of systemic compromise and subtype differentiation in systemic sclerosis. Methods: A systematic literature search was applied in the following electronic databases: Medline, PubMed, Embase, Cochrane, and Lilacs. The research question was designed based on the PICOT model, and the search strategy was built using the MeSH terms "Microscopic Angioscopy," "Scleroderma systemic," "Scleroderma diffuse," Scleroderma Limited," "Early Diagnosis" and Boolean operators. The language was restricted to papers published in Spanish or English, from 1990 to 2019. The search terms were explored for each database, and new terms were added, as appropriate. The searches were made again before the final analyses and further studies were retrieved for inclusion at that time. Reference lists of included studies and recent aligned systematic reviews were also screened. Gray literature was not considered in this review. Results: A total of 183 articles were found in the selected databases: Medline (n: 115), Embase (n: 66), Cochrane (n: 2), Lilacs (n: 0). After excluding articles due to duplication, a total of 66 studies were selected. Within these articles, a screening process was applied based on the title and abstract, taking into account the eligibility criteria, finally obtaining 21 references. Two researchers assessed the selected articles, and all disagreements were solved by consensus. Finally, a total of 14 articles were included. Conclusions: The different abnormalities found in capillaroscopy, especially loss of capillaries, have been consistently associated not only with organ involvement but also with severity of the disease, especially with vascular manifestations (digital ulcers and pulmonary hypertension). The importance of capillaroscopy is not only its diagnostic value but also its predictive value with its consequent implications in the follow-up and management of systemic sclerosis.

RESUMEN Introducción: La capilaroscopia es una herramienta esencial para el diagnóstico de la esclerosis sistémica. Usar este examen como factor pronóstico permitirá realizar una intervención temprana y probablemente retardará la progresión de la enfermedad. Se realizó una revisión de la literatura evaluando el valor pronóstico de la capilaroscopia para predecir el compromiso sistémico de la esclerosis sistémica y su diferenciación por subtipos. Métodos: Se realizó una revisión sistemática de la literatura en las siguientes bases de datos: Medline, PubMed, Embase, Cochrane y Lilacs. La búsqueda se hizo basada en el modelo PICOT y la estrategia de búsqueda fue construida mediante los términos MeSH «Microscopic angioscopy¼, «Scleroderma systemic¼, «Scleroderma diffuse¼, «Scleroderma limited¼, «Early diagnosis¼ y operadores booleanos. El lenguaje fue restringido a artículos publicados en español e inglés desde 1990 hasta 2019. Se realizó la búsqueda en cada base de datos y se adicionaron nuevos términos según fuera apropiado. La búsqueda se realizó de nuevo al final del análisis y se incluyeron los estudios más recientes. La lista de referencias de los estudios incluidos y las revisiones sistemáticas recientemente adicionadas también fueron registradas. No se consideró literatura gris en esta revisión. Resultados: Un total de 183 artículos fueron encontrados en las siguientes bases de datos: Medline (n = 115), Embase (n = 66), Cochrane (n = 2), Lilacs (n = 0). Después de excluir los que estaban duplicados, un total de 66 estudios fueron seleccionados. Dentro de estos artículos, se realizó un proceso de selección basado en título y resumen tomando en cuenta los criterios de elegibilidad, obteniendo finalmente 21 referencias. Dos investigadores revisaron los artículos seleccionados y todas las discrepancias fueron resueltas en consenso. Finalmente, un total de 14 artículos fueron incluidos. Conclusiones: Las diferentes anormalidades encontradas en la capilaroscopia, especialmente la pérdida de capilares, han sido constantemente asociadas no solo con compromiso de órganos sino también a la severidad de la enfermedad, especialmente con manifestaciones vasculares (úlceras digitales e hipertensión pulmonar). La importancia de la capilaroscopia no solo es por su valor diagnóstico sino también por su valor predictivo en relación al seguimiento y manejo de la esclerosis sistémica.

Digital ulcers in systemic sclerosis / Úlceras digitales en esclerosis sistémica

ABSTRACT Vascular compromise in systemic sclerosis is a pivotal feature of the disease and plays a fundamental role in its morbidity and mortality. Raynaud's syndrome is present in almost every patient and is often reported as the first clinical manifestation. Digital ulcers may present several etiologies, although an ischemic cause is the most frequent origin and occurs in up to 50% of patients. A profound impact on daily life is often observed due to pain and functional impairment. Their primary pathophysiological mechanism is microvascular compromise, although larger vessels may be affected as well. When recurrent lesions are observed, large vessel compromise should be assessed, which may be due to the disease itself or due to atherosclerosis, whenever risk factors are present. Further, these ulcers present an increased risk of infection and progression to gangrene. The presence of digital lesions may be a marker of severity of the disease, as some reports have suggested an association with pulmonary hypertension and cardiac involvement. Treatment strategies have progressed significantly over the last years. Vasodilatation using calcium channel inhibitors is universally offered. When ischemic signs are observed, treatment should be started readily. Prostacyclin infusions should be considered in severe cases, as they have shown the capacity to foster ulceration healing. Whenever recurring lesions are observed, bosentan may be offered. Management with phosphodiesterase inhibitors may be proposed, although their positioning is unclear. Local treatment is equally important over the course of the disease. Surgical interventions are seldom needed.

RESUMEN El compromiso vascular en la esclerosis sistémica es una característica principal de la enfermedad y desempeña un papel fundamental en su morbimortalidad. El síndrome de Raynaud está presente en casi todos los pacientes, y con frecuencia es reportado como la primera manifestación clínica. Las úlceras digitales pueden tener varias etiologías, aunque una causa isquémica es el origen más frecuente y ocurre hasta en 50% de los pacientes. A menudo se observa un profundo impacto en la vida diaria debido al dolor y al deterioro funcional. Su mecanismo fisiopatológico primario es el compromiso microvascular, aunque los vasos más grandes también pueden verse afectados. Cuando se observan lesiones recurrentes se debe evaluar el compromiso de los vasos grandes, que puede deberse a la enfermedad en sí o a aterosclerosis, siempre que existan factores de riesgo. Además, estas úlceras presentan un mayor riesgo de infección y progresión a gangrena. La presencia de lesiones digitales puede ser un marcador de la gravedad de la enfermedad, ya que algunos informes han sugerido una asociación con hipertensión pulmonar y compromiso cardíaco. Las estrategias de tratamiento han progresado significativamente en los últimos anos. La vasodilatación con inhibidores de los canales de calcio se ofrece universalmente. Cuando se observan signos isquémicos el tratamiento debe iniciarse de inmediato. Las infusiones de prostaciclina se deben considerar en casos graves, ya que han demostrado la capacidad de promover la curación de la ulceración. Siempre que se observen lesiones recurrentes se puede administrar bosentán. Se puede proponer el manejo con inhibidores de la fosfodiesterasa, aunque su posicionamiento no está claro. El tratamiento local es igualmente importante durante el curso de la enfermedad. Las intervenciones quirúrgicas rara vez son necesarias.

Infections and systemic sclerosis: an emerging challenge / Infecciones y esclerosis sistémica: un desafío emergente

ABSTRACT Mounting evidence has shown non-systemic sclerosis (SSc) related complications as a rising cause of hospital admission and mortality, out of which infections are among the top-five causes. Patients with SSc are at an increased risk of infection due to several features of the treatment options and to the disease itself. For instance, lung involvement is associated with a higher frequency of respiratory infections, whereas the presence of digital ulcers or calcinosis may result in skin and soft tissue infections, and even osteomyelitis. On the other hand, the growing trend towards immunomodulation and immunosuppression in patients with autoimmune diseases will place SSc patients at a higher risk of infectious complications, including opportunistic infections. A low suspicion threshold and an increasing awareness among treating specialists, particularly rheumatologists, are warranted for prevention, early diagnosis and management of infectious complications. Nonetheless, data on risk management strategies in SSc, such as vaccination and antimicrobial prophylaxis, are scarce. A narrative non-systematic review was performed to provide an update of infectious complications in patients with SSc.

RESUMEN La evidencia creciente muestra que las complicaciones no asociadas a la esclerosis sistémica (ES) son una causa cada vez más frecuente de hospitalización y mortalidad, dentro de las cuales las infecciones se encuentran entre las primeras cinco causas. Los pacientes con ES presentan un riesgo elevado de infección asociado con las opciones terapéuticas y con la enfermedad misma. Por ejemplo, el compromiso pulmonar se asocia con una mayor frecuencia de infecciones respiratorias, mientras que la presencia de úlceras digitales o calcinosis pueden resultar en infecciones de piel y tejidos blandos, incluso en osteomielitis. Por otro lado, la tendencia creciente hacia la inmunomodulación y la inmunosupresión, como tratamiento de las enfermedades autoinmunes, pondrá a estos pacientes en un mayor riesgo de infecciones, incluidas las infecciones oportunistas. Son necesarios un umbral bajo de sospecha y un alto nivel de alerta entre las especialidades tratantes, particularmente los reumatólogos, para la prevención, el diagnóstico temprano y el manejo de las complicaciones infecciosas. Sin embargo, la información respecto a estrategias de gestión de riesgo en ES, como la vacunación o la profilaxis antibiótica, es escasa. Se realizó una revisión narrativa no sistemática que presenta una actualización sobre las complicaciones infecciosas en pacientes con ES.

Osteoarticular manifestations of systemic sclerosis: a systematic review of the literature / Manifestaciones osteoarticulares de esclerosis sistémica: una revisión sistemática de la literatura

ABSTRACT Introduction: Osteoarticular manifestations (OAM) are frequently present in patients with systemic sclerosis (SSc). These OAM are related to important functional disability and a severe impact on patient's life quality, therefore, they require special attention from clinicians. Objective: Determining the frequency of reported OAM in SSc patients, the general impact of osteoarticular manifestations in patient's condition and the tools available for diagnosis and treatment. Methodology: A systematic review of the literature was performed for information published between January 1970 and December 2018 in the medical research databases of: Medline, Embase, Lilacs, Scielo, Cochrane and clinicaltrials.gov. Results and Conclusions: A total of 116 articles were included in this review. The type and prevalence of the different OAM reported in the literature were determined. In addition to the evolution of their diagnostic methods, there are more validated methods to assess the impact of OAM in patients with SSc. Randomized clinical trials are required to establish the best treatment strategy for these patients.

RESUMEN Introducción: Las manifestaciones osteoarticulares (MOA) están presentes de forma frecuente en pacientes con esclerosis sistémica (SSc). Generan gran discapacidad funcional con un impacto importante en la calidad de vida de los pacientes, por lo que requieren especial atención por parte de los clínicos. Objetivos: Determinar la frecuencia de las MOA dentro de la SSc, su impacto en la condición general de los pacientes y las diferentes herramientas disponibles de diagnóstico y tratamiento. Metodología: Se realizó una revisión sistemática de la literatura disponible desde enero de 1970 hasta diciembre de 2018 en las bases de datos de Medline, Embase, Lilacs, Scielo, Cochrane y clinicaltrials.gov. Resultados y conclusiones: Se incluyeron un total de 116 artículos en esta revisión. Se determinaron el tipo y la prevalencia de las diferentes MOA reportadas en la literatura. Además de la evolución en los métodos diagnósticos de las mismas, cada vez existen más métodos validados para evaluar el impacto de las MOA en los pacientes con SSC. Se requieren ensayos clínicos aleatorizados que permitan establecer la mejor estrategia de tratamiento para estos pacientes.

Pharmacological treatment of scleroderma renal crisis: A systematic literature review / Tratamiento farmacológico de la crisis renal en esclerosis sistémica: una revisión sistemática de la literatura

ABSTRACT Background: Scleroderma renal crisis is a condition that affects approximately 4-6% of patients with systemic sclerosis, especially with diffuse compromise. Clinical manifestations are variable, representing a diagnostic challenge. Objective: The study aims to describe and analyze the different pharmacological treatments available for the management of scleroderma renal crisis. Materials and methods: A systematic literature review was done based on observational studies and clinical trials about the treatment of scleroderma renal crisis, using monotherapy or combined therapy. The studies were identified using electronic scientific databases, including MEDLINE PUBMED and EMBASE, in English, published between January 1990 and August 2019. Results: Eleven studies were included (ten observational studies and one open clinical trial). Of them, seven were cohorts, one case series, and two case-control studies. Overall, 1113 patients were included in the analyzed studies. All studies used angiotensin-converting enzyme inhibitors as exposition, case definition, and/or comparison in the clinical trial. Regarding the need for dialysis, approximately 53.9% of patients required it temporarily or permanently. Approximately 6-27% of patients required temporal dialysis, and 19-78% required permanent dialysis. One-year survival range was between 64 and 84%; two-year survival was between 53 and 74%; five-year survival between 40 and 90%, and finally ten-year survival between 35 and 47%. Conclusions: Angiotensin-converting enzyme inhibitors continue to be the first line of treatment for scleroderma renal crisis by contributing to a decrease in short-term mortality. However, alternative therapeutic options are required as a high percentage of patients still require dialysis. Future clinical trials are necessary to assess the effectiveness and safety of different therapeutic options.

RESUMEN Introducción: La crisis renal es una condición que afecta aproximadamente a 4-6% de los pacientes con esclerosis sistémica, especialmente con compromiso difuso. Las manifestaciones clínicas son variables, representando un reto diagnóstico en la práctica clínica. Objetivo: El objetivo del estudio fue describir y analizar los diferentes tratamientos farmacológicos disponibles para el manejo de la crisis renal en esclerosis sistémica. Materiales y métodos: Una revisión sistemática de la literatura fue desarrollada con base en estudios observacionales y ensayos clínicos sobre el tratamiento de la crisis renal, utilizando monoterapia o terapias combinadas. Los estudios fueron identificados utilizando bases de datos científicas que incluyeron MEDLINE PUBMED y EMBASE, que estuvieran en inglés y publicados entre enero de 1990 y agosto de 2019. Resultados: Once estudios fueron incluidos (10 estudios observacionales y un ensayo clínico abierto). De estos, siete fueron cohortes, una serie de casos y dos estudios de casos y controles. En total, 1113 pacientes fueron incluidos en los estudios analizados. Todos los estudios utilizaron inhibidores de enzima convertidora de angiotensina como exposición, definición de caso y/o comparador en ensayo clínico. Sobre la necesidad de diálisis, aproximadamente 53,9% de los pacientes la requirieron de forma temporal o permanente. Aproximadamente 6-27% de pacientes requirieron diálisis temporal y 19-78% requirieron diálisis permanente. El rango de sobrevida al año fue de 64-84%; a dos arios 53-74%; a cinco arios 40-90%, y a diez arnos 35-47%. Conclusiones: Los inhibidores de enzima convertidora de angiotensina continúan siendo la primera línea de tratamiento de crisis renal en esclerosis sistémica, al contribuir en la reducción de la mortalidad a corto plazo. Sin embargo, opciones terapéuticas alternativas son requeridas, al continuar muy elevado el porcentaje de requerimiento de diálisis. Ensayos clínicos futuros son necesarios para evaluar la eficacia y seguridad de diferentes opciones terapéuticas.

Pharmacological treatment of systemic sclerosis-associated pulmonary hypertension: A systematic literature review / Tratamiento farmacológico de la hipertensión pulmonar asociada a la esclerosis sistémica: revisión sistemática de la literatura

ABSTRACT Background: Systemic sclerosis is an autoimmune disease that could significantly affect internal organs, increasing the mortality associated with the disorder. Pulmonary hypertension is one of the conditions that increase the morbidity and mortality of the disease. The aim of the study was to develop a systematic literature review about the different pharmacological treatments for systemic sclerosis-associated pulmonary hypertension. Materials and methods: A systematic literature review was made on Cochrane, PubMed and EMBASE. Randomized controlled clinical trials, controlled clinical trials, cohort and case-control studies using any of the available treatments such as prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors or soluble guanylate cyclase stimulants were included. The methodological quality of the studies was assessed using Cochrane methodology for clinical trials, and the SIGN tool was applied for cohort and case-control studies. Results: Initially, 870 studies were found, and 20 studies were finally included in the systematic review after applying inclusion and exclusion criteria. Most studies included Bosentan in the treatment strategies (N = 13). Also, most studies took data from the most important clinical trials for pharmacological treatment of pulmonary hypertension of several etiologies. Some studies using Bosentan did not give information about data regarding some outcomes. Half of the selected studies were clinical trials, of which two were randomized. The quality of these studies was good. The other half were observational studies, with moderate quality of evidence. In general, it was found that approved medications improve the 6-minute walk distance, WHO functional class, NYHA functional classification, or Borg dyspnea score, depending on the given dose in several studies, and also compound outcomes that include hospitalizations, clinical worsening, death, etc. Regarding mortality, there were significant differences in survival rates when comparing approved medications vs. placebo, being combined therapies superior to monotherapy. Measurements of hemodynamic variables such as cardiac index, pulmonary resistances, and pulmonary pressures were improved. Also, NT-proBNP levels were reduced, with some exceptions. Conclusions: In most studies with good quality of evidence, it was found an improvement in clinical and non-clinical outcomes, favoring the use of approved medications for the treatment of systemic sclerosis-associated pulmonary hypertension.

RESUMEN Antecedentes: La esclerosis sistémica es una enfermedad autoinmune que puede afectar significativamente los órganos internos, aumentando la mortalidad asociada con dicho trastorno. La hipertensión pulmonar es una de las afecciones que aumentan la morbimortalidad de la enfermedad. El objetivo del estudio fue desarrollar una revisión sistemática de la literatura sobre los diferentes tratamientos farmacológicos para la hipertensión pulmonar asociada a la esclerosis sistémica. Materiales y métodos: Se hizo una revisión sistemática de la literatura en Cochrane, PubMed y EMBASE. Se incluyeron ensayos clínicos aleatorizados controlados, ensayos clínicos controlados, así como estudios de cohortes y de casos y controles utilizando alguno de los tratamientos disponibles, tales como los análogos de la prostaciclina, los antagonistas de los receptores de endotelina, los inhibidores de la fosfodiesterasa o los estimulantes de la guanilato ciclasa soluble. Se evaluó la calidad metodológica de los estudios utilizando la metodología Cochrane para los ensayos clínicos, y se aplicó la herramienta SIGN para los estudios de cohortes y de casos y controles. Resultados: Inicialmente se encontraron 870 estudios, de los cuales finalmente se incluyeron 20 en la revisión sistemática, después de aplicar los criterios de inclusión y exclusión. La mayoría de los estudios incluyeron el bosentán en las estrategias de tratamiento (n = 13). Además, la mayoría de los estudios tomaron datos de los ensayos clínicos más importantes sobre el tratamiento farmacológico de la hipertensión pulmonar de diversas etiologías. Algunos estudios que utilizaron el bosentán no suministraron información sobre datos relacionados con algunos resultados. La mitad de los estudios seleccionados fueron ensayos clínicos, de los cuales dos fueron aleatorizados. La calidad de estos estudios fue buena. La otra mitad incluyó estudios observacionales, con evidencia de calidad moderada. En general, se encontró que los medicamentos aprobados mejoran la distancia en la caminata de seis minutos, la clase funcional de la OMS, la clasificación funcional de la NYHA, o el puntaje de disnea en la escala de Borg, dependiendo de la dosis administrada en los diferentes estudios, y también los desenlaces compuestos que incluyen hospitalizaciones, empeoramiento clínico, muerte, etc. En cuanto a la mortalidad, se encontraron diferencias significativas en las tasas de supervivencia al comparar los medicamentos aprobados versus placebo, siendo las terapias combinadas superiores a la monoterapia. Las mediciones de variables hemodinámicas tales como el índice cardíaco, las resistencias pulmonares y las presiones pulmonares mejoraron. Además, los niveles de NT-pro BNP se redujeron, con algunas excepciones. Conclusiones: En la mayoría de los estudios con buena calidad de evidencia, se encontró una mejoría en los desenlaces clínicos y no clínicos, que favorece el uso de los medicamentos aprobados para el tratamiento de la hipertensión pulmonar asociada a la esclerosis sistémica.

Treatment of systemic sclerosis-associated interstitial lung disease: A systematic literature review and meta-analysis / Tratamiento de la enfermedad pulmonar intersticial asociada con la esclerosis sistémica: revisión sistemática de la literatura y metaanálisis

ABSTRACT Background: Systemic sclerosis (SSc) is an immune-mediated disease characterized by small vessel vasculopathy and fibroblast dysfunction that leads to increased production of extracellular matrix. Interstitial lung disease represents one of the most common complications, by affecting almost 70% of patients with SSc. Objective: To evaluate the effectiveness of the pharmacological treatments available for systemic sclerosis-associated interstitial lung disease (SSc-ILD) based on pulmonary function tests and radiologic findings. Materials and methods: A systematic literature review and meta-analysis were conducted. A thorough literature search was made in EMBASE, PUBMED, and Cochrane CENTRAL to collect studies published between January 2015 and July 31 of 2019. The primary outcomes were forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLCO), and high-resolution computed tomography findings (HR-CT). Studies using medications for the treatment of SSc-ILD including cyclophosphamide (CYC), mycophenolate mofetil (MMF), nintedanib, pirfenidone, or rituximab (RTX) were included. Effect measures were calculated based on available data, and a meta-analysis was made with these results. Results: We found a total of 312 studies. 49 studies were selected for full-text assessment after reading the abstracts. Finally, 14 studies were selected to be included in the final review. 2 meta-analyses, 8 clinical trials, 3 retrospective cohorts, and one nested case-control study were identified. The available evidence supports the use of CYC and MMF as the best options for the treatment of SSc-ILD, with MMF being the preferred option based on a better safety profile. Other medications such as RTX, pirfenidone, and nintedanib show potential as alternatives to CYC. The overall quality of evidence available is adequate based on generally well-designed studies. Meta-analysis was done by assessing >5% or >10% decrease of FVC when comparing pharmacological agents vs. placebo. Results show that the use of pharmacological agents is negatively associated with the worsening of FVC. However, high heterogeneity limits the number of studies used during quantitative analysis, affecting the overall results. Conclusions: Immunosuppressive therapies remain as the cornerstone of treatment of SSc-ILD, as most evidence show improvement or slow progression of pulmonary function tests by using them, especially CYC and MMF. However, more evidence is required regarding the use of alternative pharmacological agents, in search of an improvement in the quality of life of these patients.

RESUMEN Antecedentes: La esclerosis sistémica (ES) es una enfermedad mediada por el sistema inmunitario, caracterizada por vasculopatía de pequeños vasos y disfunción de los fibroblastos, que da lugar a una mayor producción de matriz extracelular. La enfermedad pulmonar intersticial representa una de las complicaciones más comunes, ya que afecta a cerca del 70% de los pacientes con ES. Objetivo: Evaluar la efectividad de los tratamientos farmacológicos disponibles para la enfermedad pulmonar intersticial asociada a la esclerosis sistémica (EPI-ES) basándonos en las pruebas de función pulmonar y los hallazgos radiológicos. Materiales y métodos: Se llevó a cabo una revisión sistemática de la literatura y un metaanálisis. Se hizo una búsqueda exhaustiva de literatura en EMBASE, MEDLINE PubMed y Cochrane (CENTRAL) con el fin de recopilar los estudios publicados entre enero de 2015 y el 31 de julio de 2019. Los resultados primarios fueron la capacidad vital forzada (CVF), la capacidad de difusión del monóxido de carbono (diffusing capacity of the lungs for carbon monoxide, DLCO), y los hallazgos de la tomografía computarizada de alta resolución (TCAR). Se incluyeron los estudios que utilizaron medicamentos para el tratamiento de la EPI-ES, incluyendo ciclofosfamida (CYC), micofenolato de mofetilo (MMF), nintedanib, pirfenidona o rituximab (RTX). Las medidas de efecto se calcularon con base en los datos disponibles, y se hizo un metaanálisis con estos resultados. Resultados: Encontramos un total de 312 estudios. Después de leer los resúmenes, se seleccionaron 49 estudios para la evaluación del texto completo. Finalmente, se seleccionaron 14 estudios para incluirlos en la revisión final. Se identificaron dos metaanálisis, ocho ensayos clínicos, tres cohortes retrospectivas y un estudio de casos y controles anidado. La evidencia disponible respalda el uso de CYC y MMF como las mejores opciones para el tratamiento de la EPI-ES, siendo el MMF la opción preferida basada en un mejor perfil de seguridad. Otros medicamentos como RTX, pirfenidona y nintedanib muestran potencial como alternativas a la CYC. La calidad global de la evidencia disponible es adecuada ya que parte de estudios por lo general bien diseñados. El metaanálisis se realizó evaluando una disminución > 5% o > 10% de la CVF al comparar los agentes farmacológicos vs. placebo. Los resultados muestran que el uso de agentes farmacológicos se asocia negativamente con el empeoramiento de la CVF. Sin embargo, la alta heterogeneidad limita el número de estudios utilizados durante el análisis cuantitativo, afectando los resultados generales. Conclusiones: Las terapias inmunosupresoras, especialmente la CYC y el MMF, siguen siendo la piedra angular del tratamiento de la EPI-ES, ya que la mayoría de la evidencia muestra una mejoría o una progresión lenta de las pruebas de función pulmonar al usarlas. Sin embargo, se requiere más evidencia con respecto al uso de agentes farmacológicos alternativos, en busca de una mejora de la calidad de vida de estos pacientes.

Variación en la definición del examen articular para la clinimetría de la artritis reumatoide: resultados de una encuesta realizada a un grupo de reumatólogos colombianos / Variation in the definition of the examination of joints in rheumatoid arthritis: Results of a survey conducted on a group of Colombian rheumatologists

RESUMEN Introducción: En el seguimiento de los pacientes con artritis reumatoide (AR) el examen articular (determinar el número de articulaciones dolorosas e inflamadas) es la piedra angular para determinar la actividad. El objetivo del estudio fue conocer la opinión de un grupo de reumatólogos acerca del examen articular de los pacientes con AR al definir la articulación tumefacta o dolorosa y, de la misma manera, evaluar la variación en el examen articular entre los participantes. Métodos: Se aplicó un cuestionario, desarrollado por los autores, a un grupo de reumatólogos para explorar aspectos generales y específicos al examinar cada una de las articulaciones, además de conceptos de las definiciones de dolor y de inflamación en el examen físico. Resultados: El 78% de los entrevistados consideró que todos los aspectos eran importantes, como evaluar la movilización pasiva de la articulación, explorar el dolor a la palpación y el dolor espontáneo. El 53,8% consideró la movilidad pasiva sin que haya dolor o edema articular a la palpación. El 62,6% estaba de acuerdo con realizar la presión hasta cuando comienza a palidecer el lecho ungular del dedo del examinador. En el momento de palpar el margen articular para determinar la inflamación, el 55% estuvo de acuerdo y el 14,3% no estuvo seguro. Para el 47,2% eran importantes el derrame articular, la fluctuación y la alteración del rango del movimiento para definir la inflamación en el examen articular. Cerca de las tres cuartas partes estuvo de acuerdo con la técnica de las articulaciones temporomandibular, acromioclavicular, esternoclavicular, hombro y tobillo. Se evidenció que pocos estaban de acuerdo con la técnica en la articulación de la cadera. Al preguntarse por más de una técnica en algunas articulaciones, como las MCF (57,1%) y del tarso medio (45%), el porcentaje de los que estuvieron de acuerdo con una de las 2 técnicas disminuyó. Discusión: Al parecer no existe un método de examen formal, ya que hubo diferentes opiniones en las técnicas propuestas. Esto puede ser crítico, ya que el examen articular es la base de la clinimetría de la AR. Un porcentaje importante del grupo no estuvo de acuerdo o seguro acerca de algunos conceptos sobre componentes del examen, lo que denota una variación en los conceptos y esto podría llevar a la mala clasificación de los pacientes al determinar la actividad de la enfermedad, lo que impactaría en la estrategia T2T o treat to target. Conclusión: Existió una gran variación en la opinión acerca de los conceptos relacionados con el examen articular del paciente que padece AR al definir articulaciones tumefactas o dolorosas, por lo que se recomienda a futuro un proceso de estandarización como la mejor alternativa.

ABSTRACT Introduction: In the follow-up of rheumatoid arthritis (RA) patients, the physical examination of the joints in order to determine the number of painful and swollen joints is the corners-tone for determining activity. The objective of this study was to find out the opinion of a group of rheumatologists as regards the examination of joints of patients with RA to define the swollen or painful joint. At the same time an evaluation was made on the variation in the joints examination between the participants. Methods: A questionnaire was administered to a group of rheumatologists in order to determine general issues and examining each of the joints, as well as concepts of definitions of pain and inflammation in the joints. Results: The majority of the participants (78%) stated that all aspects were important, such as evaluating passive joint mobilisation, pain to palpation, and spontaneous pain. Passive mobility without having pain or swollen joint tenderness was said to be important by 53.8% of the participants, and 62.6% agreed with observing the pressure exerted by the examiner until the nail bed of the finger started to turn pale. As regards touching the margin of joint to determine swelling, 55% agreed, and 14.3% were not sure. Synovial effusion, fluctuation, and the alteration in the range of motion to define inflammation in the examination of joint were important for 47.2% of the examiners. Almost three-quarters agreed with the temporomandibular, acromioclavicular, sternoclavicular, shoulder and ankle joint technique. It was obvious that few were in accordance with the technique in the hip joint. When asked about more than one technique in some joints such as the MCF (57.1%) and mid-tarsal (45%) joints, there was a decrease in the percentage of those who agreed with one of the 2 techniques. Discussion: Apparently, there is no standard joint assessment method, since there were different opinions in the techniques proposed. This could be critical since examination of joints is the basis of the clinimetric examination in RA. A significant percentage of the group did not agree or were unsure of some components of the examination. This could lead to a variation in the concepts and a misclassification of patients in order to determine the activity of RA. This would also have an impact on the T2T or treat to target strategy. Conclusion: There was a wide variation in opinions about the concepts related to the examination of joints, such as defining swollen or painful joints in patients suffering RA. This requires a process of standardisation as the best recommended alternative.

Hallazgos ultrasonográficos a nivel de articulaciones de manos y pies en sujetos voluntarios asintomáticos / Ultrasound findings in hand and foot joints of asymptomatic volunteers

Resumen Introducción: Anormalidades ultrasonográficas se describen con cierta frecuencia en articulaciones de sujetos asintomáticos, las cuales generan incertidumbre en el contexto de evaluación y tratamiento de la enfermedad articular inflamatoria; a pesar de ello, en Colombia no existen estudios al respecto y la evidencia disponible es escasa, hecha en un bajo número de participantes y con transductores menores a 18 MHz en su gran mayoría. Objetivos: Describir los hallazgos ultrasonográficos articulares en manos y pies de un grupo de voluntarios asintomáticos, su asociación con las características sociodemográficas y la concordancia intra e interobservador de sus mediciones. Materiales y métodos: Estudio descriptivo y analítico en el que se incluyeron 182 voluntarios asintomáticos. Dos médicos con experiencia en ecografía musculoesquelética evaluaron el aspecto dorsal de 5.460 recesos articulares mediante la escala semicuantitativa de Szkudlarek y la utilización de un transductor lineal de 18 MHz. Resultados: La mediana de edad de los participantes fue de 42 arios, 60,4% de ellos mujeres. En 87% de los voluntarios se identificaron en total 232 hallazgos, el 68,1% correspondió a derrame articular, 29,3% a hipertrofia sinovial, 2,1% a erosiones y 0,4% a Doppler de poder. Los pies mostraron mayores hallazgos que las manos (70,7% vs. 29,3%). Las articulaciones en las que más se identificaron anormalidades fue la primera articulación metatarsofalángica (52%), la tercera metatarsofalángica (15%) y la radiocarpiana (9,5%). Se halló relación positiva entre el derrame articular y la hipertrofia sinovial con la edad, ocupación manual exclusiva y tiempo laboral mayor de 10 años. La concordancia intraobservador fue moderada (Kappa = 0,4591) y la interobservador fue leve (Kappa = 0,2155). Conclusiones: La ausencia de señal Doppler de poder, el no compromiso radioulnar distal, la ausencia de sinovitis acompañada de erosión y una mayor predominancia de alteraciones leves al nivel de las manos, sumado a la ausencia de hallazgos al nivel de la quinta articulación metatarsiana, constituyen hallazgos potencialmente específicos de sujetos asintomáticos que merecen ser confirmados como tal en futuros estudios.

Abstract Introduction: Ultrasound (US) abnormalities have often been described in the joints of asymptomatic subjects, which may lead to uncertainty in the evaluation and treatment of inflammatory joint disease. Despite this, the available evidence is scarce, with few participants, and in the vast majority with transducers less than 18Mhz. In Colombia there are currently no published studies about this topic. Objectives: To describe the ultrasound findings in hand and foot joints in asymptomatic volunteers, their association with sociodemographic characteristics, and intra- and inter-observer concordance of the measurements. Materials and methods: Descriptive and analytical study within 182 asymptomatic volunteers. Two physicians with musculoskeletal ultrasound experience evaluated the dorsal aspect of 5460 articular recesses using the semi-quantitative scale of Szkudlarek using a 18 MHz linear transducer. Results: The median age of the participants was 42 years, including 60.4% women. A total of 232 abnormal findings were identified in 87% of the volunteers, with 68.1% corresponding to joint effusion, 29.3% synovial hypertrophy, 2.1% erosions, and 0.4% positive power Doppler. The feet evaluation showed more findings than the hands (70.7 vs. 29.3%). The joints in which most abnormalities were identified were the first metatarsophalangeal joint (52%), third metatarsophalangeal joint (15%), and radiocarpal joint (9.5%). A positive association was found between joint effusion and synovial hypertrophy with age, exclusive manual activity, and occupation for more than ten years. The intra-observer concordance was moderate (Kappa = .4591) and the inter-observer was low (Kappa = .2155). Conclusions: The absence of power Doppler signal, the absence of abnormalities in distal radioulnar, the absence of synovitis accompanied by erosion, and a greater predominance of mild alterations in the hand joints, added to the absence of findings in the fifth metatarsal joint, can be potential specific findings of asymptomatic subjects and might be confirmed in future studies.

Rheumatoid arthritis and systemic lupus erythematosus: Pathophysiological mechanisms related to innate immune system.

Rheumatoid arthritis and systemic lupus erythematosus are two highly prevalent autoimmune diseases that generate disability and low quality of life. The innate immune system, a long-forgotten issue in autoimmune diseases, is becoming increasingly important and represents a new focus for the treatment of these entities. This review highlights the role that innate immune system plays in the pathophysiology of rheumatoid arthritis and systemic lupus erythematosus. The role of the innate immune system in rheumatoid arthritis and systemic lupus erythematosus pathophysiology is not only important in early stages but is essential to maintain the immune response and to allow disease progression. In rheumatoid arthritis, genetic and environmental factors are involved in the initial stimulation of the innate immune response in which macrophages are the main participants, as well as fibroblast-like synoviocytes. In systemic lupus erythematosus, all the cells contribute to the inflammatory response, but the complement system is the major effector of the inflammatory process. Detecting alterations in the normal function of these cells, besides its contribution to the understanding of the pathophysiology of autoimmune diseases, could help to establish new treatment strategies for these diseases.