Knowledge gap about immune checkpoint inhibitors among rheumatologists and medical students: a survey.

Previous studies found that physicians working in developed countries in Europe and in the USA declared insufficient knowledge concerning immune-related adverse events (irAE) following use of immune checkpoint inhibitors (ICI) in cancer treatment. We determined this knowledge gap among rheumatologists and medical students (MS) in Brazil. A web-based structured survey or a direct interview was applied to 1428 board-certified Brazilian rheumatologists and an adapted questionnaire was sent to 840 undergraduate MS attending the last 2 years of Medical Schools in Fortaleza-CE, Brazil, in September 2019. 228 (15.9%) rheumatologists and 145 (17.2%) MS answered the survey; 136 (60%) rheumatologists worked at Institutions with Oncology service. Rheumatologists had 22.6 ± 12.6 years of medical practice, most [116 (50.9%)] worked in private practice and 9 (3.9%) were on training. Fifty-three (23.4%) declared being familiar [40 (17.6%)] or very familiar [13 (5.8%)] with irAE. Almost two-thirds declared having never managed irAE and about a third (38.6%) felt confident in managing such patients. Knowledge among rheumatologists was similar regardless of having more or less than 10 years of practice (P = 0.758). Less than 5% MS declared being familiar with ICI and most have never heard of irAE. There is a large gap concerning knowledge about ICI and irAE among rheumatologists and MS in Brazil. Continuing medical education strategies are needed to improve this knowledge.

Lupus low disease activity (SLE) in patients treated with belimumab: a single-center real-life experience (2016-2019).

INTRODUCTION: We have been conducting an evaluation of innovative therapies in patients with SLE during the past 15 years. We combine the results observed on extension studies from four different trials in patients receiving either intravenous or subcutaneous belimumab, and evaluated, in Caucasian and Black Brazilian patients. METHODS: Seventy-four patients were part of the study. The Lupus Low Disease Activity State (LLDAS) shown to be an available tool to detect a response in trials was used in this study and statistical comparisons between the different result groups were determined. The period of evaluation was from 12 to 48 months. RESULTS: Seventy-four patients completed the initial study. Four refused to continue the extension evaluation. Seven belonged to the black group (10%); sixty-three were Caucasian (90%). One patient was discontinued due to pregnancy. Nine received a subcutaneous presentation (12.8%). In the subgroup analysis, one patient in the black group had flare (14.2%); five in the intravenous administration had severe flares (8.1%) and were discontinued. Ten had flares adjusted with steroids (eight articular or skin reactivation) and two with renal disease. Of the five severe flares, two required hospitalization. The mean time duration to achieve LLDAS was 6 months. Twenty-seven achieved a steroid-free status and the remaining two patients on 2.5 mg and seventeen were stable on daily 5.0  mg of prednisone. CONCLUSIONS: Using the LLDAS, it was possible to show that the majority of patients receiving belimumab for prolonged periods go into remission steroid-free or in low disease activity in association with the corresponding immunosuppressive treatment. Key Points • Prolonged real-life evaluation confirms the efficacy and steroid-sparing of Belimumab in SLE patients with active disease.

Treatment of knee osteoarthritis with a new formulation of a fixed-dose combination of glucosamine sulfate and bovine chondroitin: a multicenter, randomized, single-blind, non-inferiority clinical trial.

OBJECTIVES: To compare the efficacy and safety of a new formulation of a fixed dose combination of glucosamine sulfate (GS; 1500 mg) and bovine chondroitin sulfate (CS; 1200 mg) versus the reference product (RP) in patients with knee osteoarthritis (OA). METHODS: In this multicenter, randomized, single-blind trial, 627 patients with knee osteoarthritis (OA)-Kellgren-Lawrence grades 2 or 3 and mean score ≥ 40 mm in the WOMAC pain subscale-were randomized to receive GS/CS or the RP for 24 weeks. The primary efficacy endpoint was the absolute change in WOMAC pain subscale score. The secondary endpoints included the following: WOMAC total and subscale scores, overall assessment of the disease by the patient and the investigator, SF-12 score, OMERACT-OARSI response rate to the treatment, and rescue medication use. RESULTS: Mean reductions of WOMAC pain score were - 35.1 (sd = 23.2) mm in the GS/CS group and - 36.5 (sd = 24.9) mm in the RP group. The difference between the adjusted means of both treatments confirmed the non-inferiority of GS/CS versus the RP. Improvement was observed in pain, stiffness, physical function and total WOMAC score, as well as in overall OA assessment by the patient and the investigator for both groups. No improvement was observed in SF-12. The rate of OMERACT-OARSI responders was 89.4% in GS/CS group and 87.9% in the RP group. Headache and changes in glucose tolerance were the most frequent treatment-related adverse events. CONCLUSIONS: The new formulation of a fixed-dose combination of glucosamine sulfate and bovine chondroitin sulfate was non-inferior to the RP in symptomatic treatment of knee OA, with a high responder rate and good tolerability profile. TRIAL REGISTRATION: ClinicalTrials.gov; Registration number NCT02830919 ; Date of registration: July 13, 2016; First randomization date: December 05, 2016).

Atopic dermatitis: Tofacitinib, an option for refractory disease.

Atopic dermatitis (AD) is a common skin disease, associated with high burden impact in quality of live, in moderate-severe disease severity. Several targeted drugs are under development for AD. Here, we present a patient with refractory disease to systemic traditional immunosuppressive drugs, treated successfully with oral tofacitinib, with complete response.

An excellent response to tofacitinib in a Brazilian adolescent patient with alopecia areata: A case report and a review of the literature.

Alopecia areata is a common autoimmune disease, with a negative impact in health-related quality of life, especially when affecting children and adolescents. Current medical therapies, mainly for severe disease, are not effective. There are no FDA (Food and Drug Administration)- or ANVISA (Agência Nacional de Vigilância Sanitária)-approved therapy for children with alopecia areata. JAK inhibitors are emerging as a promising therapy.

Partnership for productive development of biosimilar products: perspectives of access to biological products in the Brazilian market.

The manufacturing process for biological products is complex, expensive and critical to the final product, with an impact on their efficacy and safety. They have been increasingly used to treat several diseases, and account for approximately 50% of the yearly budget for the Brazilian public health system. As the patents of biological products expire, several biosimilars are developed. However, there are concerns regarding their efficacy and safety; therefore, the regulatory agencies establish rules to approve and monitor these products. In Brazil, partnership programs between national government-owned companies and private technology holders have been implemented, aiming at knowledge sharing, capacity-building and technological transfer. Such partnerships locally promote manufacturing of these strategic drugs at reduced costs to the public health system. These agreements offer mutual advantages to both the government and patent holders: for the former, a biotechnological development flow is established and enables potential cost reduction and self-sufficient production; whereas for the latter, exclusive sales of the product are ensured during technological transfer, for a fixed period.

Ganciclovir-resistant, cytomegalic interstitial lung disease in a patient with systemic lupus erythematosus.

A patient with systemic lupus erythematosus developed interstitial lung disease initially felt to be a manifestation of the disease but that, on further workup, proved to be a manifestation of cytomegalic disease resistant to ganciclovir. Treatment with foscarnet was associated with prompt improvement.

Double-blind, randomized, double-dummy clinical trial comparing the efficacy of ketorolac trometamol and naproxen for acute low back pain.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common type of medication used in the treatment of acute pain. Ketorolac trometamol (KT) is a nonnarcotic, peripherally acting nonsteroidal anti-inflammatory drug with analgesic effects comparable to certain opioids. OBJECTIVE: The aim of this study was to compare the efficacy of KT and naproxen (NA) in the treatment of acute low back pain (LBP) of moderate-to-severe intensity. PATIENTS AND METHODS: In this 10-day, Phase III, randomized, double-blind, double-dummy, noninferiority trial, participants with acute LBP of moderate-to-severe intensity as determined through a visual analog scale (VAS) were randomly assigned in a 1:1 ratio to receive sublingual KT 10 mg three times daily or oral NA 250 mg three times daily. From the second to the fifth day of treatment, if patient had VAS >40 mm, increased dosage to four times per day was allowed. The primary end point was the reduction in LBP as measured by VAS. We also performed a post hoc superiority analysis. RESULTS: KT was not inferior to NA for the reduction in LBP over 5 days of use as measured by VAS scores (P=0.608 for equality of variance; P=0.321 for equality of means) and by the Roland-Morris Disability Questionnaire (P=0.180 for equality of variance test; P=0.446 for equality of means) using 95% confidence intervals. The percentage of participants with improved pain relief 60 minutes after receiving the first dose was higher in the KT group (24.2%) than in the NA group (6.5%; P=0.049). The most common adverse effects were heartburn, nausea, and vomiting. CONCLUSION: KT is not inferior in efficacy and delivers faster pain relief than NA.

Treatment of knee osteoarthritis with a new formulation of a fixed-dose combination of glucosamine sulfate and bovine chondroitin: a multicenter, randomized, single-blind, non-inferiority clinical trial

Abstract Objectives: To compare the efficacy and safety of a new formulation of a fixed dose combination of glucosamine sulfate (GS; 1500 mg) and bovine chondroitin sulfate (CS; 1200 mg) versus the reference product (RP) in patients with knee osteoarthritis (OA). Methods: In this multicenter, randomized, single-blind trial, 627 patients with knee osteoarthritis (OA)—Kellgren-Lawrence grades 2 or 3 and mean score ≥ 40 mm in the WOMAC pain subscale—were randomized to receive GS/ CS or the RP for 24 weeks. The primary efficacy endpoint was the absolute change in WOMAC pain subscale score. The secondary endpoints included the following: WOMAC total and subscale scores, overall assessment of the disease by the patient and the investigator, SF-12 score, OMERACT-OARSI response rate to the treatment, and rescue medication use. Results: Mean reductions of WOMAC pain score were - 35.1 (sd = 23.2) mm in the GS/CS group and - 36.5 (sd = 24.9) mm in the RP group. The difference between the adjusted means of both treatments confirmed the noninferiority of GS/CS versus the RP. Improvement was observed in pain, stiffness, physical function and total WOMAC score, as well as in overall OA assessment by the patient and the investigator for both groups. No improvement was observed in SF-12. The rate of OMERACT-OARSI responders was 89.4% in GS/CS group and 87.9% in the RP group. Headache and changes in glucose tolerance were the most frequent treatment-related adverse events. Conclusions: The new formulation of a fixed-dose combination of glucosamine sulfate and bovine chondroitin sulfate was non-inferior to the RP in symptomatic treatment of knee OA, with a high responder rate and good tolerability profile. Trial registration: ClinicalTrials.gov; Registration number NCT02830919; Date of registration: July 13, 2016; First randomization date: December 05, 2016).(AU)

Bone health in cerebral palsy and introduction of a novel therapy.

OBJECTIVE: To assess the bone health status of children with cerebral palsy and the therapeutic effect of denosumab in a subgroup of children with cerebral palsy and decreased bone mass. METHODS: Children with cerebral palsy were evaluated according to their motor disability score (classification system gross motor functions III to V), bone density and bone turnover markers. Dual X-ray energy absorption was used to measure the lumbar spine, and total body, except the head. Thereafter a group of children with cerebral palsy and osteoporosis was treated with denosumab, a fully human monoclonal antibody. Bone turnover markers were measured before and three months after treatment. RESULTS: Reduction in bone mineral density was observed, particularly in children with greater impairment evaluated by the motor score. Decreased bone turnover markers were found in a selected group of children three months after exposure to denosumab. CONCLUSION: Bone loss was present in children with significant impairment of motor function, as well as decreased serum levels of bone resorption markers with new forms.

Comparison of thromboprophylaxis patterns in arthroplasty in public and private hospitals.

OBJECTIVE: To compare therapy for prophylaxis of venous thromboembolism and costs related to hospitalization of patients undergoing total knee and hip replacement within the context of the Brazilian health system. METHODS: A retrospective study of patients undergoing arthroplasty in 2010 in a public hospital and two private hospitals in the state of São Paulo, conducted by means of medical record review. Costs were estimated based on the use of health care resources during hospitalization. A descriptive analysis was performed using frequency and mean (standard deviation) according to the type of care delivered (by public or private organization). RESULTS: A total of 215 patients were evaluated, and 56.3% were submitted to knee surgery and 43.7%, to hip replacement. Approximately 88% and 98% of patients from public and private health services, respectively, received some form of venous thromboembolism prophylaxis, and enoxaparin was the drug most widely used in both systems. The total cost of prophylaxis was R$ 1,873.01 (R$ 26.38 per patient) in the public service and R$ 21,559.73 (R$ 163.33 per patient) in the private service. For the individuals who presented with thromboembolism, the average cost of hospitalization was R$ 6,210.80 and R$ 43,792.59 per patient in public and private health services, respectively. CONCLUSION: Thromboembolism prophylaxis in patients undergoing arthroplasty is most commonly used in the private health services than public organizations, despite its high costs in both services. The cost per patient with thrombosis during hospitalization was higher than the total cost of prophylaxis, suggesting that prevention is associated to better cost-benefit ratio.

Use of rituximab as a treatment for systemic lupus erythematosus: retrospective review.

OBJECTIVE: To report the experience in three Brazilian institutions with the use of rituximab in patients with different clinical forms of lupus erythematosus systemic in activity. METHODS: The study consisted of a sample of 17 patients with LES, who were already being treated, but that at some stage of the disease showed refractory symptoms. The patients were subdivided into groups according to the clinical manifestation, and the responses for the use of rituximab were rated as complete, partial or no response. Data were collected through a spreadsheet, and used specific parameters for each group. The treatment was carried on by using therapeutic dose of 1g, and repeating the infusion within an interval of 15 days. RESULTS: The clinical responses to rituximab of the group only hematological and of the group only osteoarticular were complete in all cases. In the renal group there was a clinical complete response, two partial and one absent. In the renal and hematological group complete response, there was one death and a missing response. The pulmonary group presented a complete response and two partial. CONCLUSION: The present study demonstrated that rituximab can bring benefits to patients with lupus erythematosus systemic, with good tolerability and mild side effects; it presented, however, variable response according to the system affected.

Retention rates of infliximab and tocilizumab during a 3-year period in a Brazilian hospital.

OBJECTIVE: To compare the efficacy and the period of use of tocilizumab and infliximab during treatment of rheumatoid arthritis patients. METHODS: The period of use of two biologics with different mechanisms of action were compared in treatment of rheumatoid arthritis patients. RES ULTS: Both medications showed efficacy, but the period of use with no loss of efficacy was longer in patients receiving tocilizumab when compared to infliximab. CONCLUSION: Tocilizumab maintains a period of use significantly longer as compared with infliximab in patients with rheumatoid arthritis treated at a single organization.

Partnership for productive development of biosimilar products: perspectives of access to biological products in the Brazilian market / Parceria para o desenvolvimento produtivo com produtos biossimilares: perspectivas de acesso a produtos biológicos no mercado brasileiro

ABSTRACT The manufacturing process for biological products is complex, expensive and critical to the final product, with an impact on their efficacy and safety. They have been increasingly used to treat several diseases, and account for approximately 50% of the yearly budget for the Brazilian public health system. As the patents of biological products expire, several biosimilars are developed. However, there are concerns regarding their efficacy and safety; therefore, the regulatory agencies establish rules to approve and monitor these products. In Brazil, partnership programs between national government-owned companies and private technology holders have been implemented, aiming at knowledge sharing, capacity-building and technological transfer. Such partnerships locally promote manufacturing of these strategic drugs at reduced costs to the public health system. These agreements offer mutual advantages to both the government and patent holders: for the former, a biotechnological development flow is established and enables potential cost reduction and self-sufficient production; whereas for the latter, exclusive sales of the product are ensured during technological transfer, for a fixed period.

RESUMO O processo de manufatura de produtos biológicos é complexo, oneroso e crítico para o produto final, com impacto em sua eficácia e segurança. Seu uso está sendo cada vez mais ampliado no tratamento de diversas doenças, e cerca de 50% do orçamento anual do sistema de saúde público brasileiro é consumido por tais produtos. Com o término da proteção de patentes de produtos biológicos diversos, estão sendo desenvolvidos os biossimilares. Porém, há preocupações relacionadas com sua eficácia e segurança, fazendo com que os órgãos reguladores criem regulamentações para sua aprovação e monitoramento. No Brasil, estão sendo implantados programas de parceria entre laboratórios públicos nacionais e laboratórios detentores de tecnologia, objetivando a obtenção de conhecimento, capacitação profissional e transferência desta tecnologia. Tais parcerias visam à produção local destes medicamentos estratégicos a um custo reduzido para o Sistema Único de Saúde. Os acordos oferecem vantagens mútuas para o governo e o laboratório detentor da patente do produto biológico: ao primeiro, estabelece-se um fluxo de desenvolvimento biotecnológico, que possibilita potencial redução de custos e autossuficiência na produção, enquanto ao segundo garante-se a exclusividade da venda do produto durante a transferência da tecnologia por um prazo estabelecido.

Livedo reticularis associated with autoimmune hemolytic anemia: prolonged remission induced by peripheral blood stem cell transplantation relapse after 10 years and restoration of hemoglobin levels by rituximab.

Autoimmune hemolytic anemia (AIHA) is a disease where patients produce antibodies against erythrocytes directed towards membrane glycoproteins adsorbed onto the erythrocyte surface. Drugs and other associations have been implicated. It is described and discussed a case of livedo reticularis associated with AIHA treated with peripheral blood stem cell transplantation (PBSCT) that went into full remission for 10 years. After that period the patient relapsed and was treated with antibody anti-CD20, rituximab, and is now in full remission. The role of PBSCT and rituximab in the treatment of AIHA will be discussed.

Decreased need of large joint replacement in patients with rheumatoid arthritis in a specialized Brazilian center.

Disease-modifying antirheumatic biological and non-biological therapies are associated with reduced disease progression and joint destruction. Suggestions have been made that total knee and hip joint arthroplasty indications are decreasing as a beneficial effect of the new forms of therapy for rheumatoid arthritis. We present findings of our institution on the incidence of joint arthroplasty in the past few years in patients with rheumatoid arthritis and the increase in the numbers of procedures not associated with inflammatory arthritis.

AL amyloidosis in a young adult: remission with autologous stem cell transplantation.

Autologous stem cell transplant is one of the therapies employed in the treatment of primary amyloidosis or AL. The authors report on a 46-year-old patient with bilateral periorbital hematomas, macroglossia who presented, during the investigation, IgG-Kappa paraprotein in serum. The diagnosis of primary amyloidosis or AL was confirmed and the treatment proposed consisted of high-dose melphalan as conditioning regimen before autologous stem cell transplant, which determined complete remission of the disease, along with the disappearance of clinical signs and absence of the monoclonal component.