Anti-IL-4R versus anti-IL-5/5R after anti-IL-5/5R failure in asthma: An emulated target trial.

BACKGROUND: Switching biologics is now common practice in severe eosinophilic asthma. After insufficient response to anti-IL-5 or 5 receptor (anti-IL-5/5R), the optimal switch between an anti-IL-4R mAb (interclass) or another anti-IL-5/5R drug (intraclass) remains unknown. OBJECTIVE: We sought to compare the effectiveness of these 2 strategies in asthma control in patients with severe eosinophilic asthma and insufficient response to an anti-IL-5/5R mAb. METHODS: We emulated a target randomized trial using observational data from the Recherche sur les AsthMes SEvèreS (RAMSES) cohort. Eligible patients were switched to an anti-IL-4R mAb or another anti-IL-5/5R drug after insufficient response to an anti-IL-5/5R mAb. The primary outcome was the change in Asthma Control Test score at 6 months. RESULTS: Among the 2046 patients in the cohort, 151 were included in the study: 103 switched to an anti-IL-4R mAb and 48 to another anti-IL-5/5R. At 6 months, the difference in Asthma Control Test score improvement was not statistically significant (mean difference groups, 0.82 [-0.47 to 2.10], P = .213). The interclass group exhibited greater cumulative reduction in oral corticosteroid dose (Pinter-intra, -1.05 g [-1.76 to -0.34], P = .041). The interclass group had a better effect, although not significantly, on reducing exacerbations (Δinter-intra, -0.37 [-0.77 to 0.02], P = .124) and increasing lung function (FEV1) (126.8 mL [-12.7 to 266.4], P = .124). CONCLUSIONS: After anti-IL-5/5R mAb insufficient response, switching to dupilumab demonstrated similar improvement in Asthma Control Test scores compared with intraclass switching. However, it appeared more effective in reducing oral corticosteroid use. Larger studies are warranted to confirm these results.

Baseline characteristics and treatment response predictive of nAMD outcomes with ranibizumab therapy in treatment-naive patients: the RACER subgroup analysis.

BACKGROUND: The Ranibizumab AMD Clinical Efficacy Study (RACER) conducted in treatment-naive adult Taiwanese patients with neovascular age-related macular degeneration (nAMD) suggested the importance of early and intensive dosing of ranibizumab for optimal treatment outcomes. This subgroup analysis aims to provide clinical information on treatment response that can potentially guide on maintaining the treatment or switching anti-VEGF agents in the real-world setting. METHODS: Visual acuity (VA) and central retinal thickness (CRT) were assessed in the RACER subgroup population. Subgroup analysis sets were categorised based on: (1) baseline best-corrected VA (BCVA; ≤ 48 and > 48 letters); (2) baseline CRT (≤ 325 or > 325 µm); and (3) treatment response after three monthly initial injections: < or ≥ 5-letter gain in BCVA and reduction of < or ≥ 50 µm in CRT. RESULTS: Patient age, sex, nAMD duration and number of ranibizumab injections did not differ significantly between the treatment subgroups. Poor baseline BCVA (≤ 48 letters) and baseline CRT severity (> 325 µm) were predictors of maximum BCVA gains (9.6 ± 12.9 letters [95%CI: 6.3 to 12.9] and 5.1 ± 18.3 letters [95%CI: - 0.5 to 10.8] at Months 3 and 12, respectively) and better CRT reductions (- 127.6 ± 104.2 µm and - 104.2 ± 107.4 µm at Months 3 and 12, respectively; both P < 0.001). For the subgroup showing favourable treatment improvement with BCVA gains ≥ 5 letters after three monthly initial injections, 75.6% of patients maintained follow-up at Month 12 with a mean of 6.5 ± 14.3 letter gains (95% CI: 1.2 to 11.7). The BCVA gains < 5-letter subgroup nevertheless had stable BCVA (0.4 ± 12.1 letter gains) and CRT (- 41.9 ± 61.2 µm) at Month 12, respectively. In the subgroup with ≥ 50 µm CRT reduction after three monthly initial injections, there are significantly higher BCVA improvements vs. the < 50 µm CRT reduction subgroup at Month 3 (5.0 ± 8.6 letter gains vs. 1.5 ± 11.6 letter gains, respectively; intergroup P = 0.005). CONCLUSION: Lower baseline BCVA and higher baseline CRT were associated with BCVA gains and CRT reductions throughout the 12-month study period. Early CRT improvements after three monthly initial injections were associated with BCVA gains as early as Month 3.

Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

Switching to Tenofovir Alafenamide Fumarate in Chronic Hepatitis B Patients Who Had Detectable HBV DNA during Treatment with Entecavir.

Nucleos(t)ide analogues (NAs) suppress hepatitis B virus (HBV) replication, but the risk of hepatocellular carcinoma still remains. The presence of detectable HBV DNA in the serum during NA therapies for chronic hepatitis B patients has been reported to be associated with the risk of hepatocellular carcinoma. In this study, we investigated the antiviral effect of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in chronic hepatitis B patients who had detectable HBV DNA in the serum at least once within a year. Among a total of 77 cases in 7 hospitals that switched NAs from ETV to TAF, 23 patients with detectable HBV DNA in a year before switching were analyzed. When the detection frequencies of HBV DNA in the 1st and 2nd years after switching to TAF were analyzed, they were significantly lower than those in the year before switching (68.8% vs. 34.1% for the 1st year and 21.3% for the 2nd year, P < 0.001 for both). The HBsAg decline tended to be larger after switching than before (-2.5% vs. -3.0% for 1st year and -3.1% for 2nd year), but the difference was not significant. One patient died of a cardiovascular event 11 months after the treatment switch, but no adverse effects due to TAF including renal function were observed. In conclusion, it was suggested that switching from ETV to TAF might be effective to suppress the HBV DNA level further in patients whose HBV DNA is detectable, even if at a very low level.

Modeling time-varying exposure using inverse probability of treatment weights.

For estimating the causal effect of treatment exposure on the occurrence of adverse events, inverse probability weights (IPW) can be used in marginal structural models to correct for time-dependent confounding. The R package ipw allows IPW estimation by modeling the relationship between the exposure and confounders via several regression models, among which is the Cox model. For right-censored data and time-dependent exposures such as treatment switches, the ipw package allows a single switch, assuming that patients are treated once and for all. However, to accommodate multiple switches, we extend this package by implementing a function that allows for multiple and intermittent exposure status in the estimation of IPW using a survival model. This extension allows for the whole exposure treatment trajectory in the estimation of IPW. The impact of the estimated weights on the estimated causal effect, with both methods, is assessed in a simulation study. Then, the function is illustrated on a real dataset from a nationwide prospective observational cohort including patients with inflammatory bowel disease. In this study, patients received one or multiple medications (thiopurines, methotrexate, and anti-TNF) over time. We used a Cox marginal structural model to assess the effect of thiopurines exposure on the cause-specific hazard for cancer incidence considering other treatments as confounding factors. To this end, we used our extended function which is available online in the Supporting Information.

On an enhanced rank-preserving structural failure time model to handle treatment switch, crossover, and dropout.

It is very challenging to estimate the comparative treatment effect between a treatment therapy and a control therapy on overall survival in the presence of treatment crossover, switch to an alternative non-study therapy, and non-random patient dropout. Existing methods (e.g., intent-to-treat and per-protocol) are known to be biased. We proposed two new estimators to address these analytical challenges and evaluated their performance via a comprehensive simulation study. The new estimators were constructed by combining an enhanced rank-preserving structural failure time model and the inverse probability censoring weighting approach. In the simulation study, we assessed and compared the performance of the two new estimators with four estimators from existing methods. The simulation results show that the new estimators have much better performance in almost all considered settings compared with the existing estimators. Copyright © 2017 John Wiley & Sons, Ltd.

Rates of switching to second-line antiretroviral therapy and impact of delayed switching on immunologic, virologic, and mortality outcomes among HIV-infected adults with virologic failure in Rakai, Uganda.

BACKGROUND: Switch from first to second-line ART is recommended by WHO for patients with virologic failure. Delays in switching may contribute to accumulated drug resistance, advanced immunosuppression, increased morbidity and mortality. The 3rd 90' of UNAIDS 90:90:90 targets 90% viral suppression for persons on ART. We evaluated the rate of switching to second-line antiretroviral therapy (ART), and the impact of delayed switching on immunologic, virologic, and mortality outcomes in the Rakai Health Sciences Program (RHSP) Clinical Cohort Study which started providing ART in 2004 and implemented 6 monthly routine virologic monitoring beginning in 2005. METHODS: Retrospective cohort study of HIV-infected adults on first-line ART who had two consecutive viral loads (VLs) >1000 copies/ml after 6 months on ART between June 2004 and June 2011 was studied for switching to second-line ART. Immunologic decline after virologic failure was defined as decrease in CD4 count of ≥50 cells/ul and virologic increase was defined as increase of 0.5 log 10 copies/ml. Competing risk models were used to summarize rates of switching to second-line ART while cox proportional hazard marginal structural models were used to assess the risk of virologic increase or immunologic decline associated with delay to switch first line ART failing patients. RESULTS: The cumulative incidence of switching at 6, 12, and 24 months following virologic failure were 30.2%, 44.6%, and 65.0%, respectively. The switching rate was increased with higher VL at the time of virologic failure; compared to those with VLs ≤ 5000 copies/ml, patients with VLs = 5001-10,000 copies/ml had an aHR = 1.81 (95% CI = 0.9-3.6), and patients with VLs > 10,000 copies/ml had an aHR = 3.38 (95%CI = 1.9-6.2). The switching rate was also increased with CD4 < 100 cells/ul at ART initiation, compared to those with CD4 ≥ 100 cells/ul (aHR = 2.30, 95% CI = 1.5-3.6). Mortality in patients not switched to second-line ART was 11.9%, compared to 1.2% for those who switched (p = 0.009). Patients switched after 12 months of of virologic failure were more likely to experience CD4 decline and/or further VL increases. CONCLUSIONS: Intervention strategies that aid clinicians to promptly switch patients to second-line ART as soon as virologic failure on 1st line ART is confirmed should be prioritized.

Comparison of Intravitreal Ranibizumab, Aflibercept, and Dexamethasone Implant after Bevacizumab Failure in Macular Edema Secondary to Retinal Vascular Occlusions.

PURPOSE: To compare the visual and anatomic outcomes of macular edema secondary to retinal vein occlusion after switching from bevacizumab to ranibizumab, aflibercept, or dexamethasone implant. METHODS: Fifteen eyes were switched to ranibizumab, 12 to aflibercept, and 10 to dexamethasone. At 3, 6, 9, and 12 months, the outcome measures were visual acuity (VA) and central macular thickness (CMT). RESULTS: One year after the switch, CMT decreased from 430.11 ± 91.21 to 291.86 ± 43.87 µm (p < 0.001). VA increased in 59.5% of the eyes. No difference between the groups was found in those outcomes at 1 year, but the number of injections varied: 3.30 ± 0.95 for dexamethasone, 6.50 ± 2.11 for aflibercept, and 8.27 ± 2.37 for ranibizumab (p < 0.001). CONCLUSIONS: Most of the eyes that failed initial bevacizumab therapy benefit from switching to another modality. The number of required injections during the first year after the switch varies.

Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study.

OBJECTIVES: The primary objective was to evaluate the improvement in neuropsychiatric symptoms attributed to an antiretroviral drug after that drug was substituted with nevirapine. The secondary objective was to evaluate the impact on patient adherence and quality of life. METHODS: A prospective, observational study was carried out that included patients with HIV-1 plasma suppression for whom an antiretroviral drug was substituted with nevirapine because of central nervous system (CNS) side effects, a Pittsburgh Sleep Quality Index (PSQI) score > 5 or a Hospital Anxiety and Depression Scale (HADS) score ≥ 10, and who had not initiated psychoactive drug treatment during the prior 6 weeks. Evaluations were carried out at baseline and 1 and 3 months after the switch using the PSQI, HADS, Epworth Sleepiness Scale, Medical Outcomes Study-Short Form 30 items (MOS-SF-30) and Simplified Medication Adherence Questionnaire (SMAQ). RESULTS: A total of 129 patients were included in the study. The drug substituted was mainly efavirenz (89.9%), and reasons for the switch included sleep disturbances (75.2%), anxiety (65.1%), depression (38.7%), attention disturbances (31%), and other reasons (31%), with a mean of 2.4 neuropsychiatric disturbances per patient. A statistically significant improvement was observed in all the tests evaluating neuropsychiatric symptoms and adherence at 1 and 3 months. The CD4 lymphocyte count remained stable (P = 0.096). Three (2.3%) patients had a detectable plasma HIV-1 RNA at the end of the study. Nine patients (6.9%) withdrew because of nevirapine-related toxicity (rash in seven patients and hypertransaminasaemia in two patients, none of which were > grade 2). CONCLUSIONS: The switch to nevirapine from a drug causing neuropsychiatric disturbances (primarily efavirenz) in subjects with virological suppression was effective in resolving those disturbances, with an improvement in all the parameters studied. This led to better adherence to treatment and quality of life, with no detrimental effect on their immunological and virological control.

HIV patients' decision of switching to second-line antiretroviral therapy in India.

The objective is to examine when patients should switch to second-line antiretroviral therapy (ART) under health uncertainty and in the absence of viral load monitoring. We formalize and solve the therapeutic dilemma about whether or not, and when, to switch a therapy. The model's main value-added consists in the concrete application to patients with HIV in India. In our dynamic stochastic model, health level volatility can be understood as the variation in CD4 count and the trend of health level as increases in CD4 count and, thus, decreases in the incidence of opportunistic infections and mortality. The results of the empirical application suggest that the theoretical model can explain ART treatment switch. Treatment switch depends negatively on the volatility of patients' health, and on trend of health, i.e., the greater the variation in CD4 count and the more CD4 count increase, the fewer treatment switches one expects to occur. Treatment switch also depends negatively on the degree of irreversibility. Under irreversibility, low-risk patients must begin the second-line treatment as soon as possible, which is precisely when the second-line treatment is least valuable. The existence of an option value means that ART first-line regimen may be the better choice when considering lifetime welfare. Conversely, treatment switch depends positively on the discount rate and on the correlation between the patient's health under first- and second-line treatments. This means that treatment switch is likelier to succeed in second-line treatments that are similar to the first-line treatments, implying that a decision-maker should not rely on treatment switch as a risk diversification tool.

Subgroup analysis of the non-interventional study VIVALDI: agomelatine in treatment-naïve patients, in combination therapy and after treatment switch.

OBJECTIVE: Agomelatine has demonstrated antidepressant efficacy in randomized, controlled trials. This non-interventional study VIVALDI evaluated agomelatine treatment under practice conditions. METHODS: Psychiatrists documented the treatment of 3,317 patients over 12 weeks. According to the treatment condition three subgroups were selected: Agomelatine in treatment-naïve patients as mono-therapy (A), in pretreated patients as add-on-therapy (B), and in pretreated patients switched to agomelatine (C). Effect on depressive symptoms was evaluated via svMADRS and CGI. Daytime functioning and sleep-wake rhythm were assessed by a patient-questionnaire. RESULTS: The svMADRS decreased from values > 30 at baseline to 12.8 (total population), 10.3 (A), 15.1 (B), and 13.5 (C). 76.1%, 55.7%, and 62.5% of patients were responders in subgroups A, B, and C, respectively, 65.8% in the total population. Remission was achieved in 66.5% (A), 44.7% (B), and 50.9% (C) of patients. After 12 weeks, subjective sleep quality and daytime functioning improved in the majority of patients. Adverse drug reactions (ADR/serious ADR) were reported for 6.0%/0% (A), 11.0%/0.2% (B), and 12.6%/0.3% (C) of patients. Overall, 25.8% of patients discontinued treatment prematurely, 5.2% due to ADR. CONCLUSION: Agomelatine improved depressive symptoms, daytime functioning, and sleep-wake rhythm, and demonstrated good tolerability also in pretreated patients and combination therapy under routine practice.

The Impact of Switching to a Second Antifibrotic in Patients With Idiopathic Pulmonary Fibrosis: A Retrospective Multicentre Study From the EMPIRE Registry.

INTRODUCTION: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE). METHODS: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT). RESULTS: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001). CONCLUSION: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy.

Evaluation of drivers of treatment switch in relapsing multiple sclerosis: a study from the Italian MS Registry.

BACKGROUND: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD). METHODS: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]. RESULTS: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs. CONCLUSIONS: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.

Rationale and Design of the COPERNIC Trial: A Study of On-treatment ctDNA Changes in Chemo-refractory Colorectal Cancer Patients.

BACKGROUND: Evidence suggests that ctDNA may be a reliable biomarker to monitor metastatic colorectal cancer (CRC) evolution. Nevertheless, evidence on the potential of liquid biopsy in this setting is still low quality, mostly consisting of retrospective studies. METHODS: COPERNIC is an international, multicenter clinical trial. The pilot study aims to confirm the predictive potential of early on-treatment ctDNA dynamics, and inform the design of a larger ctDNA-driven trial. Advanced CRC patients who are candidates for ≥3rd lines of systemic therapy undergo longitudinal blood sample collection during treatment (day 1, 15 and 29 for 2- or 4-weekly treatment regimens; day 1, 22 and 43 for 3-weekly treatment regimens) and at each imaging assessment. ctDNA analyses are carried out with the FoundationOne Liquid CDx and FoundationOneMonitor assays, and ctDNA changes during treatment are correlated with radiologic response (as assessed every 8-12 weeks by RECIST v1.1). The primary objective is to select the optimal timepoint and cut-off value for early ctDNA changes (at day 15/22) to predict progressive disease as best radiological response with a high positive predictive value. The cut-off value for ctDNA will be defined based on nonparametric ROC-curves with bootstrapping. Based on the expected rate of progressive disease and statistical assumptions, 109 patients are needed to be screened to have 87 assessable patients. COPERNIC is sponsored by the Institut Jules Bordet, and supported by Roche and Foundation Medicine. Recruitment is open in 13 centres across Belgium and France. The study is registered with clinicaltrials.gov (NCT05487248).

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

INTRODUCTION: This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228 weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase 3 SELECT-COMPARE study. METHODS: Patients with non-response or incomplete response to initially prescribed upadacitinib 15 mg once daily or adalimumab 40 mg every other week were switched to the alternate therapy by week 26. Efficacy was evaluated through 228 weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week 264. RESULTS: Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week 26. Clinically relevant improvements in all efficacy measures were observed through 228 weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. CONCLUSION: Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. TRIAL REGISTRATION: NCT02629159.

The economic impact of suboptimal treatment and treatment switch among patients with Crohn's disease treated with a first-line biologic - A US retrospective claims database study.

AIMS: Suboptimal treatment indicators, including treatment switch, are common among patients with Crohn's disease (CD), but little is known about their associated healthcare resource utilization (HRU) and costs. This study assessed the impact of suboptimal treatment indicators on HRU and costs among adults with CD newly treated with a first-line biologic. METHODS: Adult patients with CD were identified in the IBM MarketScan Commercial Subset (10/01/2015-03/31/2020). The index date was defined as initiation of the first-line biologic, and the study period was defined as the 12 months following the index date. Patients were classified into Suboptimal Treatment and Optimal Treatment cohorts based on observed indicators of suboptimal treatment during the study period. Patients in the Suboptimal Treatment Cohort with a treatment switch were classified into the Treatment Switch Cohort and compared to patients with no treatment switch. All-cause HRU and costs were measured during the study period and assessed for patients with suboptimal vs optimal treatment and patients with vs without a treatment switch. RESULTS: The study included 4,006 patients (Suboptimal Treatment: 2,091, Optimal Treatment: 1,915). Treatment switch was a common indicator of suboptimal treatment (Treatment Switch: 640, No Treatment Switch: 3,366). HRU and costs were significantly higher among patients with suboptimal treatment than those with optimal treatment (annual costs: $92,043 vs $73,764; p < 0.01), and among those with a treatment switch than those with no treatment switch (annual costs: $95,689 vs $81,027; p < 0.01). Increases in the number of suboptimal treatment indicators were associated with increased costs. LIMITATIONS: Claims data were used to identify suboptimal treatment indicators based on observed treatment patterns; reasons for treatment decisions could not be assessed. CONCLUSION: This study demonstrates that patients with suboptimal treatment indicators, including treatment switch, incur substantially higher HRU and costs compared to patients receiving optimal treatment and those that do not switch treatments.

Fabry disease biomarkers in patients switched from enzyme-replacement therapy to migalastat oral chaperone therapy.

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme-replacement therapy (ERT) to migalastat. Methods: 16 Gb3 isoforms and eight lyso-Gb3 analogues were analyzed in plasma and urine by LC-MS/MS at baseline and at three different time points in naive participants and participants switching from either agalsidase α or ß to migalastat. Results: 29 adult participants were recruited internationally (seven centers). The Mainz Severity Score Index and mean biomarker levels remained stable (p ≥ 0.05) over a minimum of 12 months compared with baseline following the treatment switch. Conclusion: In this cohort of patients with Fabry disease with amenable mutations, in the short term, a switch from ERT to migalastat did not have a marked effect on the average biomarker profile.

Disease activity 4.5 years after starting cladribine: experience in 264 patients with multiple sclerosis.

Background: Cladribine is an effective immunotherapy for people with multiple sclerosis (pwMS). Whilst most pwMS do not require re-treatment following standard dosing (two treatment courses), disease activity re-emerges in others. The characteristics of pwMS developing re-emerging disease activity remain incompletely understood. Objectives: To explore whether clinical and/or paraclinical baseline characteristics, including the degree of lymphocyte reduction, drug dose and lesions on magnetic resonance imaging (MRI) are associated with re-emerging disease activity. Design: Service evaluation in pwMS undergoing subcutaneous cladribine (SClad) treatment. Methods: Demographics, clinical, laboratory and MRI data of pwMS receiving two courses of SClad were extracted from health records. To assess associations of predictor variables with re-emerging disease activity, a series of Cox proportional hazards models was fitted (one for each predictor variable). Results: Of n = 264 pwMS 236 received two courses of SClad and were included in the analysis. Median follow-up was 4.5 years (3.9, 5.3) from the first, and 3.5 years (2.9, 4.3) from the last SClad administration. Re-emerging disease activity occurred in 57/236 pwMS (24%); 22/236 received further cladribine doses (SClad or cladribine tablets) at 36.7 months [median; interquartile range (IQR): 31.7, 42.1], and 22/236 other immunotherapies 18.9 months (13.0, 30.2) after their second course of SClad, respectively. Eligibility was based on MRI activity in 29, relapse in 5, both in 13, elevated cerebrospinal fluid neurofilament light chain level in 3, deterioration unrelated to relapse in 4 and other in 3. Only 36/57 of those eligible for additional immunotherapy had received a reduced dose of SClad for their second treatment course. Association was detected between re-emerging disease activity and (i) high baseline MRI activity and (ii) low second dose of SClad. Conclusion: Re-emerging disease activity was associated with baseline MRI activity and low dose second course of SClad.

The Bone Biomarker of Quantitative Chemical Shift Imaging in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long-Term Enzyme Replacement Therapy.

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5-26) years and 30 (30-60) U/kg/month, respectively. Low FF scores (<0.30) were observed for seven patients (23%; 95% confidence interval, 10-42%) and were more common in females (n = 6) versus males (n = 1; p < 0.025); one female was menopausal. These baseline data demonstrate that prolonged low-dose ERT with imiglucerase or velaglucerase alfa led to an adequate bone response, assessed by QCSI, in the majority of patients. A minority of such patients with suboptimal bone response require therapeutic change. The next phase of the study will address the effect of switching to taliglucerase alfa on bone status for patients with less than optimal QCSI scores (<0.30).

Immunoglobulin utilization in Canada: a comparative analysis of provincial guidelines and a scoping review of the literature.

BACKGROUND: Canada has high immunoglobulin (IG) product utilization, raising concerns about appropriate utilization, cost and risk of shortages. Currently, there is no national set of standardized IG guidelines, and considerable variations exist among the existing provincial guidelines. The aims of this study were: (1) to compare the existing Canadian provincial guidelines on the use of IG products to identify their consistencies and differences and (2) to examine the existing research in Canada on IG supply and utilization following the establishment of IG guidelines to understand the scope of research and pinpoint the gaps. METHODS: A comparative analysis accounted for the differences across provincial IG guidelines. We highlighted similarities and differences in recommendations for medical conditions. A scoping review of citations from MEDLINE, PubMed, Scopus and Embase databases was conducted for studies published from January 01, 2014, to April 12, 2023. RESULTS: While provincial guidelines represented a considerable overlap in the medical conditions delineated and relatively uniform dose calculations, numerous differences were observed, including in recommendation categories, provision of pediatric dosing, and divergent recommendations for identical conditions based on patient demographics. The scoping review identified 29 studies that focused on the use of IG in Canada. The themes of the studies included: IVIG utilization and audits, the switch from IVIG to SCIG, patient satisfaction with IVIG and/or SCIG, the economic impact of self-administered SCIG versus clinically administered IVIG therapy, and the efficacy and cost-effectiveness of alternative medications to IG treatment. CONCLUSION: The differences in guidelines across provinces and the factors influencing IVIG/SCIG use, patient satisfaction, and cost savings are highlighted. Future research may focus on clarifying costs and comparative effectiveness, exploring factors influencing guideline adherence, and evaluating the impact of updated guidelines on IG use and patient outcomes.