Effect of dose adjustments on the efficacy and safety of tofacitinib in patients with rheumatoid arthritis: a post hoc analysis of an open-label, long-term extension study (ORAL Sequel)

Introduction/objectives We assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA). Methods ORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Sisease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration. Results Generally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p < 0.05) in Dose-up versus Stay-on 5 up to month 12. DAS28 remission rates were significantly greater in Dose-up versus Stay-on 5 at month 12. Change from baseline in DAS28 was similar in Dose-down and Stay-on 10. No significant differences in DAS28 LDA rates were observed between groups. Safety data were similar overall across the four groups. Conclusion In patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety. Study registration ClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points• This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator’s discretion, on efficacy and safety in patients with rheumatoid arthritis (RA).• Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy.• Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction.• These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.

Repeated, low-dose oral esketamine in patients with treatment-resistant depression: pilot study

Background Intravenous infusion of ketamine can produce rapid and large symptom reduction in patients with treatment-resistant depression (TRD) but presents major obstacles to clinical applicability, especially in community settings. Oral esketamine may be a promising addition to our TRD treatment armamentarium. Aims To explore the safety, tolerability and potential clinical effectiveness of a 3-week treatment with repeated, low-dose oral esketamine. Method Seven patients with chronic and severe TRD received 1.25 mg/kg generic oral esketamine daily, over 21 consecutive days. Scores on the Systematic Assessment for Treatment Emergent Events (SAFTEE), Community Assessment of Psychic Experiences (CAPE), Clinician Administered Dissociative States Scale (CADSS) and Hamilton Rating Scale for Depression (HRSD) instruments, as well as blood pressure and heart rate, were repeatedly assessed. Results Treatment with oral esketamine was well-tolerated. No serious side-effects occurred, and none of the participants discontinued treatment prematurely. Psychotomimetic effects were the most frequently reported adverse events. Mean HDRS score decreased by 16.5%, from 23.6 to 19.7. Three participants showed reductions in HDRS scores above the minimum clinically important difference (eight-point change), of whom two showed partial response. No participants showed full response or remission. Conclusions These results strengthen the idea that oral esketamine is a safe and well-tolerated treatment for patients with chronic and severe TRD, but therapeutic effects were modest. Results were used to design a randomised controlled trial that is currently in progress.

The association of patient education level with outcomes after elective lumbar surgery: a Michigan Spine Surgery Improvement Collaborative study

OBJECTIVE Socioeconomic factors have been shown to impact a host of healthcare-related outcomes. Level of education is a marker of socioeconomic status. This study aimed to investigate the relationship between patient education level and outcomes after elective lumbar surgery and to characterize any education-related disparities. METHODS The Michigan Spine Surgery Improvement Collaborative registry was queried for all lumbar spine operations. Primary outcomes included patient satisfaction determined by the North American Spine Society patient satisfaction index, and reaching the minimum clinically important difference of Patient-Reported Outcomes Measurement Information System Physical Function score and return to work up to 2 years after surgery. Multivariate Poisson generalized estimating equation models reported adjusted risk ratios. RESULTS A total of 26,229 lumbar spine patients had data available for inclusion in this study. On multivariate generalized estimating equation analysis all comparisons were done versus the high school (HS)/general equivalency development (GED)–level cohort. For North American Spine Society satisfaction scores after surgery the authors observed the following: at 90 days the likelihood of satisfaction significantly decreased by 11% (p < 0.001) among < HS, but increased by 1% (p = 0.52) among college-educated and 3% (p = 0.011) among postcollege-educated cohorts compared to the HS/GED cohort; at 1 year there was a decrease of 9% (p = 0.02) among < HS and increases of 3% (p = 0.02) among college-educated and 9% (p < 0.001) among postcollege-educated patients; and at 2 years, there was an increase of 5% (p = 0.001) among postcollege-educated patients compared to the < HS group. The likelihood of reaching a minimum clinically important difference of Patient-Reported Outcomes Measurement Information System Physical Function score at 90 days increased by 5% (p = 0.005) among college-educated and 9% (p < 0.001) among postcollege-educated cohorts; at 1 year, all comparison cohorts demonstrated significance, with a decrease of 12% (p = 0.007) among < HS, but an increase by 6% (p < 0.001) among college-educated patients and 14% (p < 0.001) among postcollege-educated compared to the HS/GED cohort; at 2 years, there was a significant decrease by 19% (p = 0.003) among the < HS cohort, an increase by 8% (p = 0.001) among the college-educated group, and an increase by 16% (p < 0.001) among the postcollege-educated group. For return to work, a significant increase was demonstrated at 90 days and 1 year when comparing the HS or less group with college or postcollege cohorts. CONCLUSIONS This study demonstrated negative associations on all primary outcomes with lower levels of education. This finding suggests a potential disparity linked to education in elective spine surgery.

A Systematic Review Examining the Approaches Used to Estimate Interindividual Differences in Trainability and Classify Individual Responses to Exercise Training

Background: Many reports describe statistical approaches for estimating interindividual differences in trainability and classifying individuals as “responders” or “non-responders.” The extent to which studies in the exercise training literature have adopted these statistical approaches remains unclear.Objectives: This systematic review primarily sought to determine the extent to which studies in the exercise training literature have adopted sound statistical approaches for examining individual responses to exercise training. We also (1) investigated the existence of interindividual differences in trainability, and (2) tested the hypothesis that less conservative thresholds inflate response rates compared with thresholds that consider error and a smallest worthwhile change (SWC)/minimum clinically important difference (MCID).Methods: We searched six databases: AMED, CINAHL, EMBASE, Medline, PubMed, and SportDiscus. Our search spanned the aerobic, resistance, and clinical or rehabilitation training literature. Studies were included if they used human participants, employed standardized and supervised exercise training, and either: (1) stated that their exercise training intervention resulted in heterogenous responses, (2) statistically estimated interindividual differences in trainability, and/or (3) classified individual responses. We calculated effect sizes (ESIR) to examine the presence of interindividual differences in trainability. We also compared response rates (n = 614) across classification approaches that considered neither, one of, or both errors and an SWC or MCID. We then sorted response rates from studies that also reported mean changes and response thresholds (n = 435 response rates) into four quartiles to confirm our ancillary hypothesis that larger mean changes produce larger response rates.Results: Our search revealed 3,404 studies, and 149 were included in our systematic review. Few studies (n = 9) statistically estimated interindividual differences in trainability. The results from these few studies present a mixture of evidence for the presence of interindividual differences in trainability because several ESIR values lay above, below, or crossed zero. Zero-based thresholds and larger mean changes significantly (both p &lt; 0.01) inflated response rates.Conclusion: Our findings provide evidence demonstrating why future studies should statistically estimate interindividual differences in trainability and consider error and an SWC or MCID when classifying individual responses to exercise training.Systematic Review Registration: [website], identifier [registration number].

Detecting change in community participation with the Enfranchisement scale of the community participation indicators

Objective This study determined the sensitivity to change of the Enfranchisement scale of the Community Participation Indicators in people with stroke. Data sources We analyzed data from two studies of participants with stroke: an intervention study and an observational study. Main measures The Enfranchisement Scale contains two subscales: the Importance subscale (feeling valued by and contributing to the community; range: 14–70) and the Control subscale (choice and control: range: 13–64). Data analysis Assessments were administered 6 months apart. We calculated minimum detectable change and minimal clinically important difference. Results The Control subscale analysis included 121 participants with a mean age of 61.2 and mild-moderate disability (Functional Independence Measure, mean = 97.9, SD = 24.7). On the Control subscale, participants had a mean baseline score of 51.4 (SD = 10.4), and little mean change (1.3) but with large variation in change scores (SD = 11.5). We found a minimum detectable change of 9 and a minimum clinically important difference of 6. The Importance subscale analysis included 116 participants with a mean age of 60.7 and mild-moderate disability (Functional Independence Measure, mean = 98.9, SD = 24.5). On the Importance subscale, participants had a mean baseline score of 44.1 (SD = 12.7), and again demonstrated little mean change (1.08) but with large variation in change scores (SD = 12.6). We found a minimum detectable change of 11 and a minimum clinically important difference 7. Conclusions The Control subscale required 9 points of change, and the Importance subscale required 11 points of change, to achieve statistically and clinically meaningful changes, suggesting adequate sensitivity to change.

Long-term patient-reported outcomes for open surgery of the triangular fibrocartilage complex

Aims Studies on long-term patient-reported outcomes after open surgery for triangular fibrocartilage complex (TFCC) are scarce. Surgeons and patients would benefit from self-reported outcome data on pain, function, complications, and satisfaction after this surgery to enhance shared decision-making. The aim of this study is to determine the long-term outcome of adults who had open surgery for the TFCC. Methods A prospective cohort study that included patients with open surgery for the TFCC between December 2011 and September 2015. In September 2020, we sent these patients an additional follow-up questionnaire, including the Patient-Rated Wrist Evaluation (PRWE), to score satisfaction, complications, pain, and function. Results A total of 113 patients were included in the analysis. At ≥ 60 months after an open TFCC reinsertion, we found a mean PRWE total score of 19 (SD 21), a mean PRWE pain score of 11 (SD 11), and a PRWE function score of 9 (SD 10). The percentage of patients obtaining minimum clinically important difference rose from 77% at 12 months to 83% at more than 60 months (p < 0.001). Patients reported fewer complications than surgeons, and overall complication rate was low. Conclusion Outcomes of patient-reported pain, function scores, and satisfaction are improved five years after open surgery for the TFCC. Cite this article: Bone Jt Open 2021;2(11):981–987.

Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fracture: a protocol for an overview of systematic reviews

IntroductionHip arthroplasties for the treatment of displaced femoral neck fractures in adults can be total replacement or hemiarthroplasty. Despite the high prevalence of these fractures and large number of studies on the topic, the best choice of arthroplasty to be used remains unclear. The present study aims to overview the results of systematic reviews of randomised controlled trials (RCTs) comparing outcomes between total hip replacement and hemiarthroplasty for displaced femoral neck fractures in adults.Methods and analysisFour electronic databases (Pubmed, Embase, Cochrane Library and Web of Science) and reference lists from previous reviews will be searched without language limitation. Eligible studies will be systematic reviews of RCT that compare total hip replacement and hemiarthroplasty for treatment of displaced femoral neck fractures in adults. Two reviewers will independently perform study selection, data extraction and quality assessment. Disagreements between reviewers will be resolved by a third reviewer. Comparisons of dichotomous data will report as the OR and 95% CI, and comparisons of functional and health-related quality of life outcomes are reported as the mean difference and 95% CI and as the risk difference, defined as the difference in the proportion achieving the minimum clinically important difference and 95% CI. As this overview will contribute to orthopaedic surgeons and health managers in better decision-making for the treatment of these fractures. The authors plan to complete the searches and analyses by 30 November 2021.Ethics and disseminationEthical approval was obtained at Federal University of Sao Paulo. Findings will be disseminated through peer-reviewed publication.PROSPERO registration numberCRD42021237885.

Heterogeneity of treatment response in bronchiectasis clinical trials

IntroductionRecent randomised clinical trials (RCTs) in Bronchiectasis have failed to reach their primary endpoints, suggesting a need to reassess how we measure treatment response. Exacerbations, quality of life (QOL) and lung function are the most common endpoints evaluated in bronchiectasis clinical trials. We aimed to determine the relationship between responses in terms of reduced exacerbations, improved symptoms and lung function in bronchiectasis.MethodsWe evaluated treatment response in 3 RCTs that evaluated mucoactive therapy (inhaled Mannitol), an oral anti-inflammatory/antibiotic (Azithromycin) and an inhaled antibiotic (Aztreonam). Treatment response was defined by absence of exacerbations during follow-up, an improvement of QOL above the minimum clinically important difference (MCID) and an improvement in FEV1 of ≥100 mL from baseline.Measurements and main resultsCumulatively the three trials included 984 patients. Changes in FEV1, QOL and exacerbations were heterogeneous in all trials analysed. Improvements in QOL were not correlated to changes in FEV1 in the azithromycin and aztreonam trials (r=−0.17, p=0.1 and r=0.04, p=0.4) and weakly correlated in the mannitol trial (r=0.22, p<0.0001). An important placebo effect was observed in all trials, especially regarding improvements in QOL. Clinical meaningful lung function improvements were rare across all trials evaluated, suggesting that FEV1 is not a responsive measure in bronchiectasis.ConclusionsImprovements in lung function, symptoms and exacerbation frequency are dissociated in bronchiectasis. FEV1 is poorly responsive and poorly correlated with other key outcome measures. Clinical parameters are poorly predictive of treatment response suggesting the need to develop biomarkers to identify responders

Real-World Effectiveness of Inhalation Therapy Among Patients With Symptomatic COPD in China: A Multicenter Prospective Study

Purpose: This real-world study evaluated the effectiveness of different inhalation therapies in patients with symptomatic chronic obstructive pulmonary disease (COPD) in China and also explored the relevant factors that influence the effectiveness of inhalation therapy.Patients and Methods: We conducted a multicenter prospective longitudinal study that was carried out in 12 hospitals in China from December 2016 to June 2021. A face-to-face interview was conducted to collect data. Baseline data were collected at the first visit. Minimum clinically important difference (MCID) was defined as attaining a COPD assessment test (CAT) decrease ≥2. We mainly assessed the MCID and the incidence of exacerbations at the 6 months follow-up.Results: In 695 patients, the mean age was 62.5 ± 8.2 years, with a mean CAT score of 15.1 ± 6.0. Overall, 341 (49.1%) patients attained the MCID of CAT and the incidence of exacerbation during follow-up was 22.3%. Females were significantly more likely to attain MCID than male in COPD patients (adjusted odd ratio (aOR) = 1.93, adjusted 95% confidence interval (a95%CI) = 1.09–3.42, p = 0.024). Patients treated with LABA/LAMA or ICS/LABA/LAMA (ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist) were more likely to attain MCID than patients treated with LAMA (aOR = 3.97, a95%CI = 2.48–6.35, p &lt; 0.001; aOR = 3.17, a95%CI = 2.09–4.80, p &lt; 0.001, respectively). Patients treated with LABA/LAMA had a higher incidence of severe exacerbation than patients treated with ICS/LABA/LAMA (aOR = 1.95, a95%CI = 1.04–3.66, p = 0.038).Conclusion: The incidence of MCID in symptomatic COPD patients treated with inhalation therapy was nearly 50%. Patients treated with LABA/LAMA or ICS/LABA/LAMA were more likely to attain MCID than patients treated with LAMA. Patients treated with LABA/LAMA had a higher incidence of severe exacerbations than with ICS/LABA/LAMA.