Sebastião Cezar Radominski

Five years of denosumab exposure in women with postmenopausal osteoporosis: Results from the first two years of the FREEDOM extension.

The 3‐year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long‐term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross‐over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long‐term; 2207 cross‐over). Reductions in BTMs were maintained (long‐term group) or occurred rapidly (cross‐over group) following denosumab administration. In the long‐term group, lumbar spine and total hip BMD increased further, resulting in 5‐year gains of 13.7% and 7.0%, respectively. In the cross‐over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2‐year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a “virtual untreated twin” cohort. Adverse events did not increase with long‐term denosumab administration. Two adverse events in the cross‐over group were adjudicated as consistent with osteonecrosis of the jaw. Five‐year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile.

The Effect of Three or Six Years of Denosumab Exposure in Women With Postmenopausal Osteoporosis: Results From the FREEDOM Extension

Context: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. Objective: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. Design, Setting, and Participants: This was a multicenter, international, open-label study of 4550 women. Intervention: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). Main Outcome Measures: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. Results: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. Conclusion: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

Analysis of Infections and All-Cause Mortality in Phase II, Phase III, and Long-Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis†

To determine the rate of infection and all‐cause mortality across tofacitinib phase II, phase III, and long‐term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).

Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

The efficacy and safety of subcutaneous tocilizumab (TCZ‐SC) versus subcutaneous placebo (PBO‐SC) was evaluated in patients with rheumatoid arthritis who had an inadequate response to disease‐modifying antirheumatic drugs in the BREVACTA study.

Diretrizes para prevenção e tratamento da osteoporose induzida por glicocorticoide

UNLABELLED Glucocorticoids (GC) are used in almost all medical specialties, and approximately 0.5% of the general population of the United Kingdom receives those medications. With the increased survival of patients with rheumatological diseases, morbidity secondary to the use of those medications represents an important aspect of the management of our patients. The incidences of vertebral and non-vertebral fractures are elevated, ranging from 30% to 50% of the individuals on GC for over three months. Thus, osteoporosis and frailty fractures should be prevented and treated in all patients initiating or already on GC. There are several recommendations on this topic elaborated by several international societies, but consensus still lacks. Recently, the American College of Rheumatology has published new recommendations, but they are based on the WHO Fracture Risk Assessment Tool (FRAX®) to evaluate the risk for each individual, and, thus, cannot be completely used for the Brazilian population. Thus, the Committee for Osteoporosis and Bone Metabolic Disorders of the Brazilian Society of Rheumatology, along with the Brazilian Medical Association and the Brazilian Association of Physical Medicine and Rehabilitation, has elaborated the Brazilian Guidelines for Glucocorticoid-Induced Osteoporosis (GIO), based on the better available scientific evidence and/or expert experience. METHOD OF EVIDENCE COLLECTION The bibliographic review of scientific articles of this guideline was performed in the MEDLINE database. The search for evidence was based on real clinical scenarios, and used the following keywords (MeSH terms): Osteoporosis, Osteoporosis/ chemically induced*= (Glucocorticoids= Adrenal Cortex Hormones, Steroids), Glucocorticoids, Glucocorticoids/administration and dosage, Glucocorticoids/therapeutic use, Glucocorticoids/adverse effects, Prednisone/adverse effects, Dose-Response Relationship, Drug, Bone Density/drug effects, Bone Density Conservation Agents/pharmacological action, Osteoporosis/prevention & control, Calcium, Vitamin D, Vitamin D deficiency, Calcitriol, Receptors, Calcitriol; 1-hydroxycholecalciferol, Hydroxycholecalciferols, 25-Hydroxyvitamin D3 1-alpha-hydroxylase OR Steroid Hydroxylases, Prevention and Control, Spinal fractures/prevention & control, Fractures, Spontaneous, Lumbar Vertebrae/injuries, Lifestyle, Alcohol Drinking, Smoking OR tobacco use disorder, Movement, Resistance Training, Exercise Therapy, Bone density OR Bone and Bones, Dual-Energy X-Ray Absorptiometry OR Absorptiometry Photon OR DXA, Densitometry, Radiography, (Diphosphonates Alendronate OR Risedronate Pamidronate OR propanolamines OR Ibandronate OR Zoledronic acid, Teriparatide OR PTH 1-34, Men AND premenopause, pregnancy, pregnancy outcome maternal, fetus, lactation, breast-feeding, teratogens, Children (6-12 years), adolescence (13-18 years). GRADE OF RECOMMENDATION AND LEVEL OF EVIDENCE A) Data derived from more consistent experimental and observational studies; B) Data derived from less consistent experimental and observational studies; C) Case reports (uncontrolled studies); D) Expert opinion without explicit critical appraisal, or based on consensus, physiological studies or animal models. OBJECTIVE To establish guidelines for the prevention and treatment of GIO.

A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis

Objective To demonstrate pharmacokinetic equivalence of CT-P10 and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate responses or intolerances to antitumour necrosis factor agents. Methods In this randomised phase I trial, patients with active RA were randomly assigned (2:1) to receive 1000 mg CT-P10 or RTX at weeks 0 and 2 (alongside continued methotrexate therapy). Primary endpoints were area under the serum concentration–time curve from time zero to last quantifiable concentration (AUC0–last) and maximum serum concentration after second infusion (Cmax). Additional pharmacokinetic parameters, efficacy, pharmacodynamics, immunogenicity and safety were also assessed. Data are reported up to week 24. Results 103 patients were assigned to CT-P10 and 51 to RTX. The 90% CIs for the ratio of geometric means (CT-P10/RTX) for both primary endpoints were within the bioequivalence range of 80%–125% (AUC0–last: 97.7% (90% CI 89.2% to 107.0%); Cmax: 97.6% (90% CI 92.0% to 103.5%)). Pharmacodynamics and efficacy were comparable between groups. Antidrug antibodies were detected in 17.6% of patients in each group at week 24. CT-P10 and RTX displayed similar safety profiles. Conclusions CT-P10 and RTX demonstrated equivalent pharmacokinetics and comparable efficacy, pharmacodynamics, immunogenicity and safety. Trial registration number NCT01534884.

Treatment of early rheumatoid arthritis in a multinational inception cohort of Latin American patients: the GLADAR experience.

Background Treatment of rheumatoid arthritis (RA) has evolved dramatically in the last decade. However, little is known about the way rheumatologists in Latin America treat their patients in clinical practice, outside the scope of clinical trials. Objective The objective of this study was to describe treatment patterns at disease onset in early RA with data from a large, multicenter, multinational inception cohort of Latin American patients. Methods Consecutive patients with early RA (<1 year of disease duration as diagnosed by a rheumatologist) from 46 centers in 14 Latin American countries were enrolled in the study. Clinical data, laboratory assessments, and a detailed registry on type of prescriptions were collected at baseline and at 3, 6, 12, 18, and 24 months of follow-up. Hands and feet x-rays were obtained at baseline and at 12 and 24 months. All data were captured in Arthros 6.1 database. Continuous variables were expressed as means and SDs, and categorical variables were expressed as percentages and 95% confidence intervals (95% CIs). Only therapeutic data at baseline are presented, corresponding to the period between disease onset and second visit (3 months). Results A total of 1093 patients were included. Eighty-five percent were female, and 76% had a positive rheumatoid factor. Mean age at diagnosis was 46.5 (SD, 14.2) years, and mean disease duration at the first visit was 5.8 (SD, 3.8) months. Between baseline and second visit (3 months), 75% of patients (95% CI, 72%–78%) received disease-modifying antirheumatic drugs. Methotrexate (MTX) alone or in combination was the most frequently used (60.5%), followed by antimalarials (chloroquine or hydroxychloroquine, 32.1%), sulfasalazine (7.1%), and leflunomide (LEF, 4%). In 474 patients (43%), initiation of disease-modifying antirheumatic drugs was within the first month after the first visit. In addition, 290 patients (26%; 95% CI, 23%–29%) received combination therapy as initial treatment. The most frequently used combinations were MTX + chloroquine (45%), MTX + hydroxychloroquine (25%), and MTX + sulfasalazine (16%). Eleven patients (1%; 95% CI, 0.5%–1.8%) received biologics. Sixty-four percent (95% CI, 60%–66%) received corticosteroids. Of those, 80% (95% CI, 77%–84%) received 10 mg of oral prednisone or less. Conclusions In this cohort of Latin American patients with early RA, most patients received MTX very early in their disease course. Combination therapy was used approximately in 1 of every 4 patients as initial therapy. Biologics were rarely used at this early stage, and low-dose prednisone was commonly used.

Perfil de autoanticorpos e correlação clínica em um grupo de pacientes com esclerose sistêmica na região sul do Brasil

OBJECTIVES: To assess the manifestations of systemic sclerosis (SSc), with an emphasis on the analysis of autoantibodies and their clinical correlations, in a population of patients followed up at the SSc Outpatient Clinics of the Hospital de Clinicas of the Universidade Federal do Parana. METHODOLOGY: Cross-sectional study with 96 patients followed up at the SSc Outpatient Clinics of the hospital between September 2007 and September 2009. RESULTS: Most patients were of the female sex, in their forties or fifties, and the median time of disease was ten years. The limited cutaneous form of SSc was more prevalent. The analysis of the autoantibodies showed the association of anticentromere antibody (ACA) with the following: the limited form of SSc; more advanced age at the time of diagnosis; longer disease time; longer interval between the appearance of the Raynauds phenomenon (RyP) and the first non-RyP symptom; systemic arterial hypertension (SAH); and cardiac conduction blocks. The antitopoisomerase-1 antibody (ATA-1, previously called anti-Scl-70) was more common in the presence of the diffuse form of SSc, active disease, and digital ulcers. The anti-RNA polymerase III antibody (anti-Pol III) correlated with the diffuse form of SSc, disease activity, and synovitis. CONCLUSIONS: This study emphasizes and confirms the important role of autoantibodies in assessing patients with SSc, allowing the correlation between the autoimmune profile of patients with SSc and specific manifestations of the disease

Diagnóstico e tratamento das lombalgias e lombociatalgias

DESCRICAO DO METODO DE COLETA DE EVIDENCIAS: Reuniao consensual e multidisciplinar para elaboracao do texto com inclusao das citacoes bibliograficas, numa colaboracao das especialidades de reumatologia, ortopedia e traumatologia, neurocirurgia, radiologia, medicina fisica e reabilitacao e patologia da coluna vertebral. A partir de um texto basico referencial elaborado pelo editor medico, os participantes, divididos em cinco grupos de trabalho, geraram, por acrescimos e subtracoes ao texto basico, recomendacoes aprovadas, posteriormente, em plenaria, que permitiram a edicao de um texto preliminar. O documento do consenso foi veiculado pela Internet, para consulta publica, tendo recebido varias sugestoes e comentarios de especialistas no assunto. As propostas foram devidamente avaliadas por uma comissao julgadora e revisora, que selecionou as que foram incorporadas ao texto preliminar. O editor medico, a partir da versao revisada, chegou ao texto final publicado, que recebeu da Biblioteca Nacional o ISBN n° 85-901548-1-5. Uma versao resumida do referido consenso, com algumas adequacoes, foi elaborada em trabalho colaborativo entre o editor medico e a comissao tecnica do projeto diretrizes AMB/CFM. GRAU DE RECOMENDACAO E FORCA DE EVIDENCIA: A: Grandes ensaios clinicos aleatorizados e meta-analises. B: Estudos clinicos e observacionais bem desenhados. C: Relatos e series de casos clinicos. D: Publicacoes baseadas em consensos ou opinioes de especialistas. OBJETIVOS: Oferecer informacoes sobre o diagnostico e tratamento das lombalgias e lombociatalgias. PROCEDIMENTOS: Diagnosticos e terapeuticos para as lombalgias e lombociatalgias.

Fracture risk assessment in Latin America: is Frax™ an adaptable instrument for the region?

Osteoporosis is a generalized disease of bone that increases fracture risk. Multiple factors influence this risk, besides low bone mass. To decrease osteoporotic fractures, those patients who require preventive management should be readily identified. This paper aims to review current information on the use of the fracture risk assessment tool (FRAX™) in Latin America. Bone mineral density measurement is currently the method of reference for evaluating the fracture risk and opting for treatment; but, it misses a notable proportion of individuals who have clinical risk factors for osteoporosis and fractures. FRAX™ was designed to predict the 10-year absolute risk of sustaining a major osteoporotic fracture or a hip fracture. Although data is available for several countries, from Latin America, only Argentina appears in the current version of the tool. Its present use in other Latin American countries is possible with some adaptations based in similarities of epidemiological information of each country with some of the existing databases. The cutoff value beyond which treatment should be initiated needs to be determined, based not only on clinical criteria, but also on economic considerations.