Abstract
Introduction
Sphingosine-1-phosphate (S1P) receptor modulators, regulating the S1P/S1PR pathway, lead to lymphocyte sequestration in lymphoid organs, which results in peripheral lymphopenia. This study evaluates the degree of lymphopenia induced by S1P modulators in people with Multiple Sclerosis (MS): Ozanimod, Siponimod, Ponesimod, and Fingolimod.
Methods
We conducted a retrospective multicenter study across thirteen MS centers in Italy, including 191 MS patients (mean age 46.4 years; 61.3% women). Of these, 28.8% received Siponimod, 26.2% Ozanimod, 24.1% Fingolimod, and 20.9% Ponesimod. Lymphocyte counts were measured at baseline (T0), one month (T1), three months (T3), and six months (T6) post-treatment. Lymphopenia grades range from 0 (≥ 1.0 × 10^9 cells/L) to 4 (< 0.2 × 10^9 cells/L), according to Common Terminology Criteria for Adverse Events.
Results
At T1, Ozanimod showed a significantly higher mean lymphocyte count than Siponimod and Fingolimod (p < 0.001), Ponesimod higher mean lymphocyte count than Siponimod (p = 0.006). The differences persisted between Ozanimod than Siponimod and Fingolimod at T3 (p = 0.01 and p = 0.04), and between Ponesimod and Siponimod at T6 (p = 0.03). Severe lymphopenia cases were significantly higher in Siponimod than in Ponesimod and Ozanimod, at T1 (p = 0.001 and p = 0.0001). The differences remained significant between Ozanimod and Siponimod, at T3 (p = 0.001), and between Ponesimod and Siponimod, Fingolimod and Ozanimod, at T6 (p = 0.001). Grade 4 lymphopenia was observed in Ozanimod and Siponimod at T3.
Conclusion
This is the first real-world, head-to-head observational study comparing lymphopenia among different S1P modulators. Our results might assist in therapy choice depending on patients baseline hematological characteristics.
Keywords: Multiple sclerosis, Sphingosine-1-phosphate receptor modulators, Lymphopenia
Introduction
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced by sphingosine kinase, and it interacts with five S1P receptor subtypes (S1PR1-5) to regulate various cellular functions such as immune cell proliferation, survival, adhesion, and migration [1]. S1PR1, expressed on lymphocytes, controls the egress of these cells from lymphoid organs into the bloodstream, thereby playing a pivotal role in lymphocyte trafficking [2]. Due to this function, S1P receptor modulators, which sequester lymphocytes in lymphoid tissues, have been developed and employed in autoimmune diseases like multiple sclerosis (MS).
Several S1P modulators have been approved for MS treatment: Fingolimod (FTY720) [3, 4], Siponimod (BAF312) [5], Ozanimod (RPC1063) [6, 7], and Ponesimod (ACT-128800) [8]. These drugs are effective in reducing brain lesions, annualized relapse rate and slowing disease progression [3–8]. However, they vary in their receptor affinity profiles, with Fingolimod targeting S1PR1, S1PR3, S1PR4, and S1PR5 [9], while Siponimod and Ozanimod selectively engage S1PR1 and S1PR5 [10], and Ponesimod is a selective S1PR1 modulator [11]. This differential receptor targeting may influence the degree of lymphocyte sequestration and resultant lymphopenia, which is a known safety concern.
This study aims to compare the degrees of lymphopenia induced by these S1P modulators in a real-world cohort of MS patients.
Methods
We conducted a retrospective, multicenter study across 13 MS centers in Italy. The inclusion criteria were based on a diagnosis of MS according to the McDonald criteria [12] and ongoing treatment with one of the four approved S1P modulators, as part of routine clinical care. Patients previously treated with another S1P modulator were excluded. Lymphocyte counts were measured locally, in keeping with the observational, real-world nature of the study., at baseline (T0), one month (T1), three months (T3), and six months (T6) following the initiation of S1P modulator therapy, based on clinical practice for monitoring Lymphopenia was defined and graded according to Common Terminology Criteria for Adverse Events (CTCAE) [13] as follows: grade 0 (normal): ≥ 1.0 × 109 cells/L; grade 1: 0.8–0.999 × 109 cells/L; grade 2: 0.5–0.799 × 109 cells/L; grade 3: 0.2–0.499 × 109 cells/L; grade 4: < 0.200 × 109 cells/L. The study was submitted to the local ethics committee and conducted in accordance with the Declaration of Helsinki.
Statistical analysis
Mean values and standard deviation (sd) were calculated for numerical variables such as age, Expanded Disability Status Scale (EDSS) score, disease duration and lymphocyte count.
Data were analyzed using descriptive statistics. Shapiro–Wilk test was used to assess the normality of continuous variables. The Chi-square test was used to examine differences in categorical variables. To analyze differences in mean lymphocyte values at different time points (T0, T1, T3, and T6), an Analysis of Covariance (ANCOVA) was conducted, adjusting for baseline covariates such as age, disease duration, EDSS, sex, and previous DMTs. Post hoc tests were performed to assess differences between the various S1P modulators treatment. Effect sizes were evaluated using Cohen’s d. Statistical significance was defined as p < 0.05. All analyses were conducted using Jamovi version 2.3.18.
Results
Cohort characteristics
According to inclusion and exclusion criteria, a total of 191 pwMS were enrolled in the study. Table 1 shows the demographic and clinical variables at baseline of our MS population. Mean (sd) age was 46.4 (± 11.8) years. Women were predominant (n = 117, 61.3%). The mean time (sd) since diagnosis was 127 (± 113) months.
Table 1.
Patient demographics and clinical characteristics
| Patients cohort | n = 191 | Ozanimod (n = 50) | Siponimod (n = 55) |
Ponesimod (n = 40) | Fingolimod (n = 46) |
p value |
|---|---|---|---|---|---|---|
| % of total | 26.2% | 28.8% | 20.9% | 24.1% | > 0.05 | |
| Sex, n (%) | 0.35 | |||||
| Female | 117 (61.3) | 26 (52) | 33 (60) | 27 (67.5) | 31 (67.4) | |
| Male | 74 (38.7) | 24 (48) | 22 (40) | 13 (32.5) | 15 (32.6) | |
| Age, mean (± sd) | 46.4 (± 11.8) | 46 (± 11.6) | 54.8 (± 7.7) | 44.4 (± 11.8) | 38.5 (± 9.8) | < 0.001 |
| Disease duration, mean (± sd) (months) | 127 (± 113) | 106 (104) | 199 (111) | 120 (113) | 72 (77.6) | < 0.001 |
| MS type, n (%) | < 0.001 | |||||
| Relapsing Remitting (RRMS) | 142 (74.3) | 48 (96) | 10 (18.2) | 40 (100) | 44 (95.7) | |
| Primary Progressive (PPMS) | 2 (1.1) | 0 | 2 (3.6) | 0 | 0 | |
| Secondary progressive (SPMS) | 47 (24.6) | 2 (4) | 43 (78.2) | 0 | 2 (4.3) | |
| EDSS, median (25–75 IQR) | 2.0 (3.0) | 1.5 (1.5) | 6 (1.88) | 2 (1.0) | 2 (1.0) | < 0.001 |
| Prior DMT, n (%) | ||||||
| Platform | 74 (38.7) | 12 (24) | 15 (27.3) | 13 (32.5) | 34 (74) | |
| Naive | 46 (24.1) | 19 (38) | 10 (18.2) | 10 (25) | 7 (15.2) | |
| DimethylFumarate | 29 (15.2) | 7 (14) | 9 (16.4) | 11 (27.5) | 2 (4.3) | |
| Teriflunomide | 21 (11.0) | 7 (14) | 9 (16.4) | 5 (12.5) | 0 | |
| Natalizumab | 9 (4.7) | 2 (4) | 4 (7.3) | 0 | 3 (6.5) | |
| Ocrelizumab | 5 (2.6) | 1 (2) | 4 (7.3) | 0 | 0 | |
| Other | 4 (2.1) | 0 | 3 (5.4) | 1 (2.5) | 0 | |
| Cladribine | 3 (1.6) | 2 (4) | 1 (1.7) | 0 | 0 |
The bold text indicates statistically significant values
142/191 patients (74.3%) were diagnosed with Relapsing Remitting MS (RRMS), 47 (24.6%) had Secondary Progressive MS (SPMS) and 2 (1.1%) Primary Progressive MS (PPMS). Median (IQR) EDSS was 2.0 (3.0).
55/191 (28.8%) received Siponimod, 50/191 (26.2%) Ozanimod, 46/191 (24.1%) Fingolimod and 10/191 (20.4.2%) Ponesimod.
Before S1P initiation, 74 (38.7%) patients were previously treated with platform therapies, 46 (24.1%) were naive, 29 (15.2%) had been treated with dimethylfumarate, 21 (11.0%) with teriflunomide, 9 (4.7%) with natalizumab, 5 (2.6%) with ocrelizumab, 3 (1.6%) were priorly treated with cladribine and 4 (2.1%) with other DMTs.
Analysis of mean lymphocyte counts
The trend of lymphocyte counts at the four timepoints is summarized in Fig. 1.
Fig. 1.
Trend of lymphocyte counts at the four timepoints
The differences between lymphocyte counts among the S1P modulators are shown in Table 2.
Table 2.
ALC for different S1P modulators
| S1P type | Baseline (T0) (n = 191) | T1 (n = 169) | T3 (n = 154) | T6 (n = 130) |
|---|---|---|---|---|
| Ozanimod, mean (± sd) | 1899 (± 837) | 1105 (± 521) | 880 (± 431) | 837 (± 476) |
| Siponimod, mean (± sd) | 1822 (± 784) | 608 (± 277) | 607 (± 346) | 598 (± 340) |
| Ponesimod, mean (± sd) | 1662 (± 671) | 921 (± 355) | 790 (± 377) | 818 (± 263) |
| Fingolimod, mean (± sd) | 1958 (± 947) | 751 (± 314) | 656 (± 237) | 659 (± 317) |
| Post-hoc test (Cohen’s d) | ||||
| Ozanimod—Siponimod | 0.49 | < 0.001 (1.28) | 0.01 (0.78) | 0.07 (0.66) |
| Ozanimod—Fingolimod | 0.70 | < 0.001 (0.87) | 0.04 (0.55) | 0.23 (0.35) |
| Ponesimod-Siponimod | 0.94 | 0.006 (0.89) | 0.07 (0.56) | 0.03 (0.79) |
| Fingolimod-Siponimod | 0.35 | 0.23 (0.40) | 0.50 (0.22) | 0.39 (0.31) |
| Ponesimod—Fingolimod | 0.25 | 0.06 (0.48) | 0.21 (0.33) | 0.12 (0.48) |
| Ozanimod- Ponesimod | 0.40 | 0.10 (0.38) | 0.41 (0.21) | 0.68 (0.13) |
The bold text indicates statistically significant values
At baseline, there were no significant differences in mean lymphocyte counts among the four S1P modulators. As expected, all S1P modulators induced the greatest reduction in lymphocyte counts within the first month of treatment (T0 to T1). Throughout the observation period (T1 to T6), siponimod had the lowest lymphocyte values, while ozanimod had the highest.
At T1, ozanimod showed a significantly higher mean lymphocyte count than both siponimod (1105 vs. 608; p < 0.001) and fingolimod (1105 vs. 751; p < 0.001). Another difference was highlighted between ponesimod and siponimod (921 vs. 608; p = 0.006).
At T3 the different lymphocyte counts between ozanimod and siponimod were persistently significant (p = 0.01), and between ozanimod and fingolimod (p = 0.04).
At T6, ponesimod showed significantly higher lymphocyte count than siponimod (818 vs. 598; p = 0.03).
Analysis of severe lymphopenia
The study also assessed the incidence of severe lymphopenia (grades 3 and 4) among patients treated with the S1P modulators (Fig. 2 and Table 3).
Fig. 2.
Combined percentage of cases presenting severe lymphopenia (Grade 3 + Grade 4) attributed to different S1P modulators at timepoints T1, T3, and T6
Table 3.
Comparison of severe lymphopenia (grade 3 + grade 4) among S1P modulators at T1, T3, T6
| T1 p value | T3 p value | T6 p value | |
|---|---|---|---|
| Ozanimod- Fingolimod | 0.28 | 0.56 | 0.79 |
| Siponimod-Fingolimod | 0.10 | 0.29 | 0.31 |
| Ponesimod-Fingolimod | 0.29 | 0.97 | 0.01 |
| Ponesimod-Ozanimod | 0.97 | 0.6 | 0.01 |
| Ponesimod- Siponimod | 0.01 | 0.3 | 0.01 |
| Ozanimod- Siponimod | < 0.01 | 0.01 | 0.98 |
The bold text indicates statistically significant values
At T1, cases of severe lymphopenia were significantly higher in siponimod than in ponesimod and ozanimod (p = 0,001 and p = 0,0001). At T3, the difference remained significant only between ozanimod and siponimod (p = 0,001). At T6, ponesimod had significantly less cases of severe lymphopenia compared to siponimod, fingolimod and ozanimod (p = 0,001).
We also considered grade 3 and grade 4 separately (Fig. 3 and Table 4).
Fig. 3.
Percentage of cases with grade 3 and grade 4 lymphopenia separately reported across different S1P modulators at timepoints T1, T3, and T6
Table 4.
Comparison of grade 3 and grade 4 lymphopenia among S1P modulators at T1, T3, T6
| T1 p value | T3 p value | T6 p value | ||||
|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 | Grade 3 | Grade 4 | Grade 3 | Grade 4 | |
| Ozanimod- Fingolimod | 0.28 | - | 0.37 | - | 0.79 | - |
| Siponimod-Fingolimod | 0.10 | - | - | 0.31 | - | |
| Ponesimod-Fingolimod | 0.29 | - | 0.97 | - | 0.01 | - |
| Ponesimod-Ozanimod | 0.97 | - | - | 0.01 | - | |
| Ponesimod- Siponimod | 0.01 | - | - | 0.01 | - | |
| Ozanimod- Siponimod | < 0.01 | - | 0.44 | 0.98 | - | |
The bold text indicates statistically significant values
All S1P modulators induced grade 3 lymphopenia, at each time point (from T1 to T6), with cases of grade 3 lymphopenia significantly higher in siponimod than in ponesimod and ozanimod (p = 0,001 and 0,0001) at T1.
At T6, ponesimod had significantly less cases of grade 3 lymphopenia compared to siponimod, fingolimod and ozanimod (p = 0,001).
Grade 4 lymphopenia was induced only by ozanimod and siponimod at T3, and particularly in siponimod more than in ozanimod, although the difference is not statistically significant (p = 0.44).
Discussion
Our retrospective, multicenter study is the first real-world investigation to directly compare absolute lymphocyte counts (ALCs) across the four S1PR modulators approved for MS treatment. In a cohort of 191 MS patients, we analyzed mean ALCs over six months following treatment initiation and assessed the degree of lymphopenia associated with each S1P modulator.
S1P modulators exert their pharmacodynamic effects by sequestering lymphocytes within lymphoid tissues, via interaction with S1P receptors. However, the extent of lymphocyte reduction varies among the different agents, largely due to differences in receptor binding affinity. Fingolimod binds S1PR 1,3,4 and 5; siponimod and ozanimod selectively target S1PR 1 and S1PR 5. Ponesimod, the most selective agent, exclusively binds S1PR 1.
Although lymphocyte reduction is not directly with therapeutic efficacy [14, 15], it raises safety concerns, particularly regarding increased susceptibility to viral infections [16]. Fingolimod trials have demonstrated that ALC nadirs are influenced by baseline lymphocyte levels, sex, and BMI [17]. Regulatory trials reported mean nadirs of approximately 500/μL for fingolimod, 800/μL for ozanimod, 560/μL for siponimod, and 650/μL for ponesimod [18]. The corresponding relative lymphocyte reductions were 70–80% for fingolimod and siponimod, 55% for ozanimod, and 60–70% for ponesimod [18]. Our study is the first to directly compare all four S1P modulators in a real-world context, as no head-to-head clinical trials have been conducted. All agents induced the greatest reduction in ALCs within the first month of treatment and levels remained below the normal range throughout the six-month observation period. At six months mean ALC reductions were 66.3% for fingolimod, 55.9% for ozanimod, 67.2% for siponimod, 50.8% for ponesimod, findings consistent with previous studies.
Siponimod was associated with significantly lower mean ALC compared to both ozanimod, (at months 1 and 3), and ponesimod, (at months 1 and 6).
Conversely, differences with fingolimod emerged earlier with ozanimod (at month 3). These results are in line with other recent findings [19].
Ozanimod was associated with a lower reporting frequency of lymphopenia compared to both siponimod and fingolimod. These results also align with previous findings. A comparative analysis of 1-year outcomes using matching-adjusted indirect comparisons, found ozanimod to be associated with significantly higher mean ALCs compared to fingolimod [20]. In Swallow et al. study, the difference between the two drugs in ALC was 0.4 × 109/l, in our study at T1 it was 0.35 × 109/l.
Grade 4 lymphopenia was reported in 1% of patients in both the EXPAND trial for siponimod [5] and the TRANSFORMS trial for fingolimod [4]. In the FREEDOMS trial, the incidence was 0.5% for for fingolimod [3]; for ozanimod, severe lymphopenia was observed in 2.5% and 4.2% of patients in the SUNBEAM and RADIANCE trials, respectively [6, 7]. The OPTIMUM trial for ponesimod [8] did not specify rates of grade 4 lymphopenia, although it was listed among the reasons for treatment discontinuation.
While clinical trial data indicate a range of 0.5–4.2% for severe lymphopenia, real-world studies suggest higher rates. For fingolimod, grade 4 lymphopenia has been observed in 2.2–15% of patients, and has been associated with low baseline ALC and prior treatment history [15, 21, 22]. Real-world studies on siponimod reported grade 4 lymphopenia in 8.5% of patients within the firt month of treatment, without significant clinical correlates [23]. Data on ozanimod and ponesimod in real world setting remain limited, although some insights have been drawn from studies on treatment transitions among S1P modulators [24, 25].
In our cohort, grade 4 lymphopenia occurred only in patients treated with ozanimod (2.9%) and siponimod (6.8%), consistent with findings from the SUNBEAM and RADIANCE trials and Gilmartin study [6, 7, 23]. In contrast, no cases of grade 4 lymphopenia were observed in patients treated with fingolimod, in line with the relatively low rates reported in pivotal trials [3, 4].
The differential severity and trajectory of lymphopenia associated with each S1PR modulator may guide clinicians in choosing appropriate therapy and tailoring patient monitoring strategies. Although hematologic monitoring guidelines remain consistent across all S1P modulators, the significantly lower lymphocyte counts and higher incidence of severe lymphopenia in patients treated with siponimod, especially early in treatment, compared to ponesimod and ozanimod, highlight the need for greater attention in hematologic monitoring in this subgroup. Identifying patients who are likely to develop Grade 4 lymphopenia, particularly with Ozanimod and Siponimod at T3, allows clinicians to proactively manage treatment plans based on individual risk.
Limitations
Unlike randomized clinical trials, real-world studies reflect routine clinical practice and therefore encompass a broader spectrum of patient characteristics, including variability in age, disease duration, EDSS scores, and MS phenotypes. Notably, patients treated with siponimod tend to have a higher mean age, longer disease duration, and greater disability, consistent with its indication for SPMS. Nevertheless, in our study, there were no significant differences in baseline mean ALCs among the four treatment groups.
Conclusions
This real-world analysis demonstrates significant variability in lymphocyte reduction across the four approved S1P receptor modulators. These findings offer valuable guidance for clinicians in tailoring S1P modulator therapy to individual patients, balancing efficacy with the risk of lymphopenia and potential infection. Further real-world studies are needed to evaluate the incidence and severity of long-term lymphopenia, and to explore its clinical implications, particularly infection risk and post-treatment lymphocyte recovery in pwMS receiving S1P modulators.
Funding
Open access funding provided by Università degli Studi della Campania Luigi Vanvitelli within the CRUI-CARE Agreement.
Declarations
Conflicts of interest
The authors declare that they have no conflict of interest.
References
- 1.Spiegel S, Milstien S (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11:403–415 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Baeyens AAL, Schwab SR (2020) Finding a way out: S1P signaling and immune cell migration. Annu Rev Immunol 38:759–784 [DOI] [PubMed] [Google Scholar]
- 3.Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P, FREEDOMS Study Group (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362(5):387–401 [DOI] [PubMed] [Google Scholar]
- 4.Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L (2010) TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362(5):402–415 [DOI] [PubMed] [Google Scholar]
- 5.Kappos L, BarOr A, Cree BAC, Fox RJ, Giovannoni G, Gold R et al (2018) EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double blind, randomised, phase 3 study. Lancet. 391(10127):1263–1273 [DOI] [PubMed] [Google Scholar]
- 6.Cohen JA, Comi G, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Huang V, Kappos L (2019) RADIANCE Trial Investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. Lancet Neurol. 18(11):1021–1033 [DOI] [PubMed] [Google Scholar]
- 7.Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, Hartung HP, Montalban X, Kubala Havrdová E, Cree BAC, Sheffield JK, Minton N, Raghupathi K, Ding N, Cohen JA, SUNBEAM Study Investigators (2019) Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol 18(11):1009–1020 [DOI] [PubMed] [Google Scholar]
- 8.Kappos L, Fox RJ, Burcklen M, Freedman MS, Havrdová EK, Hennessy B, Hohlfeld R, Lublin F, Montalban X, Pozzilli C, Scherz T, D’Ambrosio D, Linscheid P, Vaclavkova A, Pirozek-Lawniczek M, Kracker H, Sprenger T (2021) Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study: a randomized clinical trial. JAMA Neurol 78(5):558–567 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mehling M, Kappos L, Derfuss T (2011) Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr Neurol Neurosci Rep 11:492–497 [DOI] [PubMed] [Google Scholar]
- 10.Derfuss T, Mehling M, Papadopoulou A, Bar-Or A, Cohen JA, Kappos L (2020) Advances in oral immunomodulating therapies in relapsing multiple sclerosis. Lancet Neurol 19:336–347 [DOI] [PubMed] [Google Scholar]
- 11.Markham A (2021) Ponesimod: first approval. Drugs 81:957–962 [DOI] [PubMed] [Google Scholar]
- 12.Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G et al (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17(2):162 [DOI] [PubMed] [Google Scholar]
- 13.U.S. Department of health and human services: Common Terminology Criteria for Adverse Events (CTCAE) Version5.0 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.
- 14.Fragoso YD, Spelman T, Boz C, Alroughani R, Lugaresi A, Vucic S et al (2018) Lymphocyte count in peripheral blood is not associated with the level of clinical response to treatment with fingolimod. Mult Scler Relat Disord 19:105-108.3 [DOI] [PubMed] [Google Scholar]
- 15.Boffa G, Bruschi N, Cellerino M, Lapucci C, Novi G, Sbragia E et al (2020) Fingolimod and dimethyl-fumarate-derived lymphopenia is not associated with short-term treatment response and risk of infections in a real-life MS population. CNS Drugs 34:425–432 [DOI] [PubMed] [Google Scholar]
- 16.Arvin AM, Wolinsky JS, Kappos L et al (2015) Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol 72(1):31–39 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Warnke C, Dehmel T, Ramanujam R et al (2014) Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology 83:2153–2157 [DOI] [PubMed] [Google Scholar]
- 18.Ruggieri S, Quartuccio ME, Prosperini L (2022) Ponesimod in the treatment of relapsing forms of multiple sclerosis: an update on the emerging clinical data. Degener Neurol Neuromuscul Dis 12:61–73 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Balzano N, Di Napoli R, Fraenza F et al (2025) Lymphopenia associated with sphingosine 1-phosphate receptor modulators (S1PRMs) in multiple sclerosis: analysis of European pharmacovigilance data. Pharmacol Rep 77:775–788 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Swallow E, Patterson-Lomba O, Yin L, Mehta R, Pelletier C, Kao D, Sheffield JK, Stonehouse T, Signorovitch J (2020) Comparative safety and efficacy of ozanimod versus fingolimod for relapsing multiple sclerosis. J Comp Eff Res 9(4):275–285 [DOI] [PubMed] [Google Scholar]
- 21.Warnke C, Dehmel T, Ramanujam R, Holmen C, Nordin N, Wolfram K, Leussink VI, Hartung HP, Olsson T, Kieseier BC (2014) Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology 83(23):2153–2157 [DOI] [PubMed] [Google Scholar]
- 22.Ohtani R, Mori M, Uchida T, Uzawa A, Masuda H, Liu J, Kuwabara S (2018) Risk factors for fingolimod-induced lymphopenia in multiple sclerosis. Mult Scler J Exp Transl Clin 4(1):2055217318759692 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Gilmartin CG, Hoyle N, Garjani A, Dixon T, Jos H, Paling D, Brownlee W, Tench C, Evangelou N (2024) Real-world data on siponimod-related lymphopenia among people with secondary progressive multiple sclerosis. Mult Scler 30(4–5):600–604 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Sparaco M, Miele G, Bonavita S (2021) Severe lymphopenia switching from Fingolimod to Siponimod. Neurol Sci 42(11):4837–4838 [DOI] [PubMed] [Google Scholar]
- 25.Caliendo D, Grassia MC, Carotenuto A, Petracca M, Lanzillo R, Brescia Morra V, Moccia M (2024) Switching to ozanimod as a strategy to adjust fingolimod-related lymphopenia. Mult Scler Relat Disord 81:105135 [DOI] [PubMed] [Google Scholar]