Treatment sequence network meta-analysis in Crohn's disease: a methodological case study.

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.

Patient Perspectives on Intravenous Biologics for Rheumatologic Disease.

OBJECTIVE: Two surveys were conducted with patients with rheumatologic diseases to evaluate perceptions of different routes of administration (intravenous [IV] or subcutaneous [SC]) for biologic therapy. METHODS: In Survey I, patient preferences toward biologic treatment were evaluated at a rheumatology practice in Buffalo, New York. In Survey II, Canadian patients enrolled in the BioAdvance patient support program and scheduled to receive IV biologic therapy were asked about their opinions of IV treatment. RESULTS: In Survey I, 243 rheumatology patients participated. Median patient age was 60 years, 76% were female, and 44% were naive to treatment with biologic agents. Among biologic-naive patients, the majority (56%) were open to either SC or IV treatment; biologic-naive women were more likely than men to express a preference for the route of administration. In Survey II, 1,598 patients from the BioAdvance program (including 306 rheumatology patients) completed the full survey. Among the rheumatology patients, the median age was 49 years, 58% were female, and 61% had not previously taken biologics before enrolling in the BioAdvance program. The median rating of IV favorability (on a 10-point scale, with higher numbers indicating increased favorability) recalled by rheumatology patients was 5 prior to their first program infusion, which increased to 9 after multiple treatment infusions. CONCLUSION: These survey results indicate that patients with rheumatoid arthritis 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.

Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation.

OBJECTIVE: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada). METHODS: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs). RESULTS: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY. LIMITATIONS: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze. CONCLUSION: 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.

The Importance of Considering Differences in Study Design in Network Meta-analysis: An Application Using Anti-Tumor Necrosis Factor Drugs for Ulcerative Colitis.

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 variations in study design resulted in effect estimates that were biased against golimumab. In contrast, using the 3 alternative methods to convert outcome data from one form of adaptive design to a format more consistent with conventional parallel RCTs facilitated more transparent consideration of differences in study design. This approach is more likely to yield appropriate estimates of comparative efficacy when conducting an NMA, which includes treatments that use an alternative study design. CONCLUSIONS: RCTs based on adaptive study designs should not be combined with traditional parallel RCT designs in NMA. We have presented potential approaches to convert data from one form of adaptive design to more conventional parallel RCTs to facilitate transparent and less-biased comparisons.

BioAdvance Patient Support Program Survey: Positive Perception of Intravenous Infusions of Infliximab.

PURPOSE: To understand the perception of intravenous infusions in patients receiving infliximab (Remicade) within the BioAdvance patient support program (PSP). DESIGN: Intravenous infusion of infliximab occurs at approximately 200 clinics across Canada and is managed via the BioAdvance PSP. Patients were invited to complete a 28-question survey on demographics, disease/treatment characteristics, health rating, lifestyle, employment, and perception of intravenous infusions and the BioAdvance program. METHODOLOGY: Analyses were exploratory and descriptive; collected data were self-reported ordinal (Likert scale, unfavorable-to-favorable, 1-10). The Wilcoxon signed-rank test was used to assess statistical significance, and multinomial logistic regression identified predictors of a positive perception of intravenous infusions. RESULTS: 1,712 patients completed the survey. Most respondents had been treated with infliximab for >2 years (58%), had not been previously treated with a biologic (74%), and were receiving treatment for inflammatory bowel disease (76%). Sixty-two percent of patients were employed and most traveled for personal/work reasons (57%) and had a busy/active lifestyle (76%) while attending the BioAdvance clinics. Before treatment, participants rated their perceived favorability of intravenous infusions at 5/10 (median; interquartile range, 5-7); after multiple infusions, their rating increased significantly to 8 (7-9) (P<.001). Regression analysis identified four predictors of a positive infusion experience: French language, favorable ratings of health, accuracy of physician's description, and satisfaction with their BioAdvance coordinator. The vast majority of participants were likely to recommend the BioAdvance PSP. CONCLUSION: The survey results indicate that the majority of patients receiving infliximab have a positive infusion experience within the BioAdvance PSP.

Factors associated with changes in self-reported health status in infliximab-treated inflammatory bowel disease patients: results from a case management survey.

BACKGROUND: Canadian inflammatory bowel disease patients treated with infliximab are predominantly managed through a nationwide case management system, named BioAdvance(®). METHODS: A web-based survey was provided to patients currently receiving infliximab therapy within BioAdvance(®). Patients were categorized according to health trajectories: decliners, non-changers, moderate increasers and strong increasers. Factors associated with health trajectories were identified using multivariable multinomial logistic regression. RESULTS: 918 of 1160 respondents were inflammatory bowel disease patients reporting health status. Strong increasers were more likely to use educational tools than non-changers (adjusted odds ratio [aOR]: 1.65; 95% CI: 1.03-2.64), to be treated for ulcerative colitis (aOR: 2.05; 95% CI: 1.16-3.64) and to perceive case management as important (aOR: 2.52; 95% CI: 1.56-4.09). Younger (aOR: 0.72; 95% CI: 0.63-0.83) and French-speaking (aOR: 0.34; 95% CI: 0.18-0.63) patients were less likely to miss workdays. Patients were more likely to have missed workdays prior to joining the case management program. CONCLUSIONS: Inflammatory bowel disease patients receiving infliximab within the nationwide case management system report a positive impact on health status and absenteeism.

Mechanisms of VIP-induced inhibition of the lymphatic vessel pump.

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 effects are mainly mediated by stimulation of the VIP receptor VPAC2 located on the lymphatic muscle and the downstream involvement of protein kinase A (PKA) and ATP-sensitive K⁺ (KATP) channels. Inhibition of lymphatic pumping by VIP may compromise lymph drainage, oedema resolution and immune cell trafficking to the draining lymph nodes.

Acute response of airway muscle to extreme temperature includes disruption of actin-myosin interaction.

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 ß-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.