Retrospective Cohort Study of Syphilis-Related Stillbirths in Winnipeg, Manitoba From 2017-2020.

OBJECTIVE: Syphilis-related stillbirths (SRSBs) disproportionately affect marginalized women with 11% of all local stillbirths having maternal syphilis as a contributory factor in 2020. This study describes the incidence and perinatal factors associated with SRSB. METHODS: This was a retrospective cohort study of all stillbirths occurring from 1 January 2017 to 31 December 2020, at a single tertiary-level referral hospital in Winnipeg, Manitoba. Cases that met criteria for SRSB were identified from hospital records and included in the final analysis. Maternal demographics, comorbidities, prenatal care attendance, sexually transmitted infection testing, treatment, and diagnostic investigations at time of stillbirth were collected from hospital charts using a standardized data collection form. Descriptive statistics were performed to present the results. RESULTS: The proportion of SRSB increased over the period of study from 0%-11%. Eleven cases were identified as SRSB, with diagnosis occurring intrapartum in 7 cases and antenatally in 4 cases. Of the 4 antenatal cases, only 2 had identifiable treatment responses indicated by microbiological and pathology workup. Commonly identified risk factors for SRSB were homelessness, mental illness, substance use, sexually transmitted co-infections, and lack of prenatal care. CONCLUSIONS: Cases of SRSB are rising in Winnipeg with 11% of all stillbirths having maternal syphilis as a contributory factor by 2020. SRSBs disproportionately affect marginalized women. The dramatic and rapid changes in the epidemiology of syphilis in Winnipeg are likely shared by other Canadian regions and warrant increased prevention strategies to improve outcomes.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

Radiographic Progression of Structural Joint Damage Over 5 Years of Baricitinib Treatment in Patients With Rheumatoid Arthritis: Results From RA-BEYOND.

OBJECTIVE: To evaluate the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active rheumatoid arthritis (RA). METHODS: Patients completed 1 of 3 phase III baricitinib trials (ClinicalTrials.gov: NCT01711359, NCT01710358, or NCT01721057) and entered the long-term extension RA-BEYOND (NCT01885078), in which patients received once-daily 4 mg or 2 mg baricitinib. Across these trials, patients initially receiving methotrexate (MTX) or adalimumab (ADA) switched to baricitinib 4 mg at Week 52. Patients initially receiving placebo (PBO) switched to baricitinib 4 mg at Week 24. Radiographs were scored at baseline and Years 2, 3, 4, and 5. Change from baseline in van der Heijde modified total Sharp score (ΔmTSS) was computed. RESULTS: Overall, 2125 of 2573 (82.6%) randomized patients entered RA-BEYOND; 1837 of 2125 (86.4%) entered this analysis. From Years 3 to 5, higher proportions of disease-modifying antirheumatic drug (DMARD)-naïve patients on initial baricitinib (monotherapy or with MTX) had no progression vs initial MTX (ΔmTSS ≤ 0 at Year 5: 59.6% baricitinib 4 mg; 66.2% baricitinib 4 mg + MTX; 40.7% MTX). Higher proportions of patients with inadequate response (IR) to MTX on initial baricitinib or ADA vs PBO had no progression (ΔmTSS ≤ 0 at Year 5: 54.8% baricitinib 4 mg; 55.0% ADA; 50.3% PBO). Higher proportions of patients with conventional synthetic DMARD-IR on initial baricitinib 4 mg had less progression vs initial PBO or baricitinib 2 mg (ΔmTSS ≤ 0 at Year 5: 66.7% baricitinib 4 mg; 58.2% baricitinib 2 mg; 60.0% PBO). CONCLUSION: Oral baricitinib maintained lower levels of radiographic progression than initial conventional synthetic DMARD or PBO through 5 years in patients with active RA.

Impact of a continuous enhanced cardio-respiratory monitoring pathway on cardio-respiratory complications after bariatric surgery: A retrospective cohort study.

STUDY OBJECTIVE: To determine the impact of an enhanced monitoring pathway consisting of continuous postoperative cardio-respiratory monitoring on adverse outcomes after bariatric. DESIGN: Single-center, retrospective cohort study. PATIENTS: Adult patients who underwent bariatric surgeries between 2009 and 2016. INTERVENTIONS: We evaluated the use of an enhanced monitoring pathway consisting of a distant, continuous, non-invasive respiratory monitoring system on postoperative cardio-respiratory complications in patients undergoing bariatric surgery. Treating physicians had the option to assign patients to enhanced monitoring (intervention group) in the postoperative period for suspected or diagnosed OSA or other clinical concerns. The control group had intermittent vital sign checks as per institutional standards. MEASUREMENTS: The primary outcome was a composite of cardio-respiratory complications (rapid response team activation, intensive care admission, respiratory complications), major adverse cardiac events, and all-cause mortality. The secondary outcome was length of stay (LOS). MAIN RESULTS: Of 1450 patients, 752 patients received enhanced monitoring (intervention) and 698 patients received standard monitoring (control). Univariate analysis showed that, compared to control, enhanced monitoring was associated with lower odds of composite cardio-respiratory complications (OR: 0.41, 95%CI: 0.32-0.53, p < 0.001) and lower odds of prolonged LOS > 2 days (OR: 0.37, 95% CI: 0.28-0.49, p < 0.001. After adjusting for potential confounders, enhanced monitoring remained associated with a reduction in composite cardio-respiratory complications (OR: 0.64, 95% CI: 0.46-0.88, p = 0.005). CONCLUSIONS: Our study demonstrates that postoperative enhanced monitoring pathway was associated with a lower incidence of cardio-respiratory composite events, compared to a standard of care, in patients undergoing bariatric surgery. As our results show association rather than causation, future prospective randomized trials are needed to confirm the benefit of enhanced monitoring. Findings of our study add to the existing literature involved in clinical management pathways to reduce the incidence of adverse postoperative outcomes in high-risk patients undergoing inpatient surgeries.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74 days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4 weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.

Correction to: Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.

An amendment to this paper has been published and can be accessed via the original article.

Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.

BACKGROUND: In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. METHODS: During 4 baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. RESULTS: Across the placebo-controlled studies, interruptions occurred in larger proportions of baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes. CONCLUSIONS: Consistent with its pharmacologic properties, brief interruptions of baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

The effect of anesthetic technique on mortality and major morbidity after hip fracture surgery: a retrospective, propensity-score matched-pairs cohort study.

INTRODUCTION: Spinal anesthesia (SA) has physiological benefits over general anesthesia (GA), but there is insufficient evidence regarding a mortality benefit. We performed a retrospective propensity score-matched cohort study to evaluate the impact of anesthetic technique on mortality and major morbidity in patients undergoing hip fracture surgery. MATERIALS AND METHODS: Clinical, laboratory and outcome data were extracted from electronic databases for patients who underwent hip fracture surgery over a 13-year period at the University Health Network in Toronto, Ontario, Canada. The anesthetic technique was documented (SA or GA), and the primary outcome was 90-day mortality. Secondary outcomes included mortality at 30 and 60 days, hospital length of stay, pulmonary embolism (PE), major blood loss and major acute cardiac events. A propensity-score matched-pair analysis was performed following a non-parsimonious logistic regression model. RESULTS: Of the 2591 patients identified, 883 patients in the SA group were matched to patients in the GA group in a 1:1 ratio. There was a weak association between SA and lower 90-day mortality (risk ratio (RR) 0.74, 95% CI 0.52 to 0.96, 99% CI 0.48 to 1.00, p=0.037). SA was also associated with a lower incidence of both PE (1.3% vs 0.5%, p<0.001) and major blood loss (7.7% vs 4.8%, p<0.001) and a shorter hospital length of stay by about 2 days (median 11.9 vs 10 days, p=0.024). There was no difference in major cardiac events or mortality at 30 and 60 days. DISCUSSION: This propensity-score matched-pairs cohort study suggests that SA is weakly associated with a lower 90-day mortality following hip fracture surgery. SA was also associated with improved morbidity evidenced by a lower rate of PE and major blood loss and a shorter hospital length of stay. Given the retrospective nature of the study, these results are not proof of causality.

MRI and Dose Selection in a Phase II Trial of Baricitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis.

OBJECTIVE: Magnetic resonance imaging (MRI) was used in a phase IIb study of baricitinib in patients with RA to support dose selection for the phase III program. METHODS: Three hundred one patients with active RA who were taking stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily baricitinib (1, 2, 4, or 8 mg) for up to 24 weeks. One hundred fifty-four patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and at weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3× synovitis score) and total joint damage (erosion + 2.5× cartilage loss score) scores were calculated. Treatment groups were compared using ANCOVA adjusting for baseline scores. RESULTS: Mean changes from baseline to Week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, baricitinib 4 mg, and baricitinib 8 mg, respectively (p = 0.003 vs placebo for baricitinib 4 and 8 mg). Mean changes for osteitis were 0.00, -3.20, and -2.10 (p = 0.001 vs placebo for baricitinib 4 mg and p = 0.037 for 8 mg), respectively. Mean changes for bone erosion were 0.90, 0.10, and 0.40 (p = 0.089 for 4 mg and p = 0.275 for 8 mg), respectively, in these treatment groups. CONCLUSION: MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by baricitinib 4 and 8 mg. This corroborates previously demonstrated clinical efficacy of baricitinib and increases confidence that baricitinib 4 mg could reduce the radiographic progression in phase III studies. [Clinical trial registration number (www.ClinicalTrials.gov): NCT01185353].

Toward a phenomic analysis of chronic postsurgical pain following cardiac surgery.

Background: Despite the same surgical approach, up to 40% of patients develop chronic postsurgical pain (CPSP) following cardiac surgery, whereas the rest are chronic pain free. This variability suggests that CPSP is controlled partially through genetics, but the genes for CPSP are largely unknown. Aims: The aim of this study was to identify potential CPSP phenotypes by comparing patients who developed CPSP following cardiac surgery vs. those who did not. Methods: A research ethics board-approved, cross-sectional study of post-cardiac surgery pain was conducted at Toronto General Hospital from 2011 to 2015. Patients were recruited to complete a short survey of chronic pain scores and the Short-Form McGill Pain Questionnaire-2. A subset of patients completed a longer survey of eight validated pain phenotyping questionnaires and/or four psychophysical assessments. All surveys and psychophysical testing were conducted after surgery. Patients were stratified by presence of chronic pain and groups were compared using descriptive statistics. Results: Six hundred forty-three patients completed the short form survey. The mean postsurgery assessment time was 41.5 (SD = ±25.1) months. Over a quarter (27.8%) reported CPSP at the chest as a consequence of their surgery. Of patients reporting CPSP, 46.6% reported mild pain (0-3), 35.8% reported moderate pain (4-7), and 17.6% reported severe pain (7-10) in accordance with the numerical rating scale. Patients with moderate and/or severe CPSP were younger, had a greater body mass index, and had higher anxiety sensitivity, pain catastrophizing, and somatization scores. Conclusions: Chronic pain levels after cardiac surgery are associated with anxiety, catastrophizing, and sensory abnormalities in body parts outside the field innervated by injured nerves, indicating the presence of widespread central sensitization to incoming sensory inputs from intact nerves.

Contexte: Malgré qu'ils aient été soumis à la même approche chirurgicale, jusqu'à 40 % des patients souffrent de douleur chronique postopératoire après une chirurgie cardiaque, tandis que le reste des patients n'en souffrent pas. Cette variabilité porte à croire que la douleur chronique postopératoire est en partie maitrisée génétiquement, mais les gènes en cause dans la douleur chronique postopératoire sont très peu connus.But: Identifier les phénotypes de douleur chronique postopératoire possibles en comparant des patients souffrant de douleur chronique postopératoire à des patients n'en souffrant pas après une chirurgie cardiaque.Méthodes: Une étude transversale de la douleur après une chirurgie cardiaque approuvée par la commission d'éthique de la recherche a été menée à l'Hôpital général de Toronto de 2011 à 2015. Les patients ont été recrutés pour répondre à un court questionnaire portant sur les scores de douleur chronique et à une version abrégée du McGill Pain Questionnaire-2. Un sous-ensemble de patients a répondu à une enquête plus longue comprenant huit questionnaires validés portant sur le phénotypage de la douleur et/ou sur quatre mesures psychophysiques. Tous les questionnaires et les tests psychophysiques ont été menés après la chirurgie. Les patients ont été stratrifiés en fonction de la présence de douleur chronique et les groupes ont été comparés à l'aide de statistiques descriptives.Résultats: 634 patients ont répondu à la version courte de l'enquête. Le temps moyen de l'évaluation post-chirurgie était de 41,4 mois (écart-type ± 25,1). Plus d'un quart (27,8%) des participants ont rapporté de la douleur chronique postopératoire au thorax en tant que conséquence de la chirurgie. Parmi les patients rapportant de la douleur chronique post-opératoire, 46,6 % ont rapporée une douleur faible (0-3), 35,8 % ont rapporté de la douleur modérée (4-7) et 17,6 % ont rapporté de la douleur sévère (7-10), selon l'échelle d'évaluation numérique. Les patients souffrant de douleur chronique postopératoire de modérée à sévère étaient plus jeunes, avaient un indice de masse corporelle plus élevé et obtenaient des scores plus élevés en ce qui concerne la sensibilité à l'anxiété, la catastrophisation de la douleur et la somatisation.Conclusion: Les niveaux de douleur chronique après une chirurgie cardiaque sont associés à l'anxiété, à la catastrophisation et à des anomalies sensorielles dans des parties du corps à l'extérieur de la zone innervée par les nerfs par les nerfs endommagés, ce qui indique la présence d'une sensibilisation centrale généralisée aux signaux sensoriels provenant des nerfs intacts.

Cs Fountain Clocks for Commercial Realizations-An Improved and Robust Design.

We report on the design, assembly, testing, and delivery of a series of new cesium fountain primary frequency standards built through commercial and scientific collaboration with international users. The new design, based on proven National Physical Laboratory solutions, improves reliability, simplicity of operation, and transportability. The complete system consists of a novel physics package, a specially developed optical package, and dedicated electronics for system control. We present results showing that despite their simplified and more compact design, the new fountains have state-of-the-art performance in terms of signal-to-noise ratio and robust long-term operation. With a sufficiently low-noise local oscillator, they are capable of reaching a short-term stability below 3×10-14 (1 s) and have potential accuracy in the low 10-16 range, similar to the best cesium fountains currently in operation. This cost-effective solution could be used to increase the availability of accurate frequency references and timescales and provide redundancy in critical locations.

Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis.

OBJECTIVE: To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353). METHODS: After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose. RESULTS: In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128. CONCLUSION: In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment.

OBJECTIVE: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs. METHODS: A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24. RESULTS: The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX. CONCLUSION: Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis.

OBJECTIVE: To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis. METHODS: Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups. RESULTS: Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship. CONCLUSION: Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.

Anesthesia Technique and Mortality after Total Hip or Knee Arthroplasty: A Retrospective, Propensity Score-matched Cohort Study.

BACKGROUND: This propensity score-matched cohort study evaluates the effect of anesthetic technique on a 30-day mortality after total hip or knee arthroplasty. METHODS: All patients who had hip or knee arthroplasty between January 1, 2003, and December 31, 2014, were evaluated. The principal exposure was spinal versus general anesthesia. The primary outcome was 30-day mortality. Secondary outcomes were (1) perioperative myocardial infarction; (2) a composite of major adverse cardiac events that includes cardiac arrest, myocardial infarction, or newly diagnosed arrhythmia; (3) pulmonary embolism; (4) major blood loss; (5) hospital length of stay; and (6) operating room procedure time. A propensity score-matched-pair analysis was performed using a nonparsimonious logistic regression model of regional anesthetic use. RESULTS: We identified 10,868 patients, of whom 8,553 had spinal anesthesia and 2,315 had general anesthesia. Ninety-two percent (n = 2,135) of the patients who had general anesthesia were matched to similar patients who did not have general anesthesia. In the matched cohort, the 30-day mortality rate was 0.19% (n = 4) in the spinal anesthesia group and 0.8% (n = 17) in the general anesthesia group (risk ratio, 0.42; 95% CI, 0.21 to 0.83; P = 0.0045). Spinal anesthesia was also associated with a shorter hospital length of stay (5.7 vs. 6.6 days; P < 0.001). CONCLUSIONS: The results of this observational, propensity score-matched cohort study suggest a strong association between spinal anesthesia and lower 30-day mortality, as well as a shorter hospital length of stay, after elective joint replacement surgery.

Baricitinib in Patients with Refractory Rheumatoid Arthritis.

BACKGROUND: In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. RESULTS: Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).