Multiple sclerosis (MS) is an inflammatory, demyelinating, degenerative, and progressive autoimmune disease that affects the central nervous system (CNS). MS is the most common neurological disease in young adults and causes devastating consequences1–5. Since there is no curative treatment for MS, the therapeutic goal is to control inflammatory activity, reduce the frequency of relapses, and slow the progression of the disease and its growing disability4,5. To achieve this goal, it is necessary to use drugs capable of modifying the natural course of the disease. These agents called “disease-modifying therapies” (DMTs) have revolutionized the management of MS3–8. The number of available drugs in this group has grown in recent years with the approval of new sphingosine 1-phosphate receptor (S1PR) modulators and new monoclonal antibodies (Table 1)3–5,8–10.

Currently, first-line DMTs approved for relapsing forms include interferon β-1a, β-1b, pegylated β-1a, glatiramer acetate, and dimethyl fumarate. Second-line therapies include immunosuppressants such as alemtuzumab, ocrelizumab, natalizumab, cladribine, and S1PR modulators such as fingolimod as the main representatives4,5.

S1PR modulators are oral drugs used in relapsing-remitting MS (RRMS). Their main function is to prevent lymphocyte migration from the lymph nodes to the CNS. Consequently, lymphocytes—capable of causing lymphopenia—remain confined to the lymph node10–12. In 2010, the use of fingolimod, the first drug in this group, was approved by the U.S. Food and Drug Administration (FDA). In 2011, the European Medicines Agency (EMA) authorized its use in Europe. Since then, new drugs from this same group have gained approval10. S1PRs are distributed across multiple tissues, which explains the diversity of adverse effects associated with these drugs (Tables 2 and 3)13. These receptors are expressed in keratinocytes, with S1PR5 being the most relevant receptor subtype14–16. In animal models, the importance of the sphingosine 1-phosphate pathway in dermatoses such as psoriasis or atopic dermatitis has been demonstrated17. As a matter of fact, there is a clinical trial (CT) underway to evaluate the efficacy of oral ponesimod in the management of plaque psoriasis18. On the other hand, it has been hypothesized that S1PR modulators-induced lymphopenia could increase the risk of skin cancer (SC) by hindering the identification of malignant cells11,19. However, there are probably other mechanisms involved that could explain the theoretical increased risk of SC associated with these drugs12,19. The increased risk of SC does not seem to depend on the receptor subtype they act upon but rather is a class effect of S1PR modulators20–28.

Alemtuzumab is a humanized anti-CD52 monoclonal antibody that depletes circulating B and T lymphocytes. It has been approved by the FDA and the EMA for the management of RRMS9,29. Mild nasopharyngeal infections and headaches, and skin disorders such as rash, urticaria, and pruritus are among its most common adverse reactions9,27.

Cladribine is a purine analog that is cytotoxic to lymphocytes and, to a lesser extent, to monocytes and hematopoietic cells9. In 2013, the EMA rejected its approval on suspicion of increased malignant neoplasms9. In 2015, Pakpoor et al. published a meta-analysis of 11 CTs in which no increased neoplastic risk was reported compared to other DMTs30. In 2017, the EMA approved the drug. Rashes, pruritus, alopecia, nummular eczema, and cases of mucositis are some of its skin-related adverse effects31–33. Additionally, cladribine use has been associated with an increased risk of more severe herpetic infections32.

MS does not seem to be associated with an increased risk of neoplasms. However, since DMTs act directly on the immune system and are generally long-term therapies, whether these drugs are associated with a higher risk of cancer has been a major concern9,34. The main DMTs we should take into consideration regarding the risk of SC are S1PR modulators, which are particularly associated with basal cell carcinoma (BCC)10,20–24,27,28,35–37. This risk does not seem to be present in other DMTs9,10,38–41. However, there is controversy surrounding the use of alemtuzumab and cladribine10,29,42–46. Our objective is to review the existing evidence on the risk of DMT-related SC and provide recommendations on the dermatological follow-up of these patients.

We conducted a narrative literature review in July 2023. The search was conducted across Medline and Google Scholar databases using the terms “multiple sclerosis,” “disease-modifying therapies,” “fingolimod,” “siponimod,” “ozanimod,” “ponesimod,” “sphingosine 1-phosphate receptor modulators,” “natalizumab,” “ocrelizumab,” “teriflunomide,” “alemtuzumab,” “cladribine,” “skin,” “cutaneous cancer,” “basal cell carcinoma,” “squamous cell carcinoma,” “melanoma,” “clinical trial,” “post-authorization safety study,” “pharmacovigilance study,” and “meta-analysis.” We included studies written in Spanish and English. We selected phase 3 CTs with a follow-up of 1 or more years, post-authorization studies (PAS) and pharmacovigilance studies (PVS), meta-analyses, systematic and narrative reviews, and cohort studies. We excluded studies with ≤ 3 patients and those that did not clearly specify their methodology. In the included studies with sufficient data, we estimated the odds ratio (OR) for the development of SC. The 3 authors (MBC, MMP, DMC) conducted the search and selected the articles.

MS is a disease with extremely high morbidity and mortality rates and, until recently, with limited therapeutic options2,3,8. MS patients tend to be young, which highlights the importance of establishing a safe and effective therapeutic plan1. The present review found that S1PR modulators—particularly fingolimod and siponimod—may be associated with an increased risk of SC, especially BCC. This increase could be up to 4 to 9 times higher, though it varies considerably depending on the studies evaluated (Table 4)10,36,37. Conversely, alemtuzumab and cladribine do not seem to be associated with a significant risk10,29,42–46,50. For the remaining DMTs, the development of SC has not been consistently reported9,10,38–41.

Based on the supposed risk of SC, the EMA issued a communication back in 2015 warning about the danger of fingolimod-related BCC, contraindicating its use in the presence of an active neoplasm and recommending a dermatological exam before starting the drug and annually thereafter51. However, we have not found any clinical guidelines on the dermatological follow-up of these subjects, nor prospective studies demonstrating that such follow-up reduces SC-related morbidity and mortality.

The increased risk of SC has already been reported in widely used drugs such as hydrochlorothiazide52, whose chronic use can increase the likelihood of SC, especially cSCC (with up to 4-time higher increases), but also BCC, while, at this point, the association with melanoma remains weak53–55. Other drugs associated with a higher risk of SC include, among many others, calcium channel blockers, angiotensin-converting enzyme inhibitors, TNF inhibitors, Janus kinase (JAK) inhibitors, and classic immunosuppressants55–61. However, in most cases, there is not a single guideline on the regular dermatology follow-up, and the burden on the health care system could make the massive systematic screening and monitoring of these patients not cost-effective. We should also mention that the main studies reviewed on S1PR modulators do not provide any information on the location of the SC, its histological subtype, its progression, or response to treatment. If these drugs were associated with aggressive histological variants or high-risk locations, this would justify the comprehensive screening of these individuals. Dubrall et al. recently published a study on adverse event reporting in Germany on cases of BCC and cSCC related to various drugs, including fingolimod. They did not find any significant differences in the location of cSCC and BCC vs spontaneous occurrences52. We believe that the dermatological follow-up of patients on S1PR modulators such as fingolimod and siponimod should be individualized and based on each subject's individual risk profile, considering, among other, factors such as age, personal and family history of SC, actinic damage, and the presence of other drugs that could increase the risk. Additionally, the role of the general practitioner in monitoring these individuals, especially those at lower risk, should be taken into consideration. Individualized monitoring strategies are recommended for solid organ transplant recipients, who may have up to a 200-fold increased risk of developing SC, particularly cSCC, which tends to be more aggressive and has a higher metastasis rate62–65. These patients are currently recommended to undergo screening and follow-up based on their risk profile. Risk stratification scales such as the Skin and UV Neoplasia Transplant Risk Assessment Calculator (SUNTRAC®)65,66, which includes factors such as age, race, age at transplant, history of SC before transplant, and transplant type, have recently been validated for the European population66.

This study has the limitations of being a narrative rather than a systematic review. Additionally, the follow-up period of most studies is relatively short (<5 years), which limits the assessment of long-term risk of SC, especially for neoplasms with long latency periods.

MS is associated with high morbidity and mortality rates, predominantly affecting young people. More drugs are being approved to fight this disease. For S1PR modulators such as fingolimod and siponimod—associated with an increased risk of SC—it is essential for dermatologists and general practitioners to be well-informed on these agents and conduct necessary dermatological evaluations individualized to meet the risk profile of each patient. However, this review did not find any clinical guidelines or prospective studies demonstrating that the maintained long-term dermatological follow-up of individuals on DMTs has a positive impact on morbidity and mortality. Finally, conducting a meta-analysis/systematic review to evaluate the risk of DMT-related SC would be advisable.

None declared.

None declared.