Tobacco use, trauma exposure and PTSD: a systematic review.

Tobacco use remains one of the most significant preventable public health problems globally and is increasingly concentrated among vulnerable groups, including those with trauma exposure or diagnosed with PTSD. The goal of this systematic review was to update and extend previous reviews. Of the 7224 publications that met the initial criteria, 267 were included in the review. Summary topic areas include conceptual frameworks for the relation between trauma or PTSD and tobacco use; associations between trauma exposure or PTSD and tobacco use; number and type of trauma exposures and tobacco use; PTSD symptoms and tobacco use; Treatment-related studies; and the examination of causal relations. Evidence continues to indicate that individuals exposed to trauma or diagnosed with PTSD are more likely to use tobacco products, more nicotine dependent and less likely to abstain from tobacco even when provided evidence-based treatments than individuals without trauma. The most commonly cited causal association proposed was use of tobacco for self-regulation of negative affect associated with trauma. A small proportion of the studies addressed causality and mechanisms of action. Future work should incorporate methodological approaches and measures from which we can draw causal conclusions and mechanisms to support the development of viable therapeutic targets.

Advancing Proficiencies for Health Professionals in the Treatment of Tobacco Use Among Marginalized Communities: Development of a Competency-Based Curriculum and Virtual Workshop.

BACKGROUND: Tobacco-related disparities are a leading contributor to health inequities among marginalized communities. Lack of support from health professionals is one of the most cited barriers to tobacco cessation reported by these communities. Improving the proficiencies with which health professionals incorporate social and cultural influences into therapeutic interactions has the potential to address this critical barrier. In general, training to improve these proficiencies has shown promise, but the specific proficiencies required for treating tobacco use among marginalized communities are unknown. This project aimed to develop a competency-based curriculum to improve these proficiencies among health professionals with experience and training in the evidence-based treatment of tobacco use, and then pilot test the content delivered via an expert review of a virtual, self-paced workshop. METHODS: We used the Delphi Technique to systematically identify the specific competencies and corresponding knowledge and skill sets required to achieve these proficiencies. Educational content was developed to teach these competencies in a virtual workshop. The workshop was evaluated by 11 experts in the field by examining pre- and post-training changes in perceived knowledge, skill, and confidence levels and other quantitative and qualitative feedback. Repeated measures analysis of variance and paired sample t-tests were used to examine pre-post training differences. RESULTS: Six competencies and corresponding skill sets were identified. After exposure to the virtual workshop, the experts reported significant increases in the overall proficiency for each competency as well as increases in nearly all levels of knowledge, skill, and confidence within the competency skill sets. Qualitative and quantitative findings indicate that content was relevant to practice. CONCLUSIONS: These findings provide preliminary support for 6 competencies and skills sets needed to improve therapeutic interpersonal interactions that recognize the importance of social and cultural influences in the treatment of tobacco use.

Perceived research burden of a novel therapeutic intervention: A study of transcranial magnetic stimulation for smoking cessation.

Background: Translating repetitive transcranial magnetic stimulation (rTMS) into evidence-based clinical applications relies on research volunteers with different perspectives on the burden of study participation. Additionally, clinical applications of rTMS require multiple visits over weeks or months, the impact of research burden is an important component for these studies and translation of these findings to clinical practice. High frequency rTMS has significant potential to be developed as an evidence-based treatment for smoking cessation, however, the optimal rTMS dosing strategies have yet to be determined. Participant burden is an important component of determining optimal dosing strategy for rTMS as a treatment for long-term smoking cessation. Methods: In this double-blinded, sham-controlled, randomized design, the effects of treatment duration, intensity, and active/sham assignment of rTMS on research burden were examined. Results: Overall level of perceived research burden was low. Experienced burden (M = 26.50) was significantly lower than anticipated burden (M = 34.12). Research burden did not vary by race or income. Conclusions: Overall research burden was relatively low. Contrary to our hypotheses, we found little evidence of added significant burden for increasing the duration or intensity of rTMS, and we found little evidence for differences in research burden by race or income. Clinical Trial Registration: identifier NCT03865472.

The Roswell eND scale: Brief, valid assessment of nicotine dependence adults seeking to discontinue e-cigarette use.

BACKGROUND: Most adults who regularly use e-cigarettes or Electronic Nicotine Delivery Systems (ENDS) desire to discontinue use. ENDS use can result symptoms of nicotine withdrawal and dependence which can make it more difficult to discontinue use. Brief, valid assessment of nicotine dependence among adults who use ENDS is needed to guide treatment for nicotine dependence in this group. We sought to develop a brief, valid instrument to measure nicotine dependence among adults seeking to discontinue ENDS in a busy Quitline. METHODS: In this cross-sectional design, we examined content, construct, and concurrent validity of the Roswell ENDS Nicotine Dependence Scale (Roswell eND Scale) and the Penn State E-Cigarette Dependence Index (Penn State eCDI). Participants who called the New York Quitline from November 2019 to June 2020 seeking to discontinue ENDS use were invited to participate. Construct validity was examined with exploratory and confirmatory factor analyses. Instrument and factor scores were then correlated with cotinine, a biomarker of nicotine exposure. RESULTS: All participants (n = 209) were highly dependent and co-used combustible cigarettes to varying degrees. Both instruments demonstrated content validity and construct validity, however only the 5-item Roswell eND Scale demonstrated criterion-related validity by showing a significant positive correlation with salivary cotinine levels. CONCLUSIONS: The 5-item Roswell eND Scale can briefly and effectively assess nicotine dependence among treatment-seeking adults who co-use ENDS and cigarettes. These preliminary psychometric findings have the potential to be generalizable to other adults seeking to discontinue ENDS use, many of whom currently or formerly smoked cigarettes.

Association of Pack-Years of Cigarette Smoking With Survival and Tumor Progression Among Patients Treated With Chemoradiation for Head and Neck Cancer.

Importance: After 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear. Objective: To estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer. Design, Setting, and Participants: This single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022. Exposures: Heavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic. Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Results: A total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01). Conclusions and Relevance: In this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.

Transcranial Magnetic Stimulation for Long-Term Smoking Cessation: Preliminary Examination of Delay Discounting as a Therapeutic Target and the Effects of Intensity and Duration.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment for smoking cessation and delay discounting rate is novel therapeutic target. Research to determine optimal therapeutic targets and dosing parameters for long-term smoking cessation is needed. Due to potential biases and confounds introduced by the COVID-19 pandemic, we report preliminary results from an ongoing study among participants who reached study end prior to the pandemic. Methods: In a 3 × 2 randomized factorial design, participants (n = 23) received 900 pulses of 20 Hz rTMS to the left dorsolateral prefrontal cortex (PFC) in one of three Durations (8, 12, or 16 days of stimulation) and two Intensities (1 or 2 sessions per day). We examined direction and magnitude of the effect sizes on latency to relapse, 6-month point-prevalence abstinence rates, research burden, and delay discounting rates. Results: A large effect size was found for Duration and a medium for Intensity for latency to relapse. Increasing Duration increased the odds of abstinence 7-8-fold while increasing Intensity doubled the odds of abstinence. A large effect size was found for Duration, a small for Intensity for delay discounting rate. Increasing Duration and Intensity had a small effect on participant burden. Conclusion: Findings provide preliminary support for delay discounting as a therapeutic target and for increasing Duration and Intensity to achieve larger effect sizes for long-term smoking cessation and will provide a pre-pandemic comparison for data collected during the pandemic. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT03865472].

Methodological Investigation of Time Perspective Scoring and Quality of Life among Individuals with Multiple Sclerosis.

Achieving and maintaining a high quality of life following the diagnosis of chronic illness has a positive impact on the experience of illness, including delayed disease progression and fewer relapses. Time perspective has shown promising relationships with quality of life, though studies using the construct in samples with chronic illness are sparse and methodologically heterogeneous. Participants (n = 123) were diagnosed with relapsing-remitting multiple sclerosis at least five years prior to enrollment and were beginning a new disease modifying therapy (DMT). The Zimbardo Time Perspective Inventory (ZTPI) and the World Health Organization Quality of Life (WHOQoL-100) assessment were administered at baseline and the WHOQoL-100 was administered six-weeks after starting the new DMT. This study investigated the utility of three common methods of scoring and interpreting ZTPI (balanced vs. deviation-from-balanced, categorical, and continuous scores) to predict change in quality of life. Independent sample t-tests revealed no difference in quality of life for balanced vs. deviation-from-balanced. One-way ANOVA revealed no difference in quality of life across time perspective categories. Linear regression analysis found that past-negative scores predicted decreases in all quality of life domains as well as overall score while present hedonistic scores predicted increases in psychological and overall quality of life.

Daily Cannabis Use Is a Barrier to Tobacco Cessation Among Tobacco Quitline Callers at 7-Month Follow-up.

INTRODUCTION: Cannabis use is increasing among cigarette smokers in the United States. Prior studies suggest that cannabis use may be a barrier to smoking cessation. Yet, the extent to which this is the case among adults seeking to quit tobacco use remains unclear. Tobacco quitlines are the most common provider of no-cost treatment for adults who use smoke in the United States. This study investigated the association between cannabis use and smoking cessation outcomes among quitline callers. AIMS AND METHODS: Participants included callers to the New York State Smokers' Quitline, who were seeking to quit smoking cigarettes and were contacted for outcome assessment 7 months after intake. Thirty-day point prevalence abstinence rates were calculated and compared among cannabis use groups, based on frequency of past-30-day cannabis use at baseline (none: 0 days, occasional: 1-9 days, regular: 10-19 days, and daily: 20-30 days). RESULTS: Approximately 8.3% (n = 283) of participants (n = 3396) reported past-30-day cannabis use at baseline. Callers with daily cannabis use (20-30 days per month) had significantly lower odds of 30-day abstinence, relative to those who did not use cannabis (odds ratio = 0.5; 95% confidence interval [0.3, 0.9]). CONCLUSIONS: Daily cannabis use appears to be associated with poorer smoking cessation treatment outcomes among adults seeking to quit smoking cigarettes via a quitline. Because quitlines are among the most accessible, affordable, and frequently utilized community-based treatments available in the United States, and the prevalence of cannabis use is increasing among cigarette smokers, detailed inquiry into cannabis use might enhance cigarette smoking cessation outcomes. IMPLICATIONS: Quitlines are free of cost and accessible to millions of smokers in the United States. The current study found an inverse relationship between daily cannabis use at baseline and 30-day abstinence from cigarette smoking at 7-month follow-up among New York State Smokers' Quitline callers. Findings suggest that daily cannabis use may be a barrier to smoking cessation and sustained abstinence among those seeking help to stop smoking cigarettes.

Tobacco-Related Disparities Viewed Through the Lens of Intersectionality.

Despite remarkable progress, tobacco control efforts are not equitably distributed, and tobacco-related disparities continue to contribute to significant health disparities. Our premise in this commentary is that Intersectionality can serve as a productive analytical framework for examining tobacco-related disparities across and within multiple marginalized populations. Intersectionality is a theoretical framework for understanding the multiple interlocking societal systems that bestow privilege and oppression and is increasingly being to the study of health inequities. We present a model and describe how tobacco-related disparities can be understood via critical elements of Intersectionality. We conclude that the application of Intersectionality to understanding tobacco-related disparities has potential to stimulate meaningful discussion and lead to new and innovative multilevel and cross-cutting interventions to eliminate tobacco-related disparities and foster culturally safe environment in which all people can thrive. IMPLICATIONS: This commentary describes how Intersectionality can serve as a productive analytic framework for examining the development and maintenance of tobacco-related disparities across and within many marginalized groups.

Internal Validity of Two Promising Methods of Altering Temporal Orientation among Cigarette Smokers.

Relapse to smoking continues to be among the most urgent global health concerns. Novel, accessible, and minimally invasive treatments to aid in smoking cessation are likely to improve the reach and efficacy of smoking cessation treatment. Encouraging prospection by decreasing delay discounting (DD) is a new therapeutic target in the treatment of smoking cessation. Two early-stage interventions, delivered remotely and intended to increase prospection, decrease DD and promote cessation are Episodic Future Thinking (EFT) and Future Thinking Priming (FTP). EFT and FTP have demonstrated at least modest reductions in delay discounting, but understanding whether these interventions are internally valid (i.e., are accomplishing the stated intention) is key. This study examined the internal validity of EFT and FTP. Participants (n = 20) seeking to quit smoking were randomly assigned to active or control conditions of EFT and FTP. Linguistic Inquiry Word Count (LIWC2015) was used to examine the language participants used while engaged in the tasks. Results revealed significant differences in the language participants used in the active and control conditions. Women employed more words than men, but no other demographic differences were found in language. The active conditions for both tasks showed a greater emphasis on future orientation. Risk-avoidance was significantly higher in the active vs. control condition for EFT. Remote delivery of both EFT and FTP was valid and feasible as participants adhered to instructions in the remote prompts, and trends in DD were in the expected directions.

Increasing Physical Activity among Breast Cancer Survivors by Modulating Temporal Orientation with rTMS: Feasibility and Potential Efficacy.

Maintaining adequate amounts of physical activity is a critical component of survivorship care for women with breast cancer. Increased physical activity is associated with increases in well-being, quality of life, and longevity, but women with cancer face unique, cancer-related factors that might affect physical activity. Consistent with the Competing Neurobehavioral Decision Systems model of decision making, we proposed to decrease delay discounting and increase physical activity by stimulating the executive function system via high-frequency repetitive transcranial magnetic stimulation (HF rTMS) of the left dorsolateral prefrontal cortex (LDLPFC). This randomized, sham-controlled, double-blinded trial examined the feasibility and potential efficacy of this approach to increase physical activity in breast cancer survivors. We hypothesized that active rTMS would significantly increase the mean number of steps per day and decrease delay discounting. Participants (n = 30) were primarily middle-aged (M = 53.7, SD = 7.9) and white with a mean BMI and body mass indices below 40. Indicators of feasibility and limited efficacy testing were positive. Although repeated-measures ANOVA revealed no significant changes in delay discounting, generalized estimating equations (GEE) found that participants in the active condition increased their mean daily steps by 400 steps per day, while those in the sham condition decreased this by nearly 600 steps per day. These findings indicate that the continued investigation of HF rTMS for increasing physical activity among women with breast cancer is justified.

Future Thinking Priming Especially Effective at Modifying Delay Discounting Rates among Cigarette Smokers.

BACKGROUND: Tobacco use remains one of the world's greatest preventable causes of death and disease. While most smokers want to quit, few are successful, highlighting a need for novel therapeutic approaches to support cessation efforts. Lower delay discounting (DD) rates are associated with increased smoking cessation success. Future thinking priming (FTP) reliably reduces DD rates in large populations. Smokers consistently discount more than nonsmokers, and evidence suggests that changes in DD rates are rate dependent. This study examined whether smoking status moderated the effect of FTP on DD rates and, if so, if the moderation effect could be attributed to differences in baseline rates of DD. METHODS: Moderation analysis was conducted to determine whether the effect of FTP, versus neutral priming (NP), on DD differed among smokers and nonsmokers. RESULTS: Smoking status moderated the effect of condition (FTP vs. NP) on post-intervention DD scores (b = -0.2919, p = 0.0124) and DD change scores (b = -0.2975, p = 0.0130). There was no evidence of rate dependence effects in the current sample. CONCLUSIONS: FTP had a greater effect on decreasing DD rates among smokers than nonsmokers. FTP is effective and simple to administer, which makes it a promising therapeutic approach for aiding smoking cessation.

The Emerging Global Tobacco Treatment Workforce: Characteristics of Tobacco Treatment Specialists Trained in Council-Accredited Training Programs from 2017 to 2019.

Tobacco use is projected to kill 1 billion people in the 21st century. Tobacco Use Disorder (TUD) is one of the most common substance use disorders in the world. Evidence-based treatment of TUD is effective, but treatment accessibility remains very low. A dearth of specially trained clinicians is a significant barrier to treatment accessibility, even within systems of care that implement brief intervention models. The treatment of TUD is becoming more complex and tailoring treatment to address new and traditional tobacco products is needed. The Council for Tobacco Treatment Training Programs (Council) is the accrediting body for Tobacco Treatment Specialist (TTS) training programs. Between 2016 and 2019, n = 7761 trainees completed Council-accredited TTS training programs. Trainees were primarily from North America (92.6%) and the Eastern Mediterranean (6.1%) and were trained via in-person group workshops in medical and academic settings. From 2016 to 2019, the number of Council-accredited training programs increased from 14 to 22 and annual number of trainees increased by 28.5%. Trainees have diverse professional backgrounds and work in diverse settings but were primarily White (69.1%) and female (78.7%) located in North America. Nearly two-thirds intended to implement tobacco treatment services in their setting; two-thirds had been providing tobacco treatment for 1 year or less; and 20% were sent to training by their employers. These findings suggest that the training programs are contributing to the development of a new workforce of TTSs as well as the development of new programmatic tobacco treatment services in diverse settings. Developing strategies to support attendance from demographically and geographically diverse professionals might increase the proportion of trainees from marginalized groups and regions of the world with significant tobacco-related inequities.

Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS.

BACKGROUND: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS). METHODS: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2. RESULTS: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5. CONCLUSION: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.

Tobacco Dependence Treatment in Oncology: Initial Patient Clinical Characteristics and Outcomes from Roswell Park Comprehensive Cancer Center.

Despite the importance of smoking cessation to cancer care treatment, historically, few cancer centers have provided treatment for tobacco dependence. To address this gap, the National Cancer Institute (NCI) launched the Cancer Center Cessation Initiative (C3i). As part of this effort, this study examined implementation outcomes in a cohort of cancer survivors (CSs) who smoked cigarettes in the first year of an ongoing process to develop and implement a robust Tobacco Treatment Service at Roswell Park Comprehensive Cancer Center. We provide a comprehensive description of the new tobacco use assessment and referral process, and of the characteristics of cancer survivors who agreed to treatment including traditional tobacco-related psychosocial and cancer treatment-related characteristics and novel characteristics such as delay discounting rates. We also examine characteristic differences among those who agreed to treatment between those who attended and those who did not attend treatment. As the new tobacco assessment was implemented, the number of referrals increased dramatically. The mean number of treatment sessions attended was 4.45 (SD = 2.98) and the six-month point prevalence intention to treat abstinence rate among those who attended was 22.7%. However, only 6.4% agreed to treatment and 4% attended at least one treatment session. A large proportion of cancer survivors who agreed to treatment were women, of older age, of lower socioeconomic status (SES), and who had high levels of depressive symptomology. The findings demonstrate that the implementation of system changes can significantly improve the identification of cancer survivors who use tobacco and are referred to tobacco use treatment. Among those who attend, treatment is effective. However, the findings also suggest that a systematic assessment of barriers to engagement is needed and that cancer survivors may benefit from additional treatment tailoring. We present plans to address these implementation challenges. Systematic electronic medical record (EMR)-sourced referral to tobacco treatment is a powerful tool for reaching cancer survivors who smoke, but more research is needed to determine how to enhance engagement and tailor treatment processes.

Dosing parameters for the effects of high-frequency transcranial magnetic stimulation on smoking cessation: study protocol for a randomized factorial sham-controlled clinical trial.

BACKGROUND: Despite the considerable success of comprehensive tobacco control efforts, tobacco use remains one of the greatest preventable causes of death and disease today. Over half of all smokers in the US make quit attempts every year, but over 90% relapse within 12 months, choosing the immediate reinforcement of smoking over the long-term benefits of quitting. Conceptual and empirical evidence supports continued investigation of high frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex in reducing relapse and decreasing cigarette consumption. While this evidence is compelling, an optimal dosing strategy must be determined before a long-term efficacy trial can be conducted. The goal of this study is to determine a dosing strategy for 20 Hz rTMS that will produce the best long-term abstinence outcomes with the fewest undesirable effects. METHODS: This is a fully crossed, double-blinded, sham-controlled, 3x2x2 randomized factorial study. The three factors are duration (stimulation days: 8, 12, and 16); intensity (900 or 1800 pulses per day); and sham control. Participants (n = 258) will consist of adults (18-65) who are motivated to quit smoking cigarettes and who will be followed for 6 months post-quit. Outcomes include latency to relapse, point prevalence abstinence rates, delay discounting rates, cognitive-behavioral skills acquisition, and multiple measures of potential undesirable effects that impact participant compliance. DISCUSSION: This study integrates existing theoretical concepts and methodologies from neuropsychology, behavioral economics, brain stimulation, clinical psychology, and the evidence-based treatment of tobacco dependence in the development of a promising and innovative approach to treat tobacco dependence. This study will establish an optimal dosing regimen for efficacy testing. Findings are expected to have a significant influence on advancing this approach as well as informing future research on clinical approaches that combine rTMS with other evidence-based treatments for tobacco dependence and perhaps other addictions. TRIAL REGISTRATION: Clinical Trials NCT03865472 (retrospectively registered). The first participant was fully enrolled on November 26, 2018. Registration was posted on March 7, 2019.

Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study.

BACKGROUND: Epstein-Barr virus (EBV) infection has been associated with higher clinical activity and risk of multiple sclerosis (MS). OBJECTIVE: To evaluate associations between EBV-specific humoral response and magnetization transfer ratio (MTR)-derived measure in MS patients and healthy controls (HCs). METHODS: The study included 101 MS patients (69 relapsing-remitting multiple sclerosis (RRMS) and 32 secondary-progressive multiple sclerosis (SPMS)) and 41 HCs who underwent clinical, serological, and magnetic resonance imaging (MRI) investigations. MTR values of T1 or T2 lesion volume (LV), normal-appearing (NA) brain tissue (NABT), gray matter (NAGM), and white matter (NAWM) were obtained. Enzyme-linked immunosorbent assay was used to quantify EBV antibody levels. Partial correlations corrected for MRI strength were used, and Benjamini-Hochberg-adjusted p-values < 0.05 were considered significant. RESULTS: MS patients had significantly higher anti-EBV nuclear antigen-1 (EBNA-1) titer when compared to HCs (107.9 U/mL vs 27.8 U/mL, p < 0.001). Within the MS group, higher serum anti-EBNA-1 titer was significantly correlated with lower T1-LV MTR (r = -0.287, p = 0.035). Within the RRMS group, higher serum anti-EBNA-1 titer was associated with T1-LV MTR (r = -0.524, p = 0.001) and NAGM MTR (r = -0.308, p = 0.043). These associations were not present in HCs or SPMS patients. CONCLUSION: Greater EBV humoral response is associated with lower GM MTR changes and focal destructive lesion pathology in RRMS patients.

Aging and Brain Atrophy in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Brain atrophy accelerates at the age of 60 in healthy individuals (HI) and at disease onset in multiple sclerosis (MS) patients. Whether there is an exacerbating effect of aging superimposed on MS-related brain atrophy is unknown. We estimated the aging effect on lateral ventricular volume (LVV) and whole brain volume (WBV) changes in MS patients. METHODS: 1,982 MS patients (mean follow-up: 4.8 years) and 351 HI (mean follow-up: of 3.1 years), aged from 20 to 79 years old (yo), were collected retrospectively. Percent LVV change (PLVVC) and percent brain volume change (PBVC) on 1.5T and 3T MRI scanners (median of 3.9 scans per subject) were calculated. These were determined between all-time points and subjects were divided in six-decade age groups. MRI differences between age groups were calculated using analysis of covariance (ANCOVA). RESULTS: Compared to HI, at first MRI, MS patients had significantly increased LVV in the age groups: 30-39 yo, 40-49 yo, 50-59 yo, 60-69 yo (all P < .0001), and 70-79 yo (P = .029), and decreased WBV in the age groups: 20-29 yo (P = .024), 30-39 yo (P = .031), 40-49 yo, and 50-59 yo (all P < .0001). Annualized PLVVC was significantly different between the age groups 20-59 and 60-79 yo in MS patients (P = .005) and HI (P < .0001), as was for PBVC in MS patients (P = .001), but not for HI (P = .521). There was a significant aging interaction effect in the annualized PLVVC (P = .001) between HI and MS patients, which was not observed for the annualized PBVC (P = .380). CONCLUSIONS: Development of brain atrophy manifests progressively in MS patients, and occurs with a different pattern, as compared to aging HI. PLVVC increased across age in HI as compared to MS, while PBVC decreased across ages in both HI and MS.

Effect of Teriflunomide and Dimethyl Fumarate on Cortical Atrophy and Leptomeningeal Inflammation in Multiple Sclerosis: A Retrospective, Observational, Case-Control Pilot Study.

Background: Pathologic changes in cortical gray matter (GM) and leptomeninges contribute to disability worsening in patients with multiple sclerosis (MS), but there is little evidence whether disease-modifying treatments can slow down cortical pathology in MS. Objectives: To investigate the effect of teriflunomide (TFM) and dimethyl fumarate (DMF) in reducing cortical pathology, as determined by percentage cortical volume change (PCVC) and leptomeningeal contrast enhancement (LMCE) on MRI. Methods: This was a retrospective, single-center, observational study that selected 60 TFM- and 60 DMF-treated MS patients over 24 months. Results: TFM had a lower rate of PCVC compared to DMF over 24 months (-0.2% vs. -2.94%, p = 0.004). Similar results were observed for percentage GM volume change over 0⁻12 (p = 0.044) and 0⁻24 (-0.44% vs. -3.12%, p = 0.015) months. No significant differences were found between the TFM and DMF groups in the frequency and number of LMCE foci over the follow-up. TFM showed a numerically lower rate of whole brain atrophy over 24 months (p = 0.077), compared to DMF. No significant clinical or MRI lesion differences between TFM and DMF were detected over follow-up. Conclusions: These findings suggest that TFM has a superior effect on the preservation of cortical GM volume, compared to DMF.

Impact of fingolimod on clinical and magnetic resonance imaging outcomes in routine clinical practice: A retrospective analysis of the multiple sclerosis, clinical and MRI outcomes in the USA (MS-MRIUS) study.

BACKGROUND: The effectiveness of fingolimod on clinical and magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis (MS) has been well established in trials and, to a lesser extent, in the real world. OBJECTIVE: To evaluate clinical and MRI outcomes in patients with relapsing MS receiving fingolimod in US clinical practice. METHODS: Clinical and MRI data from 590 patients initiating fingolimod treatment at 33 MS centers in the USA were retrospectively analyzed. Clinical data were obtained from medical records. MRI data were systematically quantified at a centralized imaging facility. Patients had an index (within 6 months before and 1 month after starting fingolimod) and post-index (9-24 months after starting fingolimod) MRI scan; 184 individuals had a pre-index scan (9-24 months before starting fingolimod). RESULTS: In the index to post-index period, mean annualized relapse rates decreased from 0.36 to 0.13 and disability progression occurred in 18.5% of patients. Median T2, T1 and gadolinium-enhancing lesion volume changed by 1.15%, 2.36%, and -100% between the index and post-index scans, respectively, and median annualized percentage changes in brain volume and lateral ventricular volume were -0.32% and +0.66%, respectively. For patients with pre-index scans, MRI outcomes were unchanged or improved during treatment. Outcomes were generally comparable with those in fingolimod phase 3 trials. CONCLUSION: This real-world study highlights the effectiveness of fingolimod and the feasibility of quantifying clinical and MRI data collected from multiple centers during routine clinical practice on a group level using a systematic, quantitative methodology.