Fingolimod is an immunomodulatory drug used in the treatment of relapsing-remitting multiple sclerosis (RRMS) and approved by the European Medicines Agency (EMA) since 2011. Its mechanism of action consists of blocking lymphocyte trafficking from lymphoid tissues into the bloodstream and central nervous system through internalization of sphingosine-1-phosphate receptors.1 Since its commercialization, several adverse effects have been described, including rare cases of primary cutaneous lymphomas, as well as an overall increase in the risk of skin cancer.2

We describe the case of a 40-year-old woman diagnosed with RRMS at 22 years of age, with no other relevant medical history. She was treated first-line with intramuscular interferon beta-1a for more than 10 years; this medication was eventually discontinued because of recurrent relapses with sequelae in the form of paresis of the right lower limb. Fingolimod was subsequently started, achieving good disease control for 15 months. Seven months after treatment initiation, she exhibited multiple erythematous–desquamative papules located on the upper limbs, which resolved spontaneously with residual scaling. The condition was interpreted as a possible eczematous flare and was treated with topical clobetasol propionate. Owing to the patient's desire for pregnancy, the drug was discontinued 3 months after the dermatology consultation, with remission of the skin lesions (Figs. 1 and 2).

Fig. 1.

Clinical image of the lesions. Millimetric erythematous–violaceous papules distributed on the patient's limbs can be observed.

Fig. 2.

Histological image of the lesions. (A) Hematoxylin and eosin (H&E), 100×. A predominantly lymphocytic dermal inflammatory infiltrate with a perivascular distribution can be observed. (B) Detail of angiocentricity, H&E, 500×. (C) CD3 immunohistochemistry, 300×. (D) CD30 immunohistochemistry, 300×.

The patient restarted treatment after a 20-month pause. Two months after reintroduction of the drug, she presented again with completely asymptomatic erythematous–violaceous papules measuring 4–5mm in diameter, distributed on the trunk and limbs. The lesions involuted spontaneously in approximately 2 weeks, without ulceration, and left residual hyperpigmentation. She denied fever, constitutional syndrome, or other systemic symptoms. Physical examination revealed no organomegaly or lymphadenopathy.

A biopsy of one of the skin lesions was performed and showed a dermal infiltrate with a tendency toward angiocentricity, composed of atypical medium-to-large lymphocytes on an accompanying reactive background predominantly consisting of small lymphocytes, some eosinophils, and histiocytes. The atypical cells expressed CD30, CD3, and CD4 and were negative for CD7, CD8, ALK, and EBER ISH. A molecular study of the skin sample was performed, detecting a monoclonal peak corresponding to the T-cell receptor (TCR) beta gene. No other molecular biology techniques were performed. Laboratory tests showed lymphopenia of 520cells/mm3, with no other notable findings.

Based on these findings, the case was interpreted as angiocentric-type lymphomatoid papulosis, type E, probably associated with fingolimod treatment; therefore, discontinuation of the drug was recommended. Treatment was replaced with ocrelizumab, an anti-CD20 antibody, and complete resolution of all lesions was observed 2 weeks after the change in therapy, with no subsequent recurrences at the 6-month follow-up.

Lymphomatoid papulosis is a rare entity included among primary cutaneous CD30+ T-cell lymphoproliferative disorders.3 It is characterized by recurrent flares of inflammatory papules and nodules, which may occasionally be asymptomatic and resolve spontaneously. Diagnosis is based on clinicopathological correlation, with several subtypes distinguished according to the distribution and characteristics of the lymphoid infiltrate.

Currently, only 3 cases of fingolimod-associated lymphomatoid papulosis have been described. The first case was reported by Samaraweera et al.4 in 2015, and 2 further cases were subsequently described by Cohen et al.5 and Matoula et al.6 Similarly to our case, in the first and third cases the lesions appeared 2 months after the first administration of fingolimod, were mildly painful, and showed complete resolution at 6–8 weeks with discontinuation of the drug alone.

In the second case, cutaneous involvement occurred 2 years after treatment initiation and predominantly affected the cephalic region. Of note, in the third patient, after a 4-month remission period, new lesions appeared despite permanent discontinuation of fingolimod treatment.

Although the subtype was specified in only one of the previously reported cases, type D in Matoula et al.,6 it should be noted that our case histologically corresponds to the type E variant, which is characterized by angiocentricity and angiodestruction. This subtype is classically associated with skin lesions that tend to ulcerate and may lead to permanent scarring. We consider it important to draw dermatologists’ attention to this rare complication of fingolimod treatment in order to ensure appropriate recognition of the entity.

Furthermore, 4 cases of primary cutaneous anaplastic CD30+ T-cell lymphoma associated with fingolimod use have been described.7–10 In all of them, the lesions involuted spontaneously: in 3 cases, 2 months after treatment discontinuation, and in 1 case, remission was spontaneous.

In conclusion, we report a new case of lymphomatoid papulosis associated with fingolimod use, further supporting primary cutaneous CD30+ lymphoproliferative disorders as an uncommon adverse effect of this treatment.