Multiple environmental factors, but not nutrient addition, directly affect wet grassland soil microbial community structure: a mesocosm study.

Nutrient addition may change soil microbial community structure, but soil microbes must simultaneously contend with other, interacting factors. We studied the effect of soil type (peat, mineral), water level (low, high), and nutrient addition (unfertilized, fertilized) on wet grassland soil microbial community structure in both vegetated and un-vegetated soils after five years of treatment application in a mesocosm, using Illumina sequencing of the bacterial V4 region of the small ribosomal sub-units. Soil type, water level, and plant presence significantly affected the soil microbial structure, both singly and interactively. Nutrient addition did not directly impact microbiome structure, but acted indirectly by increasing plant biomass. The abundance of possible plant growth promoting bacteria and heterotrophic bacteria indicates the importance of bacteria that promote plant growth. Based on our results, a drier and warmer future would result in nutrient-richer conditions and changes to microbial community structure and total microbial biomass and/or abundances, with wet grasslands likely switching from areas acting as C sinks to C sources.

Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age.

BACKGROUND: Multiple sclerosis (MS) patients with stable disease course might view continued treatment as unnecessary. However, guidelines regarding treatment discontinuation are currently lacking. OBJECTIVE: To assess the clinical course after treatment discontinuation in MS patients with long disease duration. METHODS: Patients who discontinued disease-modifying treatments (DMTs) and not resume treatment (n = 216) were extracted from New York State MS Consortium (NYSMSC) and followed across three time points (average 4.6 years). Stable course was defined as no change in Expanded Disability Status Scale (EDSS) scores (<1.0 increase if EDSS<6.0 or <0.5-point increase if EDSS≥6.0) from baseline (time 1) to DMT discontinuation (time 2). Both stable and worsening MS patients were later assessed again after the DMT discontinuation (time 3). Additional analyses were performed based on disease subtype, type of medication, age cut-off of 55 and EDSS of 6.0. RESULTS: From the cohort of 216 MS patients who discontinued DMT, 161 (72.5%) were classified as stable before DMT discontinuation. After DMT discontinuation, 53 previously stable MS patients (32.9%) experienced disability worsening/progression (DWP). 29.2 and 40% of previously stable RRMS and SPMS respectively had DWP after DMT discontinuation. Over two years after DMT discontinuation, the rate of DWP was similar between patients younger or older than 55 years (31.1% vs 25.9%, respectively). MS patients with EDSS≥6.0 had greater DWP when compared to less disabled patients while remaining on therapy as well as after discontinuation (40.7% vs 15.4%, p < 0.001 and 39.6% vs 15.2%, p < 0.001, respectively). CONCLUSION: MS patients with stable disease course experience DWP after treatment discontinuation, with no clear relation to age and disease subtype. Patients with EDSS≥6.0 are at higher risk for DWP.

COVID-19 mRNA vaccination leading to CNS inflammation: a case series.

The availability of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), provides hope towards mitigation of the coronavirus disease 2019 (COVID-19) pandemic. Vaccine safety and efficacy has not been established in individuals with chronic autoimmune diseases such as multiple sclerosis (MS). Anecdotal reports suggest that the vaccines may be associated with brain, spinal cord, peripheral nervous system, and cardiac inflammation. Based on the high morbidity and unpredictable course of COVID-19, and the need to achieve herd immunity, vaccination has been recommended for patients with MS. We report clinical and MRI features of seven individuals who received the Moderna (n = 3) or Pfizer (n = 4) SARS-CoV-2 mRNA vaccines. Within one to 21 days of either the first (n = 2) or second (n = 5) vaccine dose, these patients developed neurologic symptoms and MRI findings consistent with active CNS demyelination of the optic nerve, brain, and/or spinal cord. Symptoms included visual loss, dysmetria, gait instability, paresthesias, sphincter disturbance, and limb weakness. Age ranged from 24 to 64 (mean 39.1) years; five were woman (71.4%). The final diagnosis was exacerbation of known stable MS (n = 4, two were receiving disease-modifying therapy at the time of vaccination), new onset MS (n = 2), or new onset neuromyelitis optica (n = 1). All responded to corticosteroid (n = 7) or plasma exchange (n = 1) therapy, with five returning to baseline and two approaching baseline. Large prospective studies are required to further investigate any possible relationship between COVID-19 vaccines and acute CNS demyelination.

Exacerbation of Multiple Sclerosis by BRAF/MEK Treatment for Malignant Melanoma: The Central Vein Sign to Distinguish Demyelinating Lesions From Metastases.

The emergence of immunomodulators as effective cancer treatments has been an important advance in cancer therapy. The combination therapy of BRAF/MEK inhibition with or without anti-CTLA-4 treatment causes an immunostimulatory effect that has greatly reduced death from melanoma. In this article, we present the case of a patient with prior multiple sclerosis (MS) and who later developed metastatic malignant melanoma, had a marked increase of magnetic resonance imaging (MRI) findings after treatment with the combination of trametinib (MEK) and dabrafenib (BRAF), diagnostic question of metastatic disease versus new MS lesions without brain biopsy is discussed. A healthy 49-year-old man was diagnosed with MS in October 2012. He was stable with an oral disease modifying drug until March of 2016 when the patient discovered a lump in his right groin. Biopsy was positive for S100 and BRAF V600 mutation. Combination MEK/BRAF was given and after immunotherapy an MRI showed 25 new gadolinium-enhancing lesions thought to be metastases. A brain biopsy was recommended but neurology and neuroimaging consultation showed that the MRI was consistent with demyelination (oval/ovoid, homogeneous and open-ring enhancement, and predominance of the central vein sign within lesions) rather than metastasis. Treatment for MS has been successful and there has been no return of his melanoma in 4 years. New immunotherapies are lifesaving but the modulation of the immune system can cause unpredictable events such are markedly increased MS activity. The awareness of the diagnostic value of the central vein sign provided a better outcome for this patient and could be a model in the future for others.

A pharmacokinetic and biomarker study of delayed-release dimethyl fumarate in subjects with secondary progressive multiple sclerosis: evaluation of cerebrospinal fluid penetration and the effects on exploratory biomarkers.

BACKGROUND: Biomarkers are a useful and reliable measure of disease activity in many fields of medicine. Axonal and glial biomarkers in multiple sclerosis (MS) are being applied more often as technology is improving and becoming increasingly reliable. Nonclinical studies have shown dimethyl fumarate (DMF) to have cytoprotective and anti-inflammatory effects. The purpose of this study is to explore the pharmacokinetics (PK) of DMF (by measuring MMF, the active compound) in serum and cerebrospinal fluid (CSF) as well as relevant biomarker data for patients with secondary progressive MS (pwSPMS) and whether there is objective evidence for neuroprotection in pwSPMS treated with DMF. METHODS: Sixteen pwSPMS had serum and cerebrospinal fluid (CSF) evaluation for PK studies levels of MMF at various time points after ingestion of DMF. The CSF biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxyo-terminal hydrolase isozyme L1 (UCH-L1) and total tau (T-tau) were measured at baseline, week 6 and week 28 after initiating DMF with a starting dose of 120 mg twice daily for 4 weeks, followed by a maintenance dose of 240 mg twice daily. Clinical correlation of these patients with EDSS and MRI at these same time periods were made with the biomarkers. Four normal human volunteers had CSF studies for biomarkers at baseline. RESULTS: PK data showed CSF MMF concentration 11% of plasma with Tmax of plasma at 5 hr and Tmax of CSF at 7 hr. Biomarker data showed that CS NfL and to a lesser extent, GFAP, but not UCH-L1 nor T-tau showed relevant changes with clinical data. Some pwSPMS receiving DMF showed clinical improvements in Expanded Disability Status Scale (EDSS). Biomarker changes, but not MRI, correlated with clinical measures in this group of pwSPMS over the observation period. CONCLUSIONS: PK data showed that the Tmax of CSF MMF peaked only 2 hours later than that of plasma with 11% measured in the CSF so that MMF readily crossed the blood brain barrier allowing potential direct penetration into the brain. NfL CSF levels, and to a lesser extent, GFAP CSF levels, showed correlation to disease activity in pwSPMS . These data suggest that DMF may have some benefit in reducing disease activity in pwSPMS if studied for a longer duration and larger well-controlled studies are warranted. DMF was reasonably well tolerated but 3 of the 16 patients did discontinue DMF at 6 weeks due to persistent side effects. NfL appeared to be more clinically relevant biomarker than brain MRI in this this group during the 28-week study period.

Manifestations and impact of the COVID-19 pandemic in neuroinflammatory diseases.

OBJECTIVE: To report initial results of a planned multicenter year-long prospective study examining the risk and impact of COVID-19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). METHODS: In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID-19 in persons with NID (PwNID) and change in their neurological care. RESULTS: Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj  = 1.45, 1.17-1.84). INTERPRETATIONS: Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID-19 similar to the reference population.

Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis.

BACKGROUND: In this pooled, post hoc analysis of a phase 2 trial and the phase 3 TEMSO, TOWER, and TENERE clinical trials, long-term efficacy and safety of teriflunomide were assessed in subgroups of patients with relapsing multiple sclerosis (MS) defined by prior treatment status. METHODS: Patients were classified according to their prior treatment status in the core and core plus extension periods. In the core period, patients were grouped according to treatment status at the start of the study: treatment naive (no prior disease-modifying therapy [DMT] or DMT > 2 years prior to randomization), previously treated with another DMT (DMT > 6 to ≤24 months prior to randomization), and recently treated with another DMT (DMT ≤6 months prior to randomization). In the core plus extension period, patients were re-baselined to the time of starting teriflunomide 14 mg and grouped according to prior treatment status at that time point. Efficacy endpoints included annualized relapse rate (ARR), probability of confirmed disability worsening (CDW) over 12 weeks, and Expanded Disability Status Scale (EDSS) score. The incidence of adverse events was also assessed. RESULTS: Most frequently received prior DMTs at baseline were glatiramer acetate and interferon beta-1a across treatment groups. Teriflunomide 14 mg significantly reduced ARR versus placebo in the core period, regardless of prior treatment status. In the core and extension periods, adjusted ARRs were low (0.193-0.284) in patients treated with teriflunomide 14 mg across all subgroups. Probability of CDW by Year 4 was similar across subgroups; by Year 5, the percentage of patients with 12-week CDW was similar in treatment-naive patients and patients recently treated with another DMT (33.9 and 33.7%, respectively). EDSS scores were stable over time in all prior-treatment subgroups. There were no new or unexpected safety signals. Limitations include selective bias due to patient attrition, variability in subgroup size, and lack of magnetic resonance imaging outcomes. CONCLUSIONS: The efficacy and safety of teriflunomide 14 mg was similar in all patients with relapsing MS, regardless of prior treatment history. TRIAL REGISTRATION: Phase 2 trial core: NCT01487096 ; Phase 2 trial extension: NCT00228163 ; TEMSO core: NCT00134563 ; TEMSO extension: NCT00803049 ; TOWER: NCT00751881 ; TENERE: NCT00883337 .

Efficacy and Safety of Alemtuzumab in Patients of African Descent with Relapsing-Remitting Multiple Sclerosis: 8-Year Follow-up of CARE-MS I and II (TOPAZ Study).

INTRODUCTION: Multiple sclerosis (MS) patients of African descent have increased risk for disease progression and may be less responsive to disease-modifying therapy. METHODS: Patients in the CARE-MS studies received alemtuzumab 12 mg/day [initial alemtuzumab treatment (IAT); baseline: 5 days; 12 months later: 3 days] or subcutaneous interferon beta-1a (SC IFNB-1a) 3 ×/week. Core study outcomes were compared between treatment groups. In the extension study CAMMS03409, SC IFNB-1a-treated patients switched to alemtuzumab [delayed alemtuzumab treatment (DAT)]. Data from IAT and DAT arms were pooled to assess outcomes through 6 years post alemtuzumab initiation; IAT patients had an additional 2 years of follow-up in TOPAZ. RESULTS: Of 1200 CARE-MS patients, 43 (4%) were of African descent (35 IAT; 8 DAT) and received alemtuzumab in the 2-year core and/or 6-year extension; 29 (67%) remained on study at the time of analysis (24 IAT patients completed year 8 post alemtuzumab; 5 DAT patients completed year 6 post alemtuzumab). In year 2, annualized relapse rate (ARR; 0.09 versus 0.42), percentage of patients with improved Expanded Disability Status Scale (EDSS; 18% versus 11%), 6-month confirmed disability improvement (CDI; 28% versus 13%), no evidence of disease activity (55% versus 13%), and cumulative brain volume loss (BVL; - 0.55% versus - 1.32%) favored alemtuzumab versus SC IFNB-1a. Alemtuzumab remained efficacious at year 6 (pooled IAT/DAT) and at year 8 (IAT only) post alemtuzumab (ARR: 0.15 and 0.30; improved EDSS: 17% and 25%; CDI: 47% and 55%; BVL: - 1.14% and - 0.70%, respectively). No safety signals were unique to this population. CONCLUSIONS: Alemtuzumab was efficacious in a small cohort of relapsing-remitting MS patients of African descent over 8 years. Safety was consistent with the overall CARE-MS population, although the small sample size may have prevented the detection of known low-frequency adverse events. CLINICALTRIALS. GOV REGISTRATION NUMBERS: CARE-MS I, II, extension, TOPAZ: NCT00530348, NCT00548405, NCT00930553, NCT02255656. FUNDING: Sanofi (Cambridge, MA, USA) and Bayer HealthCare Pharmaceuticals (Leverkusen, Germany).

Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis. METHODS: We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18-58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148. FINDINGS: Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment. INTERPRETATION: Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose. FUNDING: Biogen.

Teriflunomide real-world evidence: Global differences in the phase 4 Teri-PRO study.

BACKGROUND: The demographics and management of patients with multiple sclerosis (MS) differ across geographical regions, but it is unclear whether/how these differences affect treatment outcomes. The aim of this post-hoc analysis was to assess teriflunomide use and patient-reported outcomes in the United States (US) and the rest of the world (ROW) in the phase 4 Teri-PRO study (NCT01895335). METHODS: In the phase 4, real-world, Teri-PRO study, patients with relapsing forms of MS received teriflunomide for 48 weeks according to local labeling. The primary endpoint was treatment satisfaction measured using the Treatment Satisfaction Questionnaire for Medication Version 1.4 (TSQM 1.4). Secondary endpoints included scores on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Performance Scale (MSPS), and Patient-Determined Disease Steps (PDDS), and occurrence of adverse events. Primary and secondary endpoints were assessed at baseline and Week 48. An exploratory subgroup analysis assessed PROs in the black patient population. RESULTS: The US and ROW groups included 545 and 455 patients, respectively. The mean age of patients in the ROW group was lower, they had a shorter mean time since first symptoms of MS, and had lower mean EDSS scores at baseline, compared with the US group (all p < 0.0001). Black patients made up 9% of US patients vs 0.2% of ROW patients. TSQM global satisfaction scores and effectiveness, side effects, and convenience subscale scores were significantly improved from baseline to Week 48 (all p < 0.0001). Disability measures were stable from baseline to Week 48 for both groups, despite different baseline level scores between the two groups. The overall proportion of patients who experienced an AE was similar across both groups. Fewer patients in the US group vs the ROW group reported hair thinning (16.1% vs 31.2%). Black patients showed comparable baseline demographics and disease characteristics and similar change over time in PROs compared with the overall US group. CONCLUSION: Patient differences observed at baseline between the US and ROW groups suggest variation in teriflunomide prescribing practices in the real-world Teri-PRO study. Improvement in treatment satisfaction and stability of disability measures were comparable between patients in the US and ROW. This suggests that teriflunomide was effective despite differences in baseline demographics and possible cultural and management differences between these geographical regions.

Neurofilament light chain as an indicator of exacerbation prior to clinical symptoms in multiple sclerosis.

BACKGROUND: Biomarkers may be a sensitive measure of disease activity in patients with multiple sclerosis (pwMS). OBJECTIVE: A pwMS had a marked increase of neurofilament light chain (NfL) in CSF 9-weeks prior to a clinical exacerbation. METHODS AND RESULTS: Brain MRI, CSF, EDSS were measured at baseline, 6 weeks and 28 weeks. The patient had an exacerbation at week 15 of study but the NfL measured at week 6 were found to show a nearly 3-fold increase of CSF NfL levels prior to symptoms when the NfL levels were later measured. CONCLUSION: This is an example supporting the usefulness of NfL in monitoring disease activity in pwMS which may predict disease activity prior to a clinical exacerbation.

Morphology and genetics of Lythrum salicaria from latitudinal gradients of the Northern Hemisphere grown in cold and hot common gardens.

The aim of this project was to compare the phenotypic responses of global populations of Lythrum salicaria in cold/dry and hot/humid environments to determine if phenotypic plasticity varied between the native and invasive ranges, and secondarily if this variation was linked to genetic diversity. Common garden studies were conducted in Trebon, Czech Republic, and Lafayette, Louisiana, USA (cold/dry vs. hot/humid garden, respectively), using populations from latitudinal gradients in Eurasia and North America. Lythrum salicaria seeds collected from the same maternal plants across these latitudinal gradients were germinated and grown in Trebon and Lafayette. Tissue masses (above-, below-ground, inflorescence and total) of these individuals were assessed at the end of each growing season (2006-2008). Worldwide field measurements of L. salicaria height were made by volunteers from 2004-2016. Biomass and height data were analyzed using the General Linear Model framework and multivariate techniques. Molecular markers (amplified fragment length polymorphisms) of individuals used in the common garden study were analyzed using traditional genetic diversity metrics and Bayesian clustering algorithms in STRUCTURE. Reaction norms were developed from differences in maternal plant responses in Trebon versus Lafayette. In the common garden studies, stem/leaf, root and total biomass generally were highest for individuals grown from seeds collected in the southern part of the range in the cold garden, particularly by the third year of the study. In contrast, inflorescence biomass in the cold garden was higher by the third year in individuals from mid-latitude populations. As measured by volunteers, plants were taller in Eurasia than in North America moving from north to south with the pattern switching southward of 40°N latitude. Genetic diversity was similar between native and non-native invasive populations regardless of geographical origin of the seed and was not significantly different in the GLM Select model (p > 0.05). Reaction norm slopes showed that Eurasia had larger values than North America for reaction norms for above-ground and total biomass. Plants from the seeds of mother plants from Turkey had wide variation in total biomass when grown in Trebon versus Lafayette; this variation in response within certain populations may have contributed to the lack of population-level differences in plasticity. These results indicate no loss of genetic diversity for L. salicaria during its North American invasion, nor reduction in plastic tissue allocation responses to a varying environment, which may help explain some of its invasive qualities and which could be of adaptive value under changing future environments.

Patient-reported outcomes in patients with relapsing forms of MS switching to teriflunomide from other disease-modifying therapies: Results from the global Phase 4 Teri-PRO study in routine clinical practice.

BACKGROUND: Patient-reported outcomes (PROs) can assist clinicians in understanding the impact of disease-modifying therapy (DMT) on the daily lives of patients with multiple sclerosis (MS). With an increased number of DMTs becoming available, patients are now switching treatments more frequently in clinical practice. The effects of switching DMTs on a patient's daily life and their disease course may be reflected in PROs. The global, multicenter, open-label, phase 4 Teri-PRO study (NCT01895335), which was conducted in routine clinical practice, previously showed statistically and clinically significant increases in patient-reported treatment satisfaction in patients switching to teriflunomide from other DMTs. The impact of switching to teriflunomide from other DMTs on treatment satisfaction and a range of additional PROs was also evaluated. METHODS: Patients with relapsing forms of MS (N = 1000) received teriflunomide for 48 weeks per local labeling. Outcomes assessed in this analysis included treatment satisfaction (as measured by Treatment Satisfaction Questionnaire for Medication [Version 1.4]), disability worsening (as measured using the Expanded Disability Status Scale [EDSS] score, the Patient-Determined Disease Steps scale, and the Multiple Sclerosis Performance Scale), cognition (as measured using the Symbol Digit Modalities Test [SDMT]), treated relapses, quality of life (as measured by the Multiple Sclerosis International Quality of Life [MusiQoL] questionnaire and the Stern Leisure Activity Scale), and safety/tolerability over the course of the study in the subgroup of patients switching to teriflunomide from another DMT (n = 594). RESULTS: Patients reported significant improvements in treatment satisfaction scores following the switch to teriflunomide regardless of the reason for treating with teriflunomide (Global Satisfaction, disease worsening: baseline, 46.0, Week 48, 65.1; convenience: baseline, 57.4, Week 48, 72.4; intolerance: baseline, 50.9, Week 48, 71.1; side effects: baseline, 49.7, Week 48, 67.2; P < 0.0001 in all comparisons). These patients also showed improvement or stability in PROs evaluating disability worsening, cognition, and quality of life (EDSS: baseline, 3.1, Week 48, 3.0; SDMT: baseline, 0.975, Week 48, 0.978; MusiQoL: baseline, 67.5, Week 48, 69.5). The safety and tolerability profile of teriflunomide was consistent with that observed in other teriflunomide clinical trials. CONCLUSION: This analysis of the Teri-PRO study demonstrates the value of switching to teriflunomide from other DMTs in a real-world, clinical practice setting. The high levels of treatment satisfaction associated with teriflunomide in Teri-PRO may lead to improved adherence and thus improved outcomes.

Real-World Observational Evaluation of Hair Thinning in Patients with Multiple Sclerosis Receiving Teriflunomide: Is It an Issue in Clinical Practice?

INTRODUCTION: Hair thinning occurred in 10-14% of teriflunomide-treated patients in the teriflunomide multiple sclerosis clinical development program, compared with 5% of placebo-treated patients. Our objective was to examine the clinical course of hair thinning in patients in an observational real-world project. METHODS: Patients with relapsing-remitting multiple sclerosis who reported hair thinning to healthcare professionals (HCPs) during treatment with teriflunomide were eligible for inclusion. During two office visits, one at onset of hair thinning and another at follow-up, HCPs and patients completed questionnaires that categorized hair thinning as mild, moderate, or severe, or from 0 (no hair thinning) to 10 (very severe hair thinning), respectively. At the follow-up visit, patients also rated the degree of recovery. Patients were photographed at both visits with a standardized protocol and camera. RESULTS: Of the 38 patients who completed follow-up, most were women (97%) without prior history of hair thinning (87%), with the majority (68%) receiving concomitant medications potentially associated with hair thinning. The mean time to onset of hair thinning was 77 days after the first teriflunomide dose. HCPs classified the majority of hair thinning events as mild (63%) or moderate (34%), with one event classified as severe (3%). The mean patient severity perception was 5/10, and complete/near-complete resolution or marked improvement was reported by 79% of patients. CONCLUSION: Consistent with observations from the teriflunomide clinical program, hair thinning was usually mild and occurred within the first 3 months of treatment, with most patients fully recovering while remaining on teriflunomide treatment. As with any potential adverse event, it is important to ensure appropriate expectations through patient education before treatment. FUNDING: Sanofi.

Patient-reported outcomes in relapsing forms of MS: Real-world, global treatment experience with teriflunomide from the Teri-PRO study.

BACKGROUND: Patient-reported outcomes (PROs) provide clinicians with further understanding of the impact of treatment on patients' daily lives. In addition, real-world studies, which employ broader inclusion criteria than randomized trials, may help to inform prescribing decisions when selecting a disease-modifying therapy (DMT) to treat relapsing forms of MS (RMS). We sought to use PROs to determine patient treatment satisfaction and other treatment outcomes, and report safety and tolerability associated with teriflunomide, in the global, phase 4 Teri-PRO study (NCT01895335). METHODS: Patients with RMS (N = 1000) received teriflunomide for 48 weeks per local labeling. The primary endpoint was Global Satisfaction with teriflunomide treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM, V1.4). Secondary endpoints included TSQM scores at Week (W)48 vs baseline in patients switching to teriflunomide from other DMTs ('switchers'), additional PROs, and safety. RESULTS: Mean TSQM Global Satisfaction score at W48 was high (68.2). Switchers reported significant improvements across all four TSQM domains at W48 vs baseline (all p < 0.0001). Adverse events were consistent with teriflunomide clinical trials. CONCLUSION: Patients reported high treatment satisfaction with teriflunomide, with switchers also reporting improved treatment satisfaction vs baseline. High treatment satisfaction in patients with RMS may lead to improved adherence, and hence treatment outcomes.

Feasibility of the use of combinatorial chemokine arrays to study blood and CSF in multiple sclerosis.

Meningeal inflammation, including the presence of semi-organized tertiary lymphoid tissue, has been associated with cortical pathology at autopsy in secondary progressive multiple sclerosis (SPMS). Accessible and robust biochemical markers of cortical inflammation for use in SPMS clinical trials are needed. Increased levels of chemokines in the cerebrospinal fluid (CSF) can report on inflammatory processes occurring in the cerebral cortex of MS patients. A multiplexed chemokine array that included BAFF, a high sensitivity CXCL13 assay and composite chemokine scores were developed to explore differences in lymphoid (CXCL12, CXCL13, CCL19 and CCL21) and inflammatory (CCL2, CXCL9, CXCL10 and CXCL11) chemokines in a small pilot study. Paired CSF and serum samples were obtained from healthy controls (n=12), relapsing-remitting MS (RRMS) (n=21) and SPMS (N=12). A subset of the RRMS patients (n = 9) was assessed upon disease exacerbation and 1 month later following iv methylprednisone. SPMS patients were sampled twice to ascertain stability. Both lymphoid and inflammatory chemokines were elevated in RRMS and SPMS with the highest levels found in the active RRMS group. Inflammatory and lymphoid chemokine signatures were defined and generally correlated with each other. This small exploratory clinical study shows the feasibility of measuring complex and potentially more robust chemokine signatures in the CSF of MS patients during clinical trials. No differences were found between stable RRMS and SPMS. Future trials with larger patient cohorts with this chemokine array are needed to further characterize the differences, or the lack thereof, between stable RRMS and SPMS.

Evaluation of sumatriptan-naproxen in the treatment of acute migraine: a placebo-controlled, double-blind, cross-over study assessing cognitive function.

OBJECTIVE: To assess the cognitive effects of acute migraine and the subsequent impact of acute treatment in a controlled setting. BACKGROUND: Cognitive dysfunction may be an associated symptom in patients with migraine with or without aura. The loss of cognitive efficiency in migraine may be disabling and is often under recognized. METHODS: Thirty migraine patients were prospectively studied for cognitive function before and then at the beginning of a migraine using a computerized cognitive battery (Mental Efficacy Workload Test). Each patient then was treated for 2 headaches in a cross-over manner with sumatriptan-naproxen (Treximet®) or placebo in a double-blind, placebo-controlled fashion with cognitive testing repeated at 1 and 2 hours post-dose. RESULTS: Twenty-five of the 30 screened migraine subjects completed study-specific procedures and were included in the data analyses. There were no significant side effects from Treximet or placebo and no serious adverse events. At the onset of headache, there was a statistically significant decline in overall cognitive efficiency compared with the baseline cognitive testing (migraine-free) for all subjects (P = .001 paired samples t-test). For subjects taking Treximet compared with taking placebo, there was a statistically significant return to cognitive efficiency by measures of immediate and sustained attention, visual-spatial awareness, mental flexibility, and reaction time between 1 hour and 2 hours (P = .05). There was no statistical significance between patients taking Treximet or placebo in measures of complex reasoning or fine motor coordination. Subanalysis showed a correlation between headache severity and Performance Index in the Treximet group but not in the placebo group (∼Fig. ). CONCLUSIONS: There is a significant decline in global cognitive efficiency at the onset of an attack of migraine. The use of Treximet allows a significantly faster recovery time in some measures of cognitive efficiency compared with placebo. Decline of cognitive efficiency may be independent of headache severity.

Improvement of neuropsychological function in cognitively impaired multiple sclerosis patients treated with natalizumab: a preliminary study.

Treatment with natalizumab has been shown to reduce physical disability in people with multiple sclerosis (MS). However, its effect on neuropsychological dysfunction is not well understood. A single-center, open-label, retrospective study was conducted to evaluate the effect of natalizumab treatment on neuropsychological function in individuals with relapsing-remitting multiple sclerosis (RRMS) who had a measurable neuropsychological deficit prior to natalizumab treatment. A total of 40 MS patients (mean age, 48.5 years; 77.5% female) were evaluated on a neuropsychological battery of nine tests designed for MS patients before and after 6 or more months of treatment with natalizumab. Posttreatment neuropsychological testing results were compared to baseline results. The mean baseline Neuropsychological Impairment Index was 0.49, which improved to 0.41 after treatment (P = .0002) as analyzed using the Wilcoxon signed rank test. The mean Beck Depression Inventory-II (BDI-II) score improved by 2.45 points (P = .001). The mean Expanded Disability Status Scale (EDSS) score improved by 0.30 (P = .02). A total of 52.5% of patients showed neuropsychological improvement, while 30.0% showed no change and 17.5% had worsening. Magnetic resonance imaging showed no changes. The specific prior disease-modifying therapy had no influence on the results for natalizumab effect. The results of this study show that natalizumab can stabilize or improve neuropsychological function in RRMS patients. The improvement was consistent with, but apparently independent of, improvement in depression and physical disability.