Factors associated with the initiation of high-efficacy disease-modifying agents over moderate-efficacy disease-modifying agents in multiple sclerosis.

BACKGROUND: With multiple treatment options, choosing the initial disease-modifying agent (DMA) could be crucial to managing multiple sclerosis (MS). Common treatment strategies recommend starting patients with moderate-efficacy disease-modifying agents (meDMAs), while others advocate initiating high-efficacy disease-modifying agents (heDMAs). However, limited real-world evidence exists regarding the factors associated with utilizing differing treatment strategies in the MS. OBJECTIVE: This study evaluated the factors associated with the initiation of heDMAs in comparison to meDMAs among patients with MS. METHODS: A retrospective cohort study was conducted using the Merative MarketScan Commercial Claims Database. Adult (18-64 years) MS patients with ≥1 DMA prescription were identified from 2016 to 2019. Patients were classified as incident heDMA or meDMA users based on their earliest DMA prescription, with a 12-month washout period. All covariates were measured during the 12-month baseline before the index DMA date. A multivariable logistic regression model, guided by the Andersen Behavioral Model, was applied to examine the predisposing, enabling, and need factors associated with using heDMAs over meDMAs. RESULTS: There were 10,003 eligible MS patients, with the majority of users being female (74.92 %), middle-aged adults (35-54 years, 58.97 %), and enrolled in the Preferred Provider Organization (PPO, 53.10 %) healthcare plan. Overall, 2293 (22.92 %) MS patients initiated heDMAs. The multivariable logistic regression model revealed that male patients (adjusted odds ratio [aOR]: 1.46, 95 % Confidence Interval [CI]: 1.30-1.64) had higher odds of initiating heDMAs. Meanwhile, patients with bladder dysfunction medications (aOR: 1.39, 95% CI: 1.21-1.61), fatigue medications (aOR: 1.77, 95 %CI: 1.44-2.17), and impaired walking (aOR: 1.62, 95 %CI: 1.42-1.86) were more likely to initiate treatment with heDMAs. In contrast, patients with higher Elixhauser comorbidities scores, sensory symptoms (aOR: 0.47, 95 %CI: 0.42-0.53), visual symptoms (aOR: 0.63, 95 %CI: 0.54-0.73), and brainstem symptoms (aOR: 0.81, 95 %CI: 0.67-0.97) were less likely to be prescribed with heDMAs. CONCLUSION: The study found that approximately one in four MS patients initiated heDMAs. Both demographic and clinical factors influenced the selection of heDMA. More work is needed to understand the differential value of selecting heDMAs over meDMAs for personalizing DMA treatment.

Frequency, characteristics, predictors and treatment of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have a monophasic or relapsing disease course. To date, factors that may predict a relapsing disease course remain largely unknown and only limited data exist regarding the efficacy of different utilized immunotherapy regimens at preventing or reducing relapses. OBJECTIVES: To assess the characteristics, predictors, and immunotherapy of relapsing MOGAD. METHODS: This multicenter retrospective analysis included all MOGAD cases at the University of Florida, Baylor College of Medicine and the University of California San Diego with minimum follow-up time of 6 months. Cox proportional hazards regression analyses, corrected for age and sex, were performed to evaluate hazard ratios (HR) of predictors of a relapsing disease course and to compare relapse hazards for utilized immunotherapies. RESULTS: The majority of included participants (51/79 [64.6 %]) had a relapsing course, and of these individuals, 68.6 % (35/51) experienced their first relapse within the first year. However, 10/51 (19.6 %) participants experienced their first relapse ≥5 years (5-15 years) after the initial presentation. Predictors of a relapsing course were CSF pleocytosis (>150 cells/mm3; HR 3.3 [1.18 - 9.24]; p = 0.023), a pediatric disease onset at age < 9 years (HR 2.69 [1.07-6.75]; p = 0.035), and an initial presentation with the clinical syndrome of meningoencephalitis (HR 3.42 [1.28 - 9.17]; p = 0.015),. In participants with a relapsing course, 13/24 (54.2 %) patients remained relapse-free on rituximab, 4/8 (50 %) on mycophenolate mofetil, and 11/14 (78.6 %) on scheduled immunoglobulins. Patients treated with immunoglobulins had significantly fewer relapses compared to patients treated with other immunotherapies (HR: 0.1 [0.2 - 0.63]; p = 0.014). CONCLUSIONS: In our cohort, the majority of MOGAD patients relapsed. The initial relapse occurred most frequently within the first year, but first relapses also took place over a decade after the initial presentation. Prepubertal onset, severe CSF pleocytosis, and the clinical syndrome of meningoencephalitis may be predictors of a relapsing course. Of the currently available off-label steroid-sparing treatments, scheduled immunoglobulins may be the most effective in relapse prevention.

Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis.

BACKGROUND: Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. OBJECTIVES: This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. METHODS: This retrospective observational cohort study based on the 2015-2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18-64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. RESULTS: The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1-2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. CONCLUSIONS: Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.

Assessing treatment switch among patients with multiple sclerosis: A machine learning approach.

Background: Patients with multiple sclerosis (MS) frequently switch their Disease-Modifying Agents (DMA) for effectiveness and safety concerns. This study aimed to develop and compare the random forest (RF) machine learning (ML) model with the logistic regression (LR) model for predicting DMA switching among MS patients. Methods: This retrospective longitudinal study used the TriNetX data from a federated electronic medical records (EMR) network. Between September 2010 and May 2017, adults (aged ≥18) MS patients with ≥1 DMA prescription were identified, and the earliest DMA date was assigned as the index date. Patients prescribed any DMAs different from their index DMAs were considered as treatment switch. . The RF and LR models were built with 72 baseline characteristics and trained with 70% of the randomly split data after up-sampling. Area Under the Curves (AUC), accuracy, recall, G-measure, and F-1 score were used to evaluate the model performance. Results: In this study, 7258 MS patients with ≥1 DMA were identified. Within two years, 16% of MS patients switched to a different DMA. The RF model obtained significantly better discrimination than the LR model (AUC = 0.65 vs. 0.63, p < 0.0001); however, the RF model had a similar predictive performance to the LR model with respect to F- and G-measures (RF: 72% and 73% vs. LR: 72% and 73%, respectively). The most influential features identified from the RF model were age, type of index medication, and year of index. Conclusions: Compared to the LR model, RF performed better in predicting DMA switch in MS patients based on AUC measures; however, judged by F- and G-measures, the RF model performed similarly to LR. Further research is needed to understand the role of ML techniques in predicting treatment outcomes for the decision-making process to achieve optimal treatment goals.

Comparative adherence trajectories of oral disease-modifying agents in multiple sclerosis.

STUDY OBJECTIVE: This study compared the adherence trajectories of fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users with multiple sclerosis (MS) as there is limited evidence regarding the comparative adherence patterns of different oral disease-modifying agents (DMAs). DESIGN: A retrospective cohort study DATA SOURCE: 2015-2019 IBM MarketScan Commercial Claims Database. PATIENTS: Adults (≥18 years) with MS (International Classification of Diseases [ICD]-9/10-Clinical Modification [CM]:340/G35) diagnosis and ≥1 DMA prescription. INTERVENTION: Incident FIN-, TER-, or DMF use based on the index DMA with 1 year of washout period. MEASUREMENTS: The DMA adherence trajectories based on the proportion of days covered (PDC) were examined using the Group-Based Trajectory Modeling (GBTM) one year after the treatment initiation. Generalized boosting models (GBM)-based inverse probability treatment weights (IPTW) were incorporated in multinomial logistic regression to assess the comparative adherence trajectories across oral DMAs with FIN group as a reference category. MEASUREMENTS AND MAIN RESULTS: The study cohort consisted of 1913 patients with MS who were initiated with FIN (24.2%, n = 462), TER (24.0%, n = 458), and DMF (51.9%, n = 993) during 2016-2018. The adherence rate (PDC ≥ 0.8) among FIN, TER, and DMF users was found to be 70.8% (n = 327), 59.6% (n = 273), and 61.0% (n = 606), respectively. The GBTM grouped patients into three adherence trajectories: Complete Adherers-59.1%, Slow Decliners-22.6%, and Rapid Discontinuers-18.3%. The multinomial logistic regression model involving GBM-based IPTW revealed that DMF (adjusted odds ratio [aOR]: 2.32, 95% confidence interval [CI]:1.57-3.42) and TER (aOR: 2.50, 95% CI: 1.62-3.88) users had higher odds to be rapid discontinuers relative to FIN users. In addition, TER users were more likely (aOR: 1.50, 95% CI: 1.06-2.13) to be slow decliners compared with FIN users. CONCLUSION: Teriflunomide and DMF were associated with poorer adherence trajectories than FIN. More research is needed to evaluate the clinical implications of these adherence trajectories of oral DMAs to optimize the management of MS.

Health Disparities in Multiple Sclerosis among Hispanic and Black Populations in the United States.

Multiple sclerosis (MS) is an acquired demyelinating disease of the central nervous system (CNS). Historically, research on MS has focused on White persons with MS. This preponderance of representation has important possible implications for minority populations with MS, from developing effective therapeutic agents to understanding the role of unique constellations of social determinants of health. A growing body of literature involving persons of historically underrepresented races and ethnicities in the field of multiple sclerosis is assembling. Our purpose in this narrative review is to highlight two populations in the United States: Black and Hispanic persons with multiple sclerosis. We will review the current understanding about the patterns of disease presentation, genetic considerations, response to treatment, roles of social determinants of health, and healthcare utilization. In addition, we explore future directions of inquiry as well as practical methods of meeting these challenges.

Immunopathogenesis, Diagnosis, and Treatment of Multiple Sclerosis: A Clinical Update.

Multiple sclerosis (MS) is the most prevalent nontraumatic disabling neurologic condition among young adults worldwide. The diagnosis and management of MS is complex. The goal of this review is to provide an updated and practical approach to the diagnosis and treatment approaches in MS, emphasizing current understanding of immunopathogenesis, recent advances, and future directions, for both MS and non-MS clinicians.

Health-related quality of life of patients with multiple sclerosis: Analysis of ten years of national data.

BACKGROUND: Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system. Both the physical and mental burden of MS affect patients' health-related quality of life (HRQoL). However, there is limited research at the national level evaluating the humanistic burden among MS patients. OBJECTIVES: This study evaluated the HRQoL and functional limitations among MS patients using ten years of national survey data. METHODS: Guided by the conceptual framework of the Wilson and Cleary model, this study compared HRQoL between adults diagnosed with MS (Clinical Classification Code= "080″) and non-MS adults using the 2006-2015 Medical Expenditure Panel Survey (MEPS) data. The humanistic burden included HRQoL and functional limitations. The HRQoL was evaluated using physical component summary (PCS) and mental component summary (MCS) based on the Short Form Health Survey (SF-12). The study applied the multivariable Generalized Linear Models (GLM) to estimate the marginal differences in PCS and MCS based on the SF-12. In addition, seeking help for activities of daily living (ADL) and instrumental activities of daily living (IADL) were modeled with multivariable logistic regression. RESULTS: According to the MEPS, the estimated annual prevalence of MS was 0.52 million (95% Confidence Interval [CI]: 0.42-0.60). MS patients were mainly female (71.90%), middle aged (50-64 years, 40.21%), non-Hispanic whites (78.29%), and enrolled in private insurance plans (68.93%). The average PCS scores in MS and non-MS groups were 35.70 and 49.48, respectively. The average MCS scores were 45.58 and 51.25 for MS and non-MS groups, respectively. In addition, 18.26% of MS patients sought help for ADL, and 27.08% sought help for IADL. After adjusting for individual, biological, and environmental characteristics, the multivariable GLM with Poisson distribution indicated that the marginal difference of PCS score was 11.10 (95% CI: 9.50-12.61) units lower, and the MCS score was 4.89 (95% CI: 3.44-6.30) units lower among MS patients. In addition, MS patients were 17.32 (95% CI: 11.61-25.84) and 14.43 (95% CI: 10.09-20.65) times more likely to request assistance for ADL and IADL, respectively. CONCLUSIONS: MS was associated with lower physical and mental HRQoL than their non-MS counterparts and MS patients were more likely to request help for ADL and IADL. More work is needed to evaluate the effect of treatment strategies on improving the HRQoL and functional limitations in MS.

FACTORS ASSOCIATED WITH SWITCHING FROM INJECTABLE TO ORAL DISEASE MODIFYING AGENTS AMONG PATIENTS WITH MULTIPLE SCLEROSIS.

BACKGROUND: Since the introduction of oral disease-modifying agents (DMA) in 2010, the treatment options for multiple sclerosis (MS) have changed significantly. There is limited information regarding the factors associated with switching to oral DMA among prevalent injectable DMA users. OBJECTIVE: This study evaluated the factors associated with switching to oral DMAs among prevalent injectable DMA users with MS. METHODS: A retrospective observational cohort study using the TriNetX electronic medical records (EMR) data was conducted among patients with MS. The study included prevalent injectable DMA users with at least two injectable DMA (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, or glatiramer acetate) prescription records within 6 months between September 2010 and May 2018. The second injectable DMA prescription date was considered as the index date. Switching was defined as any oral DMA prescription record (fingolimod, dimethyl fumarate, or teriflunomide) within 12 months after the index date. Patients with any infusion DMA prescription after the first injectable DMA prescription, and those less than 18 years of age were excluded from the study. The Andersen Behavioral Model was used as the conceptual framework to identify predisposing, enabling, and need factors measured during the 1-year baseline period before the index date. A multivariable logistic regression model was used to examine the predisposing (age, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, MS-related medication, and healthcare utilization) associated with switching from injectable to oral DMAs. RESULTS: Among 2,943 prevalent injectable users included in this study, 8.09% (n=238) patients switched to oral DMAs. Patients who switched to oral DMAs were primarily younger adults aged 18-44 years (64.29%), females (82.77%), had sensory and visual symptoms, and had corticosteroid utilization during the one-year look-back period compared to non-switchers. Results from multivariable logistic regression model revealed that middle-aged adults (45-64 years, adjusted odds ratio [aOR]: 0.43, 95% Confidence Interval [CI]: 0.32-0.58), old adults (≥65 years, aOR: 0.30, 95% CI: 0.13-0.66) and men (aOR: 0.67, 95% CI: 0.47-0.96) were associated with decreased odds of switching to oral DMAs. Presence of MS-related sensory symptoms (aOR: 1.52, 95% CI: 1.07-2.16), visual symptoms (aOR: 1.59, 95% CI: 1.10-2.31), and corticosteroids usage (aOR: 1.44, 95% CI: 1.04-1.98) were associated with increased odds of switching to oral DMAs. CONCLUSION: The study found that about one in twelve prevalent injectable DMA users switched to oral DMA. Both demographic and clinical factors were associated with switching to oral DMAs. Further research is needed to evaluate the outcomes of switching to inform treatment decisions for MS management.

Prescribing of disease modifying agents in older adults with multiple sclerosis.

BACKGROUND: The use of disease-modifying agents (DMAs) to treat Multiple Sclerosis (MS) in older adults is debated as the disease activity decreases with aging. However, limited data exist regarding prescribing patterns of DMAs among older adults with MS. OBJECTIVE: To examine prescribing patterns of DMAs and the factors associated with DMA prescribing practices among older adults with MS using electronic medical records (EMR) data. METHODS: A retrospective longitudinal cohort study was conducted using the TriNetX, a federated EMR network from the US, data from 2016 to 2019. The study included older adults (≥60 years) with MS diagnosis and at least one prescription record during the study period. Patients with DMA prescriptions were identified and further classified into injectable, oral, or infusion users based on their last DMA prescription. A multivariable logistic regression model was used to evaluate the factors associated with prescribing of DMAs. A multinomial logistic regression model was also used to determine the factors associated with prescribing a particular dosage form of DMA. RESULTS: The study cohort consisted of 12,922 older adults with MS, with 2,455 (18.99%) receiving DMA prescriptions. The commonly prescribed DMAs were injectables (10.46%), followed by orals (6.06%) and infusions (2.40%). Multivariable logistic regression revealed that older adults between 60- to 64 years (Adjusted Odds Ratio [aOR]= 2.38) and 65-69 years (aOR=1.60) had higher odds of receiving DMA compared to older adults of 70 years and above. African Americans (aOR=1.71) had higher odds of receiving DMA prescriptions compared to Caucasians. The presence of symptoms (pain, fatigue, speech, walking difficulty) and use of symptomatic medication (anti-fatigue medication, bladder dysfunction medication, antispasmodics, antidepressants, and relapse medication) increased the odds of being prescribed DMAs. Multinomial logistic regression found that patients 60-64 years of age had higher odds of being prescribed infusion (aOR, 95% Confidence Interval [CI] =2.06, 1.35-3.15) and oral (65-69 years: aOR=1.60, 1.24-2.07) over injectable DMAs compared to the older adults aged 70 years and above.Older males (aOR=1.68, 95% CI: 1.23-2.30) were associated with increased odds of being prescribed infusion DMA over injectable DMA compared to females. The presence of comorbidities such as coagulopathy and peripheral vascular disorders decreased the odds of being prescribed oral DMA over injectable DMA. Patients with cerebellar symptoms had an increased likelihood of being prescribed with an infusion DMA over injectable DMA. Patients using drugs for treating relapses had higher odds of being prescribed an infusion DMA over an injectable DMA. In terms of healthcare utilization, older adults with outpatient visits had higher odds of being prescribed an infusion DMA over an injectable DMA, while older adults with inpatient visits had lower odds of being prescribed an infusion DMA over an injectable DMA. CONCLUSION: Nearly one in five older adults with MS are prescribed DMAs, with a majority receiving injectable DMAs. Several demographic and clinical factors were associated with DMA prescribing . This study fills the data gap regarding the utilization of DMAs in older adults with MS.

Elsberg syndrome following acute immunosuppressive treatment for multiple sclerosis relapse.

First described more than 80 years ago, Elsberg Syndrome (ES) continues to be an under-recognized cause of cauda equina syndrome (CES). ES is an infectious disorder that presents with lower thoracic and/or lumbosacral myelitis in conjunction with CES, and most often occurs in the setting of herpes simplex virus 2 (HSV-2) reactivation (Savoldi et al., 2017; Eberhardt et al., 2004; Whalen et al., 2019). Comorbid neurologic diseases like multiple sclerosis (MS) can become a detrimental confounding factor leading to delayed diagnosis and management of ES due to pre-existing diagnostic bias. We present a case of relapsing-remitting MS (RRMS) complicated by ES, likely due to reactivation of a latent HSV infection following high immunosuppression for presumed refractory MS relapses.

Clinical Reasoning: A 57-Year-Old Man With Stepwise Progressive Paraparesis, Sensory Loss, Urinary Retention, and Constipation.

We present the case of a 57-year-old man with protein S deficiency and left leg deep vein thrombosis (DVT) 5 years earlier, who developed stepwise progressive bilateral lower limb weakness, numbness/paresthesia, gait imbalance, hesitancy of micturition, and constipation in the setting of recurrent left common femoral DVT treated with apixaban. Symptoms amplified with Valsalva, corticosteroids, and postlumbar puncture, with longitudinally extensive midthoracic T2-hyperintense lesion extending to the conus associated with hazy holocord enhancement on magnetic resonance imaging (MRI), raising suspicion for spinal dural arteriovenous fistula (sDAVF). Initial digital subtraction angiography (DSA) was negative for sDAVF. However, cerebral spinal fluid (CSF) was herpes simplex virus (HSV)-2 positive, and he was treated with antiviral therapy. Unfortunately, he continued to worsen despite treatment. Repeat neuroimaging 12 months after initial presentation demonstrated persistent lower thoracic/conus lesion in addition to cauda equina enhancement and subtle dorsal T2-hypointense flow voids. We raised red flags (e.g., lack of clinical prodrome, no herpetic rash, no CSF pleocytosis, and rostral extent of the lesion) that suggested the HSV2 nucleic acid detection was perhaps unrelated to the neurologic syndrome. Given the high index of suspicion for sDAVF, we repeated spinal vascular imaging. Spinal MRA demonstrated dilated right dorsal perimedullary veins from T10 to T11. Repeat DSA revealed a right T10 sDAVF. Microsurgical treatment rather than embolization of the fistula was successful without complication, with significant improvement in motor, sphincter, and to a lesser extent sensory function, with residual gait imbalance after inpatient rehabilitation 3 weeks postoperatively.

Brain volume change after high-dose immunosuppression and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis.

BACKGROUND: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of whole-brain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT. METHODS: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a two-piecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up. RESULTS: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not. CONCLUSIONS: BVL may accelerate for months after HDIT/HCT. However, over the long-term, adequate HDIT/HCT may reduce BVL rates to those similar to normal aging at the WB level.

Fingolimod-related cryptococcal meningoencephalitis and immune reconstitution inflammatory syndrome in a patient with multiple sclerosis.

Fingolimod is an oral medication for multiple sclerosis that sequesters certain subsets of lymphocytes in lymph nodes, reducing egress into blood and their subsequent CNS migration. The initial multi-site randomized Phase III controlled trials found rates of infection similar to those in control groups. However, post-marketing surveillance has revealed an association with several opportunistic infections, including cryptococcosis. We report a case of fingolimod-related cryptococcal meningoencephalitis and IRIS after drug discontinuation and suggest a surveillance and risk mitigation strategy.

The concurrence of multiple sclerosis and glioblastoma.

INTRODUCTION: Glioblastoma rarely coincides with multiple sclerosis. Although registries have reported a higher proportion of brain tumors-most of which are glial-these events appear to be underreported. The relative contribution of JC virus (an oncogenic virus) and disease modifying therapies that may facilitate JC virus neurotropism and tumor-specific immune evasion remain unknown. CASE REPORT: We present the case of a 64-year-old woman who developed a primary glioblastoma eight years after diagnosis of multiple sclerosis while on dimethyl fumarate. CONCLUSION: Systematic reporting may help answer whether JC virus seropositivity and certain disease modifying therapies confer higher risk for glioblastoma in patients with multiple sclerosis.

Comparative treatment effectiveness of oral fingolimod and conventional injectable disease-modifying agents in multiple sclerosis.

STUDY OBJECTIVE: To compare the effectiveness of oral fingolimod and conventional injectable disease-modifying agents (DMAs) using the composite endpoint of relapse or DMA treatment switch in patients with multiple sclerosis (MS). DESIGN: A retrospective longitudinal cohort study. DATA SOURCE: IBM MarketScan Commercial Claims and Encounters Database from 2010-2012. PATIENTS: Adults (≥18 years) with MS diagnosis (ICD-9-CM:340) who newly initiated DMAs. INTERVENTION: Oral fingolimod and conventional injectable DMAs (interferon beta and glatiramer acetate). MEASUREMENTS: Composite endpoint of time to relapse or DMA treatment switch. MAIN RESULTS: The incident study cohort consisted of 1997 MS patients who initiated oral fingolimod (15.6%) or injectable (84.4%) DMAs. The proportion of patients who had a composite endpoint (relapse/DMA treatment switch) in oral fingolimod and injectable DMA users was found to be 16.72% and 27.16%, respectively. The Cox PH regression model with stabilized IPTW revealed that fingolimod is equally effective as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint of relapse or DMA switch (adjusted hazard ratio [aHR]: 0.67, 95% CI: 0.43-1.03). Additional analysis among patients who were adherent also found no significant difference in the composite endpoint (aHR: 0.70, 95% CI 0.49-1.15) between oral fingolimod and injectable DMA users. CONCLUSIONS: Oral fingolimod has similar effectiveness as conventional injectable DMAs in reducing the risk of experiencing the composite endpoint (relapse or DMA treatment switch). In addition, when assessed independently, oral fingolimod showed no difference in reducing the time to relapse or DMA treatment switch compared to injectable DMAs.

Factors associated with oral fingolimod use over injectable disease- modifying agent use in multiple sclerosis.

Background: Fingolimod is the first approved oral disease-modifying agent (DMA) in 2010 to treat Multiple Sclerosis (MS). There is limited real-world evidence regarding the determinants associated with fingolimod use in the early years. Objective: The objective of this study was to examine the factors associated with fingolimod prescribing in the initial years after the market approval. Methods: A retrospective, longitudinal study was conducted involving adults (≥18 years) with MS from the 2010-2012 IBM MarketScan. Individuals with MS were selected based on ICD-9-CM: 340 and a newly initiated DMA prescription. Based on the index/first DMA prescription, patients were classified as fingolimod or injectable users. All covariates were measured during the six months baseline period prior to the index date. Multivariable logistic regression was performed to determine the predisposing, enabling, and need factors, conceptualized as per the Andersen Behavioral Model (ABM), associated with prescribing of fingolimod versus injectable DMA for MS. Results: The study cohort consisted of 3118 MS patients receiving DMA treatment. Of which, 14.4% of patients with MS initiated treatment with fingolimod within two years after the market entry, while the remaining 85.6% initiated with injectable DMAs. Multivariable regression revealed that the likelihood of prescribing oral DMA increased by 2-3 fold during 2011 and 2012 compared to 2010. Patients with ophthalmic (adjusted odds ratio [aOR]-2.60), heart (aOR-2.21) and urinary diseases (aOR-1.37) were more likely to receive fingolimod. Patients with other neurological disorders (aOR-0.50) were less likely to receive fingolimod than those without neurological disorders. Use of symptomatic medication (for impaired walking (aOR-2.60), bladder dysfunction (aOR-1.54), antispasmodics (aOR-1.48), and neurologist consultation (aOR-1.81) were associated with higher odds of receiving fingolimod. However, patients with non-MS associated emergency visits (aOR-0.64) had lower odds of receiving fingolimod than those without emergency visits. Conclusions: During the initial years after market approval, patients with highly active MS were more likely to receive oral fingolimod than injectable DMAs. More research is needed to understand the determinants of newer oral DMAs.

Multiple Sclerosis in a Multi-Ethnic Population in Houston, Texas: A Retrospective Analysis.

Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. In addition to differences in incidence, African American (AA) and Hispanic patients have greater disease burden and disability in earlier stages of disease compared to White patients. To further characterize MS in AA and Hispanic populations, we conducted a retrospective chart analysis of 112 patients treated at an MS center in Houston, Texas. Here, we describe similarities and differences in clinical presentation, MRI findings, treatment regimens, disability progression, and relapse rate. While we found several similarities between the groups regarding mean age, disability severity, and degree of brain atrophy at diagnosis, we also describe a few divergences. Interestingly, we found that patients who were evaluated by a neurologist at symptom onset had significantly decreased odds of greater disability [defined as Expanded Disability Status Scale (EDSS) > 4.5] at last presentation compared to patients who were not evaluated by a neurologist (OR: 0.04, 95% CI: 0.16-0.9). We also found that active smokers had significantly increased odds of greater disability both at diagnosis and at last clinical encounter compared to nonsmokers (OR: 2.44, 95% CI: 1.10-7.10, OR= 2.44, 95% CI: 1.35-6.12, p = 0.01, respectively). Additionally, we observed significant differences in treatment adherence between groups. Assessment of the degree of brain atrophy and progression over time, along with an enumeration of T1, T2, and gadolinium-enhancing brain lesions, did not reveal differences across groups.

Comparative Adherence Trajectories of Oral Fingolimod and Injectable Disease Modifying Agents in Multiple Sclerosis.

BACKGROUND: Oral fingolimod is convenient to use than injectable disease modifying agents (DMAs) in patients with multiple sclerosis (MS). However, the existing literature regarding the comparative adherence trajectories between oral fingolimod and injectable DMAs is limited. OBJECTIVE: To compare the adherence trajectories between oral DMA, fingolimod, and injectable DMAs in patients with MS. METHODS: A retrospective longitudinal study was conducted using adults (≥18 years) with MS (ICD-9-CM: 340 and a DMA prescription) from the IBM MarketScan Commercial Claims and Encounters Database between 2010 and 2012. Patients were grouped into oral fingolimod or injectable DMA users based on the index DMA among patients with MS. The annual DMA adherence trajectories, based on the proportion of days covered (PDC), were examined using group-based trajectory modeling (GBTM) during the one-year follow-up period after treatment initiation. Multivariable multinomial logistic regression using stabilized inverse probability treatment weights (IPTW) was performed to assess the association between the DMA route of administration (Oral vs Injectable) and the adherence trajectory groups. The balance of covariates between oral and injectable DMAs before and after IPTW was checked against a standardized difference threshold of 0.25. RESULTS: The study cohort consisted of 1,700 MS patients who were initiated with oral (15.8%) or injectable (84.2%) DMAs between 2010 and 2012. The adherence rates (PDC≥0.8) in oral fingolimod and injectable DMA users were found to be 64.7% and 50.8%, respectively. The GBTM grouped individuals in the study cohort into three adherence trajectories - rapid discontinuers (23.5%), complete adherers (49.9%), and slow decliners (26.6%). The multinomial logistic regression model with stabilized IPTW revealed that oral fingolimod users had higher odds to be a complete adherer (adjusted odds ratio [AOR]: 2.78, 95% CI: 1.85-4.16) or a slow discontinuer (AOR: 2.62, 95% CI: 1.70-4.05) than injectable DMA users. CONCLUSIONS: Oral DMA fingolimod was associated with better adherence than injectable DMAs across group-based trajectories. Further research is warranted to evaluate the adherence trajectories with newer oral DMAs introduced in the last decade for MS.

Factors Associated with Prescribing Oral Disease Modifying Agents in Multiple Sclerosis: a Real-world Analysis of Electronic Medical Records.

BACKGROUND: Little is known about the factors associated with the selection of Disease Modifying Agents (DMA) for the management of Multiple Sclerosis (MS) since the introduction of oral DMAs in 2010. OBJECTIVES: To examine the factors associated with initiation of oral DMAs in patients with MS using data from electronic medical records (EMR). METHODS: A retrospective longitudinal study was conducted using TriNetX, a federated EMR network of over 38 million patients from the US, from 2009-2019. Adult (≥18 years) patients with MS from the United States were identified using a MS diagnosis (ICD-9-CM: 340 or ICD-10-CM: G35) and a newly prescribed DMA with a one-year baseline period. Patients with new DMA prescriptions were classified as oral or injectable users based on their index medication. A multivariable logistic regression model was used to determine the predisposing (age category, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, symptomatic medication, and healthcare utilization) associated with initiation of an oral versus injectable DMA. RESULTS: The study cohort consisted of 7,511 MS patients with a newly prescribed DMA, of whom most were 18-44 years old (48.33%), female (75.18%), and white (80.92%). About 42.32% of MS patients were diagnosed with at least one comorbidity (mean±SD: 0.86±1.37). Two thirds (66.32%) of the patients with MS started injectable DMAs, and the remaining one third (33.68%) started oral DMAs. Multivariable regression revealed that middle-aged (45-64 years; Adjusted Odds Ratio [aOR]=0.88; 95% Confidence Interval [CI]: 0.79-0.98) and older adults (≥65 years; aOR=0.67, 95% CI: 0.53-0.84) were associated with a decreased likelihood of receiving oral DMAs. The presence of general symptoms (aOR=1.26, 95% CI: 1.10-1.45) and cerebellar symptoms (aOR=1.56, 95% CI: 1.26-1.93) was associated with an increased likelihood of an oral DMA. However, the presence of sensory symptoms (aOR: 0.72, 95% CI: 0.59-0.88) was associated with a decreased likelihood of an oral DMA. Comorbidities such as renal failure (aOR=0.16, 95%% 0.04-0.62), obesity (aOR=0.60, 95% CI: 0.45-0.80), drug abuse (aOR=0.61, 95% CI: 0.38-0.99), and other neurological disorders (aOR=0.82, 95% CI: 0.69-0.96) were associated with a decreased likelihood of receiving an oral DMA prescription. While the use of analgesics (aOR=0.78, 95% CI: 0.69-0.88) was associated with decreased likelihood, the use of antispasmodics (aOR=1.14, 95% CI: 1.01-1.28) was associated with an increased likelihood of receiving an oral DMA. Relative to the time-period when first oral DMAs entered into the market (2010-11), with time, the likelihood of prescribing oral DMA increased by multiple folds (2012-13, aOR=4.30, 95% CI: 3.08-6.00; 2014-15, aOR=19.34, 95% CI: 14.10-26.54; 2016-17, aOR=17.63, 95% CI: 12.76-24.35; and 2018-19, aOR=20.73, 95% CI: 14.64-29.37). CONCLUSIONS: Oral DMA use steadily increased over the years, with one in three MS patients receiving oral agents. Both demographic and clinical factors were associated with the initiation of oral DMA over injectable DMA.