Ivermectin compared with placebo in the clinical course in Mexican patients with asymptomatic and mild COVID-19: a randomized clinical trial.

BACKGROUND: Despite the development and application of vaccines against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) around the world, the scientific community is still trying to find some therapies to avoid or ameliorate the fatal evolution of the Coronavirus disease 2019 (COVID-19). Since the publication of the potential use of ivermectin as a treatment against the disease, a pleiad of information about it has been published. However, the evidence is not strong or weak enough to conclude its usefulness in the clinical evolution of patients infected with SARS-CoV-2. We evaluate the efficacy and safety of ivermectin in the treatment of Mexican patients with asymptomatic and mild COVID-19 in a three-day administration in comparison to placebo. METHODS: A randomized, double-blind, placebo-controlled trial was carried out in 66 adults with asymptomatic and mild COVID-19. Patients were randomly assigned 1:1 ratio to ivermectin plus acetaminophen or placebo plus acetaminophen. The primary endpoint was the proportion of subjects without a disease progression to severity according to COVID-19 guidelines by the National Institutes of Health (NIH) since randomization to 14 days. RESULTS: None of the participants presented progression to a severe state in either group. Viral load was measured on Days 1, 5, and 14. No significant differences were observed in baseline or 14-day between groups (p = 0.720 and 0.362, respectively). However, on Day 5, a significant difference in viral load was observed between groups (p = 0.039). The frequency of symptoms was similar between groups, and no significant differences were observed. The most frequent symptom was cough. One severe adverse event associated with SARS-CoV-2 infection was observed in the ivermectin group. CONCLUSIONS: At standard doses, ivermectin is not effective to prevent progression to a severe state or reducing symptoms in adults with asymptomatic and mild COVID-19. Trial registration The study was registered with ClinicalTrial.gov (NCT04407507) on May 29, 2020.

Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease.

OBJECTIVE: Although blood bank-based studies have shown that rheumatoid arthritis (RA)-related autoantibodies are present before the onset of RA, information on their positive predictive value (PPV) for development of RA in healthy individuals is scarce. This study was undertaken to assess the 5-year PPV of serum IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) for the development of RA among healthy relatives of patients with RA. METHODS: Healthy relatives of RA patients were invited to participate in a cohort study. At baseline, information on participants' medical history was obtained, and serum levels of IgM-RF and anti-CCP antibodies were determined (by nephelometry and second-generation anti-CCP enzyme-linked immunosorbent assay, respectively). The subjects were followed up every 4 months via a structured interview (Community Oriented Program for Control of Rheumatic Diseases [COPCORD] questionnaire). When the COPCORD questionnaire indicated possible arthritis, subjects underwent an in-office rheumatology assessment including joint count. The study end point was defined as fulfillment of the American College of Rheumatology criteria for RA. RESULTS: Eight hundred nineteen initially healthy relatives of 252 patients with RA were included (69% female, 41% offspring, mean ± SD age 35 ± 12 years). Eleven (1.3%) were positive for both anti-CCP-2 and RF, 12 (1.5%) only for anti-CCP-2, and 16 (2%) only for RF. RA developed in 17 (2.1%) of the relatives during the 5-year followup (3,313 person-years for the seronegative group and 60.8 person-years for the anti-CCP-2-positive group). The PPV was 64% when both anti-CCP-2 and RF were positive and 58% when only anti-CCP-2 was positive. Offspring of patients with RA had an independent 3-fold increased risk of developing RA. CONCLUSION: Results of the present study indicate that the magnitude of risk for developing RA in healthy relatives of patients with RA can be estimated using simple routine laboratory tests.

Divergent perceptions in health-related quality of life between family members and patients with rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis.

The aim of this study was to assess whether family members perceive health-related quality of life (HRQoL) of family members with rheumatic illnesses differently from the perceptions of these patients themselves. Cross-sectional study of consecutive patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and ankylosing spondylitis (AS) attending two outpatient rheumatic clinics. HRQoL was assessed using the Spanish version of the World Health Organization Disability Assessment Scale (WHODAS-II) questionnaire; the "proxy" version is available for relatives. All patients and one proxy per patient separately answered the questionnaire at the clinic. Differences were determined by coefficients of determination (r (2)), Z scores, and meaningful differences of 30 %. Two hundred and ninety-one patients (111 SLE, 100 RA, and 80 AS) and their respective proxies were included. The mean age was 35 ± 13 years in SLE, 49.5 ± 14 years in RA, and 40 ± 14 years in AS patients. Divergent perceptions between patients and their proxies were found in 57 % of the SLE group, in 69 % of the RA group, and in 47 % of the AS group as per WHODAS-II global score. Stronger disagreement occurred for all the three groups in domains representing cognition and interaction with other people: around 60 % in the SLE group, 80 % in the RA group, and 40 % in the AS group. A substantial proportion of family members perceived the HRQoL of rheumatic family members differently from the perception of the patients themselves, most of the time biased toward underestimation, suggesting problems in the dynamics of efficient communication and social support.

Sustained clinical remission and rate of relapse after tocilizumab withdrawal in patients with rheumatoid arthritis.

OBJECTIVE: Data on when to stop use of biological agents in rheumatoid arthritis (RA) are scant. We assessed the length of remission and the rate of clinical relapse in patients with RA who had to discontinue treatment with tocilizumab (TCZ) because of the ending of longterm (5 yrs) open-label clinical trials. METHODS: All patients at 2 participating centers in Mexico were in remission, defined as Disease Activity Score 28 ≤ 2.6, with no swollen joints at the time of the last TCZ infusion. Patients were followed thereafter every 8 weeks for 12 months or until relapse. Relapse was defined as the presence of ≥ 1 swollen joint. Doses of methotrexate and antiinflammatory drugs were not changed during the followup period. RESULTS: Forty-five patients were analyzed, 87% were women (mean age 52 yrs, mean disease duration 14 yrs). During the 12 months of followup, 44% of patients maintained remission. Relapses occurred in 56% of patients: 14 during the first 3 months after the last TCZ administration. Retreatment using other agents achieved low disease activity or remission. CONCLUSION: Longterm clinical remission is possible in a number of patients with RA after suspension of TCZ. This effect has also been reported with other biologic agents. Additional data are required to support recommendations for discontinuing a biological agent after achieving remission.

[Anti-transglutaminase, antigladin and ultra purified anti-gladin antibodies in patients with a diagnosis of rheumatoid arthritis]. / Anticuerpos anti-transglutaminasa, anti-gliadina y anti-gliadina ultra-purificada en pacientes con diagnóstico de artritis reumatoide del adulto.

UNLABELLED: Celiac disease (CD) is an enteric disease caused by dietary gluten in individuals with genetic predisposition. One of the clinical manifestations of CD is the peripheral arthritis that may simulate RA. OBJECTIVE: To determine the frequency of anti-gliadin (aGL), anti-tissue transglutaminase (aTGT) and ultra purified anti-gliadin (AGLU) antibodies in patients with RA. METHODS: Cross-sectional study. We included consecutive patients diagnosed as RA (ACR). Demographic and clinical data was registered by direct interview and serum levels of aGL, aTGT y aGLU were determined using ELISA. RESULTS: Eighty-five RA patients were included; 87% were women. Mean age was 44±12 years, mean disease duration 12 ±9 years. aGL IgG antibodies were positive in 16 patients, IgA aGL antibodies in 29 patients, aGLU in 14 patients and only one patient had aTGT. CONCLUSIONS: It is possible that CD may be the correct diagnosis in a patient with polyarthritis, even if the patient meets the ACR criteria for RA. In other words, CD should be considered among the differential diagnoses in a patient with poly-arthritis.

Anticuerpos anti-transglutaminasa, anti-gliadina y anti-gliadina ultra-purificada en pacientes con diagnóstico de artritis reumatoide del adulto / Anti-transglutaminase, antigladin and ultra purified anti-gladin antibodies in patients with a diagnosis of rheumatoid arthritis

La enfermedad celiaca (EC) es una afección entérica ocasionada por la ingesta de granos que contienen gluten. Una manifestación clínica poco reconocida es la artritis periférica, que puede simular artritis reumatoide. Objetivo. Determinar la frecuencia de anti-Gliadina (aGL), anti Transglutaminasa Tisular (aTGT) y anti-Gliadina Ultra-purificada (aGLU) en pacientes con diagnostico de AR. Métodos. Es un estudio transversal de pacientes con AR (criterios ACR). Se registraron variables demográficas y clínicas y se les realizaron determinaciones séricas de anticuerpos aGL, aGLU y aTGT por ELISA. Resultados. Se incluyeron 85 pacientes con AR. El 87% de los pacientes fueron mujeres. El promedio de edad fue de 44 años±12, con una media de 12±9 años de evolución. Los anticuerpos aGL IgG estuvieron positivos en 16 pacientes, los aGL IgA en 29 pacientes, la aGLU en 14 pacientes y solo un paciente fue positivo para aTGT. Conclusiones. Es posible que pacientes con poliartritis y que cumplan con los criterios de clasificación de AR puedan tener de hecho EC. De otra forma, la EC debe considerarse dentro del diagnóstico diferencial de poliartritis (AU)

Celiac disease (CD) is an enteric disease caused by dietary gluten in individuals with genetic predisposition. One of the clinical manifestations of CD is the peripheral arthritis that may simulate RA. Objective. To determine the frequency of anti-gliadin (aGL), anti-tissue transglutaminase (aTGT) and ultra purified anti-gliadin (AGLU) antibodies in patients with RA. Methods. Cross-sectional study. We included consecutive patients diagnosed as RA (ACR). Demographic and clinical data was registered by direct interview and serum levels of aGL, aTGT y aGLU were detrmined using ELISA. Results. Eighty-five RA patients were included; 87% were women. Mean age was 44±12 years, mean disease duration 12 ±9 years. aGL IgG antibodies were positive in 16 patients, IgA aGL antibodies in 29 patients, aGLU in 14 patients and only one patient had aTGT. Conclusions. It is possible that CD may be the correct diagnosis in a patient with polyarthritis, even if the patient meets the ACR criteria for RA. In other words, CD should be considered among the differential diagnoses in a patient with poly-arthritis (AU)

Fifteen-year trends of long-term disability and sick leaves in ankylosing spondylitis.

The aim of this study is to assess the trends in work disability and sick leave in ankylosing spondylitis (AS). In 1993 and 2007, patients diagnosed with AS that attended to a secondary- or a tertiary-care outpatient rheumatology clinics were evaluated for demographics, disease characteristics, axial mobility, working status, and work days missed due to sick leave or permanent disability. Factors that impacted labor status were identified by multiple regression analysis. In 1993, 91 study individuals (mean age 35 years, mean disease duration 10 ± 8 years) included 28 (31%) on permanent disability and 63 currently working; of these 63, 42 (67%) had missed at least 1 work day in the previous 12 months (mean 69 ± 63 days). In the next 5 years, the annual permanent disability was 3%. In 2007, 185 study individuals (mean age 42, mean disease duration 12 ± 10 years) included 53 (39%) on permanent disability and 132 active workers; 35 (66%) out of the 53 began permanent disability between 1999 and 2007 (2.1% annual disability rate), and 53 (40%) out of 132 active workers missed at least 1 work day in the previous 12 months (mean 52 ± 63 days). Only age predicted disability, with 10% and 11% increases in risk per year in 1993 and 2007, respectively (hazard ratios 1.09 and 1.11, respectively; p = 0.03 for both). Although the impact of AS on work seems to decrease slightly during the last 15 years, the actual impact is still substantial. An important proportion of patients went on permanent disability in the three decades before retirement. Extrapolating these results to official data for the year 2005, we may infer that between 1.3 million and nearly 15 million working days were missed that year due to AS.

Tendinous and ligamentous derangements in systemic lupus erythematosus.

OBJECTIVE: We assessed the prevalence of selected clinical and radiological features of tendinous and ligamentous derangements in a consecutive sample of patients with systemic lupus erythematosus (SLE). METHODS: Consecutive patients with SLE with no comorbidities attending a tertiary care center were prospectively assessed and underwent plain radiographic evaluation of the pelvis. Radiographs were analyzed by 2 blinded observers; radiographic sacroiliitis was graded 0 to IV. To better assess sacroiliac (SI) involvement, a computed tomography (CT) scan of the SI joints was performed in patients with grade III sacroiliitis. Hip joints and pubis were also assessed as described. RESULTS: Of the 192 included patients, 89% were female, mean age was 36 years, and mean disease duration was 10 years. Inflammatory low back pain was reported by 10% of patients. Sacroiliitis of any grade was observed in 31 patients (16%), and grade III (confirmed on CT scan) sacroiliitis was observed in 6% (95% CI 3% to 9%). Osteitis pubis was diagnosed in 6% (95% CI 3% to 10%) and coxofemoral migration in 8% (95% CI 2% to 9%). Jaccoud's arthropathy was found in 23%. Demographic and clinical variables were not statistically associated with radiographic sacroiliitis. CONCLUSION: Sacroiliitis and other tendinous and ligamentous derangements are not uncommon in patients with SLE. Based on these features and on previous reports, the term "SLE-related tendinous and ligamentous derangements" may be used to establish a common framework for further research and reporting.

Latitude gradient influences the age of onset in rheumatoid arthritis patients.

The mean age of rheumatoid arthritis (RA) onset is around 50 years as reported in several clinical trials involving Caucasian patients. However, clinical observations suggest that Mexican RA patients' disease is initiated at a younger age. The objective of the study was to assess whether the age of onset of RA is different in Mexican and in Canadian RA patients. Certified rheumatologists from Canada and Mexico directly interviewed consecutive RA patients attending their clinics regarding the date patients first noticed a swollen joint. None of the participant rheumatologists were aware of the primary aim of this exploratory study at the time of the interviews. Data was gathered from 161 Mexican (91% women) and 130 Canadian (77% women) RA patients collected by three rheumatologists in each country. Duration since disease onset was not different within countries (mean 95% confidence interval [CI] for differences -10 to 16 years, p = 0.12 for Canadians, and -6 to 10 years, p = 0.26, for Mexicans). However, there was a significant difference between the two countries. Mexicans patients on average developed RA almost 12 years younger than Canadians (95% CI for difference 9 to 15 years, p < 0.001). Frequency distribution showed that 35.5% of Canadians but only 4% of Mexicans had the onset of the disease after the age of 55 (all p < 0.001). It appears that RA begins at a much younger age in Mexican than Canadian patients. If this were confirmed after controlling for different confounders and biases, it would have important societal, economic, and therapeutic implications.

Interleukin 1beta (IL-1beta), IL-10, tumor necrosis factor-alpha, and cellular proliferation index in peripheral blood mononuclear cells in patients with ankylosing spondylitis.

OBJECTIVE: To evaluate cytokine production and cellular proliferation index (CPI) in peripheral blood mononuclear cells (PBMC) of patients with ankylosing spondylitis (AS), and their association with clinical variables. METHODS: In a cross sectional study we compared the production of tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and IL-10 and CPI in response to phytohemagglutinin (PHA) in PBMC of 27 patients with AS and 24 healthy controls. We also assessed clinical characteristics including disease activity index (BASDAI) and functional index (BASFI). RESULTS: Levels of IL-1beta were higher in patients with AS (median 242 pg/ml) than in controls (median 65 pg/ml); p = 0.002. No differences were observed in median levels of TNF-alpha or IL-10 between AS and controls. Patients had a reduction in CPI (1.2 in AS vs 1.8 in controls; p < 0.001). A positive correlation was observed between IL-10 production and age (rho = 0.34, p = 0.01). A borderline negative correlation was observed between CPI and age (rho = -0.26, p = 0.07). CONCLUSION: Patients with AS had high production of IL-1beta compared with controls and a poor response in CPI. These findings may explain the lack of response for microbial antigens mediated by the innate immune response.

Evaluación de la genotoxicidad de ciclofosfamida mediante prueba de micronúcleos en pacientes con lupus eritematoso sistémico / Assessment by micronuclei assay of genotoxicity by cyclophosphamide in systemic lupus erythematosus patients

Los pacientes con lupus eritematoso sistémico (LES) tienen un mayor riesgo para desarrollar cáncer. La ciclofosfamida (CFA) representa también un riesgo para desarrollar cáncer a largo plazo. Este medicamento se utiliza en pacientes con LES. La prueba de micronúcleos (MN) se ha utilizado para valorar genotoxicidad. No se ha estudiado si el uso de este fármaco en pacientes con LES induce MN.Objetivos: Evaluar si los pacientes con LES tratados con ciclofosfamida (CFA) tienen más micronúcleos que los controles sanos. Pacientes y Métodos: Se estudiaron pacientes con LES que estuvieran manejados con bolos mensuales de CFA. Los pacientes fueron evaluados por un cuestionario estructurado para variables demográficas y clínicas. Se determinaron MN en 4 ocasiones diferentes mediante raspado de mucosa oral; la primera toma fue inmediatamente antes del bolo, la segunda a los 14 días, la tercera inmediatamente antes del siguiente bolo y la última 14 días después. Cuarenta y tres voluntarios sanos sirvieron como controles. Un técnico cegado a datos demográficos de los pacientes cuantificó los MN. Resultados: Se incluyeron 10 pacientes; todos fueron mujeres; el promedio de edad fue de 38 ñ 8 años y el de la duración de la enfermedad de 9 ñ 5 años. El promedio de SLEDAI-MEX al inicio del estudio fue de 7.1 ñ 3.5. Se hicieron 34 determinaciones de MN en 10 pacientes (7 pacientes con 4 determinaciones, 3 pacientes con 2 determinaciones). El promedio global de MN en las pacientes con LES fue de 3.6 ñ 1.3 y de los controles de 1.3 ñ 1.3 (p=0.001). El número de MN fue mayor a los 14 días en comparación con las determinaciones antes de la administración del bolo. Conclusión: El número de MN en pacientes con LES tratados con CFA es mayor que en controles sanos, lo que refleja daño citogenético. Los resultados sugieren que el incremento de MN es mayor 14 días después de la exposición a la CFA. Serán necesarios estudios con mayor número de pacientes y seguimiento a largo plazo para determinar el riesgo que representan los MN para el desarrollo de cáncer.