Double-Negative Results Matter: A Reevaluation of Sensitivities for Detecting SARS-CoV-2 Infection Using Saliva Versus Nasopharyngeal Swabs.

In a recent systematic review, Bastos et al. (Ann Intern Med. 2021;174(4):501-510) compared the sensitivities of saliva sampling and nasopharyngeal swabs in the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by assuming a composite reference standard defined as positive if either test is positive and negative if both tests are negative (double negative). Even under a perfect specificity assumption, this approach ignores the double-negative results and risks overestimating the sensitivities due to residual misclassification. In this article, we first illustrate the impact of double-negative results in the estimation of the sensitivities in a single study, and then propose a 2-step latent class meta-analysis method for reevaluating both sensitivities using the same published data set as that used in Bastos et al. by properly including the observed double-negative results. We also conduct extensive simulation studies to compare the performance of the proposed method with Bastos et al.'s method for varied levels of prevalence and between-study heterogeneity. The results demonstrate that the sensitivities are overestimated noticeably using Bastos et al.'s method, and the proposed method provides a more accurate evaluation with nearly no bias and close-to-nominal coverage probability. In conclusion, double-negative results can significantly impact the estimated sensitivities when a gold standard is absent, and thus they should be properly incorporated.

Reliability, validity, and change thresholds of the NCCN/FACT Bladder Symptom Index (NFBlSI-18) in patients with advanced urothelial cancer.

BACKGROUND: The NCCN/FACT Bladder Symptom Index-18 (NFBlSI-18) is a bladder cancer-specific instrument. We aimed to psychometrically evaluate the reliability and validity of NFBlSI-18 and estimate change thresholds for total, disease-related symptoms-physical (DRS-P), DRS-emotional (DRS-E), and function/well-being (F/WB) scales in patients with locally advanced/metastatic urothelial cancer (la/mUC). METHODS: JAVELIN Bladder 100 trial data were analyzed. Anchors to evaluate validity included: 5-level EuroQoL-5D utility index (EQ-5D-5L UI), visual analog scale (VAS), Eastern Cooperative Oncology Group (ECOG) performance status, and number of symptoms. Responsiveness to change was tested by anchoring to time to tumor progression (TTP), best overall response (BOR), and differences in means between ECOG categories to estimate meaningful between-group differences. Meaningful within-group change thresholds were estimated using receiver operating characteristic curve analysis, anchoring to change in EQ-5D-5L UI. Significant within-individual patient change thresholds were estimated with reliable and likely change indexes. RESULTS: Correlations with EQ-5D-5L UI and VAS ranged from 0.53 to 0.73. Standardized effect sizes were >0.20. Compared with patients with TTP of ≥6 months, patients with TTP of >0-2 and 3-5 months had larger declines; results for BOR were similar. Thresholds (points) for meaningful between-group differences were: total, 6-11; DRS-P, 3-6; and DRS-E and F/WB, 1. Thresholds (points) for meaningful within-group worsening were: total, 4; and DRS-P, 3, and for significant individual change they were: total, 3-9; DRS-P, 2-6; DRS-E, 1-3; and F/WB, 2-4. CONCLUSIONS: NFBlSI-18 exhibited evidence of reliability, validity, and responsiveness to assess quality of life in studies of la/mUC, and change thresholds are established for future studies. PLAIN LANGUAGE SUMMARY: The NCCN/FACT Bladder Symptom Index-18 (NFBlSI-18) is a questionnaire used to assess quality of life for people with advanced bladder cancer. People with advanced bladder cancer who took part in the JAVELIN Bladder 100 study completed the NFBlSI-18 when they joined the study and after each treatment with avelumab maintenance or best supportive care. This study showed that NFBlSI-18 is suitable for capturing bladder cancer symptoms and is able to detect important changes in a person's quality of life over time. This study also provides thresholds for changes in NFBlSI-18 scores, which will be useful for future studies.

Outcomes of male patients with HR+/HER2- advanced breast cancer receiving palbociclib in the real-world POLARIS study.

PURPOSE: Data on treatments for male breast cancer patients are limited owing to rarity and underrepresentation in clinical trials. The real-world POLARIS study gathers data on palbociclib use for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) in female and male patients. This sub-analysis describes real-world palbociclib treatment patterns, clinical outcomes, and quality of life (QoL) in male patients. METHODS: POLARIS is a prospective, noninterventional, multicenter, real-world study of patients with HR+/HER2- ABC receiving palbociclib. Assessments included medical record reviews, patient QoL questionnaires (European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30), site characteristics questionnaires, and physician treatment selection surveys. Variables included demographics, disease history, global health status/QoL, clinical assessments and adverse events. Analyses were descriptive in nature. For clinical outcomes, real-world tumor responses and progression were determined by physician assessment in routine clinical practice. Real-world progression-free survival (rwPFS) was described using the Kaplan-Meier method. RESULTS: At data cutoff, 15 male patients were enrolled (median age, 66 years). Nine patients received palbociclib as a first-line treatment and 6 as a second-line or later treatment. Patients received a median of 20 cycles of palbociclib. Neutropenia was experienced by 2 patients and grade ≥ 3 adverse events were reported in 11 patients. Global health status/QoL scores remained generally consistent during the study. One patient (6.7%) achieved a complete tumor response, 4 (26.7%) a partial response, and 8 (53.3%) stable disease. Median rwPFS was 19.8 months (95% CI, 7.4-38.0). Median follow-up duration was 24.7 months (95% CI, 20.0-35.7). CONCLUSION: This real-world analysis showed that palbociclib was well tolerated and provides preliminary data on treatment patterns and outcomes with palbociclib in male patients with HR+/HER2- ABC, helping inform the use of palbociclib in this patient subgroup. TRIAL IDENTIFIER: NCT03280303.

Comorbidities in childhood atopic dermatitis: A population-based study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with allergic comorbidities. However, studies examining comorbidities in childhood AD are incomplete, which may contribute to suboptimal care. OBJECTIVE: The objective was to compare the risk of developing different allergic and non-allergic comorbidities among children with AD to that of a matched non-AD reference cohort in Sweden. METHODS: This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. Patients with AD were identified by confirmed diagnosis in primary or specialist care. The non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients. The risk of developing the following conditions was evaluated: hypersensitivity and allergic disorders, neurological disorders, psychiatric disorders, infections, immunological and inflammatory disorders, Type 1 diabetes (T1D), endocrine and metabolic disorders, skeletal disorders, ocular disorders and malignancies. RESULTS: This study included 165,145 patients with AD (mild-to-moderate [n = 126,681] and severe [n = 38,464]) and an equally sized reference cohort. Patients with AD displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D and skeletal disorders, compared with the reference cohort. The highest risk compared with the reference cohort was observed for hypersensitivity and allergic disorders (hazard ratio [HR]: 3.87), followed by malignancies (HR: 2.53) and immunological and inflammatory disorders (HR: 2.36). Patients with AD also had higher risk of developing multiple comorbidities (≥2). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission. CONCLUSIONS: The clinical burden of AD is substantial for children with AD and patients are at an increased risk of developing several comorbid conditions extending beyond the atopic march. Our results also showed a positive association between worsening severity of AD and an increased risk of comorbidity onset.

Single-arm studies involving patient-reported outcome data in oncology: a literature review on current practice.

Patient-reported outcomes (PROs) are increasingly used in single-arm cancer studies. We reviewed 60 papers published between 2018 and 2021 of single-arm studies of cancer treatment with PRO data for current practice on design, analysis, reporting, and interpretation. We further examined the studies' handling of potential bias and how they informed decision making. Most studies (58; 97%) analysed PROs without stating a predefined research hypothesis. 13 (22%) of the 60 studies used a PRO as a primary or co-primary endpoint. Definitions of PRO objectives, study population, endpoints, and missing data strategies varied widely. 23 studies (38%) compared the PRO data with external information, most often by using a clinically important difference value; one study used a historical control group. Appropriateness of methods to handle missing data and intercurrent events (including death) were seldom discussed. Most studies (51; 85%) concluded that PRO results supported treatment. Conducting and reporting of PROs in cancer single-arm studies need standards and a critical discussion of statistical methods and possible biases. These findings will guide the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Data in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) in developing recommendations for the use of PRO-measures in single-arm studies.

Comparing g-computation, propensity score-based weighting, and targeted maximum likelihood estimation for analyzing externally controlled trials with both measured and unmeasured confounders: a simulation study.

OBJECTIVES: To have confidence in one's interpretation of treatment effects assessed by comparing trial results to external controls, minimizing bias is a critical step. We sought to investigate different methods for causal inference in simulated data sets with measured and unmeasured confounders. METHODS: The simulated data included three types of outcomes (continuous, binary, and time-to-event), treatment assignment, two measured baseline confounders, and one unmeasured confounding factor. Three scenarios were set to create different intensities of confounding effect (e.g., small and blocked confounding paths, medium and blocked confounding paths, and one large unblocked confounding path for scenario 1 to 3, respectively) caused by the unmeasured confounder. The methods of g-computation (GC), inverse probability of treatment weighting (IPTW), overlap weighting (OW), standardized mortality/morbidity ratio (SMR), and targeted maximum likelihood estimation (TMLE) were used to estimate average treatment effects and reduce potential biases. RESULTS: The results with the greatest extent of biases were from the raw model that ignored all the potential confounders. In scenario 2, the unmeasured factor indirectly influenced the treatment assignment through a measured controlling factor and led to medium confounding. The methods of GC, IPTW, OW, SMR, and TMLE removed most of bias observed in average treatment effects for all three types of outcomes from the raw model. Similar results were found in scenario 1, but the results tended to be biased in scenario 3. GC had the best performance followed by OW. CONCLUSIONS: The aforesaid methods can be used for causal inference in externally controlled studies when there is no large, unblockable confounding path for an unmeasured confounder. GC and OW are the preferable approaches.

Characteristics, clinical outcomes and patient-reported outcomes of patients with ulcerative colitis receiving tofacitinib: a real-world survey in the United States and five European countries.

BACKGROUND: To describe variations in treatment patterns, clinical outcomes, patient-reported outcomes (PRO), and physician and patient satisfaction in patients with moderate-to-severe ulcerative colitis (UC) treated with tofacitinib in a real-world setting. METHODS: Data were drawn from the Adelphi UC Disease Specific Programme™, a point-in-time survey of physicians and their consulting patients in the US and Europe. For inclusion in this analysis, gastroenterologists completed medical record forms for the next seven consecutive consulting patients with confirmed UC, plus a further two patient record forms for patients treated with tofacitinib. Those same patients then completed a patient-reported questionnaire. RESULTS: Gastroenterologists (n = 340) provided data for 2049 patients with UC, including 642 patients receiving tofacitinib. Physicians' most frequent reason for choosing tofacitinib was overall efficacy (71.3% of patients). The proportion of patients in remission increased with length of treatment, from 13.7% at [0, 4) weeks to 68.3% at [52+] weeks. Both physicians and patients reported that the Mayo components of stool frequency and blood in stool were reduced with time on treatment. Improvement in symptoms (bloody diarrhea, abdominal pain/cramps, urgency, rectal bleeding, fatigue/tiredness) was reported in the first weeks of treatment, and increased with time. At week [52+], mean score reductions from treatment initiation to current in overall symptom severity, pain, and fatigue were 2.2 (to a current mean score of 1.1), 2.2 (to 0.9), and 2.1 (to 1.0), respectively. Comparing patients at weeks [0, 4) and [52+] (all PROs, p < 0.0001), the increase in EQ-5D-5L index total score was 0.29 points and in SIBDQ total score was 20.5 points; percent reductions in WPAI absenteeism was 34.4%, presenteeism 26.8%, overall work impairment 40.9% and activity impairment was 28.3%. These changes reached the thresholds for minimally clinically important differences. The majority of physicians (91.9%) and patients (93.5%) were satisfied with tofacitinib at week [52+]. CONCLUSION: Patients with moderate-to-severe UC treated with tofacitinib show considerable improvement in symptoms and quality of life from tofacitinib initiation to one year and beyond, with high rates of remission. Physicians and patients report satisfaction with UC control at recommended doses in a mostly biologic experienced population.

Improvements in Disease Activity Partially Mediate the Effect of Tofacitinib Treatment on Generic and Disease-Specific Health-Related Quality of Life in Patients with Ulcerative Colitis: Data from the OCTAVE Program.

BACKGROUND: Patients with ulcerative colitis (UC) often report impaired health-related quality of life (HRQoL). Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of UC. In addition to previous demonstrations of improved clinical measures (e.g., Mayo score), tofacitinib has been shown to improve HRQoL in patients with UC. This analysis explored the interrelationships among tofacitinib treatment, HRQoL, and disease activity (measured using Mayo subscores) using mediation modeling. METHODS: Data were collected from two 8-week induction studies (OCTAVE Induction 1 and 2) in patients with moderate to severe UC treated with tofacitinib or placebo. Two mediation models were specified. First, Mayo subscores were mediators between the binary treatment variable (tofacitinib vs. placebo) and the eight Short Form-36 Health Survey (SF-36) domain scores as outcomes. Second, the four Inflammatory Bowel Disease Questionnaire (IBDQ) domain scores served as outcomes. Both models used data collected at week 8. RESULTS: Overall, 1,073 and 1,079 patients were included in the SF-36- and IBDQ-based models, respectively. For all SF-36 domains, improvements in Mayo subscores were estimated to explain 65.6% (bodily pain) to 92.9% (mental health) of the total treatment effect on SF-36 domain scores (all p < 0.05). For all IBDQ domains, improvements in Mayo subscores explained 71.6% (systemic symptoms) to 84.7% (emotional function) of the total treatment effect (all p < 0.05). CONCLUSION: Mayo scores and Mayo subscores are significant but incomplete contributors to tofacitinib's effect on HRQoL in patients with moderate to severe UC. CLINICALTRIALS: gov: NCT01465763; NCT01458951.

Assessment of retrospective collection of EQ-5D-5L in a US COVID-19 population.

BACKGROUND: It is imperative to evaluate health related quality of life (HRQoL) pre-COVID-19, but there is currently no evidence of the retrospective application of the EuroQol 5-Dimension, 5 level version (EQ-5D-5L) for COVID-19 studies. METHODS: Symptomatic patients with SARS-CoV-2 at CVS Health US test sites were recruited between 01/31/2022-04/30/2022. Consented participants completed the EQ-5D-5L questionnaire twice: a modified version where all the questions were past tense to retrospectively assess pre-COVID-19 baseline QoL, and the standard version in present tense to assess current HRQoL. Duncan's new multiple range test was adopted for post analysis of variance pairwise comparisons of EQ visual analog scale (EQ VAS) means between problem levels for each of 5 domains. A linear mixed model was applied to check whether the relationship between EQ VAS and utility index (UI) was consistent pre-COVID-19 and during COVID-19. Matching-adjusted indirect comparison was used to compare pre-COVID-19 UI and EQ VAS scores with those of the US population. Lastly, Cohen's d was used to quantify the magnitude of difference in means between two groups. RESULTS: Of 676 participants, 10.2% were age 65 or more years old, 73.2% female and 71.9% white. Diabetes was reported by 4.7% participants and hypertension by 11.2%. The estimated coefficient for the interaction of UI-by-retrospective collection indicator (0 = standard prospective collection, 1 = retrospective for pre-COVID-19), -4.2 (SE: 3.2), P = 0.197, indicates that retrospective collection does not significantly alter the relationship between EQ VAS and UI. After adjusting for age, gender, diabetes, hypertension, and percent of mobility problems, the predicted means of pre-COVID-19 baseline EQ VAS and UI were 84.6 and 0.866, respectively. Both means were close to published US population norms (80.4 and 0.851) compared to those observed (87.4 and 0.924). After adjusting for age, gender, diabetes, and hypertension, the calculated ES between pre-COVID-19 and COVID-19 for UI and EQ VAS were 0.15 and 0.39, respectively. Without retrospectively collected EQ-5D-5L, using US population norms tended to underestimate the impact of COVID-19 on HRQoL. CONCLUSION: At a group level the retrospectively collected pre-COVID-19 EQ-5D-5L is adequate and makes it possible to directly evaluate the impact of COVID-19 on HRQoL. ( ClinicalTrials.gov NCT05160636).

Overall and complete response rates as potential surrogates for overall survival in relapsed/refractory multiple myeloma.

Aim: The correlation between response and survival has not been well-studied in relapsed or refractory multiple myeloma (RRMM). Materials & methods: A systematic literature review of Medline, Embase and Cochrane databases (2010-06/2020) and relevant congresses (2018-2020) was performed to identify randomized clinical trials in RRMM reporting median overall survival (mOS), progression-free survival and response end points. The relationship between mOS and response end points was analyzed using Pearson's product-moment correlation. Results: A total of 81 records for 65 original studies, representing 12,827 patients were included. The correlation was moderate for mOS with overall response rate (Pearson r = 0.79), very good partial response (r = 0.73) and duration of response (r = 0.78); all were statistically significant. In linear regression models, estimated mOS gain was 0.48, 0.47 and 1.94 months per percentage point of overall response rate, very good partial response and complete response, respectively (all p < 0.001). Significance was maintained after adjustment for age, relapsed versus refractory multiple myeloma and study year. The analysis was limited by small sample sizes and inconsistent reporting of study-level covariates. Conclusion: These findings support short-term response-based end points as surrogates to survival in RRMM.

Treatments for multiple myeloma may not work for every patient and the cancer may come back. In clinical trials, it is difficult to find out how well new treatments work in allowing patients to live longer. This is especially true when patients have advanced disease that has returned or has not responded to treatment. How well a patient responds to treatment (i.e., has a decreased extent of disease) could indicate whether the drug will help the patient live longer, but the relationship between response to treatment and survival is not fully understood. We conducted a systematic review and meta-analysis to better understand how response rates and survival are related. A systematic review collects all the published research on a specific subject, and a meta-analysis is a statistical method that creates a single finding from several separate studies. This study found a moderate relationship between how long patients live after receiving treatment for multiple myeloma and their response to treatment. This would allow response-to-treatment data from clinical trials to be used to predict better survival and show the drug can help patients.

Special Issue PRO-Analysis of Clinically Meaningful Change on Patient-Reported Outcomes: Renewed Insights About Covariate Adjustment.

Determining clinically meaningful change (CMC) in a patient-reported (PRO) measure is central to its existence in gauging how patients feel and function, especially for evaluating a treatment effect. Anchor-based approaches are recommended to estimate a CMC threshold on a PRO measure. Determination of CMC involves linking changes or differences in the target PRO measure to that in an external (anchor) measure that is easier to interpret than and appreciably associated with the PRO measure. One type of anchor-based approach for CMC is the "mean change method" where the mean change in score of the target PRO measure within a particular anchor transition level (e.g. one-category improvement) is subtracted from the mean change in score of within an adjacent anchor category (e.g. no change category). In the literature, the mean change method has been applied with and without an adjustment for the baseline scores for the PRO of interest. This article provides the analytic rationale and conceptual justification for keeping the analysis unadjusted and not controlling for baseline PRO scores. Two illustrative examples are highlighted. The current research is essentially a variation of Lord's paradox (where whether to adjust for a baseline variable depends on the research question) placed in a new context. Once the adjustment is made, the resulting CMC estimate reflects an artificial case where the anchor transition levels are forced to have the same average baseline PRO score. The unadjusted estimate acknowledges that the anchor transition levels are naturally occurring (not randomized) groups and thus maintains external validity.

Meaningful within-patient change for clinical outcome assessments: model-based approach versus cumulative distribution functions.

OBJECTIVES: The FDA recommends the use of anchor-based methods and empirical cumulative distribution function (eCDF) curves to establish a meaningful within-patient change (MWPC) for a clinical outcome assessment (COA). In practice, the estimates obtained from model-based methods and eCDF curves may not closely align, although an anchor is used with both. To help interpret their results, we investigated and compared these approaches. METHODS: Both repeated measures model (RMM) and eCDF approaches were used to estimate an MWPC on a target COA. We used both real-life (ClinicalTrials.gov: NCT02697773) and simulated data sets that included 688 patients with up to six visits per patient, target COA (range 0 to 10), and an anchor measure on patient global assessment of osteoarthritis from 1 (very good) to 5 (very poor). Ninety-five percent confidence intervals for the MWPC were calculated by the bootstrap method. RESULTS: The distribution of the COA score changes affected the degree of concordance between RMM and eCDF estimates. The COA score changes from simulated normally distributed data led to greater concordance between the two approaches than did COA score changes from the actual clinical data. The confidence intervals of MWPC estimate based on eCDF methods were much wider than that by RMM methods, and the point estimate of eCDF methods varied noticeably across visits. CONCLUSIONS: Our data explored the differences of model-based methods over eCDF approaches, finding that the former integrates more information across a diverse range of COA and anchor scores and provides more precise estimates for the MWPC.

A systematic review of primary care-focused, self-reported medication adherence tools.

BACKGROUND: Clinician recognition of nonadherence is generally low. Tools that clinicians have used to assess medication adherence are self-reported adherence instruments that ask patients questions about their medication use experience. There is a need for more structured reviews that help clinicians comprehensively distinguish which tool might be most useful and valuable for their clinical setting and patient populations. OBJECTIVES: This systematic review aimed to (1) identify validated, self-reported medication adherence tools that are applicable to the primary care setting and (2) summarize selected features of the tools as an assessment of clinical feasibility and applicability. METHODS: The investigators systematically reviewed MEDLINE via Ovid, Embase via Ovid, International Pharmaceutical Abstracts, and CINAHL from inception to December 1, 2020. Investigators independently screened 3394 citations, identifying 43 articles describing validation parameters for 25 unique adherence tools. After screening each tool, 17 tools met the inclusion criteria and were qualitatively summarized. RESULTS: Findings highlight 25 various tool characteristics (i.e., descriptions, parameters and diseases, measures and validity comparators, and other information), which clinicians might consider when selecting a self-reported adherence tool with strong measurement validity that is practical to administer to patients. There was much variability about the nature and extent of adherence measurement. Considerable variation was noted in the objective measures used to correlate to the self-reported tools' measurements. There were wide ranges of correlation between self-reported and objective measures. Several included tools had relatively low to moderate criterion validities. Many manuscripts did not describe whether tools were associated with costs, had copyrights, and were available in other languages; how much time was required for patients to complete self-report tools; and whether patient input informed tool development. CONCLUSION: There is a critical need to ensure that adherence tool developers establish a key list of tool characteristics to report to help clinicians and researchers make practical comparisons among tools.

Real-world characteristics, treatment experiences and corticosteroid utilisation of patients treated with tofacitinib for moderate to severe ulcerative colitis.

BACKGROUND: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database. METHODS: Patients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation). RESULTS: Among patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3-6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib. CONCLUSIONS: Among patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

Effectiveness of crizotinib versus entrectinib in ROS1-positive non-small-cell lung cancer using clinical and real-world data.

Aims: To compare clinical trial results for crizotinib and entrectinib in ROS1-positive non-small-cell lung cancer and compare clinical trial data and real-world outcomes for crizotinib. Patients & methods: We analyzed four phase I-II studies using a simulated treatment comparison (STC). A STC of clinical trial versus real-world evidence compared crizotinib clinical data to real-world outcomes. Results: Adjusted STC found nonsignificant trends favoring crizotinib over entrectinib: objective response rate, risk ratio = 1.04 (95% CI: 0.85-1.28); median duration of response, mean difference = 16.11 months (95% CI: -1.57- 33.69); median progression-free survival, mean difference = 3.99 months (95% CI: -6.27-14.25); 12-month overall survival, risk ratio = 1.01 (95% CI: 0.90-1.12). Nonsignificant differences were observed between the trial end point values and the real-world evidence for crizotinib. Conclusions: Crizotinib and entrectinib have comparable efficacy in ROS1-positive non-small-cell lung cancer.

Efficacy of non-intensive therapies approved for relapsed/refractory acute myeloid leukemia: a systematic literature review.

Aim: De novo relapsed and/or refractory acute myeloid leukemia (rrAML) has limited treatment options for patients not eligible ('unfit') to receive intensive chemotherapy-based interventions. The authors aimed to summarize outcomes for licensed therapies in this setting. Materials & methods: A systematic literature review identified licensed therapies in this setting. A feasibility assessment was made to conduct a network meta-analysis to evaluate comparative efficacy. Results: Seven unique trials were identified. Median survival months were 13.8 for gemtuzumab ozogamicin (GO), 9.3 for gilteritinib (FLT3 mutated rrAML), 5.6 for low-dose cytarabine and 3.2 for best supportive care; transplant rates with gilteritinib and GO were 25.5 and 19%, respectively. A network meta-analysis was not feasible. Conclusion: There remains a high unmet need in de novo rrAML patients not eligible for intensive therapy, with GO and gilteritinib (only FLT3-mutated AML) providing the best current options.

Some patients with acute myeloid leukemia (AML) have no response to initial treatment or have a response that is subsequently lost. Follow-on treatment options after that initial stage are limited, especially for patients who are not able to have intensive therapy, such as chemotherapy, due to age, physical or cognitive function, existing comorbidities or symptoms. This study aimed to review the published literature to identify data associated with treatments that are licensed for use in patients ineligible for intensive therapy who do not maintain a response from their initial therapy. The study found that the drug gilteritinib was an option for the subgroup of AML patients with FLT3-mutated disease with an average life expectancy just under 1 year, while gemtuzumab ozogamicin was an option for a wider group of AML patients with a life expectancy just over 1 year. Between a fifth and a quarter of patients went on to receive a stem-cell transplant after treatment with one of these. With limited options, this patient group needs further attention; however, the availability of the previously mentioned treatments is promising.

Concern about addiction is associated with lower quality of life in patients with osteoarthritis: an exploratory, real-world data analysis.

PURPOSE: To evaluate the relationship between self-reported concerns about becoming addicted to a medication and health-related quality of life (HRQoL) in patients with osteoarthritis (OA). METHODS: This real-world study used patient-level cross-sectional survey data collected from the US Adelphi Disease Specific Programme (DSP). The DSP for OA selected 153 physicians who collected de-identified data on their next nine adult patients with OA. Each patient completed a disease-relevant survey, which included the Likert-scale question, "I am concerned about becoming addicted to my medicine," (CAA) with responses ranging from "completely disagree" [1] to "completely agree" [5]. HRQoL was measured by the EQ-5D-5L index value and the EQ Visual Analogue Scale (VAS). A set of ordinary least squares regressions using HRQoL measures as outcomes and CAA as a continuous predictor were estimated. Standardized effect size (ES) was used to gauge the magnitude of effects. RESULTS: A total of 866 patients with OA completed the survey (female, 61.2%; White, 77.7%; mean age, 64.2 years). Of the 775 patients who completed the CAA question, almost one-third responded that they "agree" (18%) or "completely agree" (11%), while 27% responded "completely disagree" and 20% "disagree." Regression analyses found that patients who have concerns about medication addiction have significantly different EQ-5D-5L index values and EQ VAS scores compared with patients who do not have this concern (p < 0.0001). CONCLUSION: Our findings suggest that concern about medication addiction in patients with OA may have an impact on patient HRQoL, with more concerned patients reporting poorer HRQoL outcomes.

Factors associated with physician-reported treatment status of patients with osteoarthritis pain.

BACKGROUND: Osteoarthritis (OA) is typically associated with pain, but many patients are not treated. METHODS: This point in time study explored factors associated with treatment status, using logistic regression of data from the Adelphi OA Disease Specific Programme conducted in the United States. Patients' treatment status was based on physician-reported, current: 1) prescription medication for OA vs. none; and 2) physician treatment (prescription medication and/or recommendation for specified nonpharmacologic treatment for OA [physical or occupational therapy, acupuncture, transcutaneous electrical nerve stimulation, or cognitive behavior therapy/psychotherapy]) vs. self-management (no prescription medication or specified nonpharmacologic treatment). RESULTS: The 841 patients (including 57.0% knee OA, 31.9% hip OA) reported mild (45.4%) or moderate or severe (54.6%) average pain intensity over the last week. The majority were prescribed medication and/or recommended specified nonpharmacologic treatment; 218 were not prescription-medicated and 122 were self-managed. Bivariate analyses showed less severe patient-reported pain intensity and physician-rated OA severity, fewer joints affected by OA, lower proportion of joints affected by knee OA, better health status, lower body mass index, and lower ratings for cardiovascular and gastrointestinal risks, for those not prescribed medication (vs. prescription-medicated). Multivariate analyses confirmed factors significantly (p < 0.05) associated with prescription medication included (odds ratio): physician-rated current moderate OA severity (vs. mild, 2.03), patient-reported moderate OA severity 6 months ago (vs. mild, 1.71), knee OA (vs. not, 1.81), physician-recommended (0.28) and patient-reported (0.43) over-the-counter medication use (vs. not), prior surgery for OA (vs. not, 0.37); uncertain income was also significant. Factors significantly (p < 0.05) associated with physician treatment included (odds ratio): physician-recommended nonpharmacologic therapy requiring no/minimal medical supervision (vs. not, 2.21), physician-rated current moderate OA severity (vs. mild, 2.04), patient-reported over-the-counter medication use (vs. not, 0.26); uncertain time since diagnosis was also significant. Patient-reported pain intensity and most demographic factors were not significant in either model. CONCLUSIONS: Approximately 1 in 4 patients were not prescribed medication and 1 in 7 were self-managed, although many were using over-the-counter medications or nonpharmacologic therapies requiring no/minimal medical supervision. Multiple factors were significantly associated with treatment status, including OA severity and over-the-counter medication, but not pain intensity or most demographics.

Burden of chronic low back pain: Association with pain severity and prescription medication use in five large European countries.

OBJECTIVE: This study assessed associations between severity of, and prescription medication use for, chronic low back pain (CLBP) and health-related quality of life, health status, work productivity, and healthcare resource utilization. METHODS: This cross-sectional study utilized SF-12, EQ-5D-5L, and work productivity and activity impairment (WPAI) questionnaires, and visits to healthcare providers among adults with self-reported CLBP participating in the National Health and Wellness Survey in Germany, France, UK, Italy, and Spain. Respondents were stratified into four groups according to pain severity (mild or moderate/severe) and prescription medication use (Rx-treated or Rx-untreated). Differences between groups were estimated using generalized linear models controlling for sociodemographics and health characteristics. RESULTS: Of 2086 respondents with CLBP, 683 had mild pain (276 Rx-untreated, 407 Rx-treated) and 1403 had moderate/severe pain (781 Rx-untreated, 622 Rx-treated). Respondents with moderate/severe pain had significantly worse health-related quality of life (SF-12v2 physical component summary), health status (EQ-5D-5L), and both absenteeism and presenteeism compared with those with mild pain, including Rx-untreated (moderate/severe pain Rx-untreated vs. mild pain Rx-untreated, p ≤ 0.05) and Rx-treated (moderate/severe pain Rx-treated vs. mild pain Rx-treated, p ≤ 0.05) groups. Significantly more visits to healthcare providers in the last 6 months were reported for moderate/severe pain compared with mild pain for Rx-treated (least squares mean 13.01 vs. 10.93, p = 0.012) but not Rx-untreated (8.72 vs. 7.61, p = 0.072) groups. Health-related quality of life (SF-12v2 physical component summary) and health status (EQ-5D-5L), as well as absenteeism and presenteeism, were significantly worse, and healthcare utilization was significantly higher, in the moderate/severe pain Rx-treated group compared with all other groups (all p ≤ 0.05). CONCLUSION: Greater severity of CLBP was associated with worse health-related quality of life, health status, and absenteeism and presenteeism, irrespective of prescription medication use. Greater severity of CLBP was associated with increased healthcare utilization in prescription medication users.

Are pain severity and current pharmacotherapies associated with quality of life, work productivity, and healthcare utilisation for people with osteoarthritis in five large European countries?

OBJECTIVES: Although the osteoarthritis (OA) burden is well-recognised, the benefit of currently available OA pharmacological therapy is not clear. This study aimed to assess whether the impact of OA pain on health-related quality of life (HRQoL), work, and healthcare resource utilisation (HRU) differed by both pain severity and prescription medication status. METHODS: This cross-sectional study used pooled data from the 2016/2017 European National Health and Wellness Survey. Respondents with self-reported physician-diagnosed OA and pain were included. Outcomes examined included HRQoL, health utility, health status, work productivity and activity impairment, and HRU. Groups derived from self-reported pain severity and prescription medication use were compared using chi-square tests, analysis of variance, and generalised linear models controlling for socio-demographics, health behaviours, and health status. RESULTS: Respondents with OA (n=2417) reported mild (40.4%, of which 44.9% prescription-treated) and moderate to severe pain (59.6%, of which 54.0% prescription-treated). HRQoL, health utility, health status, and work and activity impairment were substantially worse among the moderate/severe pain prescription-treated group compared to the rest (e.g. SF-12v2 physical component score [PCS] for moderate/severe pain prescription-treated=34.5 versus mild pain prescription-treated =39.3, moderate/severe pain prescription-untreated=40.6, and mild pain prescription-untreated=45.6; p<0.01). HRU such as the mean number of emergency room visits for >6 months was higher in the prescription-treated groups (0.51-0.52, 95% CI 0.437-0.71) than the prescription-untreated groups (0.30-0.34, 95% CI 0.21-0.46; p<0.05). CONCLUSIONS: Persons with moderate to severe OA pain treated with available prescription medications have poor health status and HRQoL and increased HRU compared to those not receiving prescription medications.