Despite the emerging use of bronchial thermoplasty in asthma therapy, the response of airway smooth muscle (ASM) to extreme temperatures is unknown. We investigated the immediate effects of exposing ASM to supraphysiologic temperatures. Isometric contractions were studied in bovine ASM before and after exposure to various thermal loads and/or pharmacologic interventions. Actin-myosin interactions were investigated using a standard in vitro motility assay. We found steep thermal sensitivity for isometric contractions evoked by acetylcholine, with threshold and complete inhibition at less than 50°C and greater than 55°C, respectively. Contractile responses to serotonin or KCl were similarly affected, whereas isometric relaxations evoked by the nitric oxide donor S-nitrosyl-N-acetylpenicillamine or the β-agonist isoproterenol were unaffected. This thermal sensitivity developed within 15 minutes, but did not evolve further over the course of several days (such a rapid time-course rules out heat shock proteins, apoptosis, autophagy, and necrosis). Although heat-sensitive transient receptor potential (TRPV2) channels and the calmodulin-dependent (Cam) kinase-II-induced inactivation of myosin light chain kinase are both acutely thermally sensitive, with a temperature producing half-maximal effect (T(1/2)) of 52.5°C, the phenomenon we describe was not prevented by blockers of TRPV2 channels (e.g., ruthenium red, gadolinium, zero-Ca(2+) or zero-Na(+)/zero-Ca(2+) media, and cromakalim) or of Cam kinase-II (e.g., W7, trifluoperazine, and KN-93). However, direct measurements of actin-myosin interactions showed the same steep thermal profile. The functional changes preceded any histologic evidence of necrosis or apoptosis. We conclude that extreme temperatures (such as those used in bronchial thermoplasty) directly disrupt actin-myosin interactions, likely through a denaturation of the motor protein, leading to an immediate loss of ASM cell function.

Key points• Lymphatic pumping is characterized by the ability of collecting lymphatic vessels to contract in a phasic manner to propel lymph. This activity is critical for tissue fluid homeostasis and immune cell transport to lymph nodes.• Vasoactive intestinal peptide (VIP) is a neuro-immuno-modulator with anti-inflammatory properties released by peptidergic nerves and by inflammatory cells patrolling the interstitium and lymph.• Here we report that VIP is present in lymphatic vessels as well as in the lymph and that it potently inhibits lymphatic pumping and hyperpolarizes the lymphatic muscle via stimulation of VPAC2 VIP receptors, activation of protein kinase A and opening of ATP-sensitive K + channels.• These results suggest an important role for VIP in inhibiting lymphatic pumping. This process might become critical during inflammation, where it would lead to decreased lymph drainage, oedema formation and compromised immune cell trafficking.Abstract Lymphatic vessels serve as a route by which interstitial fluid, protein and other macromolecules are returned to the blood circulation and immune cells and antigens gain access to lymph nodes. Lymph flow is an active process promoted by rhythmical contraction-relaxation events occurring in the collecting lymphatic vessels. This lymphatic pumping is an intrinsic property of the lymphatic muscles in the vessel wall and consequent to action potentials. Compromised lymphatic pumping may affect lymph and immune cell transport, an action which could be particularly detrimental during inflammation. Importantly, many inflammatory mediators alter lymphatic pumping. Vasoactive intestinal peptide (VIP) is a neuro-and immuno-modulator thought to be released by nerve terminals and immune cells in close proximity to lymphatic vessels. We demonstrated the presence of the peptide in lymphatic vessels and in the lymph and examined the effects of VIP on mesenteric collecting lymphatic vessels of the guinea pig using pharmacological bioassays, intracellular microelectrode electrophysiology, immunofluorescence and quantitative real-time PCR. We showed that VIP alters lymphatic pumping by decreasing the frequency of lymphatic contractions and hyperpolarizing the lymphatic muscle membrane potential in a concentration-dependent manner. Our data further suggest that these channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes.

These survey results indicate that RA patients are generally open to IV treatment and express high satisfaction with IV therapy. Additional patient and provider education may improve shared decision-making regarding biologic therapy administration options. This article is protected by copyright. All rights reserved.

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn's disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1 year of treatment. Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards. Results: Thirteen RCTs were identified. Ustekinumab 90 mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300 mg. For clinical remission, ustekinumab 90 mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300 mg q8w. Findings from sub-population analyses had similar results but were not statistically significant. Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1 year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.

Background and Aims. Adaptive trial designs present a methodological challenge when performing network meta-analysis (NMA), as data from such adaptive trial designs differ from conventional parallel design randomized controlled trials (RCTs). We aim to illustrate the importance of considering study design when conducting an NMA. Methods. Three NMAs comparing anti-tumor necrosis factor drugs for ulcerative colitis were compared and the analyses replicated using Bayesian NMA. The NMA comprised 3 RCTs comparing 4 treatments (adalimumab 40 mg, golimumab 50 mg, golimumab 100 mg, infliximab 5 mg/kg) and placebo. We investigated the impact of incorporating differences in the study design among the 3 RCTs and presented 3 alternative methods on how to convert outcome data derived from one form of adaptive design to more conventional parallel RCTs. Results. Combining RCT results without considering

Issue: Recent health technology reviews by CADTH, including a national Environmental Scan of biologics for PsO across public drug plans and a review of the clinical evidence on the comparative effectiveness of biologics for PsO, have suggested that the appropriate use of biologics for the treatment of plaque psoriasis (PsO) may favour new-generation biologics (i.e., anti-interleukin [IL]-17 and anti-IL-23 inhibitors) over old-generation biologics (i.e., anti–tumour necrosis factor and anti-IL-12/23 biologics). Specifically, these reviews found: New-generation biologics for PsO consistently demonstrated greater efficacy compared to old-generation biologics in recent head-to-head trials (e.g., AMAGINE-2 and AMAGINE−3, FIXTURE, IMMvent, NAVIGATE, UltIMMA-1 and UltIMMA−2, UNCOVER-2 and UNCOVER-3, and VOYAGE-1 and VOYAGE−2). Formulary listings of the old-generation biologics mostly predate any pan-Canadian Pharmaceutical Alliance (pCPA) agreements, which increases the likelihood of fewer product listing agreements (PLAs) with public payers for these drugs, whereas all new-generation biologics have all undergone pCPA negotiations. For private payer formulary listings, PLAs are not publicly disclosed although, according to the Canadian Life and Health Insurance Association (CLHIA), they are likely to occur. Old-generation biologics have reached the expiration of their exclusivity periods (i.e., time when an originator biologic is protected from biosimilar competition), whereas all new-generation biologics currently have active exclusivity status. Approach: A national utilization study was conducted to assess the utilization patterns of old- versus new-generation biologics in PsO for both public payers (using Canadian Institute for Health Information [CIHI] data) and private payers (using Reformulary and CLHIA data), prescribing patterns (market share and average costs) for old- versus new-generation biologics for both public and private insurance among new and existing users, and expenditures (excluding PLAs) on biologics for PsO after LoE by public and private payers. Findings: Although new-generation biologics in PsO are associated with greater efficacy, approximately 44% of patients newly initiating a biologic across public and private drug plans in Canada were prescribed an old-generation biologic in 2020. Average annual cost per new patient was typically higher for old-generation originator biologics (range = $11,645 to $16,047) versus new-generation biologics (range = $8,303 to $15,229) across public payers. Ustekinumab is associated with the highest cost estimate among new patients within public drug plans and, despite having expired exclusivity status, does not have a marketed biosimilar option available. Canadian taxpayers (i.e., public and private drug spending) have spent up to $9 billion (gross expenditures) on all claims for originator biologics indicated for PsO that have lost exclusivity between 2016 and 2020. To put this in perspective, analyses of data from the National Prescription Drug Utilization Information System (NPDUIS) revealed that, in Canada, spending on oncology drugs in the latest reported year (2019) was $3.9 billion and spending on the top 50 drugs in the 2019–2020 fiscal year was $4.3 billion. Implications for policy-makers: Given the potential for improved efficacy and lower costs of new-generation biologics, the promotion of the appropriate use of biologics in PsO should be considered by payers.

Health Canada has approved 11 biologics for the treatment of adults with moderate-to-severe plaque psoriasis (PsO). These biologics can be divided into 2 groups based on mechanisms of action and market authorization dates: Old-generation biologics (5): include anti–tumour necrosis factor (TNF) agents (etanercept, adalimumab, infliximab, and certolizumab pegol) and an anti-interleukin (IL)-12/IL-23 inhibitor (ustekinumab) which were approved in Canada before 2010. New-generation biologics (6): include anti-IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) and anti-IL-23 inhibitors (guselkumab, tildrakizumab, and risankizumab) which were approved in Canada in 2015 or later. Patent protection has expired for infliximab, certolizumab, and ustekinumab. There is no valid data protection status for all 5 older generation biologics. However, only 3 of the old-generation biologics have biosimilar versions (adalimumab, etanercept, and infliximab) that are available in the Canadian market. Biosimilar versions for adalimumab and etanercept were marketed for PsO approximately 3 years to 4 years after their initial Notice of Compliance was issued, respectively. This delay can be attributed to various factors, including litigation and global agreements between manufacturers. Despite the expiry of data and patent protection for both ustekinumab and certolizumab, no biosimilar versions are available in Canada. Data protection for both biologics expired more than 4 years ago, and the patents have expired in 2021. A lack of a biosimilar entrant in Canada could be attributed to various factors, including clinical trial development based on exclusivity timelines in the US, where data protection is 4 years longer for biologics versus Canada. CADTH has reviewed 3 of 5 of the old-generation biologics and all 6 of the new-generation biologics; all drugs received similar CADTH Canadian Drug Expert Committee (CDEC) recommendations. The clinical programs of most of the new-generation biologics included direct evidence demonstrating superiority or statistically significantly higher efficacy outcomes compared with the active comparator of the old-generation biologics. The clinical trials for new-generation biologics also incorporated more stringent primary outcome measures. The old-generation biologics predated the pan-Canadian Pharmaceutical Alliance (pCPA) process (except for certolizumab), which could imply disparate product listing agreements across public drug plans for these drugs. The only biologics not included on any public formularies are certolizumab, guselkumab, and tildrakizumab (although tildrakizumab has yet to begin pCPA negotiations). Listing status for biologics fell under restricted benefit, but differed in terms of active (e.g., review through special authorization forms) versus passive (e.g., Limited Use codes in Ontario) procedures across public drug plans. Moreover, 3 public drug plans employed 2-tiered formularies (i.e., Alberta, Manitoba, and Correctional Services Canada) which required a trial of new-generation biologics or old-generation biosimilars before reimbursement of old-generation originators. Utilization patterns of old- versus new-generation biologics within the Ontario Public Drug Programs demonstrated that a significant proportion of new patients were treated with old-generation biologics (54% in 2019 and 37% in 2020) despite the availability of multiple new-generation biologics. In conclusion, formulary management is warranted for biologics for PsO given the significant utilization of old-generation originators in the current context of delayed marketing of their biosimilar versions for PsO and their reimbursement predating the pCPA process. New-generation biologics underwent pCPA negotiations and direct evidence was submitted that demonstrated superiority versus old-generation biologic active comparators, which may ultimately prove to be a greater value for patients and payers.

This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000-$100,000 per QALY.