Impact of Switching to Fingolimod Versus Injectable Disease-Modifying Therapy Cycling on Risk of Multiple Sclerosis-Related Relapses: A Retrospective Analysis.

BACKGROUND: Clinical and real-world studies have shown significant reductions in multiple sclerosis (MS) relapses with fingolimod versus injectable disease-modifying therapies (DMTs). Multiple sclerosis relapse rate and incidence were compared in patients switching from an injectable DMT to fingolimod and those cycling from one injectable DMT to another or remaining on their original injectable DMT. METHODS: Retrospective analysis was performed using Commercial and Medicare Supplemental claims data (July 1, 2010, to June 30, 2016) of adults with MS receiving ≥1 injectable DMT. Relapses were identified from MS-related hospitalization, outpatient emergency department or office visit, and corticosteroid administration. Annualized relapse rate ratio was estimated. RESULTS: Of 16,352 patients, 1110 were switchers to fingolimod, 908 were injectable DMT cyclers, and 14,334 were nonswitchers. At baseline, rate and incidence of MS relapses were higher in switchers and injectable DMT cyclers versus nonswitchers (P < .001); mean ± SD relapse rates declined from 0.4 ± 0.7, 0.4 ± 0.7, and 0.2 ± 0.5 at baseline to 0.2 ± 0.5, 0.3 ± 0.6, and 0.1 ± 0.4 after follow-up in switchers, injectable DMT cyclers, and nonswitchers, respectively. Relapse incidence declined in each cohort. The highest reductions in relapse rate and incidence were in switchers to fingolimod, where relapse risk was significantly reduced versus injectable DMT cyclers (22%, P = .0433) and nonswitchers (47%, P < .001). CONCLUSIONS: This study provides evidence that patients switching from an injectable DMT to fingolimod have the highest reductions in annualized rate and incidence of MS relapses and significantly reduced risk of relapse versus injectable DMT cyclers and nonswitchers.

Time to treatment failure following initiation of fingolimod versus teriflunomide for multiple sclerosis: a retrospective US claims study.

Objective: Disease modifying therapies (DMTs) for multiple sclerosis (MS) aim to delay progression and reduce relapses. Evidence is limited on the comparative effectiveness of the oral DMTs fingolimod and teriflunomide. This study evaluated time to treatment failure among patients with MS who initiated fingolimod versus teriflunomide in real-world settings.Methods: The retrospective cohort included 18-64 year old patients diagnosed with MS who initiated fingolimod or teriflunomide during 12 September 2012 to 30 September 2015 within MarketScan Commercial and Medicare Claims. Patients were followed from treatment initiation (index date) until first treatment failure or censoring. Treatment failure was defined as the first occurrence of MS relapse (identified using a validated algorithm) or treatment discontinuation (≥60 day supply gap). Treatment failure was examined through Kaplan-Meier analysis and multivariable Cox regression adjusting for 1 year baseline factors (age, gender, plan type, region, index year, prior DMT use, baseline relapses, Charlson Comorbidity Index [CCI] and MS symptoms).Results: On average, patients treated with fingolimod (n = 2704) were younger (43.6 versus 49.8 years) with lower CCI (0.4 versus 0.7) and more relapses at baseline (0.46 versus 0.42) than those treated with teriflunomide (n = 1859). Median time to treatment failure was 19.5 months with fingolimod versus 9.6 months with teriflunomide (p < .001). After controlling key demographic and clinical characteristics through multivariable regression, fingolimod was associated with 38.9% lower hazards of treatment failure versus teriflunomide (adjusted hazard ratio = 0.611; 95% CI: 0.559-0.669; p < .001).Conclusions: In a large cohort of US adults with MS, controlling for key baseline characteristics, fingolimod was associated with significantly longer time to treatment failure and lower risk of treatment failure compared with teriflunomide.

A Review of Available Treatments, Clinical Evidence, and Guidelines for Diagnosis and Treatment of Pediatric Multiple Sclerosis in the United States.

Pediatric multiple sclerosis is associated with challenges in prompt diagnosis and uncertainty regarding optimal treatment. This review aimed to identify treatment guidelines or consensus statements for pediatric patients with multiple sclerosis, US Food and Drug Administration (FDA)-approved treatment options for pediatric multiple sclerosis, and any randomized controlled trials and observational studies examining available pharmacologic treatments in the pediatric multiple sclerosis population. Literature searches were performed in MEDLINE (1946-2016), EMBASE (1974-2016), and the Cochrane Central Register of Controlled Trials to identify treatment guidelines or consensus statements, pediatric multiple sclerosis treatment approvals, and randomized controlled trials and observation studies that examine the safety and effectiveness of available disease-modifying therapies. Only 3 consensus statements provided recommendations for pharmacologic treatments for children, all 3 published before the most recent revisions of the pediatric multiple sclerosis diagnostic guidelines. Despite the changes to the clinical landscape of pediatric multiple sclerosis with the introduction of diagnostic guidelines, fingolimod is the only FDA-approved treatment for pediatric multiple sclerosis in the United States. The effectiveness and safety of other disease-modifying therapies suggested by consensus statements have been reported in relatively small prospective and retrospective observational studies. Clinical evidence from a recently completed randomized controlled trial and future global registries can inform treatment decisions for the pediatric multiple sclerosis population.

Real-world durability of relapse rate reduction in patients with multiple sclerosis receiving fingolimod for up to 3 years: a retrospective US claims database analysis.

OBJECTIVE: To assess real-world durability of reduction in relapse rates among patients with multiple sclerosis (MS) receiving fingolimod therapy over a longer-term period of follow-up. METHODS: Patients with MS who initiated fingolimod were identified from a US claims database (January 1, 2009 to September 30, 2016) and followed for 3 years post-initiation. Annualized relapse rates (ARRs) were calculated during the 1-year pre-initiation period, and during each year over the 3-year follow-up period. Time from fingolimod initiation to discontinuation (≥60-day treatment gap) was also summarized. RESULTS: Among 1599 fingolimod initiators, 1158 (72%) had continuous fingolimod use up to the start of year 2 and 937 (59%) had continuous fingolimod use up to the start of year 3. The mean baseline ARR during the 1-year pre-initiation period for all initiators was 0.51. After fingolimod initiation, mean ARRs were consistently lower in each year of follow-up: 0.25 (95% CI: 0.22, 0.28) in year 1 for all fingolimod initiators, 0.22 (0.18, 0.25) in year 2 for patients with continuous fingolimod use up to the start of year 2, and 0.23 (0.19, 0.27) in year 3 for patients with continuous fingolimod use up to the start of year 3. Median time on treatment was 33 months for all patients initiating fingolimod. CONCLUSIONS: Patients with MS who received continuous fingolimod therapy experienced a sustained reduction in relapse rates (>50% vs. baseline) during each year of a 3-year follow-up period.

Real-world persistence with fingolimod for the treatment of multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: To systematically review reports of fingolimod persistence in the treatment of relapsing-remitting multiple sclerosis (RRMS) across data sources and practice settings, and to develop a consensus estimate of the 1-year real-world persistence rate. METHODS: A systematic literature review was conducted (MEDLINE, EMBASE, and abstracts from selected conferences [2013-2015]) to identify observational studies reporting 1-year fingolimod persistence among adult patients with RRMS (sample size ≥50). A random-effects meta-analysis was performed to estimate a synthesized 1-year persistence rate and to assess heterogeneity across studies. RESULTS: Of 527 publications identified, 25 real-world studies reporting 1-year fingolimod persistence rates were included. The studies included patients from different data sources (e.g., administrative claims, electronic medical records, or registries), used different definitions of persistence (e.g., based on prescriptions refills, patient report, or prescription orders), and spanned multiple geographic regions. Reported 1-year persistence rates ranged from 72%-100%, and exhibited statistical evidence of heterogeneity (I2 = 93% of the variability due to heterogeneity across studies). The consensus estimate of the 1-year persistence rate was 82% (95% confidence interval: 79%-85%). CONCLUSIONS: Across heterogeneous study designs and patient populations found in real-world studies, the consensus 1-year fingolimod persistence rate exceeded 80%, consistent with persistence rates identified in the recently-completed trial, PREFERMS.

Tofacitinib Versus Biologic Treatments in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Tumor Necrosis Factor Inhibitors: Results From a Network Meta-analysis.

PURPOSE: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis compared the efficacy and safety of tofacitinib with biologic disease-modifying antirheumatic drugs in patients with RA and a prior inadequate response (IR) to tumor necrosis factor inhibitors (TNFi). METHODS: A systematic literature review identified 5 randomized placebo-controlled trials that evaluated tofacitinib or biologic disease-modifying antirheumatic drugs (bDMARDs) against placebo in patient populations with RA with a prior IR to TNFi. The definition of TNFi-IR varied across studies, and included patients with an IR or who had failed treatment with TNFi for any reason. A network meta-analysis was conducted comparing study data with regard to American College of Rheumatology response rates and Health Assessment Questionnaire-Disability Index improvement at weeks 12 and 24, rates of treatment withdrawal due to all causes; adverse events (AEs) and lack of efficacy; and rates of AEs, serious AEs, and serious infections. FINDINGS: The 5 trials included a total of 2136 patients. Tofacitinib 5 mg twice daily combined with methotrexate was found to have relative risk estimates of American College of Rheumatology responses and change from baseline in Health Assessment Questionnaire-Disability Index score comparable with abatacept, golimumab, rituximab, and tocilizumab combined with conventional synthetic disease-modifying antirheumatic drugs. Withdrawal rates from trials due to all causes and AEs were comparable between treatments, and tofacitinib had a lower rate of withdrawals due to lack of efficacy. Rates of AEs and HAQ-DI were comparable between tofacitinib, other active treatments, and placebo. No serious infections were reported with tofacitinib during the placebo-controlled period (up to week 12) in this study population; rates of serious infection with other active treatments were generally low and similar to placebo. IMPLICATIONS: During a 24-week period, tofacitinib had efficacy and rates of AEs comparable with currently available bDMARDs in the treatment of patients with RA who had a prior IR to TNFi. ClinicalTrials.gov identifiers: ORAL Step, NCT00960440; ATTAIN, NCT00124982; GO-AFTER, NCT00299546; RADIATE, NCT00106522; REFLEX, NCT00462345.

Slot 0, 018" ou 0,022": por que existem duas opções ? Um guia para a escolha / The 0.018" or 0.022" slot systems: why two options are available? A guide for indications

The first Edgewise brackets were utilized with gold wire and the slot designed with 0.022" high to present sufficient rigidity. When gold was replaced by stainless steel, cheaper and stiffer, it was proposed to reduce the slot size to 0.018". The two different sizes of brackets are used in contemporary orthodontics and many clinical orthodontists are unaware of the advantages they may have. The aim of this paper is to present, based on the orthodontic literature, the main characteristics influenced by the brackets slot size and compile data to drive orthodontists in choosing the bracket that best meets their clinical needs.

Os primeiros braquetes Edgewise eram utilizados com fios de ouro e concebidos com o slot de 0,022" de altura, para que apresentassem rigidez suficiente. Com a substituição do ouro pelo aço inoxidável, mais barato e mais rígido, foi proposta a redução do slot para 0,018". As duas diferentes dimensões de braquetes são utilizadas na Ortodontia contemporânea e muitos ortodontistas clínicos desconhecem suas vantagens. O objetivo deste artigo foi apresentar, baseando-se na literatura ortodôntica, as principais características influenciadas pelo tamanho do slot dos braquetes e compilar os dados para direcionar o ortodontista na escolha do braquete que melhor atenda às suas necessidades clínicas.

Tratamento interdisciplinar da agenesia dos incisivos laterais superiores: interação entre Ortodontia, Implantodontia e Prótese / Interdisciplinary treatment of agenesis of the maxillary lateral incisors: interaction between Orthodontics, Implantology and Prosthesis

Atualmente, a busca pela estética tem aumentado a procura por tratamento ortodôntico na população adulta. A agenesia dentária tem uma grande influência na estética do sorriso. Consequentemente, na harmonia da face, a ausência dos incisivos laterais contribui de maneira significativa. Dentre as várias formas de tratamento, pode-se optar pelo fechamento de espaço, com substituição do incisivo lateral pelo canino ou abertura de espaço para uma posterior reabilitação implantoprotética. Neste artigo, foi descrito o tratamento da agenesia dos incisivos laterais superiores e revisadas na literatura as suas possibilidades de tratamento, com enfoque na abertura do espaço associado ao planejamento 3D e reabilitação estética através da reabilitação implantoprotética

Nowadays, the seek for aesthetics has been the subject of increased demand for orthodontic treatment in adults. The tooth agenesis has a great influence on the smile esthetics and consequently the harmony of the face, which is significantly affected by the absence of lateral incisors. Among the various treatment forms, the clinician can decide for space closure with replacement of the lateral incisor or canine space opening for later prosthetic implant rehabilitation. In this article we described the treatment of agenesis of the maxillary lateral incisors and made a literature review about the treatment options, focusing on space opening associated with the planning and 3-D aesthetic management through the prosthetic implant rehabilitatio

Meta-analysis of long-term joint structural deterioration in minimally treated patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint structural deterioration. Driven by recent expectations that patients in clinical trials randomized to placebo should be 'rescued' with active therapy within 6 months of starting treatment, the relative benefit of arresting joint damage with biologic agents beyond this period is unclear. With longer-term evidence of the rate of joint deterioration with minimal treatment, the efficacy of biologic agents and novel treatments might be projected beyond the placebo-controlled phase observed in clinical trials. The aim of this study was to estimate radiographic structural deterioration over time in patients with moderate-to-severe RA minimally treated with DMARDs. METHODS: A literature review identified evidence of joint structural deterioration in patients with (DMARD-IR population) and without (non-DMARD-IR population) a history of inadequate response to DMARDs. Patients were minimally treated with one non-biologic DMARD or palliative care (non-DMARD-IR population only). Outcomes of interest were the (modified) Total Sharp Score (TSS) and subscales (Erosion Subscore [ES] and Joint Space Narrowing [JSN] Subscore), and Larsen score. Pooled joint-deterioration curves over time were obtained with meta-analysis models. RESULTS: Mean change from baseline in TSS increased in the DMARD-IR population from 1.14 (95 % credible interval [CrI] 0.66, 1.67) to 9.84 (5.68, 14.46) at Weeks 12 and 104, respectively, and a non-linear increase of 1.56 (0.79, 2.34) and 5.13 (-1.35, 11.67) in the non-DMARD-IR population. At the same time points, mean changes (95 % CrI) were 0.51 (0.27, 0.83) and 4.43 (2.38, 7.21) for ES and 0.36 (0.09, 0.67) and 3.14 (0.80, 5.78) for JSN in the DMARD-IR population, whereas corresponding changes in the non-DMARD-IR population were 0.69 (0.31, 1.12) and 2.93 (0.92, 5.02), and 0.29 (0.17, 0.44) and 2.55 (1.45, 3.80), respectively. Larsen scores were only available for the non-DMARD-IR population, with mean changes (95 % CrI) of 0.08 (0.04, 0.11) and 0.65 (0.36, 0.96) at Weeks 12 and 104, respectively. CONCLUSION: Minimal treatment of RA with one non-biologic DMARD results in deterioration of joint structure in patients with or without a history of inadequate response to non-biologic DMARDs.

In vitro and in vivo analysis of the antithrombotic and toxicological profile of new antiplatelets N-acylhydrazone derivatives and development of nanosystems: determination of novel NAH derivatives antiplatelet and nanotechnological approach.

BACKGROUND: Cardiovascular diseases are the most frequent cause of morbidity and mortality worldwide. Among the most important cardiovascular diseases are atherothrombosis and venous thromboembolism that present platelet aggregation as a key event. Currently, the commercial antiplatelet agents display several undesirable effects, which prompt the search for new compounds with better therapeutic index, more efficient body distribution and mechanism. METHODS: In this work we characterized in vivo and in vitro the antithrombotic and toxicological profiles of novel antiplatelet N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides derivatives also comparing them with aspirin. In addition we also analyzed the stability of the more active compound after encapsulation in PLGA or PCL nanoparticles and the release profile of these new nanosystems. RESULTS: The biological results revealed not only the selective effect against arachidonic acid-induced platelet aggregation mainly for compounds 2c, 2e and 2h but also their in vivo active profile on thromboembolism pulmonary animal model with better survival rates (e.g. 82%) than aspirin (33%). The overall toxicological profile was determined by in vitro (MTT reduction tests, neutral red uptake in kidney VERO cells and hemolysis assays) and in vivo (pulmonary embolism) assays that pointed 2c as the most promising derivative with potential as a lead compound. By using the nanoprecipitation technique 2c was loaded into PLGA and PCL nanoparticles showing controlled release profile over 21days according to our drug release tests. CONCLUSION: According to our results compound 2c is the most interesting derivative for further studies as it showed the best activity and toxicological profile also allowing the nanoencapsulation process. Thus 2c may assist in determining a new potential therapy with favorable pharmacokinetics for treatment of thrombotic disorders.

Comparative effectiveness of efavirenz, protease inhibitors, and raltegravir-based regimens as first-line treatment for HIV-infected adults: a mixed treatment comparison.

OBJECTIVE: Compare the efficacy of 2 NRTIs combined with raltegravir (RAL), efavirenz (EFV), or protease inhibitors (PI) in the management of antiretroviral-naïve HIV adult patients. METHODS: By means of a systematic literature view, 7 randomized controlled trials were identified: 2 RAL vs EFV trials; 1 ritonavir-boosted lopinavir (LPV/RTV) vs EFV trial; 1 ritonavir-boosted atazanavir (ATV/RTV) vs LPV/RTV trial; 1 ritonavir-boosted darunavir (DRV/RTV) vs LPV/RTV trial; 1 ritonavir-boosted fosamprenavir (FPV/RTV) vs LPV/RTV trial; and 1 FPV/RTV vs ATV/RTV trial. Endpoints concerned virological suppression and immunologic efficacy. Trials were analyzed with Bayesian mixed treatment comparison meta-analysis. RESULTS: For up to 24 weeks of treatment, a PI-based regimen resulted in a lower proportion of patients with virological response than an EFV-based regimen, whereas RAL seems more efficacious than EFV up to at least 12 weeks. After 48 weeks, the odds ratio (OR) of virological suppression with RAL relative to EFV was 1.34 (95% credible interval [CrI], 0.87-2.07). ORs for PIs relative to EFV varied from 0.68 (0.41-1.07) with LPV/RTV to 0.99 (0.52-1.84) with DRV/RTV. RAL demonstrated a greater improvement in CD4+ T cell counts than EFV at 48 weeks. The PI regimens showed all similar improvements relative to EFV. CONCLUSION: Based on available RCTs, the fastest virological suppression is expected with RAL followed by EFV and PIs. Over time, RAL appears to be at least as good as PI and EFV regimens. CD4+ cell recovery seems the greatest with LPV/RTV, DRV/RTV, and RAL. Given the limited number of RCTs, additional studies are recommended.