Sphingosine 1-phosphate Receptor Modulator Research Articles

Clinical effectiveness of coronavirus disease 2019 vaccination in patients with multiple sclerosis stratified by disease-modifying treatment.

Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.

Long-term Efficacy of the Sphingosine 1-Phosphate Receptor Modulator Ozanimod by Age Category in Patients with Relapsing Multiple Sclerosis: Final Results from Two Phase 3 Trials and an Open-label Extension Trial (P2-6.007)

Long-term Efficacy of the Sphingosine 1-Phosphate Receptor Modulator Ozanimod by Age Category in Patients with Relapsing Multiple Sclerosis: Final Results from Two Phase 3 Trials and an Open-label Extension Trial (P2-6.007)

Peripheral oedema as an adverse effect of treatment of secondary progressive multiple sclerosis with siponimod: A case series

Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator used to treat secondary progressive multiple sclerosis (SPMS). We report 3 SPMS patients treated with siponimod who developed new or worsening peripheral oedema soon after commencing treatment. In one case, peripheral oedema resulted in immobility. Siponimod-related peripheral oedema deserves wider recognition due to the potential for morbidity and over-investigation. Clinicians should assess for pre-existing oedema and coexisting conditions that may predispose to developing peripheral oedema prior to commencing siponimod.

Incidence and determinants of seizures in multiple sclerosis: a meta-analysis of randomised clinical trials

BackgroundSeizures are reported to be more prevalent in individuals with multiple sclerosis (MS) compared with the general population. Existing data predominantly originate from population-based studies, which introduce variability in methodologies...

Sphingosine 1-phosphate receptor modulators in multiple sclerosis treatment: A practical review.

Four sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head-to-head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real-world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

P543 Patients in trials of moderate-to-severe UC who are exposed to placebo are more likely to suffer harm than those receiving active treatment: The lack of clinical equipoise in traditional study designs

Abstract Background Ulcerative Colitis (UC) is a relapsing-remitting inflammatory disease of the colon and rectum. There are many challenges to the recruitment of eligible individuals into clinical trials for IBD, including the availability of multiple standard-of-care treatment options and patient refusal to participate in randomized placebo (PBO)-controlled trials due to fear of receiving PBO. Patient harm across clinical trials for moderate-to-severe UC has not been adequately examined. We sought to quantify the potential harm to patients recruited to PBO. Methods We reviewed phase 3 clinical trials of therapies for moderate-to-severe UC including anti-TNF-alpha (infliximab, adalimumab, golimumab), anti-integrin (vedolizumab), anti-interleukin (IL) 12/23 (ustekinumab), anti-IL23 (mirikizumab, guselkumab), Janus kinase inhibitors (tofacitinib, upadacitinib), and sphingosine-1 phosphate receptor modulators (ozanimod, etrazimod). We analyzed the proportions (# of pts. with events/cohort size) of adverse events (AEs), serious adverse events (SAEs), disease exacerbation AEs (DEAEs), and disease exacerbation SAEs (DESAEs). We calculated Number Needed to Harm (NNH = 1/Incidence rate in cohort) for PBO (NNHPBO) and experimental therapy (NNHRx) in each trial. Maintenance phase NNHs were categorized as treat-through (TT) or re-randomized (RR). Results We identified an increased probability of AEs in the PBO arm of 7/11 induction (NNHPBO= 2.18-11.06; NNHRx=2.47-16.52), 1/8 TT maintenance, and 5/11 RR maintenance (NNHTTPBO = 1.2-3.1; NNHTTRx =1.1-16.4; NNHRRPBO = 1.3-10.8). We identified an increased probability of SAEs for 8/11 induction (NNHPBO=14.5-58.0; NNHRx=22.13-101.0), 4/8 TT, and 5/11 RR (NNHTTPBO = 3.9-23.3; NNHTTRx =4.2-29.9; NNHRRPBO = 8.8-35.0). Patients were at increased probability of DEAEs in the PBO arm of 8/11 induction (NNHPBO=7.38-43.20; NNHRx=12.50-106.33), 7/8 TT, and 7/10 RR (NNHTTPBO = 3.0-11.1; NNHTTRx =4.3-15.0; NNHRRPBO = 2.7-25.2). DESAEs were at increased probability of harm in the PBO arm of 8/9 induction (NNHPBO=29.00-116.00; NNHRx=47.43-119.75), 3/5 TT, and 7/10 RR (NNHTTPBO = 14.4-52.0; NNHTTRx =13.2-230.0; NNHRRPBO = 11.2-25.2). Conclusion In PBO-controlled clinical trials of therapies for moderate-to-severe UC, there are increased AEs and SAEs for patients who receive PBO, especially for DEAEs and DESAEs. Induction treatment responders re-randomized for maintenance to PBO experienced greater harms (i.e. lower NNH) than TT PBO patients. These findings raise concern about clinical equipoise in moderate-to-severe UC clinical trials and support ongoing efforts to design trials with active comparator arms and adaptive or platform methodologies.

P1157 Burden of herpes zoster in patients with inflammatory bowel disease treated with immunosuppressive agents

Abstract Background Patients with inflammatory bowel disease (IBD) are at increased risk of infections such as herpes zoster (HZ) due to immunosuppressive (IS) therapy. We conducted a targeted literature review to identify the burden of HZ in patients with IBD treated with IS agents. Methods We conducted a PubMed search to collate publications reporting on HZ in patients with IBD receiving IS treatment (from 01/01/2013 to 01/11/2023; excluding preclinical studies, narrative reviews and case reports). Findings were supplemented with a second PubMed search specific to paediatric patients with IBD (aged ≤18 years). Additional publications were included based on authors’ expertise as well as relevant abstracts presented at ECCO and DDW in 2022 and 2023. Results Overall, 178 publications were identified and 77 were included, along with ten recent congress abstracts. The most common IS treatments were Janus kinase inhibitors (JAKi), including tofacitinib and upadacitinib, followed by tumour necrosis factor inhibitors (TNFi). Additional treatments included anti-interleukin (IL)-23 agents (risankizumab, ustekinumab, mirikizumab) and sphingosine-1-phosphate (S1P) receptor modulators (etrasimod, ozanimod). HZ incidence rates are typically higher in patients with IBD compared with non-IBD populations (7.02–18.34 vs 3.22–11.29 per 1000 patient years, respectively). In paediatric patients, incidence rates are as high as 8.49/1000 patient years, with a standardised incidence ratio of 3.38 compared with the general population. Two studies reported a significant association between IBD and risk of hospitalisation for HZ in children and adolescents. Patients with IBD aged <50 years may have higher incidence of HZ compared with those aged >60 years without IBD. Risk factors for HZ in IBD patients include older age, lower weight, geographic region, prior TNFi failure and use, dose, and combination of IS medications. Increased incidence of HZ is associated with IS medication, particularly JAKis. Limited data exists on novel anti IL-23 agents and S1P receptor modulators, with some studies reporting a similar risk of HZ in treated patients compared with placebo, and others reporting an increased risk. HZ-related discontinuation is rare. Vaccination can reduce the risk of HZ in treated IBD populations, and studies have identified areas to improve vaccination adherence. Conclusion Patients with IBD of all ages, but specifically those aged <50 years, are at higher risk of HZ compared with non-IBD cohorts, and IS medications contribute to this risk. Vaccination against HZ prior to initiating IS treatment could benefit patients with IBD.

P687 Ozanimod as a once-daily oral therapy for Japanese patients with ulcerative colitis: results from the induction period of a Phase 2/3 study (J-True North)

Abstract Background Ozanimod is an oral, small molecule sphingosine 1-phosphate (S1P) receptor modulator that selectively targets the S1P1 and S1P5 receptor subtypes. Ozanimod is approved in multiple countries outside Japan for the treatment of moderately to severely active ulcerative colitis (UC) and/or relapsing forms of multiple sclerosis. We herein report the efficacy and safety results during the induction period of J-True North, a multi-centre, randomised, double-blind, placebo-controlled clinical Phase 2/3 study consisting of a 12-week induction period, followed by a 40-week maintenance period and an open-label extension period in Japanese patients with moderately to severely active UC. Methods Japanese male and female UC patients aged 18 to 75 years with moderately to severely active UC (defined as Mayo score of 6 to 12, with endoscopic subscore ≥2, rectal bleeding score (RBS) ≥1, and stool frequency score ≥1) were randomised in a 1:1:1 ratio to receive either 0.46 mg or 0.92 mg ozanimod, or placebo capsules orally once daily. All patients had received prior treatment with aminosalicylates or corticosteroids. The primary endpoint was clinical response at Week 12 (defined as a reduction from baseline in the complete Mayo score of ≥ 3 points and ≥ 30%, and a reduction from baseline in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 point), and key secondary endpoints were clinical remission, clinical response, endoscopic improvement, mucosal healing and safety at Week 12 and 52. Results Patients were randomised to the ozanimod 0.46 mg group (n=68), 0.92 mg group (n=65), and the placebo group (n=65). At baseline, 36.4% of patients were female, mean age was 42.6 y and mean complete Mayo score was 8.4. The clinical response rate at Week 12 was 52.9%, 61.5%, and 32.3% in the ozanimod 0.46 mg, 0.92 mg, and placebo groups, respectively, demonstrating a statistically significant improvement of ozanimod vs placebo (Figure 1). Similarly, higher improvement rates were observed in all key secondary clinical and endoscopic endpoints in the ozanimod groups compared with the placebo group at Week 12. Frequent adverse events (AEs) observed in the induction period were nasopharyngitis, headache, et.al. (Table 1). AEs observed in the study were similar to those in the global phase 3 True North study with 0.92 mg ozanimod, and there were no new safety signals with ozanimod in the J-True North study. Conclusion Ozanimod as a once-daily oral therapy was effective as induction therapy for Japanese patients with moderately to severely active UC, and the safety profile was consistent with the results of previous studies. Figure 1 Table 1

P567 Impact of recent thiopurine use on ozanimod safety in patients with ulcerative colitis: a post hoc analysis of the phase 3 True North study

Abstract Background Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved for the treatment of moderately to severely active ulcerative colitis (UC) in adults based on results from the phase 3 True North study (NCT02435992). Reductions in absolute lymphocyte count (ALC) are expected with ozanimod but not associated with treatment-emergent adverse events (TEAEs). This post hoc analysis explored the effect of recent use of thiopurines on ALC and safety outcomes in patients treated with ozanimod. Methods True North was a phase 3 trial of ozanimod induction and maintenance therapy in moderately to severely active UC. Patients in Cohort 1 were randomised to once-daily double-blind treatment with ozanimod 0.92 mg or placebo; patients in Cohort 2 received open-label ozanimod for a 10-week induction period. Patients on concomitant thiopurines were required to stop therapy at study start without a washout period. In this post hoc analysis, patients were stratified by recent prior thiopurine use (within 90 days of ozanimod initiation). ALC was assessed at baseline; ALC, TEAEs, and infectious outcomes were assessed during the induction period at Weeks 5 and 10. Results Of the 1012 patients in True North, 796 were treated with ozanimod and analysed (n=57 with recent thiopurine exposure; n=739 without recent thiopurine exposure). At baseline, mean ALC (×109/L [SD]) was slightly lower in patients with than without recent thiopurine use (Table). Both groups had similar baseline incidence of ALC <200 cells/µL (0%) and <500 cells/µL (range 0.0–0.3%). While ALC <200 cells/µL and <500 cells/µL were more prevalent among patients with than without recent thiopurine use (Figure), the reductions from baseline to Week 10 in ALC were similar in both groups (Table). Rates of infection were also similar in patients with recent thiopurine use (14.7% in Cohort 1 and 13.0% in Cohort 2) and without recent thiopurine use (10.4% and 12.5%, respectively). The most frequent infection was nasopharyngitis in both groups: 8.8% in Cohort 1 and 0% in Cohort 2 in patients with recent thiopurine use; 3.0% and 2.9%, respectively, in patients without recent thiopurine use. There were no serious adverse events (AEs) related to ozanimod treatment, and treatment discontinuations were similar in patients with and without recent thiopurine exposure. Conclusion Lower ALC was observed in patients starting ozanimod within 90 days of thiopurine use but was not associated with an increased incidence of infection or serious AEs. The findings suggest switching from thiopurines to ozanimod without a washout period may be safe and tolerable.

The sphingosine-1-phosphate receptor 1 modulator ponesimod repairs cuprizone-induced demyelination and induces oligodendrocyte differentiation.

Sphingosine-1-phosphate receptor (S1PR) modulators are clinically used to treat relapse-remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα-coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone-induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation invitro.

Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials.

One sphingosine-1-phosphate (S1P) receptor modulator is approved (ozanimod) and another (etrasimod) is under investigation for the induction and maintenance of remission of ulcerative colitis (UC). We aim to evaluate the efficacy and safety of S1P modulators in patients with active UC. We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through May 13th, 2023. We used the fixed-effect model to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI). Five RCTs with a total of 1990 patients were included. S1P receptor modulators were significantly associated with increased clinical response during both the induction (RR 1.71 with 95% CI [1.50, 1.94], P = 0.00001) and maintenance phases (RR 1.89 with 95% CI [1.33, 2.69], P = 0.0004); clinical remission rates during both induction (RR 2.76 with 95% CI [1.88, 4.05], P = 0.00001) and maintenance phases (RR 3.34 with 95% CI [1.41, 7.94], P = 0.006); endoscopic improvement during both induction (RR 2.15 with 95% CI [1.71, 2.70], P = 0.00001) and maintenance phases (RR 2.41 with 95% CI [1.15, 5.05], P = 0.02); and histologic remission during both induction (RR 2.60 with 95% CI [1.89, 3.57] [1.17, 2.10], P = 0.00001) and maintenance phases (RR 2.52 with 95% CI [1.89, 3.37], P = 0.00001). Finally, there was no difference regarding safety outcomes as compared to placebo in both the induction and maintenance phases. S1P receptor modulators are effective in inducing and maintaining remission in patients with moderate to severe UC.

Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease

The motor impairments brought on by the loss of dopaminergic neurons in the substantia nigra are the most well-known symptoms of Parkinson's disease (PD). It is believed that dopaminergic neurons are especially vulnerable to mitochondrial malfunction. For the maintenance of mitochondrial integrity, selective autophagic removal of dysfunctional mitochondria via mitophagy primarily regulated by PINK1/Parkin pathway is essential. Moreover, newer studies also implicate the role of phospholipid metabolism, such as that of Sphingosine-1-phosphate (S1P) as a contributor to PD. S1P receptors have been reported to influence mitochondrial function in neurodegenerative diseases. Fingolimod (FTY720), an S1P receptor-1 modulator has been proven effective in PD but its regulation of mitophagy in PD is still elusive. In this study, the neuroprotective effect of FTY720 by modulating mitophagy, has been explored against rotenone (ROT) induced neurotoxicity in in-vivo. The animals were randomly divided into 5 groups namely, Normal Control (NC); Disease control (DC): ROT (1.5 mg/kg); Low dose (LD): ROT + FTY720 (0.5 mg/kg); High dose (HD): ROT + FTY720 (1 mg/kg) and Vehicle control (VC): 1 % DMSO. ROT was administered through i.p. and FTY720 through p.o. for 21 days. At the end of the study, various neurobehavioral studies (rotarod test and actimeter), western blot techniques, and immunofluorescence studies were performed. FTY720 restored the neurobehavioural functions and protein expression of PINK1, Parkin and BNIP3 in ROT-induced PD mice. The results obtained in our study suggest that FTY720 has a neuroprotective effect in ROT-induced mice model of PD via PINK1-Parkin mediated mitophagy.

Mechanical loading of joint modulates T cells in lymph nodes to regulate osteoarthritis

ObjectiveThe crosstalk of joint pathology with local lymph nodes in osteoarthritis (OA) is poorly understood. We characterized the change in T cells in lymph nodes following load-induced OA and established the association of the presence and migration of T cells to the onset and progression of OA. MethodsWe used an in vivo model of OA to induce mechanical load-induced joint damage. After cyclic tibial compression of mice, we analyzed lymph nodes for T cells using flow cytometry and joint pathology using histology and microcomputed tomography. The role of T-cell migration and presence of T-cell type was examined using TCRα-/- and an immunomodulatory drug, Sphingosine-1-phosphate (S1P) receptor inhibitor-treated mice, respectively. ResultsWe demonstrate a significant increase in T-cell populations in local lymph nodes in response to joint injury in 10, 16, and 26-week-old mice, and as a function of load duration, 1, 2, and 6 weeks. T-cell expression of inflammatory cytokine markers increased in the local lymph nodes and was associated with load-induced OA progression in the mouse knee. Joint loading in TCRα-/- mice reduced both cartilage degeneration (OARSI: TCRα 0.568, 0.981-0.329 CI; WT 1.328, 2.353-0.749 CI) and osteophyte formation. Inhibition of T-cell egress from lymph nodes attenuated load-induced cartilage degradation (OARSI: Fingolimod: 0.509, 1.821-0.142 CI; Saline 1.210, 1.932-0.758 CI) and decreased localization of T cells in the synovium. ConclusionsThese results establish the association of lymph node-resident T cells in joint damage and suggest that the S1P receptor modulators and T-cell immunotherapies could be used to treat OA.

Bioavailable central nervous system disease-modifying therapies for multiple sclerosis.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

Etrasimod (Velsipity) for ulcerative colitis.

The oral sphingosine 1-phosphate (S1P) receptor modulator etrasimod (Velsipity – Pfizer) has been approved by the FDA for treatment of moderately to severely active ulcerative colitis in adults. It is the second oral S1P receptor modulator to be approved in the US for this indication; ozanimod (Zeposia) was the first.

Cardiovascular Safety of Ozanimod in Patients With Ulcerative Colitis: True North and Open-Label Extension Analyses

Evaluating cardiovascular safety of sphingosine 1-phosphate (S1P) receptor modulators is warranted due to S1P receptor expression on cardiomyocytes and vascular endothelial cells. This analysis reports the cardiovascular safety of ozanimod, an S1P receptor modulator, in patients with moderately to severely active ulcerative colitis from the phase 3 True North (TN) and open-label extension (OLE). All patients who received ozanimod in TN (n= 796) and all eligible TN patients who entered the OLE (n= 823) were included. Cardiovascular-related adverse events were evaluated in patients with up to 146 weeks of ozanimod exposure (2219 patient-years), which included 52 weeks during TN. On TN day 1, first-dose ozanimod resulted in a 0.2 beats per minute mean decrease in heart rate from pretreatment to hour 6; 2 patients experienced bradycardia, which resolved without treatment modification. Mean systolic and diastolic blood pressure increases of 5.1 and 2.2 mm Hg, respectively, were observed at TN week 52. No second-degree Mobitz type II atrioventricular block events were reported; 1 third-degree atrioventricular block unrelated to ozanimod occurred in the OLE. Cardiac and vascular treatment-emergent adverse events were infrequent (3.8% [31 of 823] and 8.5% [70 of 823]); no ozanimod-related cardiovascular deaths occurred. The incidences of deep-vein thrombosis (0.2%; 2 of 823), pulmonary embolism (0.2%; 2 of 823), and ischemic stroke (0.4%; 3 of 823) in the OLE were low. No new cardiovascular safety signals were identified, consistent with findings from previous ozanimod studies. There were few major adverse cardiovascular events or thromboembolic events, which were unrelated or unlikely related to ozanimod. Ozanimod has a well-tolerated cardiovascular safety profile when prescribed in accordance with the label. Clinical trial registry website and trial numbers: ClinicalTrials.gov numbers: NCT02435992 and NCT02531126.

Post-vaccination SARS-Cov-2 T-cell receptor repertoires in patients with multiple sclerosis and related disorders.

Attenuation in post-vaccination SARS-CoV-2 humoral responses has been demonstrated in people treated with either anti-CD20 therapies or sphingosine-1-phosphate (S1P) receptor modulators. In the setting of disease modifying therapy (DMT) use, humoral response may not correlate with effective immunity, and analysis of vaccine-mediated SARS-CoV-2-specific memory T-cell responses is crucial. While vaccination in patients treated with anti-CD20 agents leads to deficient antibody production, emerging data from live cell assays suggests intact T-cell responses to vaccination. We evaluated post-vaccination SARS-CoV-2 T-cell receptor (TCR) repertoires in DMT-treated patients using the ImmunoSeqR assay, an assay that does not require live cells. Adults 18-80 years old without prior COVID-19, with neuroimmune conditions, who had been vaccinated with two doses of Pfizer-BioNTech or Moderna mRNA vaccines at least 3 weeks and up to 6 months prior, were recruited. Whole blood was obtained for immunosequencing, and matched serum was obtained for humoral analysis. Immunosequencing of the CDR3 regions of human TCRβ chains was completed using the immunoSEQR Assay (Adaptive Biotechnologies). TCR sequences were mapped across a set of TCR sequences reactive to SARS-CoV-2. Clonal diversity (breadth) and frequency (depth) of TCRs specific to SARS-CoV-2 spike protein were calculated and relationships with clinical variables were assessed. Forty patients were recruited into the study, aged 25-77, and 27 female. 37 had MS, 2 had neuromyelitis optica spectrum disorder (NMOSD), and 1 had hypophysitis. Subjects treated with anti-CD20 agents and S1P receptor modulators had severely attenuated humoral responses, but SARS-CoV-2-spike-specific TCR clonal depth and breadth were robust across all treatment classes except S1P modulators. No spike-specific or non-spike-specific SARS-CoV-2-associated TCRs were found in those treated with S1P modulators (p=0.002 for both breadth and depth). Subjects treated with fumarates exhibited somewhat lower spike TCR breadth than subjects treated with other or no DMTs (median 2.27×10^-5 for fumarates and 4.96×10^-5 for all others, p=0.008), but no statistically significant difference was demonstrated with spike TCR depth. No other significant associations with DMT type were found. We found no significant correlations between depth or breadth and age, duration of treatment, type of vaccination, or time interval since vaccination. This is the first study to characterize post-vaccination SARS-CoV-2 TCR repertoires in DMT-treated individuals. We demonstrated a dichotomous response to SARS-CoV-2 vaccination in anti-CD20-treated patients, with severely attenuated humoral response but intact TCR depth and breadth. It is unclear to what degree each arm of the adaptive immune system impacts post-vaccine immunity, both from the standpoint of incidence of post-vaccine infections and that of infection severity, and further clinical studies are necessary. S1P modulator-treated subjects exhibited both severely attenuated humoral responses and absent spike-specific TCR depth and breadth, information which is crucial for counseling of patients on these agents. Our methodology can be used in larger studies to determine the benefit of repeated vaccination doses, including those that are modified to better target modern or seasonal variants, without the use of live cell assays.

Does cardiovascular risk matter in IBD patients?

Cardiovascular and thromboembolic risks are increasing in the population as a whole and therefore also in inflammatory bowel disease (IBD) patients. Obesity is a worldwide challenge also affecting the IBD population, and a causal association with Crohn's disease may exist. IBD itself, particularly when active, is also associated with a significant risk of thromboembolic and cardiovascular events such as myocardial infarction and stroke. Cardiovascular risk is also a significant consideration when using Janus kinase (JAK) inhibitors and sphingosine 1 phosphate (S1P) receptor modulators to treat IBD. JAK inhibitors - such as tofacitinib - are associated with several cardiovascular and venous thromboembolic risks, including hypertension and alterations in lipid profiles - specifically, increased LDL cholesterol and triglycerides - which may contribute to atherosclerosis and cardiovascular disease. S1P receptor modulators pose a slightly different set of cardiovascular risks. Initially, these drugs can cause transient bradycardia and atrioventricular (AV) block, leading to bradycardia. Moreover, they may induce QT interval prolongation, which increases the risk of life-threatening arrhythmias such as torsades de pointes. Some patients may also experience hypertension as a side effect. In this context, IBD healthcare providers need to be alert to the assessment of cardiovascular risk - particularly as cardiovascular events appear to be confined to specific patient groups with pre-existing risk factors. In addition, the potential for S1P modulator drug interactions requires a higher level of vigilance in patients with polypharmacy compared to biologics. Cardiovascular risk is not static, and updated assessment will need to become part of the routine in many IBD units.

Benefits of sphingosine-1-phosphate receptor modulators in relapsing MS estimated with a treatment sequence model

BackgroundThree sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient's lifespan. MethodsIncorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naïve patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes. ResultsIn deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod. ConclusionOur model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care.

Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors

Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. This trafficking is interdicted by S1P receptor modulators, and it is expected that S1P transporter (Spns2) inhibitors, by reshaping S1P concentration gradients, will do the same. We previously reported SLF1081851 as a prototype Spns2 inhibitor, which provided a scaffold to investigate the importance of the oxadiazole core and the terminal amine. In this report, we disclose a structure–activity relationship study by incorporating imidazole as both a linker and surrogate for a positive charge in SLF1081851. In vitro inhibition of Spns2-dependent S1P transport in HeLa cells identified 7b as an inhibitor with an IC50 of 1.4 ± 0.3 µM. The SAR studies reported herein indicate that imidazolium can be a substitute for the terminal amine in SLF1081851 and that Spns2 inhibition is highly dependent on the lipid alkyl tail length.