Endogenous defense mechanism-based neuroprotection in large-vessel acute ischemic stroke: A hope for future.

BACKGROUND: Stroke is a leading cause of morbidity and mortality worldwide and a leading cause of disability. None of the neuroprotective agents have been approved internationally except edaravone in Japanese guidelines in acute ischemic stroke. We here discuss that there are two types of endogenous defense mechanisms (EDMs) after acute stroke for neuromodulation and neuroregeneration, and if both can be activated simultaneously, then we can have better recovery in stroke. AIMS AND OBJECTIVES: We aimed to study the effect of combination of neuroprotection therapies acting on the two wings of EDM in acute large-vessel middle cerebral artery (LMCA) ischemic stroke. METHODS: Sixty patients of LMCA stroke were enrolled and randomized within 72 h into two groups of 30 patients each. The control group received standard medical care without any neuroprotective agents while the intervention group received standard medical care combined with oral citicoline with vinpocetine for 3 months with initial 1 week intravenous and edaravone and cerebrolysin injection, started within 72 h of onset of stroke. Patients were assessed on the basis of the National Institutes of Health Stroke Scale, Fugl-Meyer Assessment Score, Glasgow Coma Scale, and Mini-Mental Status Examination at admission, discharge, and after 90 days. RESULTS: The intervention group showed significant and early improvements in motor as well as cognitive recovery. CONCLUSION: Combination therapy for neuroprotection which is acting on two pathways of EDM can be useful in functional recovery after acute ischemic stroke.

Effectiveness of Intermediate Cervical Plexus Block in Whiplash-Associated Disorder: A Prospective Observational Trial in Fifty Patients.

BACKGROUND: Whiplash trauma can result in a range of symptoms, including chronic neck pain, headache, facial pain, upper back pain, and tinnitus, which comprises whiplash-associated disorder (WAD). Intermediate cervical plexus block (iCPB) is a novel intervention that targets the upper cervical nerves and anecdotal reports suggest benefits in WAD. OBJECTIVES: We hypothesized that the cervical plexus may have a role in the pathogenesis of WAD and blocking the cervical plexus may provide analgesia. STUDY DESIGN: Prospective observational trial. SETTING: Tertiary pain medicine unit at a university teaching hospital. METHODS: Adult patients who presented with refractory chronic neck pain following whiplash were included in a prospective observational trial. The pragmatic trial studied the effectiveness of 2 sequential cervical plexus blocks (iCPB with local anesthetic [iCPB-LA] and iCPB with steroid and LA mixture [iCPB-Steroid]) in refractory chronic neck pain following whiplash. Patients who reported < 50% relief at 12 weeks after iCPB-LA were offered iCPB-Steroid. Primary outcome was "neck pain at its worst in the last 24 hours" at 12 weeks. Secondary outcomes included change in neck disability index, employment status, and mood. RESULTS: After excluding cervical zygapophyseal joint dysfunction, 50 patients underwent the iCPB-LA between June 2020 and August 2022. Five patients reported > 50% relief (durable relief) at 12 weeks and 3 patients were lost to follow-up. Forty-two patients received iCPB-Steroid. iCPB-Steroid was associated with significant reduction in neck pain, neck disability, and improvement in mood at 12 weeks when compared to the block with LA. In addition, iCPB-Steroid was associated with significant reduction in neck pain and disability at 24 weeks. Due to functional improvement, 34 patients (34/50, 78%) were able to maintain employment. LIMITATIONS: This is an open-label, observational, single-center study in a limited cohort under a single physician. Cervical facet joint dysfunction was ruled out clinically and radiologically. CONCLUSIONS: Cervical plexus may play a central role in the pathogenesis of WAD. iCPB could potentially be a treatment option in this cohort.

Effect of Upadacitinib on Quality of Life and Work Productivity in Active Non-radiographic Axial Spondyloarthritis: Results From Randomized Phase 3 Trial SELECT-AXIS 2.

INTRODUCTION: To evaluate the effect of upadacitinib vs. placebo on health-related quality of life (HRQoL) and work productivity in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) enrolled in the SELECT-AXIS 2 phase 3 randomized controlled trial. METHODS: Adult patients with active nr-axSpA and an inadequate response to non-steroidal anti-inflammatory drugs were randomized 1:1 to receive upadacitinib 15 mg once daily or placebo. Mean changes from baseline in measures of HRQoL (Ankylosing Spondylitis QoL [ASQoL], Assessment of SpondyloArthritis international Society Health Index [ASAS HI], Short-Form 36 Physical Component Summary [SF-36 PCS] score) and Work Productivity and Activity Impairment (WPAI) were assessed through 14 weeks based on mixed-effects repeated measures or analysis of covariance models. The proportions of patients with improvements ≥ minimum clinically important differences (MCID) were assessed in HRQoL measures at week 14 using non-responder imputation with multiple imputation. RESULTS: At week 14, upadacitinib- vs. placebo-treated patients reported greater improvements from baseline in ASQoL and ASAS HI (ranked, P < 0.001) and in SF-36 PCS and WPAI overall work impairment (nominal P < 0.05). Improvements were observed as early as week 2 in ASAS HI. Greater proportions of upadacitinib vs. placebo-treated patients reported improvements ≥ MCID in ASQoL (62.6 vs. 40.9%), ASAS HI (44.8 vs. 28.8%), and SF-36 PCS (69.3 vs. 52.0%), with numbers needed to treat < 10 for all (nominal P ≤ 0.01). Improvements ≥ MCID were consistently observed irrespectively of prior exposure to tumor necrosis factor inhibitors. CONCLUSIONS: Upadacitinib provides clinically meaningful improvements in HRQoL and work productivity in patients with active nr-axSpA. CLINICAL REGISTRATION NUMBER: NCT04169373, SELECT-AXIS 2.

Discovery of Nanomolar DCAF1 Small Molecule Ligands.

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 µM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 µM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

Effect of Upadacitinib on Disease Activity, Pain, Fatigue, Function, Health-Related Quality of Life and Work Productivity for Biologic Refractory Ankylosing Spondylitis.

INTRODUCTION: Patients with ankylosing spondylitis (AS) have significant unmet treatment needs, despite advancements in biologic therapies. This study evaluated the impact of upadacitinib on clinically meaningful improvement in patient-reported outcomes (PROs) assessing disease activity, pain, fatigue, function, health-related quality of life (HRQoL), and work productivity in patients with AS with inadequate responses or intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR). METHODS: Patients enrolled in the phase 3 SELECT-AXIS 2 AS bDMARD-IR study received blinded once-daily oral upadacitinib 15 mg or placebo for 14 weeks. The percentage of patients achieving improvements ≥ minimum clinically important differences (MCID) at week 14 were compared between treatment groups for disease activity (Bath Ankylosing Spondylitis Disease Activity Index, BASDAI), patient global assessment of disease activity (PtGA), total and nocturnal back pain, fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F), physical function (Bath Ankylosing Spondylitis Functional Index, BASFI), HRQoL (Assessment of SpondyloArthritis international Society Health Index [ASAS HI], Ankylosing Spondylitis Quality of Life [ASQoL], Short form-36 [SF-36] physical [PCS] and mental [MCS] component summary scores), and work productivity (Work Productivity and Activity Impairment [WPAI] Questionnaire). Mean changes from baseline through week 14 in fatigue and HRQoL were compared between treatment groups. RESULTS: A total of 420 patients with active AS who were bDMARD-IR were included. A higher proportion of patients reported MCIDs at week 14 across all PROs with upadacitinib compared with placebo (nominal p ≤ 0.05). Greater improvements in mean change from baseline through week 14 were reported with upadacitinib compared with placebo across FACIT-F, HRQoL, and WPAI, with improvements differentiated as early as week 1 for ASAS HI, ASQoL and SF-36 PCS and week 4 for SF-36 MCS. CONCLUSIONS: Upadacitinib 15 mg demonstrated rapid and clinically meaningful improvements in disease activity, pain, FACIT-F, function, HRQoL, and WPAI among bDMARD-IR patients with active AS. TRIAL REGISTRY: Clinical Registration number: NCT04169373, SELECT-AXIS 2.

Continuity of Care Within a Single Patient Support Program for Patients with Rheumatoid Arthritis Prescribed Second or Later Line Advanced Therapy.

INTRODUCTION: Guidelines suggest patients with rheumatoid arthritis (RA) inadequately controlled by tumor-necrosis-factor-inhibitors (TNFis) may benefit from switching to Janus-kinase-inhibitors (JAKis); however, care coordination and access can be complicated. Disruptions in transitioning to JAKi treatment could lead to disease flares requiring hospitalization; however, transitioning between products within the same patient support program (PSP) services aimed at ensuring continuity of care may minimize disruptions. METHODS: A retrospective, longitudinal cohort study of adult patients with RA newly prescribed JAKi following TNFi treatment in the Symphony Health claims database. Patients with baseline TNFi use and ≥ 6 months of data before (baseline) and after (follow-up) the initial JAKi claim (approved or denied) were included. Cohorts were defined by transitions between products within the same PSP [adalimumab (ADA) and upadacitinib (UPA)] or not. Disruptions were defined as gap in care ≥ 15 days due to failure/delay in receiving coverage approval or picking up an approved prescription. Disruptions followed by JAKi dispense were considered temporary and those without permanent. Odds ratios (ORs) of disruption and hospitalization were estimated from logistic regressions controlling for patient characteristics and treatment history. RESULTS: A total of 2371 patients were included: 317 transitioning from ADA-UPA, 321 TNFi-UPA, 860 ADA-another JAKi, and 873 another TNFi-another JAKi. Temporary and permanent disruptions increased odds of hospitalization by 47% and 123% (both p < 0.05). Temporary disruption rates were lowest for ADA-UPA patients (19%) compared to other TNFi-UPA (25%; OR = 1.46), ADA-other JAKi (29%; OR = 1.59), and other TNFi-other JAKi (31%; OR = 1.74), all p < 0.05. For transitions to UPA, temporary disruptions were lower for patients using the PSP (17%) versus not (24%; OR = 1.45, p < 0.05). No differences were found for permanent disruptions. CONCLUSION: Disruptions for patients with RA transitioning from TNFi to JAKi treatment are associated with increased hospitalization rates. Transitioning between drugs within the same PSP could lower the risk of disruption.

CD38-mediated Inhibition of Bruton's Tyrosine Kinase in Macrophages Prevents Endotoxemic Lung Injury.

TLR4 signaling via endotoxemia in macrophages promotes macrophage transition to the inflammatory phenotype through NLRP3 inflammasome activation. This transition event has the potential to trigger acute lung injury (ALI). However, relatively little is known about the regulation of NLRP3 and its role in the pathogenesis of ALI. Here we interrogated the signaling pathway activated by CD38, an ectoenzyme expressed in macrophages, in preventing ALI through suppressing NLRP3 activation. Wild-type and Cd38-knockout (Cd38-/-) mice were used to assess inflammatory lung injury, and isolated macrophages were used to delineate underlying TLR4 signaling pathway. We showed that CD38 suppressed TLR4 signaling in macrophages by inhibiting Bruton's tyrosine kinase (Btk) through the recruitment of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) and resulting in the dephosphorylation of activated Btk. Cd38-/- mice show enhanced lung polymorphonuclear leukocyte extravasation and severe lung injury. LPS- or polymicrobial sepsis-induced mortality in Cd38-/- mice were markedly augmented compared with wild types. CD38 in macrophages functioned by inhibiting Btk activation through activation of SHP2 and resulting dephosphorylation of Btk, and thereby preventing activation of downstream targets NF-κB and NLRP3. Cd38-/- macrophages displayed markedly increased activation of Btk, NF-κB, and NLRP3, whereas in vivo administration of the Btk inhibitor ibrutinib (a Food and Drug Administration-approved drug) prevented augmented TLR4-induced inflammatory lung injury seen in Cd38-/- mice. Our findings together show upregulation of CD38 activity and inhibition of Btk activation downstream of TLR4 activation as potential strategies to prevent endotoxemic ALI.

Polymyositis Presenting with Respiratory Symptoms.

Polymyositis is a group of muscle disease characterised by progressive muscle inflammation and predominantly muscle weakness. It usually presents subacutely with proximal weakness and mild diffuse muscular pain. Some patients have atypical presentation like early respiratory difficulty, Motor neuron disease (MND), or isolated dysphagia which leads to delay in diagnosis and treatment. We present one such case.

Impact of Medication Adherence on Healthcare Resource Utilization, Work Loss, and Associated Costs in a Privately Insured Employed Population Treated With Adalimumab in the United States.

OBJECTIVE: The aim of this study was to evaluate the impact of adherence to adalimumab on all-cause work loss, healthcare resource utilization (HRU), and direct medical and indirect costs over 2 years using real-world data. METHODS: This was a retrospective cohort study using a large, United States administrative claims database. Adult patients treated with adalimumab were grouped into adherent and non-adherent cohorts and followed for up to 2 years. Outcomes were compared between cohorts. RESULTS: Over 2 years, adherent patients had $10,214 lower per patient medical and indirect costs compared to non-adherent patients, resulting from lower HRU, fewer days of absenteeism, and lower rates of work loss events. CONCLUSION: Patient and societal benefits of adherence to adalimumab are significant over 2 years. These findings highlight the importance of policies aimed at improving adherence to self-administrated medications.

Risk of infection within 4 weeks of corticosteroid injection (CSI) in the management of chronic pain during a pandemic: a cohort study in 216 patients.

OBJECTIVES: Targeted corticosteroid injections (CSI) are one of the treatments that can provide pain relief and thereby, enhance quality of life in patients with chronic pain. Corticosteroids (CS) are known to impair immune response. The objective was to evaluate the risk of developing post-procedural infection within 4 weeks of receiving depot CSI for chronic pain as part of on going quality improvement project. We hypothesised that interventional treatment with depot steroids will not cause a significant increase in clinical infection in the first 4 weeks. METHODS: Telephone follow-up was performed as a part of prospective longitudinal audit in a cohort of patients who received interventional treatment for chronic pain at a multidisciplinary pain medicine centre based at a university teaching hospital. Patients who received interventional treatment in the management of chronic pain under a single physician between October 2019 and December 2020 were followed up over telephone as part of on going longitudinal audits. Data was collected on any infection within 4 and 12 weeks of receiving the intervention. Outcomes collected included type of intervention, dose of depot steroids and pain relief obtained at 12 weeks following intervention. RESULTS: Over a 15 month period, 261 patients received pain interventions with depot CS. There was no loss to follow-up. Nine patients reported an infection within 4 weeks of receiving depot steroids (9/261, 3.4%). None of the patients tested positive for Covid-19. Eight patients (8/261, 3%) reported an infection between 5 and 12 weeks following the corticosteroid intervention. Although none of the patients tested positive for Covid-19, two patients presented with clinical and radiological features suggestive of Covid-19. Durable analgesia was reported by 51% (133/261) and clinically significant analgesia by 30% (78/261) at 12 weeks following the intervention. Failure rate was 19% (50/261). CONCLUSIONS: Pain medicine interventions with depot steroids do not appear to overtly increase the risk for Covid-19 infection in the midst of a pandemic.

Sustained long-term benefits of patient support program participation in immune-mediated diseases: improved medication-taking behavior and lower risk of a hospital visit.

BACKGROUND: Patient support programs (PSPs) improve medication-taking behavior in the first 12 months of treatment for patients with immune-mediated diseases, but it is unknown if these benefits are sustained. As immune-mediated diseases continue to increase in prevalence and economic burden, understanding the potential value of PSPs in helping patients adhere to their long-term treatment plan and avoid costly hospital visits is crucial. Launched nationally in 2015, HUMIRA Complete (a PSP for adalimumab patients) provides an opportunity to study long-term effects of PSP participation, including the impact on medication-taking behavior and hospital visits. OBJECTIVE: To evaluate the sustained relationship between PSP participation, long-term medication-taking behavior, and hospital visits. METHODS: A longitudinal, retrospective matched-cohort study was conducted of patients initiating adalimumab between January 2015 and February 2016 with or without enrolling in the PSP, using patient-level data from the HUMIRA Complete PSP linked with Symphony Health claims. The sample included adult, commercially insured patients diagnosed with an indicated disease who were biologic-naive and had data available for ≥ 6 months before and ≥ 12 months after initiating adalimumab. Adherence (proportion of days covered) and hospital visits were assessed at 12, 24, and 36 months for patients with sufficient follow-up data. Multivariable generalized models estimated differences between cohorts, controlling for baseline characteristics and hospital visits. Duration of persistence and time to a hospital visit were compared using Kaplan-Meier analyses. Hazard ratios were estimated using multivariable Cox proportional hazards models. RESULTS: The matched cohort included 2,268 patients (1,134 per cohort), and patient attrition was similar across cohorts. The PSP cohort consistently demonstrated higher adalimumab adherence than the non-PSP cohort at 12 (64.8% vs. 50.1%, P < 0.0001; 29% greater), 24 (49.4% vs. 38.4%; P < 0.0001; 29% greater), and 36 (39.4% vs. 35.1%; P = 0.02; 12% greater) months. PSP participation was associated with a 30% lower hazard of discontinuation (P < 0.0001), and median duration of persistence was 4.8 months longer for the PSP cohort (13.2 vs. 8.4 months; P < 0.0001). The PSP cohort had lower rates of hospital visits at 12 (30% vs. 37%; P < 0.001; 19% lower), 24 (44% vs. 53%; P = 0.01; 17% lower), and 36 (55% vs. 65%; P < 0.01; 16% lower) months, and PSP participation was associated with a 25% lower hazard of a hospital visit (P < 0.0001). Median time to a hospital visit was 10.8 months longer for the PSP cohort (32.7 vs. 21.9 months; P < 0.0001). Findings were consistent across therapeutic areas: hazard of a hospital visit was 28%, 27%, and 37% lower for rheumatology, gastroenterology, and dermatology patients participating in the PSP (all P < 0.05). CONCLUSIONS: Patients with immune-mediated diseases receiving adalimumab and utilizing this PSP had improved long-term medication-taking behavior and lower risk of hospital visits, demonstrating the potential of PSPs to improve patient outcomes and lower the burden to the health care system. DISCLOSURES: Design, study conduct, and financial support for the study were provided by AbbVie Inc., which participated in the interpretation of data, review, and approval of the manuscript. Fendrick has received personal fees from Merck, AstraZeneca, Trizetto, Amgen, Lilly, AbbVie, Johnson & Johnson, and Sanofi; grants from the National Pharmaceutical Council, PhRMA, the Gary and Mary West Health Foundation, the states of New York and Michigan, the Laura and John Arnold Foundation, the Robert Wood Johnson Foundation, and the Agency for Healthcare Research and Quality; and equity in Zansors, Sempre Health, Wellth, and V-BID Health. Brixner has received consulting fees from AbbVie, Novartis, Xcenda, Elevar Therapeutics, Sanofi, UCB Pharma, and the Millcreek Outcomes Group. Rubin has received consulting fees from AbbVie, Abgenomics, Allergan Inc., Amgen, Celgene Corporation, Forward Pharma, Genentech/Roche, Janssen Pharmaceuticals, Merck & Co., Miraca Life Sciences, Mitsubishi Tanabe Pharma Development America, Napo Pharmaceuticals, Pfizer, Salix Pharmaceuticals Inc., Samsung Bioepis, Sandoz Pharmaceuticals, Shire, Takeda, and Target Pharmaceuticals; and research support from AbbVie, Genentech/Roche, Janssen Pharmaceuticals, Prometheus Laboratories, Shire, Takeda, and UCB Pharma. Mease has received grant/research support from AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; consulting fees from AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, SUN Pharma, and UCB; and has served on the speakers bureau for AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB. Liu has no financial conflict of interest. Davis is an employee of Medicus Economics, which received payment from AbbVie to participate in this research. Mittal is an employee and stockholder of AbbVie. This study used a cohort of patients previously described in Brixner D, Rubin DT, Mease P, et al. Patient support program increased medication adherence with lower total health care costs despite increased drug spending. J Manag Care Spec Pharm. 2019 Jul;25(7):770-79 (doi: 10.18553/jmcp.2019.18443). As such, the sample selection and select baseline characteristics and 12-month outcomes have been published previously; however, the hospital visit outcomes and the longer-term medication-taking behavior outcomes have not been previously published or presented.

Higher Medication Adherence and Lower Opioid Use Among Individuals with Autoimmune Disease Enrolled in an Adalimumab Patient Support Program in the United States.

INTRODUCTION: Opioid use is prevalent among patients with autoimmune conditions, despite not being a recommended treatment. Tumor necrosis factor inhibitor (anti-TNF) therapy is an effective treatment for these autoimmune conditions, and patient support programs (PSPs) have been developed to help patients manage their prescribed treatments. This study was conducted to evaluate the impact of PSPs on anti-TNF adherence and opioid use using data on adalimumab (ADA), an anti-TNF. METHODS: The study used insurance claims data linked to ADA PSP data on patients who initiated ADA after 01/2015, were commercially insured, and had data coverage for 1 year before and after (i.e., during the follow-up period) ADA initiation. Patients with opioid use in the 3 months before ADA initiation were excluded. PSP patients enrolled in the PSP within 30 days of ADA initiation and had 2+ PSP nurse ambassador interactions; non-PSP patients had no PSP engagement. ADA adherence [proportion of days covered (PDC), persistence], opioid initiation, 2+ opioid fills, and opioid supply during follow-up were compared between cohorts using regression models that controlled for patient characteristics. RESULTS: Results were obtained for 1952 PSP and 728 non-PSP patients. PSP patients demonstrated better adherence to ADA than non-PSP patients, including higher PDC and persistence (all p < 0.001). PSP patients were 13% less likely to initiate opioids and 26% less likely to have at least 2 fills than non-PSP patients, and they had fewer days of opioid supply (all p < 0.01). CONCLUSIONS: This study supports the benefit of PSPs and suggests that the ADA PSP is associated with improved adherence and potentially lower opioid use.

Experience with Low-Dose Sodium Valproate in Idiopathic Generalized Epilepsy Patients: A Long-Term Follow-Up Study on Selective Cohort from North India.

Background Idiopathic generalized epilepsy (IGE) is found in 20 to 30% of all patients presenting with seizures. Most of the patients require lifelong drug treatment. Efficacy and tolerability are important issues while selecting the most appropriate drug for a person with IGE. Objective The aim of this study was to look for usefulness of small dose valproate (<1,000 mg/day) in long-term treatment of IGE patients. Methods Diagnosis of IGE made with standard criteria among all patients presenting with seizures. Patients put on full doses of valproate (>1,000 mg/day) in first year, then reduction started in next year in patients with full seizure remission, and finally maintained on lowest possible dose of valproate. Lowest dose was defined as the minimum dose without seizures (between 200 and 900 mg/day). Patients, who were refractory on monotherapy, were put on add-on drug and followed for remission and reduction in doses of valproate at minimum possible dose. Results IGE was diagnosed in 21% of all patients presenting with seizures. Among 420 patients of IGE 368 (87.5%) were started on high-dose valproate monotherapy, 155 (42.1%) were responsive to single drug while 213 (57.9%) had been given add-on drug either lamotrigine or clonazepam or both. After minimum 3-year follow-up, 298 (81%) could be managed on low-dose valproate (<1,000 mg) without any relapse during 12 to 80 months follow-up. Conclusion Significant number of patients with IGE can be managed on low-dose valproate with good seizure control and less side effects.

Improving clinical outcomes of very low birth weight infants: Implementation of standardized management guidelines in tertiary care hospital in Haryana.

BACKGROUND: Standardized written guidelines and protocols in NICU are known to impact neonatal outcomes and improve survival. OBJECTIVE: To study and compare the morbidity and mortality outcomes of very low birth weight (VLBW) neonates before and after introduction of structured approach to standardized management guidelines on four interventions in a tertiary care hospital in North India. METHODOLOGY: Structured approach to standardized management guidelines on four interventions were implemented for VLBW infants in NICU. a) Humidified and Heated High Flow Nasal Cannula (HHHFNC) as the initial mode of ventilator support in preterm VLBW babies. b) Expressed breast milk for feeding preterm VLBW babies and absolutely no formula milk. c) Hand washing and following "Bundle Care Approach" for Central lines as the cardinal cornerstones for maintaining strict asepsis. d) Development and supportive care to be regularly followed. Data was collected prospectively from July 2015 to December 2016 (Intervention Group) and compared with retrospective matched controls from the previous year (July 2014-June 2015) (Control Group). RESULTS: There was a significant decrease in culture positive sepsis in the intervention group compared to control group (3 (2.97%) CI:0.006-0.08 vs 11 (19.64%) CI:0.10-0.32; P = .0004). There was no significant difference in the mortality (5.35% vs3.96% P = .74) amongst the two groups. CONCLUSION: Implementing structured approach to above mentioned interventions in the form of standardized management guidelines for preterm VLBW neonates was associated with significant reduction in culture proven sepsis and mechanical ventilation days without affecting mortality or other co-morbidities.

Participation in an innovative patient support program reduces prescription abandonment for adalimumab-treated patients in a commercial population.

PURPOSE: Nonadherence to indicated therapy reduces treatment effectiveness and may increase cost of care. HUMIRA Complete, a Patient Support Program (PSP), aims to reduce nonadherence in patients prescribed adalimumab (ADA). The objective of this study was to assess the relationship between participation in the PSP and prescription abandonment rates among ADA-treated patients. PATIENTS AND METHODS: This longitudinal study using patient-level data from AbbVie's PSP linked with medical and pharmacy claims data included patients ≥18 years with an ADA-approved indication, ≥1 pharmacy claim for ADA, and available data ≥3 months before and ≥6 months after the index date (defined as the initial ADA claim [01/2015 to 02/2017]). Abandonment was defined as reversal of initial ADA prescription with no paid claim during 3-month follow-up. Abandonment rates were compared between PSP and non-PSP cohorts using multivariable logistic regression controlling for potentially confounding baseline characteristics. RESULTS: In 17,371 patients (9,851 PSP; 7,520 non-PSP), the overall abandonment rate was 10.8-16.8% across indications. The odds of ADA abandonment were 70% less for PSP vs non-PSP patients (5.6% vs 20.4%, odds ratio [OR]=0.30, [95% confidence interval (CI)=0.27-0.33] P<0.001), 38% less for patients using specialty vs retail pharmacy (OR=0.62, 95% CI=0.56-0.69, P<0.001), 20% less for those with income of $50-99K vs $0-49K (OR=0.80, 95% CI=0.69-0.92, P<0.01), and 78% greater for those with copayment of $26-100 vs $0-25 (OR=1.78, 95% CI=1.55-2.05, P<0.001). CONCLUSION: Participation in the PSP, higher income, and using a specialty pharmacy were associated with lower odds of abandoning ADA therapy, whereas increased copayments were associated with greater abandonment. PSPs should be considered to improve initiation of ADA therapy.

STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation.

Efferocytosis of apoptotic neutrophils (PMNs) by alveolar macrophages (AMФs) is vital for resolution of inflammation and tissue injury. Here, we investigated the role of AMФ polarization and expression of the efferocytic ligand Gas6 in restoring homeostasis. In the murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI), we observed augmented temporal generation of cytokines IL-4 and TSG6 in bronchoalveolar fluid (BALF). Interestingly, we also observed increased expression of antiinflammatory markers consistent with a phenotype shift in AMФs. In particular, AMФs expressed the efferocytic ligand Gas6. In vitro priming of bone marrow-derived macrophages (BMMФs) with IL-4 or TSG6 also induced MФ transition and expression of Gas6. TSG6- or IL-4-primed BMMФs induced efferocytosis of apoptotic PMNs compared with control BMMФs. Adoptive transfer of TSG6- or IL-4-primed BMMФs i.t. into LPS-challenged mice more rapidly and effectively cleared PMNs in lungs compared with control BMMФs. We demonstrated that expression of Gas6 during AMФ transition was due to activation of the transcription factor signal transducer and activator of transcription-6 (STAT6) downstream of IL-4 or TSG6 signaling. Adoptive transfer of Gas6-depleted BMMФs failed to clear PMNs in lungs following LPS challenge and mice showed severely defective resolution of lung injury. Thus, activation of STAT6-mediated Gas6 expression during macrophage phenotype transition resulting in efferocytosis of PMNs plays a crucial role in the resolution of inflammatory lung injury.

Impact of a co-pay accumulator adjustment program on specialty drug adherence.

OBJECTIVES: To assess the impact of a co-pay accumulator adjustment program (CAAP) on usage patterns of autoimmune specialty drugs, comparing health savings account (HSA) or preferred provider organization (PPO) plan enrollees before and after implementation of the CAAP. STUDY DESIGN: Retrospective cohort analysis. METHODS: Data on HSA and PPO patients with autoimmune specialty drug use were drawn from the Conduent pharmacy benefit manager for January 2016 to October 2017 from 15 self-insured employers initiating a CAAP in January 2017. Outcomes included monthly mean fills per person, therapy discontinuation, and proportion of days covered (PDC). Linear regressions, Kaplan-Meier survival curves, and Cox proportional hazards models assessed differences while adjusting for patient characteristics. RESULTS: There were 365 HSA and 238 PPO patients. After the CAAP implementation, for HSA versus PPO patients, adjusted trends in monthly fills per person decreased more rapidly, the risk of treatment discontinuation was significantly higher, and PDC was significantly lower. Prior to the CAAP, these metrics were not statistically different between groups except in 1 case. To help place the post-CAAP adjusted differences in trends in context, by the end of October 2017, 10 months after the CAAP start, HSA patients had 233 fewer autoimmune drug fills per 1000 patients, 20 percentage points higher treatment discontinuation, and 12 percentage points lower PDC. CONCLUSIONS: After the CAAP, HSA patients on autoimmune drugs had significantly lower monthly fill rates, higher risk of discontinuation, and lower PDC than did PPO patients, suggesting that CAAPs have the potential to negatively affect specialty drug use.

Impact of Online Prescription Management Systems on Biologic Treatment Initiation.

INTRODUCTION: Pharmaceutical firms have begun offering online prescription management systems to facilitate prescription processing. This study evaluated the impact of the HUMIRA Complete Pro (HCPro) online prescription management system on the rate of abandonment and the time to first fill for patients prescribed adalimumab (ADA). A retrospective cohort analysis of patients initiating ADA treatment with or without use of the HCPro online prescription processing system was used to evaluate the impact of HCPro on treatment initiation outcomes. METHODS: Patient-level data for patients with an ADA prescription processed through HCPro were mapped to Symphony Health claims for patients initiating ADA between January 2012 and January 2015. The sample included patients aged ≥ 18 years with a diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis who had data available 3 months before and after their first ADA claim (index date). Baseline characteristics, prescription abandonment rate, and time-to-first-prescription fill were compared between patients with a prescription processed through HCPro (HCPro cohort) and those without (non-HCPro cohort). The odds of abandonment were evaluated in the 3 months following the index date using a multivariate logistic regression model. RESULTS: The study included 24,767 patients (535 HCPro; 24,232 non-HCPro). HCPro patients had a greater frequency of initiation at a specialty pharmacy (66% vs. 56%; P < 0.001) and enrollment in AbbVie's patient support program (71% vs. 51%; P < 0.001) as well as a lower copay for ADA ($206 vs. $265; P = 0.011). HCPro patients had a lower abandonment rate (6.4% vs. 13.9%; P < 0.001) and reduced days to prescription fill (7.0 vs. 14.4; P < 0.001). After controlling for baseline characteristics, abandonment odds were 43% lower for patients using HCPro (odds ratio = 0.57; P = 0.004). CONCLUSION: Initiating ADA treatment with an online prescription management system (HCPro) significantly reduces the odds of abandonment and time to first prescription fill. FUNDING: AbbVie Inc., Chicago, USA.

Patient Support Program Increased Medication Adherence with Lower Total Health Care Costs Despite Increased Drug Spending.

BACKGROUND: The U.S. health care system is currently evolving from a volume-based care to a value-based care approach, which is in part supported by the introduction of patient support programs (PSP). For patients treated with adalimumab (ADA), the addition of a dedicated, trained nurse to the PSP (HUMIRA Complete, rolled out nationally in 2015) provides further emphasis on value-based care. OBJECTIVE: To determine the effectiveness of the HUMIRA Complete PSP, including the Nurse Ambassador component, in a real-world setting for patients receiving ADA across a broad range of approved indications (rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis, uveitis, and hidradenitis suppurativa). METHODS: A longitudinal retrospective study was conducted using patient-level data from the HUMIRA Complete PSP data linked to the real-world, patient-level Symphony Health Solutions administrative claims database. Commercially insured patients were included who were aged ≥ 18 years with ≥ 2 diagnoses of an indicated disease who were biologically naive before initiating ADA or who had no claims for synthetic-targeted immune modulator therapy before their earliest ADA claim in the database between January 2015 and February 2017. The first claim had to have occurred in 2015 or later, and continuous medical and drug data coverage were required for ≥ 6 months before and ≥ 12 months after the first ADA claim and index date. PSP patients (with at least an initial and follow-up dedicated nurse call) were matched 1:1 to non-PSP patients based on pharmacy type, indication, and propensity score, estimated with covariates for age, sex, year of first ADA use, and baseline comorbidities. Adherence to ADA was compared using proportion of days covered along with discontinuation of ADA, defined as a gap in treatment greater than the previous days supply with no additional ADA claim, total costs, medical costs, and drug costs (2017 U.S. dollars) over 12 months. Baseline demographic and clinical characteristics were summarized descriptively. Differences between cohorts were assessed using t-tests for adherence and costs and log-rank tests for discontinuation. RESULTS: 2,268 patients (1,134 per group) were included. Baseline characteristics were similar between cohorts after matching. Participation in the PSP was associated with 29.3% higher ADA adherence (64.8% vs. 50.1%; P < 0.0001) and 22.0% lower ADA discontinuation rate (51.4% vs. 65.9%; P < 0.0001). Disease-related medical costs and all-cause medical costs were significantly lower by 35% ($10,162 vs. $15,511; P = 0.005) and 29.2% ($25,074 vs. $35,419; P = 0.0004), respectively, for PSP versus non-PSP patients. Total costs were also lower by 9% ($62,421 vs. $68,706; P = 0.056), and drug costs were 12.2% higher ($37,347 vs. $33,287; P = 0.0016). CONCLUSIONS: This retrospective study demonstrates that participation in the PSP augments value-based care by improving outcomes for patients with chronic diseases by helping them not only manage a complex treatment regimen but also lower annual health care costs. DISCLOSURES: Design, study conduct, and financial support for this study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript; all authors contributed to the development of the publication and maintained control over the final content. Brixner reports consulting fees from AbbVie, AstraZeneca, Becton Dickinson, Millcreek Outcomes Group, Sanofi, and UCB Pharma. Rubin reports consulting fees from AbbVie, Abgenomics, Allergan, Forward Pharma, Genentech/Roche, Janssen Pharmaceuticals, Merck & Co., Napo Pharmaceuticals, Pfizer, Shire, Takeda, and Target Pharmaceuticals and research support from AbbVie, Genentech/Roche, Janssen Pharmaceuticals, Prometheus Laboratories, Shire, and Takeda. Mease reports grant/research support from AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; consulting fees from AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; and served on the speakers bureaus for AbbVie, Amgen, BMS, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, and UCB. Mittal and Ganguli are employees and stockholders of AbbVie. Liu has no financial conflict of interest. Davis is an employee of Medicus Economics, which reports payment from AbbVie to participate in this research. Fendrick reports personal fees from Merck, AstraZeneca, Trizetto, Amgen, Lilly, AbbVie, Johnson & Johnson, and Sanofi; grants from the National Pharmaceutical Council, PhRMA, the Gary and Mary West Health Foundation, the states of New York and Michigan, the Laura and John Arnold Foundation, the Robert Wood Johnson Foundation, and the Agency for Healthcare Research and Quality; and has equity in Zansors, Sempre Health, Wellth, and V-BID Health. Data from this study were presented in part at the Academy of Managed Care & Specialty Pharmacy Annual Meeting; April 25, 2018; Boston, MA.