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S1P receptor modulators in Multiple Sclerosis: Detecting a potential skin cancer safety signal
Vasileios-Periklis Stamatellos1, Antigony Rigas2, Eleni Stamoula3
1Department of Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Introduction:
S1P receptor modulators are oral Disease-Modifying Therapies (DMTs) for Multiple Sclerosis, which were associated with cases of basal cell carcinoma in clinical trials. This study aims at investigating in a real-world adverse event reporting system whether S1P receptor modulators increase the risk of skin cancer reporting, compared to other DMTs.
Methods:
Adverse event reports from the FDA Adverse Event Reporting System (FAERS) were extracted, cleaned, and analyzed from 2004Q1 until 2020Q4. The crude and adjusted Reported Odds Ratios (cROR, aROR) for the outcomes: basal cell carcinoma, squamous cell carcinoma, or melanoma were calculated for all DMTs. In a sensitivity analysis, we looked at each outcome separately.
Results:
The aROR (95%CI) of siponimod was: 9.68 (5.48-15.79) and of fingolimod 4.54 (3.86-5.32), indicating a safety signal of S1P receptor modulators for skin cancer. Ozanimod had only 52 complete reports without any cases. In the sensitivity analysis, siponimod showed a signal only for basal cell carcinoma: 22.83 (12.27-38.83), while fingolimod for all outcomes separately, including melanoma: 3.02 (2.31-3.89). Notably, among the other DMTs, alemtuzumab: 4.40 (2.98-6.25) and cladribine: 3.28 (1.17-7.13) presented also a signal for disproportionate reporting, while ocrelizumab showed a signal in the sensitivity analysis only for melanoma 2.55 (1.21-4.65).
Conclusions:
S1P receptors seem to increase skin cancer reporting on FAERS, and the association is strongest for basal cell carcinomas. Therefore, close dermatologic surveillance before- and during therapy is needed. Whether fingolimod and ocrelizumab also increase the risk of melanoma needs further investigation.
Insights
Sphingosine-1-phosphate (S1P) receptor modulators may increase skin cancer reporting, particularly basal cell carcinoma, in multiple sclerosis patients. Close dermatologic monitoring is recommended during treatment with these disease-modifying therapies.
Area of Science:
- Neurology
- Dermatology
- Pharmacovigilance
Background:
- Sphingosine-1-phosphate (S1P) receptor modulators are oral Disease-Modifying Therapies (DMTs) for Multiple Sclerosis (MS).
- Clinical trials noted associations between S1P receptor modulators and basal cell carcinoma.
- This study investigates the real-world risk of skin cancer reporting with S1P receptor modulators compared to other MS DMTs.
Purpose of the Study:
- To determine if S1P receptor modulators increase the risk of skin cancer reporting in a real-world setting.
- To compare the risk of skin cancer reporting between different MS DMTs.
- To identify specific skin cancer types associated with S1P receptor modulators.
Main Methods:
- Analysis of adverse event reports from the FDA Adverse Event Reporting System (FAERS) between 2004Q1 and 2020Q4.
- Calculation of crude and adjusted Reported Odds Ratios (cROR, aROR) for basal cell carcinoma, squamous cell carcinoma, and melanoma.
- Sensitivity analysis examining each outcome separately.
Main Results:
- S1P receptor modulators (siponimod and fingolimod) showed a safety signal for skin cancer reporting.
- Siponimod demonstrated a strong signal for basal cell carcinoma (aROR 22.83).
- Fingolimod indicated a signal for all skin cancer types, including melanoma (aROR 3.02).
- Other DMTs like alemtuzumab and cladribine also showed signals for disproportionate reporting; ocrelizumab showed a signal for melanoma.
Conclusions:
- S1P receptor modulators appear to increase skin cancer reporting in FAERS, with basal cell carcinoma being the most strongly associated.
- Close dermatologic surveillance is recommended before and during treatment with S1P receptor modulators.
- Further investigation is needed to confirm if fingolimod and ocrelizumab increase melanoma risk.
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