Secukinumab in patients with moderate-to-severe hidradenitis suppurativa based on prior biologic exposure: an efficacy and safety analysis from the SUNSHINE and SUNRISE phase III trials.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a substantial disease burden. Secukinumab has previously been reported to have sustained efficacy with a favourable safety profile in patients with moderate-to-severe HS. It is unknown whether prior biologic exposure affects the efficacy and safety of secukinumab. OBJECTIVES: To investigate the efficacy and safety of secukinumab in patients with moderate-to-severe HS based on prior exposure to -biologics. METHODS: This was an analysis of the SUNSHINE and SUNRISE phase III trials of secukinumab in patients with moderate-to-severe HS. Patients were randomized at baseline to receive secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W), or placebo for 16 weeks. After week 16, patients on the SECQ2W and SECQ4W schedules remained on the same treatment regimen, while patients randomized to placebo were switched to either SECQ2W or SECQ4W up to week 52. Assessments based on prior exposure to biologics included Hidradenitis Suppurativa Clinical Response (HiSCR), abscess and inflammatory nodule (AN) count, flare rates, HS-related pain [numerical rating scale 30 (NRS30)], 55% reduction in the International Hidradenitis Suppurativa Severity Score System (IHS4-55), Dermatology Life Quality Index, EuroQol-5D and safety. RESULTS: Overall, 1084 patients were randomized in the SUNSHINE and SUNRISE trials and included in this analysis; 255 (23.5%) were biologic-experienced [SECQ2W (n = 80); SECQ4W (n = 81); placebo (n = 94)] and 829 (76.5%) were biologic-naïve [SECQ2W (n = 281); SECQ4W (n = 279); placebo (n = 269)]. At week 16, responses were more efficacious for secukinumab than for placebo with regard to HiSCR in patients who were biologic-experienced {SECQ2W 37.0% [odds ratio (OR) 1.60, 95% confidence interval (CI) 0.83-3.08]; SECQ4W 38.8% [OR 1.67, 95% CI 0.86-3.22]; placebo 27.3%} and biologic-naïve [SECQ2W 45.6% (OR 1.64, 95% CI 1.15-2.33); SECQ4W 45.4% (OR 1.61, 95% CI 1.13-2.29); placebo 34.2%]. Similar results were observed for AN count, NRS30 and IHS4-55. The higher response seen at week 16 with secukinumab was sustained, with a trend toward improvement over time, through to week 52 in both subgroups. Additional efficacy was observed for quality-of-life assessments, and no differences in safety between subgroups were observed. CONCLUSIONS: Regardless of prior biologic exposure, secukinumab was efficacious in improving the signs and symptoms of HS. This finding positions secukinumab as the first option in patients who are biologic-naïve, as well as in patients who have previously been treated with other biologic therapy, based on individual patient needs.

Hidradenitis suppurativa (HS) is a chronic skin disease that causes painful boils. HS is common and affects about 0.4% of the world's population. Treating the condition is difficult, but drugs called 'biologics' can help to improve the symptoms. For example, secukinumab is a biologic drug that has been shown to be effective and well-tolerated for the treatment of HS. In this analysis, we investigated whether previous treatment with biologics could affect the effectiveness and tolerability of secukinumab. This analysis included data from two identical clinical trials (called SUNSHINE and SUNRISE) that recruited adult patients with HS who had moderate-to-severe disease. In these trials, patients took secukinumab 300 mg every 2 weeks or every 4 weeks for 1 year, or a placebo for 4 months and then switched to secukinumab until 1 year. At regular intervals, the effectiveness and tolerability of secukinumab were examined and the results were compared between patients who had previously used another biologic and patients who had never used a biologic before. After 16 weeks, patients who took secukinumab had better results than the patients who took a placebo, independent of previous biologic use. Secukinumab was still effective and had improved results over 1 year of treatment in both subgroups. Regardless of whether patients had previously been taking another biologic, secukinumab was just as tolerable as placebo and there were no new safety risks. Our analysis shows that secukinumab is effective and tolerable, regardless of whether patients have previously used another biologic drug.

Diagnostic Accuracy of Amyloid versus 18 F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia.

OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients. METHODS: One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC). RESULTS: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. INTERPRETATION: In our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.

Case-control versus case-only estimates of gene-environment interactions with common and misclassified clinical diagnosis.

Genetic studies provide valuable information to assess if the effect of genetic variants varies by the nongenetic "environmental" variables, what is traditionally defined to be gene-environment interaction (GxE). A common complication is that multiple disease states present with the same set of symptoms, and hence share the clinical diagnosis. Because (a) disease states might have distinct genetic bases; and (b) frequencies of the disease states within the clinical diagnosis vary by the environmental variables, analyses of association with the clinical diagnosis as an outcome variable might result in false positive or false negative findings. We develop estimates for this setting to be able to assess GxE in a case-only study and we compare the case-control and case-only estimates. We report extensive simulation studies that evaluate empirical properties of the estimates and show the application to a study of Alzheimer's disease.

Reach, engagement and effectiveness of in-person and online lifestyle change programs to prevent diabetes.

BACKGROUND: COVID-19 has accelerated interest in and need for online delivery of healthcare. We examined the reach, engagement and effectiveness of online delivery of lifestyle change programs (LCP) modelled after the Diabetes Prevention Program (DPP) in a multistate, real-world setting. METHODS: Longitudinal, non-randomized study comparing online and in-person LCP in a large multistate sample delivered over 1 year. Sample included at-risk adults (n = 26,743) referred to online (n = 9) and in-person (n = 11) CDC-recognized LCP from a multi-state registry (California, Florida and Colorado) between 2015 and 2018. The main outcome was effectiveness (proportion achieving > 5% weight loss) at one-year. Our secondary outcomes included reach (proportion enrolled among referred) and engagement (proportion ≥ 9 sessions by week 26). We used logistic regression modelling to assess the association between participant- and setting -level characteristics with meaningful weight loss. RESULTS: Online LCP effectiveness was lower, with 23% of online participants achieving > 5% weight loss, compared with 35% of in-person participants (p < 0.001). More adults referred to online programs enrolled (56% vs 51%, p < 0.001), but fewer engaged at 6-months (attendance at ≥9 sessions 46% vs 66%, p < 0.001) compared to in-person participants. CONCLUSIONS: Compared to adults referred to in-person LCP, those referred to online LCP were more likely to enroll and less likely to engage. Online participants achieved modest meaningful weight loss. Online delivery of LCP is an attractive strategy to deliver and scale DPP, particularly with social distancing measures currently in place. However, it is unclear how to optimize delivery models for maximal impact given trade-offs in reach and effectiveness.

A simple approximation to bias in the genetic effect estimates when multiple disease states share a clinical diagnosis.

Case-control genome-wide association studies (CC-GWAS) might provide valuable clues to the underlying pathophysiologic mechanisms of complex diseases, such as neurodegenerative disease and cancer. A commonly overlooked complication is that multiple distinct disease states might present with the same set of symptoms and hence share a clinical diagnosis. These disease states can only be distinguished based on a biomarker evaluation that might not be feasible in the whole set of cases in the large number of samples that are typically needed for CC-GWAS. Instead, the biomarkers are measured on a subset of cases. Or an external reliability study estimates the frequencies of the disease states of interest within the clinically diagnosed set of cases. These frequencies often vary by the genetic and/or nongenetic variables. We derive a simple approximation that relates the genetic effect estimates obtained in a traditional logistic regression model with the clinical diagnosis as the outcome variable to the genetic effect estimates in the relationship to the true disease state of interest. We performed simulation studies to assess the accuracy of the approximation that we have derived. We next applied the derived approximation to the analysis of the genetic basis of the innate immune system of Alzheimer's disease.

A simple approximation to the bias of gene-environment interactions in case-control studies with silent disease.

One of the most important research areas in case-control Genome-Wide Association Studies is to determine how the effect of a genotype varies across the environment or to measure the gene-environment interaction (G × E). We consider the scenario when some of the "healthy" controls actually have the disease and when the frequency of these latent cases varies by the environmental variable of interest. In this scenario, performing logistic regression with the clinically diagnosed disease status as an outcome variable and will result in biased estimates of G × E interaction. Here, we derive a general theoretical approximation to the bias in the estimates of the G × E interaction and show, through extensive simulation, that this approximation is accurate in finite samples. Moreover, we apply this approximation to evaluate the bias in the effect estimates of the genetic variants related to mitochondrial proteins a large-scale prostate cancer study.

Bias in parameter estimates due to omitting gene-environment interaction terms in case-control studies.

Genetic studies are continuing to generate volumes and variety of data that can be used to examine the genetic effects. Often the effect of a genetic variant varies by nongenetic measures, what is traditionally defined as gene-environment interaction (G×E). If the G×E term is neglected, estimates of the main effects can be substantially biased. We derive a general and convenient approximation to the magnitude of bias in the estimates due to omitting the G×E term. We show that the approximation is reasonably accurate in finite samples. We then apply the approximation in a study of Alzheimer's disease.

Gene-environment interactions in case-control studies with silent disease.

Genome-wide association studies (GWAS) often measure gene-environment interactions (G × E). We consider the problem of accurately estimating a G × E in a case-control GWAS when a subset of the controls have silent, or undiagnosed, disease and the frequency of the silent disease varies by the environmental variable. We show that using case-control status without accounting for misdiagnosis can lead to biased estimates of the G × E. We further propose a pseudolikelihood approach to remove the bias and accurately estimate how the relationship between the genetic variant and the true disease status varies by the environmental variable. We demonstrate our method in extensive simulations and apply our method to a GWAS of prostate cancer.

The impact of technical parameters on ablation volume during MR-guided focused ultrasound of desmoid tumors.

PURPOSE: Desmoid tumors are benign, locally aggressive soft tissue tumors derived from fibroblasts. Magnetic resonance-guided focused ultrasound (MRgFUS) is a safe and effective treatment for desmoid tumors. The purpose of this study was to retrospectively review the MRgFUS treatments of desmoid tumors at our institution to determine which technical treatment parameters contributed most significantly to the accumulation of thermal dose. MATERIALS AND METHODS: The study protocol was approved by the local IRB. We retrospectively reviewed data from MRgFUS treatments performed in histologically-confirmed desmoid tumors, over a period of 18 months. Sonication parameter means were compared with ANOVA. Mixed effects and linear regression models were used to evaluate the relative contribution of different parameters to thermal dose volume. RESULTS: Nine-hundred thirty-six sonications were reviewed in 13 treatments. Accumulated dose per sonication was greatest for elongated sonications (0.96 cc ± 0.90) compared to short (0.88 ± 0.93 cc) and nominal (0.55 ± 0.70 cc) sonications, p < .001. 65.2% of short sonications resulted in high percentage ablations, compared to 46.0% of nominal and 35.1% of elongated sonications. Standardized beta coefficients (anticipated increased volume in cc per unit) for power, duration, energy and average temperature were 0.006, 0.057, 0.00035 and 0.03, p < .001. Regarding dose efficacy, dose area contributed the greatest to this variability - 50.7% (45.5-54.8%), followed by distance - 16.6% (12.9-20.0%). CONCLUSIONS: A variety of sonication parameters significantly contributed to thermal ablation volume following MRgFUS of desmoid tumors, in reproducible patterns. This work can serve as the basis for future models working toward improved planning for MRgFUS treatments.

Tau prions from Alzheimer's disease and chronic traumatic encephalopathy patients propagate in cultured cells.

Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimer's disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R- or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.