Abstract
Background
Fingolimod was approved in 2010 for the treatment of relapsing-remitting multiple sclerosis, generally as second-line therapy. While its efficacy in reducing the relapse rate is well-recognized, the dermatologic complications of fingolimod remain unexplored. Herein, we aimed to report our experience with multiple sclerosis patients treated with fingolimod who underwent periodic dermatologic examinations.
Materials and Methods
A prospective cohort of 323 patients with multiple sclerosis treated with fingolimod were assessed for dermatologic manifestations over 60 months. The neurologic and dermatologic examinations were done biannually to identify and categorize skin-related adverse events.
Results
Over a mean follow-up of 60 months, of the 323 patients, 32.19% (104 patients) developed skin abnormalities after a mean interval of 25.77 ± 24.36 months since fingolimod initiation. The majority of patients (91.34%) were female, with a mean age of 36.40 ± 7.45 years and a mean disease duration of 122 ± 58.56 months. The most common findings included melanocytic nevus (65.38%) and infectious lesions (11.53%). The severity of skin lesions varied, with most cases manageable with topical treatments. However, ten patients (9.61%) who developed refractory genital human papillomavirus (n = 2), melanocytic nevus (n = 3), dysplastic nevi (n = 3), fibrous papules (n = 1), and molluscum contagiosum (n = 1) had to discontinue their treatment.
Conclusion
Fingolimod treatment in patients with multiple sclerosis is associated with a range of dermatologic findings, predominantly mild to moderate in severity. This population warrants awareness of these potential adverse events and regular follow-up.
Introduction
Multiple sclerosis (MS) is an autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. (1) The approval of various disease-modifying therapies (DMTs) in recent years has significantly changed the course of the disease.1–3 Fingolimod (FTY720, Gilenya, Novartis Pharmaceuticals AG, Basel, Switzerland) was the first oral DMT approved by the FDA in 2010 for the treatment of patients with highly active relapsing-remitting (RR) form of MS. It is a sphingosine 1-phosphate (S1P) receptor modulator derived from the fungus Isaria sinclairii as its metabolic product, which blocks lymphocyte egress from secondary lymphoid organs to the peripheral blood circulation leading to reduced peripheral lymphocyte counts, including potentially encephalitogenic T cells.4–6
In Iran, fingolimod was registered in 2011 and has been widely launched since 2012 in the pharmaceutical market. 7 Apart from the most common adverse events associated with fingolimod, there are few reports of serious cutaneous adverse effects concerning fingolimod treatment in the literature, such as Kaposi sarcoma, peripheral vascular adverse effects, ecchymotic angioedema-like cutaneous lesions, and lymphomatoid papulosis. 8 Further, there are a few reports highlighting a possible association between the use of fingolimod and the occurrence of malignant melanoma in patients with MS (PwMS).9–11
Owing to the fact that little information exists about skin complications in patients after treatment with fingolimod, we aimed to report the dermatologic abnormalities in PwMS treated with fingolimod with a mean follow-up time of 5 years.
Materials and methods
Study design
This observational study was conducted between April 2011 and April 2021 at the Arya Neurological Center, Tehran, Iran, to identify the dermatological findings in PwMS treated with fingolimod. The study was reviewed and approved by the local Institutional Review Board (Royan Institute). Moreover, according to the Helsinki Declaration, all individuals were provided with written informed consent for participation and publication.
Study population
Patients diagnosed with RRMS based on the latest McDonald's criteria (McDonald 2010 and then up to 2017, according to the long enrolling time) who started treatment with fingolimod were included. Patients with incomplete follow-up, patients without a dermatologic examination at fingolimod initiation, patients with a history of skin disorder before fingolimod initiation, and those who did not consent to participate were excluded. Ultimately, 323 patients met the eligibility criteria. Then the findings have been categorized into pigmented, infectious, and inflammatory lesions. If a dermatological finding would not fit into this categorization, we put it as “other lesions.”
Study measures and objectives
First, a questionnaire of demographic and MS-related characteristics of the patients consisting of age, sex, comorbidities, disease duration, neurological status based on the Expanded Disability Status Scale (EDSS), and previous DMT was filled out. Then, the patients underwent skin examination by a dermatologist at initiation and biannually for 2 years according to our protocol, followed by annual skin screening for a mean follow-up of 36 months. In each visit, the dermatologic findings were recorded. In patients with skin lesions, the distribution of the lesions, the supplementary investigations, and treatment, including fingolimod cessation and the recovery of skin lesions, were all reported.
We classified the dermatological findings into four groups:
Pigmented lesions, including nevus formation, atypical melanocytic neoplasms (AMN), post-inflammatory hyperpigmentation (PIH), melasma, cherry angioma, bruises, solar lentigo, freckles, and any other skin neoplasms. Infectious lesions, including herpes zoster virus (HZV), herpes simplex virus (HSV), human papillomavirus (HPV), onychomycosis, molluscum contagiosum, tinea versicolor, and fungal infection. Inflammatory lesions: Urticaria, vasculitis, oral aphthous, eczematous eruption, and psoriasis. Others: Skin dryness, nail changes, pruritus, local hypertrichosis, and acne vulgaris.
Statistical analysis
Statistical analyses were conducted using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± SD and categorical variables as numbers (percentage). The normality of the variables was checked with the Kolmogorov-Smirnov test.
Results
Baseline characteristics
We identified 487 PwMS who started fingolimod at the time of study, of whom 323 completed skin examinations during the follow-up period. A total of 104 patients developed dermatologic complications, about whom we are discussing in the following.
As shown in Table 1, 91.34% of the patients were female with a mean age of 36.40 ± 7.45 years and a mean disease duration of 122.54 ± 58.56 months. A total of 47.11% of the patients had a concomitant comorbidity, of which the most frequent one was migraine and mood disorder. The mean baseline EDSS of the patients was estimated to be 2.05 ± 1.48 at the baseline. The majority of patients (92.30%) were escalated to fingolimod. The most frequently used DMT prior to fingolimod was subcutaneous and intramuscular interferon beta 1a (INF-β 1a) (46.1%).
The demographic and MS-related characteristics of PwMS treated with fingolimod who developed dermatologic complications.
MS: multiple sclerosis; PwMS: patients with MS; PMH: past medical history; EDSS: expanded disability status scale; DMT: disease-modifying treatment; INF-β: interferon beta; GA: glatiramer acetate.
Dermatological manifestations
Among 487 patients treated with fingolimod, 323 patients completed their skin examinations during the follow-up period, of whom 104 (32.19%) developed skin abnormalities. The dermatologic abnormalities mainly appeared after a mean interval of 25.77 ± 24.36 months following fingolimod initiation. Based on the results, the occurrence of skin lesions was not associated with any of the demographic and MS-related characteristics, including age, sex, disease duration, duration of fingolimod usage, EDSS, and absolute lymphocyte count (Figure 1).
Study the flowchart.
As demonstrated in Table 2, we categorized the dermatological findings in four groups: pigmented lesions, infections, inflammatory lesions, and others, of which the former accounted for the majority of skin complications (75%). The melanocytic nevus was the main frequently observed (65.38%) pigmented lesion, which led to treatment discontinuation in three cases. Notably, the dermatological follow-up for at least 3 months post-fingolimod discontinuation revealed the complete disappearance of the nevus formations. The severity of skin manifestations varied, with most cases being mild to moderate and manageable with topical treatments. A total of 19 patients (18.26%) had a complete recovery of the skin lesions. In 75 patients (72.11%), the skin lesion was not considered an obstacle to continuing the treatment with fingolimod. However, ten patients (9.61%) had to discontinue their treatment for other reasons.
The prevalence of dermatologic abnormalities among PwMS treated with fingolimod who developed skin lesions.
PwMS: patients with multiple sclerosis; HPV: human papillomavirus.
Including seven cases of HPV infection.
Skin dryness, nail changes, pruritus, local hypertrichosis, and acne vulgaris.
Disease course
Except for dermatologic abnormalities, 21 patients (4.31%) developed urinary tract infection (UTI), and eight patients (1.64%) developed transiently elevated liver enzymes. In terms of the MS course, over 5 years, 20 patients (4.10%) encountered treatment failure either due to disease activity or progression, of whom all escalated to anti-CD20 monoclonal antibodies. Moreover, two patients deescalated to INF-β due to pregnancy. The summary of DMT changes over a five-year period of follow-up is described in Table 3.
The prevalence of fingolimod discontinuation in PwMS over a five-year follow-up.
PwMS: patients with multiple sclerosis; DMT: disease-modifying treatment; RTX: rituximab; OCR: ocrelizumab; NTZ: natalizumab; INF-β: interferon beta; HPV: human papilloma virus.
Discussion
Fingolimod, an oral S1P modulator, has been instrumental in treating RRMS since 2010. While its efficacy in reducing relapse rate and disability progression has been well-documented, there is limited data on dermatologic abnormalities in association with fingolimod.8,9,12–14
The present prospective cohort study was designed to investigate a range of dermatologic manifestations in PwMS treated with fingolimod over 5 years. Our results revealed that 32.19% of patients developed dermatologic findings, of which the melanocytic nevus was the main frequently observed (65.38%). A critical concern for such lesions is the potential risk of serving as a precursor to melanoma. Our findings align with recent reviews, which have reported an increased risk of both melanoma and non-melanoma skin cancer in patients receiving fingolimod, with a focus on the results of both the FREEDOMS study and the FREEDOMS II study.8,11,15,16 Ogretmen and Hannun 10 have suggested considering fingolimod as a tumor-promoting agent, as it affects several key events in tumorigenesis, such as cell growth, migration, and angiogenesis, and is therefore regarded as a tumor-promoting agent. While the associated physiopathological mechanisms of skin cancer associated with fingolimod are not fully understood, its impact on immune surveillance, lymphocyte function, ultraviolet sensitivity, and keratinocyte behavior might be considered other predisposing factors. Notably, we reported no cases of melanoma or non-melanoma skin cancer in our cohort.
However, three patients (2.88%) developed dysplastic melanocytic nevus, leading to permanent discontinuation of fingolimod. Two more patients changed their treatment due to the increase and persistence of melanocytic nevus. Furthermore, we observed skin lesions in all followed patients with different demographic and MS-related characteristics, including age, sex, disease duration, duration of fingolimod usage, EDSS, and absolute lymphocyte count. Our results were in line with the literature, highlighting an unclear association between the duration of fingolimod usage and skin cancer.16,17
Animal studies, as LaMontagne et al. show, fingolimod inhibits melanoma metastasis in VEGF-dependent models, but not primary tumor growth-and these models don’t fully mimic human tumor biology. This may explain why most of the cases of melanoma reported in the rather short clinical trials were in situ.18,19,20,21
Perhaps due to regular dermatological follow-up of these patients, we did not have any well-manifested skin neoplasm, and we had only three atypical skin lesions suspicious of being neoplasm, and after pathologic examination, they were revealed as dysplastic nevus (premalignant).
In terms of infection safety concerns, our findings were consistent with the findings of Diogo Carneiro et al., who reported a rate of 9.15% of infectious lesions, including HPV infection-related warts, genital condylomas, molluscum contagiosum, and recurrent herpetic vesicles of a limb in 142 PwMS treated with fingolimod who developed cutaneous adverse events. However, while two of our patients had to discontinue their treatment due to refractory genital HPV infection, infectious lesions were no indication of therapeutic change in any other patients.
Taking all considerations into account, while fingolimod remains a cornerstone in treating RRMS, its association with dermatological complications and increased risk of skin cancer necessitates vigilant skin monitoring in PwMS treated with fingolimod. In this regard, early detection of skin lesions, particularly dysplastic nevi, and early-stage malignancies could significantly improve patient outcomes. 22
Limitations and strengths
The present study is the first report of adverse dermatologic events related to fingolimod in Iranian PwMS. A good sample size and a five-year follow-up could be our strengths. However, our study had several limitations. We did not have a control group of a healthy population or PwMS treated with other DMTs, which limits the appropriate interpretations. Larger and multi-center studies with a control group and longer follow-ups are needed to provide additional information regarding dermatological safety concerns about fingolimod. Moreover, future studies should focus on establishing standardized screening protocols and investigating the underlying mechanisms contributing to these adverse events.
One other important limitation in our study, because of its descriptive nature, is the lack of comparison between fingolimod-treated patients who developed any skin findings and those who did not develop the findings.
Conclusion
The present descriptive study emphasized the dermatological complications associated with long-term fingolimod therapy in PwMS. A prevalence of 32.19% of skin lesions, including melanocytic nevi, underscores the need for vigilant skin monitoring to ensure optimal patient outcomes and minimize treatment-related adverse effects.
Footnotes
Acknowledgements
We would like to express our gratitude to our colleagues at the Royan Institute, Regenerative Medicine Department.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
