When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib: insights from trajectories analyses of patients enrolled in two phase III trials.

BACKGROUND: Baricitinib is approved for the treatment of adults with severe alopecia areata (AA). In the absence of robust data on the patterns of regrowth during treatment of severe AA, there is a gap in the knowledge regarding treatment expectations. OBJECTIVES: To examine whether different clinical response subgroups could be identified in baricitinib-treated patients with severe AA and factors that contribute to these subgroups. METHODS: The BRAVE-AA1 and BRAVE-AA2 phase III trials enrolled patients with severe AA [Severity of Alopecia Tool (SALT) score ≥ 50 (≥ 50% scalp hair loss)]. Patients randomized to baricitinib 4 mg or 2 mg retained their treatment allocation for 52 weeks. Based on patterns identified through growth mixture modelling (GMM), patients were categorized into responder subgroups according to when they first achieved ≥ 30% improvement from baseline in SALT score (SALT30). For each responder subgroup, trajectories of response (i.e. achievement of a SALT score ≤ 20, SALT score ≤ 10 and ≥ 50% change from baseline in SALT score) and baseline disease characteristics are reported. RESULTS: Respectively, 515 and 340 patients were randomized to once-daily baricitinib 4 mg and 2 mg at baseline; 69% and 51%, respectively, achieved SALT30 at least once by week 52. Based on GMM findings, we identified three responder subgroups: early (SALT30 by week 12), gradual (SALT30 after week 12-week 36) and late (SALT30 after week 36-week 52). The proportions of early, gradual and late responders and nonresponders were, respectively, 33%, 28%, 8% and 31% among patients treated with baricitinib 4 mg, and 20%, 23%, 9% and 49%, respectively, among those treated with baricitinib 2 mg. Early responders had a shorter trajectory to maximal clinical outcomes (e.g. > 78% achieved a SALT score ≤ 20 by week 36) vs. gradual or late responders. Early responders were more frequent among patients with baseline severe AA (SALT score 50 to < 95) vs. very severe AA (SALT score 95-100). Overall, responders (early to late) were more frequent in patients with short (< 4 years) episodes of hair loss. CONCLUSIONS: These analyses identified early, gradual and late responder subgroups for scalp hair regrowth in baricitinib-treated patients with severe AA, and that these subgroups are influenced by baseline characteristics. Findings from these analyses will help to inform treatment expectations for scalp hair regrowth.

Early improvements in signs and symptoms predict clinical response to baricitinib in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Early prediction of therapeutic response can optimize treatment strategies in atopic dermatitis (AD). Baricitinib is approved for moderate-to-severe AD in Europe, Japan and other countries. OBJECTIVES: To identify early clinical improvements that can reliably predict a later clinical response to baricitinib in adults with moderate-to-severe AD. METHODS: Using data from one topical corticosteroid combination study [BREEZE-AD7 (NCT03733301)] and data pooled from two monotherapy studies [(BREEZE-AD1 (NCT03334396) and BREEZE-AD2 (NCT03334422)], we calculated the sensitivity and specificity, along with the positive predictive value (PPV) and negative predictive value (NPV), of predefined changes in single and combined clinical scores at weeks 2, 4 and 8, to predict clinical response at week 16. Clinical response was defined as ≥ 75% improvement in Eczema Area and Severity Index (EASI 75), ≥ 4-point improvement in Itch Numeric Rating Scale (Itch NRS ≥ 4), or a combination of both. RESULTS: Composite predictors had higher predictive accuracy for week 16 response outcomes than did single parameters. This was evident as early as week 4 for the combination of EASI 50 or Itch NRS ≥ 3 and of validated Investigator Global Assessment for AD (vIGA-AD) score ≤ 2 or Itch NRS ≥ 3 (sensitivity 87-100%; NPV 68-100%). The predictive accuracy of these composite clinical predictors for week 16 response outcomes was highest at week 8 (sensitivity 92-100%; NPV 80-100%). At both weeks 4 and 8, EASI 50 or Itch NRS ≥ 3 had higher sensitivity and NPV than did vIGA-AD score ≤ 2 or Itch NRS ≥ 3. CONCLUSIONS: Improvement in signs and symptoms early during treatment with baricitinib 4 mg once daily predicts clinical response at week 16, providing a tool for dermatologists when choosing treatment strategies for patients with moderate-to-severe AD.

Long-term efficacy (up to 68 weeks) of Baricitinib in combination with topical corticosteroids in adult patients with moderate-to-severe atopic dermatitis: Analysis of treatment responders, partial responders and nonresponders originating from study BREEZE-AD7.

BACKGROUND: Baricitinib demonstrated efficacy in treating adults with moderate-to-severe atopic dermatitis (AD) in Phase 3 clinical trials. OBJECTIVE: To examine long-term efficacy of baricitinib combined with topical corticosteroids (TCS) in adult patients from a Phase 3 study, BREEZE-AD7 (NCT03733301), enrolled in ongoing extension study, BREEZE-AD3 (NCT03334435). METHODS: Upon BREEZE-AD7 completion, responders or partial responders (RPR [vIGA-AD™ ≤2]) receiving baricitinib 2-mg or 4-mg + TCS maintained their original treatment doses in BREEZE-AD3. Nonresponders (NR; vIGA-AD 3,4) receiving baricitinib 2-mg were rerandomized 1:1 to baricitinib 2-mg or 4-mg; NR receiving baricitinib 4-mg remained on same dose. Integrated data from all patients (RPR + NR = baricitinib 4-mg intent-to-treat [ITT] cohort) receiving continuous baricitinib 4-mg in BREEZE-AD7 through BREEZE-AD3 were analysed, along with baricitinib 4-mg or 2-mg RPR cohorts. Primary endpoint was proportion of patients with vIGA-AD (0,1) at Weeks 16, 36 and 52 (Weeks 32, 52 and 68 of continuous therapy). Additional outcomes included improvement in EASI75 and Itch NRS (up to Week 32). Missing data were imputed by last observation carried forward. RESULTS: In baricitinib 4-mg ITT cohort (N = 102), proportions of patients achieving vIGA-AD (0,1) at Week 32, Week 52, and Week 68 were 21.6%, 26.5% and 23.5%; EASI75 were 46.1%, 40.2% and 43.1%, respectively. Itch NRS ≥4-point improvement (Itch ≥4) were 47.3% at Week 16 and 40.6% at Week 32. In baricitinib 4-mg RPR cohort (N = 63), proportions of patients achieving vIGA-AD (0,1) at Week 32, Week 52 and Week 68 were 31.7%, 33.3% 34.9%, respectively; EASI75 were 57.1%, 49.2% and 49.2%, respectively. Itch ≥4 were 53.6% at Week 16 and 46.4% at Week 32. Corresponding proportions for baricitinib 2-mg RPR cohort (N = 53) for vIGA-AD (0,1) were 39.6%, 45.3% and 30.2%; EASI75 were 77.4%, 69.8% and 58.5%, respectively. Itch ≥4 were 56.3% at Week 16 and 47.9% at Week 32. CONCLUSION: Baricitinib 4-mg and 2-mg combined with TCS maintained clinically meaningful sustained efficacy over 68 weeks of continuous treatment.

The contribution of itch and skin severity improvements to the Dermatology Life Quality Index in patients with atopic dermatitis in baricitinib phase III trials.

With data from three monotherapy baricitinib phase III randomized clinical trials (RCTs), we conducted a posthoc mediator analysis to assess whether changes in itch or skin severity mediated the treatment effect over placebo on changes in health-related quality of life. In this analysis, baricitinib demonstrated significant improvement in the Dermatology Life Quality Index for which itch mediated approximately half of the changes at weeks 4 and 16.

Baricitinib 2 mg for the treatment of atopic dermatitis in North America: Long-term efficacy and patient-reported outcomes.

To address the need for long-term efficacy and patient-reported outcomes (PROs) data for patients with atopic dermatitis (AD) treated with baricitinib 2 mg, a study was conducted to evaluate the efficacy of baricitinib 2 mg in adult patients with moderate-to-severe AD. Data presented here provided efficacy and outcomes data for patients treated for 52 weeks. Patients who participated in the originating study, BREEZE-AD5 (NCT03435081), and met additional eligibility criteria could enroll in the multicenter, open-label, Phase 3, long-term extension study BREEZE-AD6 (NCT03559270). Patients received baricitinib 2 mg for the duration of BREEZE-AD6. In BREEZE-AD6, the proportion of patients who achieved a 75% improvement in the Eczema Area and Severity Index (EASI75) and validated Investigator Global Assessment for AD (vIGA-AD™) of 0 (clear) or 1 (almost clear) were assessed through 52 weeks, in addition to several PROs. At week 52, the proportion of patients treated with baricitinib 2 mg daily achieving EASI75 was 48.6% (70/144), and 31.3% (45/144) of patients achieved a vIGA-AD score of 0 or 1 (clear or almost clear). Improvements in PROs such as SCORing Atopic Dermatitis (SCORAD, itch and sleep) scores, Dermatology Life Quality Index (DLQI) total score, and DLQI ≤5 response were observed, and these responses were sustained through 52 weeks. Long-term efficacy of baricitinib in patients with AD was demonstrated by both clinician and patient-reported outcome measures.

Antischistosomiasis Liver Fibrosis Effects of Chlorogenic Acid through IL-13/miR-21/Smad7 Signaling Interactions In Vivo and In Vitro.

This study investigated the antischistosomiasis liver fibrosis effects of chlorogenic acid (CGA) on interleukin 13 (IL-13)/microRNA-21 (miR-21)/Smad7 signaling interactions in the hepatic stellate LX2 cell line and schistosome-infected mice. The transfection was based on the ability of the GV273-miR-21-enhanced green fluorescent protein (EGFP) and GV369-miR-21-EGFP lentiviral system to up- or downregulate the miR-21 gene in LX2 cells. The mRNA expression of miR-21, Smad7, and connective tissue growth factor (CTGF) and the protein expression of Smad7, CTGF, Smad1, phosphor-Smad1 (p-Smad1), Smad2, p-Smad2, Smad2/3, p-Smad2/3, transforming growth factor ß (TGF-ß) receptor I, and α-smooth muscle actin (α-SMA) was assayed. Pathological manifestation of hepatic tissue was assessed for the degree of liver fibrosis in animals. The results showed that CGA could inhibit the mRNA expression of miR-21, promote Smad7, and inhibit CTGF mRNA expression. Meanwhile, CGA could significantly lower the protein levels of CTGF, p-Smad1, p-Smad2, p-Smad2/3, TGF-ß receptor I, and α-SMA and elevate the Smad7 protein level. In vivo, with treatment with CGA, the signaling molecules of IL-13/miR-21/Smad7 interactions were markedly regulated. CGA could also reduce the degree of liver fibrosis in pathological manifestations. In conclusion, CGA could inhibit schistosomiasis-induced hepatic fibrosis through IL-13/miR-21/Smad7 signaling interactions in LX2 cells and schistosome-infected mice and might serve as an antifibrosis agent for treating schistosomiasis liver fibrosis.

Use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 solanezumab trials.

INTRODUCTION: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. METHODS: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. RESULTS: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. DISCUSSION: Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.

Effect of diabetes on caregiver burden in an observational study of individuals with Alzheimer's disease.

BACKGROUND: The burden on caregivers of patients with Alzheimer's disease (AD) is associated with the patient's functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed. METHODS: Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression. RESULTS: Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p < 0.05), compared with caregivers of patients without diabetes (n = 1307). Analyses showed caregivers of patients with diabetes spent significantly more time on iADL (+16 %; p = 0.03; increases were also observed for basic ADL and total caregiver time but did not reach statistical significance) and had a trend towards increased ZBI score. Patients with diabetes had a 63 % increase in the odds of requiring supervision versus those without diabetes (p = 0.01). Caregiver and patient HCRU did not differ according to patient diabetes. Caregivers with diabetes (n = 127) did not differ from those without diabetes (n = 1367) regarding burden/time, but caregivers with diabetes had a 91 % increase in the odds of having outpatient visits (p = 0.01). CONCLUSIONS: This cross-sectional analysis found caregiver time on iADL and supervision was higher for caregivers of patients with AD and diabetes versus without diabetes, while HCRU was unaffected by patient diabetes. Longitudinal analyses assessing change in caregiver burden over time by patient diabetes status may help clarify the cumulative impact of diabetes and AD dementia on caregiver burden.

Amyloid status imputed from a multimodal classifier including structural MRI distinguishes progressors from nonprogressors in a mild Alzheimer's disease clinical trial cohort.

INTRODUCTION: Mild-Alzheimer's disease (AD) subjects without significant Aß pathology represent a confounding finding for clinical trials because they may not progress clinically on the expected trajectory, adding variance into analyses where slowing of progression is being measured. METHODS: A prediction model based on structural magnetic resonance imaging (MRI) in combination with baseline demographics and clinical measurements was used to impute Aß status of a placebo-treated mild-AD sub-cohort (N = 385) of patients participating in global phase 3 trials. The clinical trajectories of this cohort were evaluated over 18 months duration of the trial, stratified by imputed Aß status within a mixed-model repeated measures statistical framework. RESULTS: In the imputed Aß-positive cohort, both cognitive (ADAS-Cog14 and MMSE) and functional (ADCS-iADL) measures declined more rapidly than in the undifferentiated population. DISCUSSION: Our results demonstrate imputing Aß status from MRI scans in mild-AD subjects may be a useful screening tool in global clinical trials if amyloid measurement is not available.

Protection of Nerve Injury with Exosome Extracted from Mesenchymal Stem Cell.

OBJECTIVE: To investigate the protective effect of Exosomes from human adipose-derived mesenchymal stem cells (hAMSCs) in neural injury induced by glutamate and its possible mechanism. METHODS: Characteristics of Exosomes from hAMSCs were identified by electron microscopy and Western blot analysis. Cytokines that might play a major role in the protective effect were tested by enzyme-linked immunosorbent assay (ELISA). The protective action of Exosome and its possible signaling pathway were researched by the in vitro neural injury induced by glutamate, including control group (without Glu), Glu group (dealing with Glu), Glu+Exo group (dealing with Glu +100 ng/ml Exo), Glu+Exo+Akt group (dealing with Glu+100 ng/ml Exo+10 µmol/L Akt), Glu+Exo+Erk group (dealing with 100 ng/ml Glu+100 ng/ml Exo+10 µmol/L Erk), and Glu+Exo+TrkB group (dealing with Glu+100 ng/ml Exo +10 µmol/L TrkB). RESULTS: Exosomes from hAMSCs had similar sizes to those isolated from other kinds of cells, and expressed the characteristic proteins such as CD63, CD81, HSP70, and HSP90. Cytokines that had neurotrophic effects on Exosomes were mainly insulin-like growth factor and hepatocyte growth factor, with the concentration being 9336.49±258.63 and 58,645.50±16,014.62, respectively; brain derived neurotrophic factor, nerve growth factor,and vascular endothelial growth factor had lower levels, with the concentration being 1928.25±385.47, 1136.94±5.99, and 33.34±9.43, respectively. MTS assay showed that the PC12 cell survival rates were 0.842±0.047, 0.306±0.024, 0.566±0.026, 0.461±0.016, 0.497±0.003, and 0.515±0.034 in the control group, Glu group, Glu+Exo group, Glu+Exo+Akt group, Glu+Exo+Erk group, and Glu+Exo+TrkB group; obviously, it was significantly lower in Glu group than in control group (P=0.02), significantly higher in Glu+Exo group than in Glu group (P=0.01), and significantly lower in Glu+Exo+Akt group than in Glu+Exo group (P=0.01). CONCLUSION: Exosomes secreted from hAMSCs have protective effect against neuron damage induced by glutamate, which may be mediated through activating the PI3/K-Akt signalling pathway.

Improvement in Measures of Quality of Life and Symptoms of Anxiety and Depression in Patients with Severe Alopecia Areata Achieving Sustained Scalp Hair Regrowth with Baricitinib.

INTRODUCTION: Alopecia areata (AA) is an autoimmune disease associated with high rates of emotional and psychosocial distress. The analysis reported here describes the evolution of measures assessing health-related quality of life (HRQoL) and symptoms of anxiety and depression up to week 104 in patients who achieved sustained scalp hair regrowth during treatment with baricitinib in the BRAVE-AA phase III trials. METHODS: This post-hoc analysis included data from the double-blind, parallel-group, randomized, placebo-controlled phase III trials BRAVE-AA1 (ClinicalTrials.gov number: NCT03570749) and BRAVE-AA2 (ClinicalTrials.gov number: NCT03899259). Adults with severe AA (defined as a Severity of Alopecia Tool [SALT] score ≥ 50) randomized to baricitinib 4 mg or baricitinib 2 mg at baseline who achieved SALT score ≤ 20 by week 36 and maintained SALT score ≤ 20 through week 104 on the same dose of baricitinib were included in this analysis of integrated data. Scalp hair regrowth (SALT score) and improvements in Skindex-16 AA Scale and Hospital Anxiety and Depression Scale (HADS) domain scores were analyzed over the 104-week period using descriptive statistics. RESULTS: In total, 131 patients (88 on baricitinib 4 mg and 43 on baricitinib 2 mg) were included in this analysis. Across the two groups, the mean age (standard deviation) was 37.2 years (12.7), and 84 (64.1%) patients were female. The interquartile range) for time to achieve a SALT score ≤ 20 for patients treated with baricitinib 4 mg and baricitinib 2 mg was 13.1 and 19.6 weeks, respectively. By week 104, 91% (baricitinib 2 mg) and 96% (baricitinib 4 mg) of patients had achieved a SALT score ≤ 10 on baricitinib treatment. In both groups, progressive improvements in the Skindex-16 AA and HADS domain scores were observed up to week 104. CONCLUSION: This analysis of adults with severe AA treated with baricitinib revealed that achievement of sustained clinically meaningful scalp hair regrowth (SALT score ≤ 20) was associated with improvements in both measures of HRQoL and symptoms of anxiety and depression up to week 104.

Baricitinib Improvement Across Regions in Atopic Dermatitis Patients with Baseline Body Surface Area up to 40% and Severe Itch.

INTRODUCTION: Patients with moderate-to-severe atopic dermatitis (AD) who are most likely to respond to the Janus kinase (JAK) 1/2 inhibitor baricitinib (BARI) are known to have an impacted body surface area (BSA) ≤ 40% and severe itch (numerical rating scale [NRS] ≥ 7], collectively termed 'BARI itch-dominant' patients. Our objective is to build on our previous work by providing a body region-specific, clinical characterization of the BARI itch-dominant patient at baseline and their response to BARI 4 mg. METHODS: BREEZE-AD7 was a phase 3 trial in adults with moderate-to-severe AD receiving placebo or 2 mg or 4 mg BARI in combination with topical corticosteroids. Assessing only data from BARI itch-dominant patients, we summarized the baseline characteristics and conducted body region-specific analyses on Eczema Area and Severity Index (EASI) data in order to report the response to placebo versus BARI 4 mg within this patient subtype. RESULTS: BARI 4 mg was highly effective across all body regions; at week 16, 75% improvement was seen in EASI scores (EASI75), and response rates with BARI 4 mg (head/neck, 58.3%; trunk, 69.2%; upper extremities, 61.5%; lower extremities, 87.5%) all exceeded those with placebo (head/neck: 37.5%; trunk, 40.6%; upper extremities, 18.8%; lower extremities, 40.6%) as well as the overall EASI75 rates of the intent-to-treat (ITT) population (BARI, 48.0%; placebo, 23.0%). At baseline, most BARI itch-dominant patients presented with involvement of all regions (mean regional BSA 22.7%-40.3%), highest in the head and neck, mean EASI region scores of 15.7-24.0, and considerably severe sign ratings (mean EASI sub-scores: 1.4-2.3, out of 3), especially for erythema. CONCLUSION: BARI itch-dominant patients exhibit AD involvement across all body regions and considerable sign severity, especially erythema. In response to BARI 4 mg, EASI quickly improved across regions, substantially more so in this subtype than in the ITT population.

A fusion learning method to subgroup analysis of Alzheimer's disease.

Uncovering the heterogeneity in the disease progression of Alzheimer's is a key factor to disease understanding and treatment development, so that interventions can be tailored to target the subgroups that will benefit most from the treatment, which is an important goal of precision medicine. However, in practice, one top methodological challenge hindering the heterogeneity investigation is that the true subgroup membership of each individual is often unknown. In this article, we aim to identify latent subgroups of individuals who share a common disorder progress over time, to predict latent subgroup memberships, and to estimate and infer the heterogeneous trajectories among the subgroups. To achieve these goals, we apply a concave fusion learning method to conduct subgroup analysis for longitudinal trajectories of the Alzheimer's disease data. The heterogeneous trajectories are represented by subject-specific unknown functions which are approximated by B-splines. The concave fusion method can simultaneously estimate the spline coefficients and merge them together for the subjects belonging to the same subgroup to automatically identify subgroups and recover the heterogeneous trajectories. The resulting estimator of the disease trajectory of each subgroup is supported by an asymptotic distribution. It provides a sound theoretical basis for further conducting statistical inference in subgroup analysis.

Robust analyses for radiographic progression in rheumatoid arthritis.

Demonstrating inhibition of the structural damage to joints as a statistically significant difference in radiographic progression as measured by the van der Heijde modified Total Sharp Score (mTSS) is a common objective in trials for rheumatoid arthritis treatments. The frequently used analysis of the covariance model with missing data imputed using linear extrapolation (analyses of covariance, ANCOVA+LE) may not be ideal for long-term extension studies or for paediatric studies. The random coefficient (RC) model may represent a better alternative.A two-arm (active treatment and placebo) setting with a week 44 study period was considered. RC model, ANCOVA+LE and ANCOVA with last observation carried forward imputation were compared under different scenarios in bias, root mean square error (RMSE), power and type I error rate.The RC model outperformed ANCOVA+LE in metrics measuring bias, RMSE, power and type I error rate under the evaluated scenarios. ANCOVA and RC provide similar performance when there are no missing data. With missing data, RC+observed (OBS) provides similar or better results than ANCOVA+LE in power and bias.Our simulations support that RC is both a more sensitive and a more precise alternative to the commonly used ANCOVA+LE as a primary method for analysing mTSS in long-term extension and paediatric studies with a higher likelihood of missing data. The RC model can provide a reference at time points with missing data by estimating a slope; mTSS change by one unit change in time. ANCOVA+LE is recommended as a sensitivity analysis.

[Bushen Anshen acupuncture for perimenopausal insomnia of kidney-yin deficiency: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of Bushen Anshen acupuncture (acupuncture for tonifying kidney and calming spirit ) in treating perimenopausal insomnia (PMI) of kidney-yin deficiency. METHODS: A total of 72 patients with PMI of kidney-yin deficiency were randomized into an observation group (36 cases, 1 case dropped off) and a control group (36 cases, 1 case dropped off). Acupuncture was applied at Baihui (GV 20) and bilateral Shenshu (BL 23), Taixi (KI 3), Anmian (Extra) in the observation group, while sham acupuncture of shallow needling at non-acupoints was applied in the control group. The treatment was required once every other day, 3 times a week for 10 times in the two groups. Before and after treatment, Pittsburgh sleep quality index (PSQI) was used to evaluate the subjective sleep quality, and polysomnography (PSG) was used to monitor the objective sleep quality in the two groups. RESULTS: After treatment, the scores of sleep quality, sleep latency, sleep duration, sleep efficiency, hypnotic, daytime dysfunction and total score of PSQI were decreased compared with those before treatment in the observation group (P<0.01), the scores of sleep duration, sleep efficiency and total score of PSQI were decreased compared with those before treatment in the control group (P<0.05); the scores of sleep quality, sleep latency, sleep efficiency, hypnotic and total score of PSQI in the observation group were lower than those in the control group (P<0.05). After treatment, the sleep time was prolonged, the sleep efficiency was improved, the sleep latency and the awake time after falling asleep were shortened, the arousal awake index was reduced (P<0.01) when PSG indexes were monitored, and the percentage of non-rapid eye movement sleep period 1 (N1%) was decreased while the percentage of non-rapid eye movement sleep period 3 (N3%) was increased (P<0.05) compared with those before treatment in the observation group; there was no statistical difference in the PSG indexes compared with those before treatment in the control group (P>0.05). After treatment, compared with the control group, the sleep time was prolonged, the sleep efficiency was improved, the sleep latency and the awake time after falling asleep were shortened, the arousal awake index and N1% were decreased in the observation group (P<0.01). CONCLUSION: Bushen Anshen acupuncture can effectively improve the subjective and objective sleep quality in PMI patients of kidney-yin deficiency.

Clinical Benefits of Baricitinib Therapy According to Scalp Hair Regrowth in Patients with Severe Alopecia Areata.

OBJECTIVES: The present analyses report integrated results from BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) on the clinical benefits of baricitinib treatment on the basis of the amount of scalp hair regrowth through 52 weeks of treatment. METHODS: This post hoc analysis was conducted with data from patients who were treated continuously for 52 weeks with baricitinib 4 mg or 2 mg. Clinical outcomes were assessed using the Severity of Alopecia Tool (SALT) and Clinician-Reported Outcome (ClinRO) for Eyebrow (EB) and Eyelash (EL) hair. Secondary measures included the Hospital Anxiety and Depression Scale and Skindex-16 adapted for alopecia areata. At week 52, patients were classified into three subgroups: SALT ≤ 20 response, intermediate response (achieved a 30% improvement from baseline (SALT30) without a SALT score ≤ 20), or nonresponse (never achieved SALT30). The criterion of SALT30 approximates a minimal clinical meaningful response to therapy. RESULTS: At week 52, with baricitinib 4 mg treatment, the greatest (70%) improvement in EB and EL was observed in responders, but approximately 50% of patients with intermediate response and 20% of nonresponders experienced complete/nearly complete EB and EL regrowth. Improvement in emotional distress was directionally related to improvements in scalp hair regrowth, while impact on quality of life was proportionately greater for the responder subgroup. CONCLUSIONS: Clinically meaningful regrowth in eyebrow and eyelash hair can occur in the absence of complete scalp hair regrowth after treatment with baricitinib. Emotional distress and quality of life improvement is most associated with obtaining a clinical meaningful improvement in scalp hair. TRIAL REGISTRATION NUMBER: BRAVE-AA1, ClinicalTrials.gov number, NCT03570749, start date, 24 September 2018; BRAVE-AA2, ClinicalTrials.gov number, NCT03899259, start date, 8 July 2019.

Scalp hair regrowth is associated with improvements in health-related quality of life and psychological symptoms in patients with severe alopecia areata: results from two randomized controlled trials.

INTRODUCTION: This post hoc analysis assessed association between scalp hair regrowth and improvements in health-related quality of life (HRQoL) and psychological burden in patients with severe alopecia areata (AA). METHODS: Data were pooled from two phase-3 trials (N = 1200). Patients randomized to once-daily placebo, baricitinib 2-mg, or 4-mg were analyzed independently of treatment allocation, and categorized according to scalp hair regrowth (at Week 36): meaningful regrowth (Severity of Alopecia Tool (SALT) score ≤20); intermediate regrowth (≥30% SALT improvement [SALT30] at any post-baseline visit to Week 36, but SALT score > 20 at Week 36); no/minimal regrowth (never achieved SALT30). Skindex-16 for AA score change-from-baseline and proportion of patients with baseline Hospital Anxiety and Depression Scale (HADS) scores ≥8 that shifted to <8 (normal) were assessed. RESULTS: Patients with meaningful regrowth achieved greater improvements in all Skindex-16 AA domains versus no/minimal regrowth. More patients with meaningful versus no/minimal regrowth shifted from HADS ≥8 to <8 (anxiety:46.8% versus 26.4%; depression:52.3% versus 24.0%). Improvements occurred with intermediate regrowth but to a lesser extent versus meaningful regrowth. CONCLUSIONS: Patients with severe AA and scalp hair regrowth at Week 36 experienced greater improvements in HRQoL and anxiety and depression versus patients with no/minimal regrowth. The highest benefit was observed in patients with meaningful regrowth (SALT score ≤20).ClinicalTrials.gov listing: NCT03570749 and NCT03899259.

Baseline Body Surface Area and Itch Severity Define Response to Baricitinib in Patients with Moderate-to-Severe Atopic Dermatitis at Week 16.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by heterogeneous clinical phenotypes and high symptom burden, especially through itch. Baricitinib (BARI), an oral Janus Kinase 1/2 inhibitor, is approved in Europe, Japan, and other countries, for treatment of adults with moderate-to-severe AD who are candidates for systemic therapy. This post hoc analysis of a Phase 3 topical corticosteroid (TCS) combination therapy trial (BREEZE-AD7) aims to characterize patients who might benefit most from BARI. METHOD: Classification and regression tree (CART) analysis was used to identify baseline predictors for patients treated with BARI 4-mg, who achieved ≥ 75% improvement in Eczema Area and Severity Index (EASI75), or EASI75 or Itch Numerical Rating Scale (NRS) ≥ 4-point improvement at week 16 (responders), versus non-responders. Subgroup efficacy analyses were performed based on identified predictor variables, combined with Itch NRS < 7/ ≥ 7. Missing data were imputed as non-responder. RESULTS: Baseline body surface area (BSA) was identified by CART as strongest variable predicting response to BARI at week 16, with a cut-off around 40% (BSA ≤ 40%). When combining BSA with itch severity, highest response rates were achieved by BARI patients with BSA ≤ 40%/Itch NRS ≥ 7 at baseline. In this subgroup, 69% and 58% of patients treated with BARI 4-mg achieved EASI75 and Itch NRS ≥ 4-point response at week 16, respectively. While these response rates were 65% and 50% for BARI 4-mg patients with baseline BSA ≤ 40%/Itch NRS < 7, they were 33% and 11% in BSA > 40%/Itch NRS < 7, and 32% and 49% in BSA > 40%/Itch NRS ≥ 7 subgroups, respectively. CONCLUSION: Using a machine learning approach, patients with moderate-to-severe AD and a BSA affecting 10-40% and Itch NRS ≥ 7 were characterized as likely to benefit most from BARI 4-mg TCS combination therapy. This was confirmed by subgroup analyses, which showed that these patients are most likely to show favorable response rates in improving AD signs and symptoms, specifically itch, after 16 weeks of treatment.

Patient Disease Trajectories in Rheumatoid Arthritis Patients Treated with Baricitinib 4-mg in Four Phase 3 Clinical Studies.

INTRODUCTION: We sought to identify and compare treatment response groups based on individual patient responses (rather than group mean response) over time on the Clinical Disease Activity Index (CDAI) for rheumatoid arthritis (RA), in patients treated with baricitinib 4-mg in 4 phase 3 studies. METHODS: Trajectory subgroups were identified within each study using growth mixture modeling. Following grouping, baseline characteristics and disease measures were summarized and compared. RESULTS: In each study, three response trajectories were identified. In the three studies of patients naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs) patients had, on average, high disease activity, as measured by CDAI. In these studies, a group of rapid responders (65-71% of patients) had the lowest baseline CDAI scores and achieved mean CDAI ≤ 10 by week 16. Gradual responders (10-17%) had higher baseline CDAI, but generally achieved low disease activity (CDAI ≤ 10) by week 24. A group of partial responders (18-22%) had higher baseline CDAI and did not achieve mean CDAI ≤ 10. In bDMARD-experienced patients, the subgroups were rapid responders, who achieved mean CDAI ≤ 10 (42% of patients); partial responders, with mean CDAI decrease of ~ 15 points from baseline (42% of patients); and limited responders (15% of patients). Changes in modified total sharp score (mTSS; assessed only in biologic-naïve patients) were below the smallest detectable difference at 24/52 weeks for > 90% of patients in each group, excepting partial responders in RA-BEGIN (≥ 75% no detectable change). CONCLUSION: In patients receiving baricitinib 4-mg, lower baseline CDAI was generally associated with rapid response, while higher baseline CDAI scores were generally seen for patients who either reached treatment targets more gradually, or who had a partial or limited response. Maintenance of response was observed with continued baricitinib treatment in all response groups and generally included maintenance of mTSS.

Baricitinib is an oral agent widely approved for the treatment of moderately to severely active rheumatoid arthritis). Although baricitinib (and other agents) have demonstrated efficacy at the population level, treatment responses vary considerably between individual patients. This study assessed four baricitinib phase 3 clinical studies and categorized patient responses into response groups based on the Clinical Disease Activity Index (CDAI) using a growth mixture model. We then evaluated baseline characteristics and corresponding disease measures within the response groups. In patients with no prior treatment with biological disease-modifying anti-rheumatic drugs (bDMARDs), 65­71% of patients had rapid responses to treatment, while smaller groups had gradual (10­17%) or partial (18­22%) responses. In patients with prior bDMARD experience, rapid and partial responders each comprised 42% of patients while 15% had limited response. Gradual responders generally had higher baseline CDAI versus rapid responders, but achieved low disease activity (LDA) by 24, versus 12 weeks for rapid responders. Across response groups, patients who continued treatment generally maintained their response up to 52 weeks, and where joint erosion was assessed (in bDMARD-naïve patients), generally saw maintenance of joints during continued therapy. The identification of a gradual responder group, which demonstrated good response but required more time to achieve LDA, is relatively novel and should be considered when setting treatment expectations, particularly in patients with high baseline disease activity. In addition, in bDMARD-experienced patients, many patients did not achieve LDA but maintained a substantial partial response with continued therapy.