The patient-reported outcomes for the new brand-generic teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND: Patient-reported outcomes (PROs) provide valuable insights into the impact of disease-modifying therapies (DMTs) on patients' daily lives and disease progression. This study evaluates treatment satisfaction and tolerability among patients using a brand-generic Teriflunomide (Tebazio®, 14 mg tablet) manufactured by Zistdaru Danesh Biopharmaceuticals. MATERIALS AND METHODS: A Phase IV observational study was conducted on patients with Relapsing-Remitting Multiple Sclerosis (RRMS) who were either initiated on or switched to Teriflunomide 14 mg. The primary focus was on the medication's safety. Patient satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication [Version 1.4] (TSQM-14). Additionally, medication adherence and discontinuation rates were monitored. RESULTS: Of the 235 RRMS patients enrolled, participated in this study, all received the Teriflunomide treatment orally on a daily basis. Over the 18-month follow-up period, 25.96 % of patients discontinued the treatment. Discontinuation was mainly due to adverse events (11 %), lack of patient willingness to continue (12.7 %), and disease progression (4.2 %). The most commonly reported adverse events included dermatologic disorders, elevated liver enzymes, and gastrointestinal issues. TSQM-14 scores demonstrated significant improvements over the 18-month period. A high medication adherence rate of 98.1 % was also recorded. CONCLUSION: Patients reported notable satisfaction with Teriflunomide, as reflected in their TSQM scores, which suggests a likelihood of improved patient adherence. The 14 mg brand-generic Teriflunomide was well-accepted by Iranian RRMS patients, with no significant concerns arising during the study. These findings also highlight the significance of patient-reported outcomes in DMTs, with potential benefits for adherence and clinical practice.

Teriflunomide, cognition and MRI: A longitudinal study.

BACKGROUND: As cognitive impairment in multiple sclerosis (MS) is a frequent and disabling symptom, it is particularly important to identify treatments that have proven efficacy in this aspect of the disease. Several disease-modifying therapies for MS have been evaluated and shown to have a potential effect on cognition and its neurobiological correlates, but to date there is very little data on Teriflunomide (TRF). The aim of this study is to explore the influence of TRF on comprehensive cognitive function and its MRI correlations (global and focal brain volume) in relapsing-remitting multiple sclerosis (RRMS) after two years of therapy. METHODS: Twenty-four patients with RRMS were evaluated at baseline and after two years of treatment with BCcogSEP, a French translation of the Brief Repeatable Battery (BRB-N) including 3 additional tests. We explored the performance evolution for each test and correlation with MRI data for all patients. We also differentiated MS patients with and without cognitive impairment. RESULTS: After two years of treatment, an improvement is observed at the Selective Reminding Test for mean number of words (p = 0.044), learning (p = 0.018), and delayed recall (p = 0.002) and at GoNoGo task (p = 0.022). At MRI, the corpus callosum volume variation correlates positively with SRT total recall test (p = 0,047). Intergoup analysis shows that the evolution of group performance differs only for the SRT total recall test. The comparison of patients with or without cognitive impairment showed a clear difference in white matter substance volume (p = 0,003) and in the Percentage Brain Volume Change (p = 0,016). CONCLUSION: Results suggest that TRF treatment in RRMS has a positive effect in cognitive function, and specifically on long term verbal memory and inhibition. Neuroimaging data suggest a link between cognition and global and focal white matter volume, particularly in the corpus callosum which is involved in anatomical disconnection syndrome and therefore brain plasticity capacities.

Antirheumatic drug leflunomide attenuates atherosclerosis by regulating lipid metabolism and endothelial dysfunction via DHODH/AMPK signaling pathway.

The probability of cardiovascular events has been reported lower in rheumatoid arthritis (RA) patients treated with leflunomide. However, the anti-atherosclerotic and cardiovascular protective effects and metabolism of leflunomide are not explored. In this study, we assessed the potential benefits of leflunomide on atherosclerosis and revealed the underlying mechanism. ApoE-/- mice were fed a western diet (WD) alone or supplemented with leflunomide (20 mg/kg, oral gavage, once per day) for 12 weeks. Samples of the aorta, heart, liver, serum, and macrophages were collected. We found that leflunomide significantly reduced lesion size in both en-face aortas and aortic root in WD-fed ApoE-/- mice. Leflunomide also obviously improved dyslipidemia, reduced hepatic lipid content, and improved disorders of glucose and lipid metabolism in vivo. RNA-Seq results showed that leflunomide effectively regulated the genes' expression involved in the lipid metabolism pathway. Importantly, leflunomide significantly increased the phosphorylation levels of AMPKα and acetyl-CoA carboxylase (ACC) in vivo. Furthermore, leflunomide and its active metabolite teriflunomide suppressed lipid accumulation in free fatty acid (FFA)-induced AML12 cells and improved endothelial dysfunction in palmitic acid (PA)-induced HUVECs through activating AMPK signaling and inhibiting dihydroorotate dehydrogenase (DHODH) signaling pathway. We present evidence that leflunomide and teriflunomide ameliorate atherosclerosis by regulating lipid metabolism and endothelial dysfunction. Our findings suggest a promising use of antirheumatic small-molecule drugs leflunomide and teriflunomide for the treatment of atherosclerosis and related cardiovascular diseases (CVDs).

Underdosed generic specialty medications: A prescription for patient harm?

The use of generic specialty medications amongst individuals with multiple sclerosis (MS) has expanded due to an increase in the number of available agents. We describe a woman who was denied continued use of brand name teriflunomide (AubagioⓇ), despite being clinically stable for 2.5 years, and switched to generic teriflunomide. She experienced a significant spinal cord exacerbation within a few months of starting treatment. We analyzed 3 generic teriflunomide agents, including the one used for treatment, in addition to AubagioⓇ. The generic teriflunomide used by our patient contained 55.5 % content of the labeled amount, well below U.S. FDA specifications.

Comparative effectiveness and safety of ozanimod versus other oral DMTs in relapsing-remitting multiple sclerosis: a synthesis of matching-adjusted indirect comparisons.

Background: Several oral disease-modifying therapies (DMTs) have been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head randomized data, matching-adjusted indirect comparisons (MAICs) can evaluate the comparative effectiveness and safety of ozanimod versus other oral DMTs in RRMS. Objectives: To synthesize results from the published MAICs of ozanimod and other oral DMTs for 2-year outcomes in RRMS. Methods: Published MAICs involving ozanimod for the treatment of RRMS were identified. Extracted data elements included efficacy [annualized relapse rate (ARR), confirmed disability progression (CDP), and brain volume loss] and safety [adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and infection] outcomes. Results: The four MAIC studies identified compared ozanimod with fingolimod, teriflunomide, dimethyl fumarate (DMF), and ponesimod. All comparisons were adjusted for differences in age, sex, relapses within the previous year, Expanded Disability Status Scale score, and percentage of patients with prior DMTs. Outcomes at 2 years were analyzed based on comparisons that lacked a common comparator arm. Ozanimod was associated with significantly lower ARR versus teriflunomide [ARR ratio (95% CI) 0.73 (0.62, 0.84) and DMF 0.80 (0.67, 0.97)], with no significant difference versus fingolimod or ponesimod. The proportions of patients treated with ozanimod or fingolimod had similar 3- and 6-month CDP. Compared with teriflunomide and DMF, ozanimod was associated with a significantly lower risk of 3-month CDP; 6-month CDP was comparable. Ozanimod was associated with significantly lower rates of any AE and AEs leading to discontinuation compared with the other oral DMTs evaluated. Ozanimod also had significantly lower rates of SAEs versus teriflunomide and DMF and lower rates of reported infection outcomes versus fingolimod and ponesimod. Conclusion: Compared with the other oral DMTs evaluated in MAICs, ozanimod was associated with a favorable safety profile and improved or comparable efficacy outcomes.

An indirect comparison of ozanimod vs other oral treatments in relapsing-remitting multiple sclerosis The many treatment options available for relapsing-remitting multiple sclerosis (RRMS) make treatment decisions difficult. While direct head-to-head treatment comparisons provide useful information, these studies are not available for every pair of treatments. Indirect comparisons of published study results can help fill that evidence gap. A technique called matching-adjusted indirect comparison (MAIC) offers a statistically robust way to compare safety/efficacy outcomes from different studies by accounting for important differences across the studies. We collected data from four MAIC studies that compared 2-year treatment outcomes in patients treated with ozanimod versus those treated with fingolimod, teriflunomide, dimethyl fumarate (DMF), or ponesimod. Each study accounted for differences in age, sex, relapses within the previous year, disability status, and previous therapy use. We found ozanimod was either better than or similar to other treatments based on the outcomes measured. The annual rate of RRMS relapse was lower for patients treated with ozanimod than for patients treated with teriflunomide or DMF and similar for patients treated with ponesimod or fingolimod. Ozanimod-treated patients saw their RRMS progress at rates similar to those treated with fingolimod at 3 and 6 months and teriflunomide and DMF at 6 months; RRMS was more likely to progress at 3 months in patients treated with teriflunomide and DMF versus those treated with ozanimod. Our analyses also found that patients treated with ozanimod had lower rates of side effects, including those serious enough to cause treatment discontinuation, compared with patients receiving other treatments. By comparing findings from existing MAIC studies, we found that patients with RRMS treated with ozanimod had fewer side effects and better or similar efficacy outcomes compared with patients who received other treatments for RRMS. These findings can potentially inform treatment decisions for patients with RRMS.

Old and New Strategies in the Treatment of Pediatric Multiple Sclerosis: A Personal View for a New Treatment Approach.

Up to 10 years ago the most common approach to the treatment of pediatric MS (ped-MS) was to start with IFNB or GA (so-called first-line therapies or moderate-efficacy disease-modifying therapies [ME-DMTs]) and to switch to more aggressive treatments (or high-efficacy disease-modifying therapies [HE-DMTs]) in non-responder patients. The use of HE-DMTs as first choice was recommended in selected cases with an active, aggressive form of MS. Indications for the treatment of ped-MS were essentially derived from data of observational studies. Recently, results of three randomized clinical trials have been published as well as data from many observational studies evaluating the effect of new and more active DMTs, with clear evidence that HE-DMTs are more effective than ME-DMTs. Therefore, the paradigm of treatment for patients with MS onset before 18 years of age should be changed, offering treatment with HE-DMTs as first option, because of their superior effectiveness to prevent relapses and disease progression. HE-DMTs present an overall reassuring safety profile and obtain better adherence to treatment.

Validated chromatographic methods for determination of teriflunomide and investigation of its intrinsic stability.

Two rapid, precise, and sensitive stability-indicating high performance chromatographic methods for the measurement of Teriflunomide in its degradation products' existence were developed. These were RP-HPLC and HPTLC using UV detector. HPLC separation was accomplished utilizing Thermo BDS hypercil C18 column (250 × 4.6 mm, 5 µm) and acetonitrile: 0.03 M potassium dihydrogen phosphate: triethylamine (50:50:0.1%, by volume) as mobile phase at flow rate of 1mL/min. The separated peaks were detected at 250.0 nm. The densitometric approach was conducted utilizing HPTLC 60 F254 silica gel plates, and a developing system of benzene: ethanol: acetic acid (7.5:1:0.25, by volume) and detection was done at 250.0 nm. The developed approaches were evaluated regarding the International Conference on Harmonization (ICH) instructions. The calibration curves of both techniques were constructed with linearity ranges of (5-100) µg/mL and (2-10) µg /band, for HPLC and densitometric determination, consecutively. Teriflunomide was exposed to base and acid hydrolysis, oxidation using H2O2 and finally, thermal degradation as stated in ICH guidelines. The degradation product structures' elucidation was achieved through LC-MS.

TAURUS-MS II: real-world use of teriflunomide in Germany and changes in treatment patterns over time.

Background: Teriflunomide is a once-daily oral disease-modifying therapy (DMT) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Only limited information is available about its real-world use and changes over time. Objectives: To collect real-world data on teriflunomide use in clinical routine (and comparison to the previously conducted study TAURUS-MS). Design: National, open, non-interventional, prospective, multicenter study. Methods: TAURUS-MS II was conducted at 220 German sites between July 2017 and March 2022, including RRMS patients treated with teriflunomide. Data on patient demographics, MS history, previous treatment, therapy satisfaction, and safety were collected. Results: In total, 752 patients were included (65% female) with a mean age (±standard deviation) of 43 ± 11 years. Sixty-six percent had DMT before, and 46% had discontinued their last pretreatment ≤6 months prior to study entry. Among the latter, previous DMTs were interferon (21%), glatiramer acetate (11%), and dimethyl fumarate (9%), and reasons for discontinuation were adverse events (AEs; 55%) and insufficient efficacy (16%). Over 24 months, the mean treatment Satisfaction Questionnaire for Medication scores improved by 6 ± 29 points on effectiveness, 8 ± 20 on convenience, and 12 ± 25 on global satisfaction. The mean number of MS relapses decreased from 0.81 ± 0.81 in the 24 months prior to 0.27 ± 0.57 within 24 months after study entry. Non-serious AEs occurred in 423 patients (56%) and serious AEs in 49 patients (7%). Most reported AEs were alanine aminotransferase increase (11%), hypertension (8%), and alopecia (7%). Compared to TAURUS-MS, patients in TAURUS-MS II were younger, had a higher employment rate, and a higher share of treatment-naïve patients. Conclusion: Mean number of relapses was significantly reduced. Patient satisfaction was significantly improved compared to previous DMT. Tolerability was comparable to previous trials. Trial registration: Bundesinstitut für Arzneimittel und Medizinprodukte public database for non-interventional studies, number 7138.

Mitigating cognitive deficits with teriflunomide: unraveling PI3K-modulated behavioral outcomes in mice.

BACKGROUND: Alzheimer's disease is a leading neurological disorder that gradually impairs memory and cognitive abilities, ultimately leading to the inability to perform even basic daily tasks. Teriflunomide is known to preserve neuronal activity and protect mitochondria in the brain slices exposed to oxidative stress. The current research was undertaken to investigate the teriflunomide's cognitive rescuing abilities against scopolamine-induced comorbid cognitive impairment and its influence on phosphatidylinositol-3-kinase (PI3K) inhibition-mediated behavior alteration in mice. METHODS: Swiss albino mice were divided into 7 groups; vehicle control, scopolamine, donepezil + scopolamine, teriflunomide (10 mg/kg) + scopolamine; teriflunomide (20 mg/kg) + scopolamine, LY294002 and LY294002 + teriflunomide (20 mg/kg). Mice underwent a nine-day protocol, receiving scopolamine injections (2 mg/kg) for the final three days to induce cognitive impairment. Donepezil, teriflunomide, and LY294002 treatments were given continuously for 9 days. MWM, Y-maze, OFT and rota-rod tests were conducted on days 7 and 9. On the last day, blood samples were collected for serum TNF-α analysis, after which the mice were sacrificed, and brain samples were harvested for oxidative stress analysis. RESULTS: Scopolamine administration for three consecutive days increased the time required to reach the platform in the MWM test, whereas, reduced the percentage of spontaneous alternations in the Y-maze, number of square crossing in OFT and retention time in the rota-rod test. In biochemical analysis, scopolamine downregulated the brain GSH level, whereas it upregulated the brain TBARS and serum TNF-α levels. Teriflunomide treatment effectively mitigated all the behavioral and biochemical alterations induced by scopolamine. Furthermore, LY294002 administration reduced the memory function and GSH level, whereas, uplifted the serum TNF-α levels. Teriflunomide abrogated the memory-impairing, GSH-lowering, and TNF-α-increasing effects of LY294002. CONCLUSION: Our results delineate that the improvement in memory, locomotion, and motor coordination might be attributed to the oxidative and inflammatory stress inhibitory potential of teriflunomide. Moreover, PI3K inhibition-induced memory impairment might be attributed to reduced GSH levels and increased TNF-α levels.

Sustained Effectiveness and Safety Over Time of Teriflunomide in Chinese Patients with Relapsing Multiple Sclerosis in the Greater Bay Area of China: Insights from Real-World Data.

INTRODUCTION: The real-world data on the medium- to long-term effectiveness and safety of teriflunomide in Chinese patients with relapsing multiple sclerosis (MS) is limited. Therefore, this study aims to assess the treatment outcomes of teriflunomide in Chinese patients with MS over a medium- to long-term period. METHODS: This cohort study was carried out in three tertiary hospitals and regional MS centers located in the Greater Bay Area of China. We obtained the historical clinical data of patients who underwent teriflunomide treatment for at least 6 months. The primary objective was to evaluate the proportion of patients achieving no evidence of disease activity (NEDA)-3 status, which is characterized by the absence of relapses, confirmed disability worsening, and new or enlarging MRI lesions, over time. Secondary objectives included assessing the proportion of patients meeting each NEDA-3 criterion, changes in motor and cognitive function, as well as the incidence of adverse events and treatment discontinuations. RESULTS: A total of 160 patients with MS were enrolled, including 125 patients treated with teriflunomide for at least 1 year (≥ 1-year completers) and 71 patients treated for at least 2 years (≥ 2-year completers). A total of 85.63% of the overall population achieved clinical NEDA-3 status at 6 months of teriflunomide treatment, and 71.20% of ≥ 1-year completers achieved NEDA-3 status at 12 months of teriflunomide treatment. The median timed 25-foot walk test (T25FW), nine-hole peg test (9-HPT), and paced auditory serial addition test (PASAT) results were relatively stable before and after treatment. CONCLUSION: Medium- to long-term MS disease activity, as indicated by NEDA-3 status, is well controlled in patients treated with continuous teriflunomide treatment in real-world settings.

Antidepressant effect of teriflunomide via oligodendrocyte protection in a mouse model.

Addressing the treatment of depression is crucial; nevertheless, the etiology and pathogenesis remain unelucidated. Therefore, this study investigated the effects of teriflunomide (TF) on corticosterone (CORT)-induced depression-like behaviors in mice. Notably, TF administration resulted in a substantial amelioration of anxiety and depression-like behaviors observed in CORT-treated mice. This was evidenced by behavioral assessments conducted via the sucrose preference test (SPT), open-field test (OFT), novelty-suppressed feeding test (NSFT), forced swimming test (FST), and tail suspension test (TST). The administration of CORT inflicts damage upon oligodendrocytes and neurons within the hippocampus. Our findings indicate that TF offers significant protective effects on oligodendrocytes, mitigating apoptosis both invivo and invitro. Additionally, TF was found to counteract the CORT-induced neuronal loss and synaptic damage, as demonstrated by an increase in Nissl-positive cells across hippocampal regions CA1, CA3, and the dentate gyrus (DG) alongside elevated levels of synapse-related proteins including PSD-95 and synaptophysin. Additionally, TF treatment facilitated a reduction in the levels of apoptosis-related proteins while simultaneously augmenting the levels of Bcl2. Our findings indicate that TF administration effectively mitigates CORT-induced depression-like behaviors and reverses damage to oligodendrocytes and neurons in the hippocampus, suggesting TF as a promising candidate for depression.

Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS.

BACKGROUND: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. METHODS: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. RESULTS: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. CONCLUSION: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108.

Real-world experience of teriflunomide in relapsing multiple sclerosis: paramagnetic rim lesions may play a role.

Objectives: The aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing-remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden. Methods: This is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated. Results: Over a treatment period of 19.7 (3.1-51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0-11.5) mL, accounting for 2.3% (0.0%-49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced (p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study. Conclusion: Teriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision.

Brain-Derived Neurotrophic Factor in Multiple Sclerosis Disability: A Prospective Study.

Multiple sclerosis (MS) is a demyelinating central nervous system disease that leads to neurological disability. Brain-derived neurotrophic factors (BDNFs) are neurotrophins involved in neurodegenerative disorders. This study analysed the relationship between serum BDNF, neurological disability and different MS treatments. We included 63 people with MS (PwMS), with relapsing-remitting MS or clinically isolated syndrome, and 16 healthy controls (HCs). We analysed the serum levels of BDNF and MS specific disability tests (Expanded Disability Status Scale, timed 25-foot walk test, nine-hole peg test), at baseline (V0) and after one year of interferon beta1a or teriflunomide treatment (V1). Baseline BDNF values were not different between the PwMS and HCs (p = 0.85). The BDNF levels were higher in PwMS vs. HCs after treatment (p = 0.003). BDNF was not related to last-year relapses or by the disease duration (all p > 0.05). The overall values for the PwMS decreased after one year (p < 0.001). Both treatments implied a similar reduction. BDNF was not related to neurological disability (p > 0.05). BDNF values were not influenced by the lesion burden, active lesions, or new lesions on MRI (p > 0.05). In our cohort, the PwMS had higher BDNF levels compared to the HCs after one year of treatment. BDNF was not related to clinical or paraclinical disease severity signs.

Vulnerability of Store-Operated Calcium Entry to Inhibitors and Microenvironment in Cells of Different Breast Cancer Subtypes.

The incidence and development of cancer are highly dependent on pathological disturbances in calcium homeostasis of the cell. One of the major pathways for calcium entry is store-operated calcium entry (SOCE), which functions in virtually all cell types. Changes in the expression level of the main proteins organizing SOCE are observed during the development of various cancer types, particularly breast cancer (BC). This leads to unique SOCE with characteristics individual for each type of BC and requires particular therapeutic approaches. In this study, we tested the sensitivity of SOCE in various BC cells to selective ORAI channel inhibitors and the less selective compounds Leflunomide and Teriflunomide, approved by the FDA for clinical use. We also analyzed the vulnerability of SOCE to the influence of factors typical of the tumor microenvironment: hypoxia and acidification. We have observed that the SOCE inhibitors Leflunomide and Teriflunomide suppress SOCE in the triple-negative BC cell line MDA-MB-231, but not in the luminal A BC cell line MCF-7. MDA-MB-231 cells also demonstrate higher pH dependence of SOCE compared to MCF-7 cells. In addition, the oxygen scavenger sodium dithionide also affects SOCE, stimulating it in MDA-MB-231 cells but inhibiting in MCF-7 cells. Overall, our data highlight the importance of considering the different sensitivities of various BC cell types to inhibitors and to microenvironmental factors such as hypoxia and acidification when developing targeted drugs.

Simultaneous onset of Crohn's disease and Psoriasis in a Multiple Sclerosis patient treated with Teriflunomide: A novel case report highlighting potential autoimmune interactions.

Teriflunomide (TFN) is an oral Disease-modifying therapy (DMT) widely used in the treatment of relapsing forms of Multiple Sclerosis (MS). Although TFN has demonstrated efficacy in reducing MS activity, recent evidence suggests a possible association between TFN and the onset of rare and severe medical conditions. We present a novel case report of a 47-year-old woman with a history of MS who developed concurrent Crohn's disease and Psoriasis following TFN treatment. This unique occurrence has not been previously documented in the literature. The patient experienced gastrointestinal symptoms and changes in nail color while on TFN. Colonoscopy and biopsy revealed crypt architectural distortion and lamina propria expansion, indicative of Crohn's disease, while dermatological evaluation suggested Psoriasis. Consequently, TFN was discontinued and switched to alternative therapy (Glatiramer acetate), and the patient underwent close observation and regular evaluations. Three months after stopping the TFN, the patient's nail lesions disappeared completely, her abdominal pain and diarrhea were resolved, and the follow-up colonoscopy was completely normal. In this regard, the association between MS, Inflammatory Bowel Disease (IBD), and Psoriasis has been reported in previous studies, with potential involvement of Th17 and IL-17 pathways. Although gastrointestinal side effects with TFN use are typically mild and transient, rare cases of TFN-induced IBD have been reported. Dermatological disorders, including Psoriasis, have also been linked to TFN use, with similarities to our case report. Further research and awareness are warranted to better understand the potential side effects and long-term implications of TFN in the management of MS.

Acute Ischemic Stroke in a Patient with Multiple Sclerosis after Initiating Teriflunomide Treatment: A Challenging Case.

Multiple sclerosis is an autoimmune disease of the central nervous system, during which vascular events, including atherosclerosis, are more common and progress faster. Teriflunomide (TFN) is an oral drug that studies have indicated has low side effects alongside high efficiency. In this article, a middle-aged woman with multiple sclerosis was introduced, whose medication was changed to TFN. Thirty-five days later, she presented with focal neurologic symptoms, and investigations reported a lacunar infarction. Having excluded potential causes of acute ischemic stroke, such as vascular and rheumatologic factors, the only identifiable factor was the introduction of a new medication. The process of conclusively attributing TFN as the causative agent requires further clarification in future studies.

Serum teriflunomide concentrations in routine multiple sclerosis therapy: A cross-sectional pilot study.

BACKGROUND: Teriflunomide is administered orally to treat relapsing-remitting multiple sclerosis. In this prospective pilot study, the free and total serum concentrations of teriflunomide obtained during routine health care were measured and their relationship with disease activity was evaluated. METHODS: Eighty-nine patients were included in this study. Blood samples were collected from April 2021 to February 2022, and free and total teriflunomide serum concentrations were measured. Patient assessment involved monitoring of blood counts and potential adverse effects of teriflunomide. RESULTS: In the steady-state group, total teriflunomide concentrations ranged from 14.7 to 144.2 mg/L, while free concentrations from 31.1 to 389.7 µg/L. In the non-steady-state group, the total concentration ranged from 2.2 to 59.3 mg/L, with free concentrations ranging from 6.8 to 143.5 µg/L. In the steady-state group, a significant inverse correlation was found between absolute peripheral blood lymphocyte count and both total and free teriflunomide serum concentrations. CONCLUSION: Although all patients were treated with the same dose, up to a 10-fold difference in total and free teriflunomide serum concentrations, and up to a 5-fold difference in steady-state trough concentrations were observed. This vast interindividual variability can potentially lead to toxicity or, conversely, to suboptimal therapeutic concentrations of teriflunomide, with the risk of further worsening of multiple sclerosis compensation.

Efficacy and Safety of Ponesimod Compared with Teriflunomide in Female Patients with Relapsing Multiple Sclerosis: Findings from the Pivotal OPTIMUM Study.

Background: Multiple sclerosis (MS) is threefold more prevalent in women than men. However, sex-specific efficacy analysis for MS disease-modifying therapies is not typically performed. Methods: Post hoc analyses of data from female patients enrolled in the phase 3, double-blind OPTIMUM study of relapsing MS were carried out. Eligible adults were randomized to ponesimod 20 mg or teriflunomide 14 mg once daily for up to 108 weeks. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included change in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, number of combined unique active lesions (CUALs) per year on magnetic resonance imaging, and time to 12- and 24-week confirmed disability accumulation (CDA). Results: A total of 735 female patients (581 of childbearing potential) were randomized to ponesimod (n = 363, 49.4%) or teriflunomide (n = 372, 50.6%). Relative risk reduction in the ARR for ponesimod versus teriflunomide was 33.1% (mean, 0.192 vs. 0.286, respectively; p < 0.002). Mean difference in FSIQ-RMS for ponesimod versus teriflunomide was -4.34 (0.12 vs. 4.46; p = 0.002); rate ratio in CUALs per year, 0.601 (1.45 vs. 2.41; p < 0.0001), and hazard ratio for time to 12- and 24-week CDA risk estimates, 0.83 (10.7% vs. 12.9%; p = 0.38) and 0.91 (8.8% vs. 9.7%; p = 0.69), respectively. Incidence of treatment-emergent adverse events was similar between treatment groups (89.0% and 90.1%). Conclusions: Analyses demonstrate the efficacy and safety of ponesimod, versus active comparator, for women with relapsing MS, supporting data-informed decision-making for women with MS. Clinical Trial Registration Number: NCT02425644.