Two Phase 3 Trials of Baricitinib for Alopecia Areata.

BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata. METHODS: We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36. RESULTS: We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo. CONCLUSIONS: In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.).

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.

Efficacy and safety of baricitinib in combination with topical corticosteroids in paediatric patients with moderate-to-severe atopic dermatitis with an inadequate response to topical corticosteroids: results from a phase III, randomized, double-blind, placebo-controlled study (BREEZE-AD PEDS).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved in many countries for moderate-to-severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. OBJECTIVES: To evaluate the efficacy and safety of three doses of baricitinib in combination with low-to-moderate potency topical corticosteroids in paediatric patients with moderate-to-severe AD. METHODS: Patients (aged 2 to < 18 years) were randomized (1 : 1 : 1 : 1) to once-daily baricitinib low dose (1 mg equivalent), medium dose (2 mg equivalent), high dose (4 mg equivalent) or placebo for 16 weeks. The primary endpoint was the proportion of patients achieving a validated Investigator Global Assessment® (vIGA-AD) of 0/1 with a ≥ 2-point improvement at week 16. Key secondary endpoints included the proportions of patients achieving ≥ 75% and ≥ 90% improvement in the Eczema Area and Severity Index (EASI-75 and EASI-90, respectively), ≥ 75% improvement in the SCORing Atopic Dermatitis (SCORAD 75), mean change from baseline in EASI score and proportion of patients achieving a 4-point improvement in the Itch Numeric Rating scale (NRS) for patients aged ≥ 10 years. Primary and key secondary efficacy analyses were conducted on the intent-to-treat population and adjusted for multiplicity. Safety analyses included all randomized patients who received ≥ 1 dose of study treatment. RESULTS: A total of 483 patients were randomized (mean age 12 years). The baricitinib 4 mg equivalent achieved a statistically significant (P < 0.05) improvement vs. placebo on all 16-week endpoints (vIGA 0/1 with ≥ 2-point improvement, EASI-75, EASI-90, SCORAD 75, mean change in EASI score and Itch NRS 4-point improvement for patients aged ≥ 10 years). Improvement (P < 0.05, non-multiplicity adjusted) was also observed for baricitinib 4 mg equivalent vs. placebo in the ability to fall asleep and in reduction of topical corticosteroid use. Few patients discontinued due to adverse events (1.6% for placebo and 0.6% for those treated with baricitinib). There were no deaths, venous thromboembolic events, arterial thrombotic events, major adverse cardiovascular events, malignancies, gastrointestinal perforations or opportunistic infections seen. CONCLUSIONS: The results indicate that baricitinib offers a potential therapeutic option with a favourable benefit-risk profile for paediatric patients with moderate-to-severe AD who are candidates for systemic therapies.

Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

BACKGROUND: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. OBJECTIVES: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. METHODS: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. RESULTS: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. CONCLUSIONS: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.

Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population.

BACKGROUND: LAVOLTA (L)I, LII, and ACOUSTICS were randomized, placebo-controlled, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting IL-13 in patients with uncontrolled asthma. Failure to demonstrate efficacy may have been related to patient selection in those trials. OBJECTIVE: To assess the efficacy in a well-defined subpopulation of patients with elevated blood eosinophil counts and a minimum number of prior asthma exacerbations. We performed an additional analysis in a subpopulation of patients with elevated FeNO and prior exacerbations. METHODS: Adult (LI and LII) and adolescent patients (aged 12-17 years weighing ≥40 kg, ACOUSTICS) with uncontrolled asthma received lebrikizumab (125 mg, n = 832; or 37.5 mg, n = 829) or placebo (n = 833) subcutaneously every 4 weeks. Post hoc analysis of the annualized adjusted exacerbation rate (AER) was performed in a subpopulation of patients with baseline blood eosinophils of 300 cells/µL or greater and history of one or more exacerbations. In this subpopulation, there were 227 patients in the placebo group, 222 in the lebrikizumab 37.5-mg group, and 217 in the lebrikizumab 125-mg group. We summarized safety in patients who received at least one dose of lebrikizumab using adverse events. RESULTS: Lebrikizumab significantly reduced AER compared with placebo in adults (AER reduction: 125 mg [38%]; and 37.5 mg [41%]) and adolescents (AER reduction:125 mg [59%]; 37.5 mg [64%]) with baseline blood eosinophils of 300 cells/µL or greater and one or more exacerbations. Most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. CONCLUSION: Lebrikizumab significantly reduced asthma exacerbations in a subpopulation of patients with elevated blood eosinophils, elevated FeNO, and a history of asthma exacerbation.

[Research on electron density in DC needle-plate corona discharge at atmospheric pressure].

Using needle-plate discharge device, corona discharge experiment was done in the atmosphere. Through photo of spot size of light-emitting area, the relationship between the voltage and thickness of corona layer was discussed. When the distance between tip and plate is fixed, the thickness of corona layer increases with the increase in voltage; when the voltage is fixed, the thickness of corona layer decreases with the increase in the distance between tip and plate. As spectral intensity of N2 (C3pi(u)) (337.1 nm)reflects high energy electron density, it was measured with emission spectrometry. The results show that high energy electron density is the biggest near the needle tip and the relationship between high energy electron density and voltage is basically linear increasing. Fixing voltage, high energy electron density decreases with the increase in the distance between tip and plate. When the voltage and the distance between tip and plate are fixed, the high energy electron density increases with the decrease in the curvature radius of needle tip. These results are of great importance for the study of plasma parameters of corona discharge.

Efficacy of Baricitinib in Patients with Various Degrees of Alopecia Areata Severity: Post-Hoc Analysis from BRAVE AA1 and BRAVE AA2.

BACKGROUND: Baricitinib, an oral selective JAK1/JAK2 inhibitor, is approved for the treatment of adults with severe alopecia areata (AA). OBJECTIVE: To evaluate differences in response up to week 52 among subgroups based on the baseline severity of AA assessed with the Severity of Alopecia Tool (SALT) score. METHODS: Data were pooled from BRAVE-AA1 and BRAVE-AA2, two randomized, placebo-controlled, phase 3 trials, which enrolled adults with a SALT score ≥ 50. Patients were subdivided by the degree of AA severity at baseline. RESULTS: Among the 855 patients treated with baricitinib 2 mg and 4 mg, improvements in scalp hair growth continued through to week 52. A superior response was observed in patients with a SALT score of 50-94 versus a score of 95-100. Patients on baricitinib 4 mg had a faster and higher response rate compared to baricitinib 2 mg. CONCLUSION: Across all degrees of severity for baricitinib 2 mg and 4 mg doses, the proportion of patients responding was yet to plateau up to week 52. Response to treatment was longer for patients with a baseline SALT score 95-100. Further studies are needed to analyze other parameters that may impact observed response rates.

Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2).

BACKGROUND: The oral Janus kinase (JAK) inhibitor baricitinib has demonstrated efficacy for severe alopecia areata (AA) over 36 weeks. There are limited data on the longer-term treatment of AA. OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of baricitinib for AA in adults with ≥50% scalp hair loss through 52 weeks of continuous therapy in two phase III trials (BRAVE-AA1 and BRAVE-AA2). METHODS: Patients randomized to baricitinib at baseline in BRAVE-AA1 (N = 465) and BRAVE-AA2 (N = 390) retained their treatment allocation through Week 52. Efficacy outcomes included the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤ 20 (≤ 20% scalp hair loss). Data were censored after permanent treatment discontinuation or if collected remotely due to the coronavirus disease 2019 (COVID-19) pandemic. RESULTS: Response rates for hair regrowth increased over the 52-week period. Of patients treated with baricitinib 4 mg and 2 mg, respectively, 40.9% and 21.2% in BRAVE-AA1 and 36.8% and 24.4% in BRAVE-AA2 achieved a SALT score ≤ 20 at Week 52. The most frequent treatment-emergent adverse events included upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, creatine phosphokinase elevation, and COVID-19 infection. LIMITATION: There were no comparisons with placebo. CONCLUSION: Efficacy of baricitinib for adults with severe AA continuously improved over 52 weeks, indicating that long-term treatment may be necessary to observe maximum clinical benefit. There were no new safety signals. CLINICALTRIALS REGISTRATION: ClinicalTrials.gov NCT03570749 and NCT03899259. Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: Week-52 Results from BRAVE-AA1 and BRAVE-AA2.

Alopecia areata (AA) is an autoimmune disease that causes patchy hair loss on the scalp, face, and body. Baricitinib is a Janus kinase inhibitor that is approved to treat AA in several countries, based on results from two studies, BRAVE-AA1 and BRAVE-AA2. In these studies, adults with at least 50% scalp hair loss were treated with baricitinib for 36 weeks. Long-term therapy is important in AA, and hair regrowth can take longer in some patients with severe disease. Therefore, we assessed outcomes from a longer course of therapy. In this study, we report the results after 52 weeks of continuous treatment with baricitinib 4 mg or 2 mg in 465 patients in BRAVE-AA1 and 390 patients BRAVE-AA2. The goal was to reduce scalp hair loss to 20% or less by Week 52. In BRAVE-AA1, 40.9% of patients who took baricitinib 4 mg and 21.2% of patients who took baricitinib 2 mg had 20% or less missing scalp hair by Week 52. Similarly, in BRAVE-AA2, 36.8% of patients who took baricitinib 4 mg and 24.4% of patients who took baricitinib 2 mg had 20% or less missing scalp hair by Week 52. The most common adverse effects that were reported during the study period were upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, creatine phosphokinase elevation, and coronavirus disease 2019 (COVID-19) infection. The results of longer-term treatment indicate that hair regrowth continues to improve without any new safety concerns for adults with severe AA taking baricitinib.

Breast cancer recurrence prediction with ensemble methods and cost-sensitive learning.

Breast cancer is one of the most common cancers in women all over the world. Due to the improvement of medical treatments, most of the breast cancer patients would be in remission. However, the patients have to face the next challenge, the recurrence of breast cancer which may cause more severe effects, and even death. The prediction of breast cancer recurrence is crucial for reducing mortality. This paper proposes a prediction model for the recurrence of breast cancer based on clinical nominal and numeric features. In this study, our data consist of 1,061 patients from Breast Cancer Registry from Shin Kong Wu Ho-Su Memorial Hospital between 2011 and 2016, in which 37 records are denoted as breast cancer recurrence. Each record has 85 features. Our approach consists of three stages. First, we perform data preprocessing and feature selection techniques to consolidate the dataset. Among all features, six features are identified for further processing in the following stages. Next, we apply resampling techniques to resolve the issue of class imbalance. Finally, we construct two classifiers, AdaBoost and cost-sensitive learning, to predict the risk of recurrence and carry out the performance evaluation in three-fold cross-validation. By applying the AdaBoost method, we achieve accuracy of 0.973 and sensitivity of 0.675. By combining the AdaBoost and cost-sensitive method of our model, we achieve a reasonable accuracy of 0.468 and substantially high sensitivity of 0.947 which guarantee almost no false dismissal. Our model can be used as a supporting tool in the setting and evaluation of the follow-up visit for early intervention and more advanced treatments to lower cancer mortality.

Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis.

BACKGROUND: Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA. METHODS: Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naïve to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ and HBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy. RESULTS: In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ at some point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29 IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100 IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used. CONCLUSION: HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.

Safety of baricitinib in East Asian patients with moderate-to-severe active rheumatoid arthritis: An integrated analysis from clinical trials.

AIM: We evaluated the safety of baricitinib in an East Asian (EA) patient population with moderate-to-severely active rheumatoid arthritis (RA), through an integrated sub-analysis of data from the overall baricitinib RA clinical program. METHODS: Data from EA patients who received any dose of baricitinib from five completed studies (1 Phase 2, 4 Phase 3) and an ongoing long-term extension study were pooled up to 1 September, 2016. Exposure-adjusted incidence rates (EAIR) and incidence rates (IRs), both per 100 patient-years (PY), were calculated. RESULTS: This analysis included 740 EA patients with 1294 PY of total baricitinib exposure (maximum 3.5 years). Overall, 109 patients discontinued baricitinib due to adverse events (AEs); EAIR: 8.4. No deaths were reported in this cohort. Serious AEs were reported by 125 patients (EAIR: 9.7). Serious infections were the most common serious AEs (n = 53, IR: 4.15). IR of herpes zoster infection was 6.2; the majority of events were of mild-to-moderate severity. Three cases (IR: 0.23) of tuberculosis were reported. The IRs of malignancy (excluding non-melanoma skin cancer) was 0.99 and EAIR specifically of lymphoma was 0.1. The IR of major adverse cardiovascular events was 0.26, and deep vein thrombosis was reported in four patients (EAIR: 0.3). Two cases of gastrointestinal perforations (EAIR: 0.2) were reported. CONCLUSION: Integrated data show that baricitinib is well-tolerated in EA patients with moderate-to-severely active RA in the context of demonstrated efficacy, which is generally consistent with safety results of the overall study population.

Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis.

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK2, approved for the treatment of patients with active rheumatoid arthritis. Because baricitinib, like other disease-modifying antirheumatic drugs, is used chronically, continuous assessment of its long-term safety profile is important. Here we provide updated data supporting the existing safety profile of baricitinib in this patient population. METHODS: In this safety analysis, integrated data were included from nine phase 3, phase 2, and phase 1b clinical trials, and one long-term extension study with data up to 360 weeks, ending Feb 13, 2018. We analysed three integrated datasets, the largest of which was the all-bari-RA dataset, which includes patients who received any dose of baricitinib. We compared the safety of baricitinib with placebo on the basis of data from seven studies with baricitinib 4 mg and placebo and four studies with baricitinib 2 mg, including placebo to week 24 (placebo-controlled dataset). We did a dose-response assessment based on four studies with baricitinib 2 mg and 4 mg, including long-term extension data (2-4 mg extended dataset). We did an exploratory analysis of deaths and venous thromboembolic events in a subset of data from the all-bari-RA dataset that included patients who had ever taken baricitinib 2-mg or baricitinib 4-mg. We did an analysis for malignancies (excluding non-melanoma skin cancer) in the as-randomised population (patients not censored at rescue or dose change). FINDINGS: We collected data for 3770 patients who were given baricitinib for 10 127 patient-years of exposure in the all-bari-RA dataset (median 1115 days [IQR 426-1441], maximum 2520 days). The placebo-controlled dataset comprised 2836 patients, with 1215 in the placebo group, with 451 patient-years of exposure data; 479 in the baricitinib 2 mg group, with 186 patient-years of exposure data; and 1142 in the baricitinib 4 mg group, with 472 patient-years of exposure data. The 2-4 mg extended dataset comprised 958 patients, with 479 in both the 2 mg and 4 mg groups. No significant differences were seen for baricitinib 4 mg or 2 mg versus placebo, or for 4 mg versus 2 mg in the incidence of death, malignancy, serious infection, or major adverse cardiovascular events. Incidence of herpes zoster per 100 patient-years was higher for baricitinib (4 mg: 4·4 [95% CI 2·7-6·7]; 2 mg: 3·1 [1·1-6·8]) versus total placebo group (1·1 [0·4-2·5]), as were treatment-emergent infections (4 mg: 89·7 [81·3-98·6]; 2 mg: 84·0 [71·3-98·2] vs placebo 75·4 [67·6-83·9]). Consistent with previous reports, incidences in the all-bari-RA dataset for venous thromboembolic events was 0·5 (95% CI 0·4-0·6) per 100 patient-years, deep-vein thrombosis was 0·3 (0·2-0·5) per 100 patient-years, and pulmonary embolism was 0·2 (0·2-0·4) per 100 patient-years. Incidences of malignancy (excluding non-melanoma skin cancer) in the 2-4 mg extended dataset were 0·8 (0·4-1·5) per 100 patient-years for baricitinib 2 mg and 1·0 (0·5-1·7) per 100 patient-years for baricitinib 4 mg, without censoring patients who had dose changes or received rescue treatment. We found no indication of higher incidence of venous thromboembolic events in the baricitinib 4 mg group compared with the 2 mg group in the 2-4 mg extended dataset. INTERPRETATION: In this updated integrated analysis of patients with active rheumatoid arthritis exposed to baricitinib for a maximum of almost 7 years, baricitinib 2 mg and 4 mg maintained a similar safety profile to earlier analyses. No new safety signals were identified. Patients in the long-term extension study continue to be followed up to date. FUNDING: Eli Lilly and Company, under license from Incyte Corporation.

Teriparatide in East Asian Postmenopausal Women with Osteoporosis in a Real-World Setting: A Baseline Analysis of the Asia and Latin America Fracture Observational Study (ALAFOS).

PURPOSE: The aim of this analysis is to describe the baseline characteristics of patients who are prescribed teriparatide for the treatment of postmenopausal osteoporosis in a real-world setting in East Asia. PATIENTS AND METHODS: The Asia and Latin America Fracture Observational Study (ALAFOS) is a prospective, multinational, observational study designed to evaluate real-world use of teriparatide in the treatment of postmenopausal osteoporosis in 20 countries across Asia, Latin America, the Middle East, and Russia. This subregional analysis focuses on the East Asian subpopulation of the ALAFOS study. Here we report baseline clinical characteristics, details regarding the history of fractures, risk factors for osteoporosis, comorbidities, osteoporosis treatment, and health-related quality of life in patients enrolled in China, Hong Kong, South Korea, and Taiwan. RESULTS: The East Asian subgroup of ALAFOS included 1136 postmenopausal women, constituting 37.5% (1136/3031) of the overall ALAFOS patient population. The mean (SD) age was 75.0 (9.6) years. The mean (SD) bone mineral density T-scores were -3.11 (1.54), -2.58 (1.11), and -2.86 (1.09) at the lumbar spine, total hip, and femoral neck, respectively; 69.6% of patients had experienced at least one fragility fracture and 40.4% had experienced ≥2 fragility fractures after 40 years of age. Overall, 63.3% of patients had used medications for osteoporosis in the past. The mean (SD) EQ-5D-5L Visual Analog Scale (VAS) score at baseline was 59.7 (20.8); the mean (SD) back pain numeric rating scale score for worst pain in the last 24 hrs was 5.2 (3.2). CONCLUSION: Our results indicate that patients who are prescribed teriparatide in East Asia were elderly women with severe osteoporosis, low bone mineral density, high prevalence of fractures, back pain and poor health-related quality of life. Most of the patients received teriparatide as a second-line treatment.

Estimating the response and economic burden of rheumatoid arthritis patients treated with biologic disease-modifying antirheumatic drugs in Taiwan using the National Health Insurance Research Database (NHIRD).

BACKGROUND: Previous studies in Taiwan utilizing the Taiwan's National Health Insurance Database (NHIRD) have estimated the direct healthcare costs of RA patients, but they have not focused on patients on bDMARDs, or considered patients' response to therapy. OBJECTIVES: The objective of this study was to estimate the rate of inadequate response for patients newly treated with biologic disease-modifying antirheumatic drugs (bDMARDs) as well as their costs and resource use. METHODS: Data were from the catastrophic illness file within the NHIRD from 1/1/2009 to 12/31/2013. Patients with RA, which was categorized by the presence of a catastrophic illness card, that were previously bDMARD-naïve, were included in this study if they initiated their first bDMARD during the index period. The index period included all of 2010, a pre-index period consisting of the index date- 365 days, and a follow-up period including the index date to 365 days post-index, were also included. Previously biologically-naïve patients were indexed into the study on the date of their first claim for a bDMARD. A validated algorithm was used to examine the rate of inadequate response (IR) in the biologically-naïve cohort of patients. Inadequate responders met one or more of the following criteria during their year of follow-up: low adherence (proportion of days covered <0.80); switched to or added a second bDMARD; added a new conventional synthetic DMARD (csDMARD); received ≥1 glucocorticoid injection; or increased oral glucocorticoid dosing. All-cause mean annual direct costs and resource use were measured in the year of follow-up. Costs were converted from NT$ to USD using 1 NT$ = 0.033 USD. RESULTS: A total of 818 patients with RA initiated their first bDMARD (54% etanercept and 46% adalimumab) in 2010. After one year of follow-up, 32% (n = 258) were classified as stable, 66% (n = 540) had an IR, and 2% (n = 20) were lost to follow-up. During the follow-up period mean annual total direct costs were $16,136 for stable patients compared to $14,154 for patients with IR. Mean annual non-medication direct costs were $937 for stable patients and $1,574 for patients with IR. Mean annual hospitalizations were higher for patients with IR (0.46) compared to stable patients (0.10) during the one year follow-up period. CONCLUSIONS: The majority of patients that were previously naïve to bDMARDs had an IR to their first bDMARD during the year of follow-up. Patients with an IR had numerically increased all-cause resource utilization and non-medication costs during the follow-up period compared to patients with stable disease. This level of IR suggests an unmet need in the RA treatment paradigm.

Brain metastasis features and association with tumor epidermal growth factor receptor mutation in patients with adenocarcinoma of the lung.

AIM: Epidermal growth factor receptor (EGFR) mutations are frequent in pulmonary adenocarcinoma patients. The association between tumor EGFR mutation and characteristics of brain metastasis (BM) is still unclear. METHODS: We retrospectively reviewed pulmonary adenocarcinoma patients with and without BMs, and characteristics of BM to analyze the association between tumor EGFR mutation and characteristics of BM. RESULTS: Of 374 cases, 239 had EGFR mutations; 69 had BM at initial diagnosis, and 82 with BMs after treatment. All eligible patients received EGFR-tyrosine kinase inhibitors treatment. Older patients (≥70 years old) were less likely to have BMs than younger patients (25.8% vs 48%, P < 0.001). Patients with higher N stage had higher proportion of BMs (P = 0.006). Patients with exon 19 deletion were more likely to have BMs than those without EGFR mutation (48.1% vs 34.1%, P = 0.021). Patients with exon 19 deletion didn't have significantly higher chance of BMs at initial diagnosis but had higher chance to develop BM after treatment than those without EGFR mutation (35.6% vs 21.2%, P = 0.019). Patients with exon 19 deletion survived longer than those without EGFR mutation (1-year survival rate 95.8% vs 78.7%, P = 0.003). Thus, longer survival may lead to higher proportion of BM occurrence in patients with exon 19 deletion than those without EGFR mutation. CONCLUSIONS: In pulmonary adenocarcinoma, there is no significant difference in frequency of BMs at initial diagnosis between patients with EGFR mutation and wild type. However, after treatment, patients with EGFR mutations are significantly more likely to develop BM.

Predictive factors for EGFR-tyrosine kinase inhibitor retreatment in patients with EGFR-mutated non-small-cell lung cancer - A multicenter retrospective SEQUENCE study.

BACKGROUND: Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations experiencing a response to EGFR-tyrosine kinase inhibitor (TKI) initially. We investigated EGFR-TKI retreatment in patients who had previously received EGFR-TKI followed by chemotherapy. MATERIALS AND METHODS: This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR-TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment. RESULTS: In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4-92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR-TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR-TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR-TKI was 8.0 months (95% CI 7.3-8.2), and retreatment EGFR-TKI was 4.1 months (95% CI 2.7-4.6). The median OS since the start of the first-line EGFR-TKI therapy was 35.9 months (95% CI 28.8-50.9), and since the start of EGFR-TKI retreatment was 12.6 months (95% CI 10.4-20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR-TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR=0.62, 95% CI 0.44-0.86; HR=0.6, 95% CI 0.43-0.86), both p<0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR=0.51, 95% CI 0.30-0.86; HR=0.52 (0.31-0.88), both p<0.05). CONCLUSIONS: EGFR-TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR-mutated NSCLC patients after failure of first-line EGFR-TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR-TKI and in females with the exon 21 mutation.

Effectiveness of acupuncture in the treatment of fibromyalgia.

CONTEXT: Fibromyalgia syndrome (FMS) is a prevalent musculoskeletal disorder associated with pain, mood state alteration, and disability. A structured and effective treatment plan for palliative care has not been established. The genesis of FMS is not clear. FMS occurs primarily in adult women. DESIGN: Using a quasi-experimental clinical design and following the criteria of the American College of Rheumatology (ACR), for FMS, 21 participants completed the study. The mean age was 53.6 years. The data were collected at baseline and at 1 and 2 months. Acupuncture treatments included 17 points for FMS symptoms, and 8 outcome measures were collected. RESULTS: The Fibromyalgia Impact Questionnaire (FIQ) showed significant differences at 1 and 2 months. For the SF-12, 3 subscales showed significant differences between baseline and 2 months. Four of 6 items were significantly changed. The mean number of general health symptoms was significantly decreased by 2 months. For the Catastrophe Index, significant differences were found for baseline vs 2 months. Pain threshold scores were significantly different at end of treatment for 5 bilateral tender points. There was significant improvement in Beck Depression items for both 1- and 2-month periods. In a multivariate regression model, 5 covariates were included--age, number of weeks in treatment, number of doctors treating, number of general symptoms, and baseline FIQ score. The results indicated significant age effect. This analysis showed that the higher the FIQ score, the more positive the change experienced by study participants. Number of weeks in treatment, number of doctors who treated, and total number of general health symptoms did not have a significant effect on outcomes. CONCLUSIONS: Significant improvement was experienced by participants at 8 weeks of treatment. Acupuncture treatment as delivered was effective at reducing FMS symptoms in this outcome study.

Erlotinib Salvage Therapy in Pulmonary Adenocarcinoma Patients With Disease Progression After Previous EGFR-TKI Treatment.

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with promising efficacy in treating pulmonary adenocarcinoma. Treatment choices are few when patients with pulmonary adenocarcinoma have failed both EGFR-TKI and chemotherapy. The purpose of this study was to demonstrate the efficacy of erlotinib as salvage treatment for these nonresponsive patients. METHODS: We retrospectively reviewed the chart records of our stage IV pulmonary adenocarcinoma patients who were diagnosed and treated between July 2004 and June 2013. Clinical data, including type of response to treatment, time to disease progression, duration between the end of first-line EGFR-TKI treatment and starting erlotinib treatment, and overall survival time, were collected. RESULTS: A total of 98 patients were enrolled, and all had been treated with EGFR-TKI, either as a first-line therapy or following platinum-based chemotherapy; of them, 60 patients had a response to initial EGFR-TKI treatment. All received erlotinib as salvage treatment after their disease had progressed following EGFR-TKI treatment. Ninety-three (93.3%) patients had also received previous platinum-based chemotherapy. The median progression-free survival with erlotinib as salvage treatment for patients with and without a response to front-line EGFR-TKI was 4.9 and 3.4 months (P=0.869), respectively. The progression-free survival with erlotinib treatment in the sensitizing EGFR mutation group was 4.3 months, and in the EGFR wild-type group it was 2.6 months (P=0.22). CONCLUSIONS: In pulmonary adenocarcinoma patients who had been heavily treated, erlotinib could still be a choice, regardless of the EGFR mutation status, or whether the patients had responded to previous EGFR-TKI treatment.

Re-Treatment with EGFR-TKIs in NSCLC Patients Who Developed Acquired Resistance.

In the era of personalized medicine, epidermal growth factor receptor (EGFR) inhibition with tyrosine kinase inhibitor (TKI) has been a mainstay of treatment for non-small cell lung cancer (NSCLC) patients with an EGFR mutation. Acquired resistance, especially substitution of methionine for threonine at position 790 (T790M), which has accounted for more than half of the cases, developed inevitably in patients who were previously treated with EGFR-TKI. At present, there is no standard treatment for patients who have developed a resistance to EGFR-TKI. Several strategies have been developed or suggested to treat such patients. This article aimsto review the EGFR-TKI re-treatment strategy and the efficacy of different generations of EGFR-TKIs in patients with acquired resistance to prior EGFR-TKI.

The epidermal growth factor receptor-tyrosine kinase inhibitor era has changed the causes of death of patients with advanced non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective against tumor EGFR-mutated non-small cell lung cancer (NSCLC). Patients with the tumor EGFR-activating mutation (EGFRmu) had superior survival, compared to patients with EGFR wild-type tumors (EGFRwt). Many patients with the EGFRmu have had disease progression with EGFR-TKI treatment because of central nervous system (CNS) metastases. The objective of this retrospective study was to compare the causes of death in patients with a known tumor EGFR mutation status who had been treated with EGFR-TKIs. METHODS: We retrospectively reviewed the chart records of our patients with advanced NSCLC who had received diagnosis, treatment, and supportive and hospice care in our hospital between July 2005 and June 2010. The tumor EGFR mutation status was analyzed by using a DNA sequence method. All enrolled patients had a documented cause of death. RESULTS: Ninety-four patients had documented tumor EGFR data, had received EGFR-TKI treatment (either erlotinib or gefitinib), and were with or without previous or salvage systemic chemotherapy. Of the 94 patients, 36 patients had EGFRwt and 58 patients had EGFRmu. The overall patient survival after starting EGFR-TKI treatment was significantly longer in the EGFRmu patients (median 17.2 months) than in the EGFRwt patients (median 11.6 months; p = 0.0058). Twenty-nine patients died of CNS metastases and 65 died of organ failure (other than the CNS). Patients who died of CNS metastases had undergone EGFR-TKI treatment significantly longer than patients who died of other organ failure (median, 8 months vs. 1.9 months; p = 0.0003) with a hazard ratio of 2.308 [95% confidence interval (C.I.), 1.452-3.668; p = 0.0004]. A significantly higher proportion of EGFRmu patients (26 of 58 patients; 44.8%) than EGFRwt patients (3 of 36 patients; 8.3%) (p < 0.001) died of CNS metastases. CONCLUSION: The EGFRmu NSCLC patients survived longer and had a significantly higher probability of mortality due to CNS metastases, compared to the EGFRwt patients. This change in the causes of death was noted after the era of EGFR-TKI treatment, and will have an important impact on the strategies and management of supportive and hospice care for patients.