Immune Profiling Reveals the T-Cell Effect of Ocrelizumab in Early Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology. METHODS: A first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest. RESULTS: Using an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4+ T cells: one corresponding to naive CD4+ T cells was increased, the other clusters corresponded to effector memory (EM) CD4+CCR6- T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8+ T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8+CCR5+ T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells. DISCUSSION: Our study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5.

Factors associated with therapeutic inertia among pharmacists caring for people with multiple sclerosis.

INTRODUCTION: Pharmacists play a critical role on therapeutic decisions in multiple sclerosis (MS) care. Therapeutic inertia (TI) is defined as the lack of treatment initiation or escalation when there was evidence of clinical and radiological disease activity. The aim of this study was to assess factors associated with TI among pharmacists involved in MS care. METHODS: A multicenter, non-interventional, cross-sectional study involving hospital pharmacists in Spain was conducted. Participants answered questions regarding their standard practice, risk preferences, and management of nine simulated MS case-scenarios. We created a score defined as the number of case-scenarios that fit the TI criteria over the total number of presented cases (score range from 0-6). Similarly, an optimal treatment score (OTS) was created to determine the degree of appropriate pharmacological decisions (ranging from 0-lowest to 9-highest). Candidate predictors of TI included demographic data, practice setting, years of practice, MS expertise, number of MS patients managed at hospital/year, participation in MS clinical trials, and participants' risk preferences. RESULTS: Overall, 65 pharmacists initiated and completed the study (response rate: 45.5%). The mean age was 43.5 ± 7.8 years and 67.1% were female. Forty-two (64.6%) participants had specialization in MS management. Overall, the mean TI score was 3.4 ± 1.1. Of 390 individual responses, 224 (57.4%) met the TI criteria. All participants failed to recommend treatment escalation in at least one of the six case-scenarios. The mean OTS was 4.1 ± 1.4. Of 585 individual responses, 264 (45.1%) met the optimal choice criteria. Only 40% of participants (23/65) made five or more optimal treatment choices. Lower experience in dispensing MS drugs and lack of specialization in MS were the most common factors associated with TI and optimal management. The multivariable analysis revealed that more years of experience (p = 0.03), being a co-author of a peer-reviewed publication (p = 0.03), and specialization in MS (p = 0.017) were associated with lower TI scores (adjusted R2 = 0.23). CONCLUSION: Therapeutic inertia was observed in all pharmacist participants, affecting over fifty percent of MS treatment choices. Continuing education and specialization in MS may facilitate therapeutic decisions in MS care.

Comparison of Physician Therapeutic Inertia for Management of Patients With Multiple Sclerosis in Canada, Argentina, Chile, and Spain.

Importance: There is growing interest in understanding and addressing factors that govern the decision-making process in multiple sclerosis (MS) care. Therapeutic inertia (TI) is the failure to escalate therapy when goals are unmet. Limited data are available on the prevalence of TI and factors affecting therapeutic decisions in the management of patients with MS worldwide. Objectives: To compare TI across 4 countries (Canada, Argentina, Chile, and Spain) and to identify factors contributing to TI. Design, Setting, and Participants: Prospective cohort study conducted between July 10, 2017, and May 4, 2018. Participants were exposed to behavioral experiments in which instruments were used to assess their risk preferences (eg, aversion to ambiguity) and therapeutic decisions in 10 simulated MS case scenarios. Mixed-effects linear and logistic regression analyses were performed to determine the association between the participants' baseline characteristics and TI. The association of unmeasured confounders was assessed by the E-value and a bootstrapping analysis. This multicenter study included neurologists practicing at academic and community centers in Canada, Argentina, Chile, and Spain who make therapeutic decisions for patients with MS. Main Outcomes and Measures: The primary outcome was the prevalence of TI. The TI score was calculated by dividing the number of case scenarios in which participants showed TI by the number of case scenarios that measured TI. Higher TI scores indicated greater degrees of TI. The secondary outcome was the identification of factors that contributed to TI. Results: Of 300 neurologists with expertise in MS care who were invited to be part of the study, 226 (75.3%) agreed to participate. Among those who initially showed interest in participating, 195 physicians (86.3%) completed the study, while 31 did not. The mean (SD) age of participants was 43.3 (11.2) years; 52.3% were male. Therapeutic inertia was present in 72.8% (142 of 195) of participants, leading to suboptimal decisions in 20.4% (318 of 1560) of case scenarios. The prevalence of TI among the Canadian group was the lowest compared with the other 3 countries (60.0% [33 of 55] vs 77.9% [109 of 140]; P = .01). For the primary outcome, the TI score in the Canadian group (mean [SD], 0.98 [1.15]) was significantly lower compared with groups from other countries (mean [SD], 1.70 [1.43] for Argentina, 2.24 [1.54] for Chile, and 2.56 [1.64] for Spain) (P = .001). The mixed-effects linear models revealed that participants from Argentina, Chile, and Spain (combined) had higher TI scores compared with their Canadian counterparts (ß coefficient, 0.90; 95% CI, 0.52-1.28; P < .001). A higher number of patients with MS per week (OR, 0.44; 95% CI, 0.22-0.88), years of practice (OR, 0.93; 95% CI, 0.86-0.99), and participation from Canada (OR, 0.47; 95% CI, 0.23-0.96) were associated with a lower likelihood of TI. Aversion to ambiguity was associated with a 2-fold higher likelihood of TI (OR, 2.25; 95% CI, 1.02-5.00). All 95% CIs of the ß coefficients of covariates were lower than the E-value of 2.35, making it unlikely for the results to be due to the association of unmeasured confounders. Conclusions and Relevance: This study showed that Canadian participants had the lowest prevalence and magnitude of TI. Higher TI scores were associated with a lower expertise in MS care and with a greater tendency for aversion to ambiguity.

Emotional expressions associated with therapeutic inertia in multiple sclerosis care.

BACKGROUND: Emotions play a critical role in our daily decisions. However, it remains unclear how and what sort of emotional expressions are associated with therapeutic decisions in multiple sclerosis (MS) care. Our goal was to evaluate the relationship between emotions and affective states (as captured by muscle facial activity and emotional expressions) and TI amongst neurologists caring for MS patients when making therapeutic decisions. METHODS: 38 neurologists with expertise in MS were invited to participate in a face-to-face study across Canada. Participants answered questions regarding their clinical practice, aversion to ambiguity, and the management of 10 simulated case-scenarios. TI was defined as lack of treatment initiation or escalation when there was clear evidence of clinical and radiological disease activity. We recorded facial muscle activations and their associated emotional expressions during the study, while participants made therapeutic choices. We used a validated machine learning algorithm of the AFFDEX software to code for facial muscle activations and a predefined mapping to emotional expressions (disgust, fear, surprise, etc.). Mixed effects models and mediation analyses were used to evaluate the relationship between ambiguity aversion, facial muscle activity/emotional expressions and TI measured as a binary variable and a continuous score. RESULTS: 34 (89.4%) neurologists completed the study. The mean age [standard deviation (SD)] was 44.6 (11.5) years; 38.3% were female and 58.8% self-identified as MS specialists. Overall, 17 (50%) participants showed TI in at least one case-scenario and the mean (SD) TI score was 0.74 (0.90). Nineteen (55.9%) participants had aversion to ambiguity in the financial domain. The multivariate analysis adjusted for age, sex and MS expertise showed that aversion to ambiguity in the financial domain (OR 1.56, 95%CI 1.32-1.86) was associated with TI. Most common muscle activations included mouth open (23.4%), brow furrow (20.9%), brow raise (17.6%), and eye widening (13.1%). Most common emotional expressions included fear (5.1%), disgust (3.2%), sadness (2.9%), and surprise (2.8%). After adjustment for age, sex, and physicians' expertise, the multivariate analysis revealed that brow furrow (OR 1.04; 95%CI 1.003-1.09) and lip suck (OR 1.06; 95%CI 1.01-1.11) were associated with an increase in TI prevalence, whereas upper lip raise (OR 0.30; 95%CI 0.15-0.59), and chin raise (OR 0.90; 95%CI 0.83-0.98) were associated with lower likelihood of TI. Disgust and surprise were associated with a lower TI score (disgust: p < 0.001; surprise: p = 0.008) and lower prevalence of TI (ORdisgust: 0.14, 95%CI 0.03-0.65; ORsurprise: 0.66, 94%CI 0.47-0.92) after adjusting for covariates. The mediation analysis showed that brow furrow was a partial mediator explaining 21.2% (95%CI 14.9%-38.9%) of the association between aversion to ambiguity and TI score, followed by nose wrinkle 12.8% (95%CI 8.9%-23.4%). Similarly, disgust was the single emotional expression (partial mediator) that attenuated (-13.2%, 95%CI -9.2% to -24.3%) the effect of aversion to ambiguity on TI. CONCLUSIONS: TI was observed in half of participants in at least one case-scenario. Our data suggest that facial metrics (e.g. brow furrow, nose wrinkle) and emotional expressions (e.g. disgust) are associated with physicians' choices and partially mediate the effect of aversion to ambiguity on TI.

Therapeutic Inertia in Multiple Sclerosis Care: A Study of Canadian Neurologists.

Introduction: According to previous studies, therapeutic inertia (TI) may affect 7 out of 10 physicians who care for MS patients, particularly in countries where clinical guidelines are not widely used. Limited information is available on the prevalence of TI and its associated factors across Canada. Objectives: (i) To evaluate factors associated with TI amongst neurologists caring for MS patients across Canada; (ii) to compare the prevalence of TI observed in Canadian neurologists to the prevalence of TI observed in Argentinean, Chilean, and Spanish neurologists (historical controls from prior studies). Design: One hundred and eight neurologists with expertise in MS were invited to participate in an online study in Canada. Participants answered questions regarding their clinical practice, risk preferences, management of 10 simulated case-scenarios. The design of that study was similar to that of the prior studies completed in Argentina and Chile (n = 115). TI was defined as lack of treatment initiation or escalation when there was clear evidence of clinical and radiological disease activity (8 case-scenarios, 440 individual responses). A TI score was created & defined as the number of case-scenarios that fit the TI criteria over the total number of presented cases (score range from 0 to 8), with a higher score corresponding to a higher TI. TI scores observed in the Canadian study were compared with those observed in Argentina and Chile, as both studies followed the same design, case-scenarios and methodologies. Predictors of TI included demographic data, MS specialist vs. general neurologist, practice setting, years of practice, volume of MS patients and risk preferences. Results: Fifty-five Canadian neurologists completed the study (completion rate: 50.9%). The mean age (±SD) was 38.3 (±15) years; 47.3% of the participants were female and 56.4% self-identified as MS specialists. Overall, 54 of 440 (12.3%) individual responses were classified as TI. 60% of participants displayed TI in at least one case-scenario. The mean TI score across Canada [0.98 (SD = 1.15)] was significantly lower than the TI score observed in the Argentinean-Chilean [1.82 (SD = 1.47); p < 0.001] study. The multivariable analysis revealed that older age (p = 0.018), years of experience (p = 0.04) and willingness to risk further disease progression by avoiding treatment initiation or treatment change (p = 0.043) were independent predictors of TI. Conclusions: TI in Canada was observed in 6 out of 10 neurologists, affecting on average 1 in 8 therapeutic decisions in MS care. TI in Canada is significantly lower than in the other studied countries. Factors associated with TI include older age, lower years of experience, and willingness to risk disease progression by avoiding treatment initiation or treatment change. Differences in clinical practice patterns and adherence/access to accepted MS guidelines may explain how TI in Canada differs significantly from TI in Argentina-Chile.