Livedo Reticularis in Association with Fingolimod: A Case Report

Sir,

Livedo reticularis (LR) is an ischemic dermopathy characterized by transient or persistent, blotchy, violaceous reticular or net-like cyanotic pattern. LR is caused by abnormalities within the cutaneous microvascular system, and it is mostly a benign disorder affecting young to middle-aged females. The discoloration of LR is symmetric, uniform, and reversible and can occur as a physiological response to cold. Livedo reticularis is either physiological, primary, and idiopathic or is due to an associated systemic disease. In adults, the most frequently associated conditions are characterized by vessel wall disease or intravascular obstruction. Some of these diseases include antiphospholipid syndrome, systemic lupus erythematosus (SLE), and other connective tissue diseases, cryoglobulinemias, various types of vasculitis, infections, and malignancies.[1] Here, we report a patient with multiple sclerosis (MS) who developed LR within 3 months of starting treatment with fingolimod.

A 43-year-old female with MS applied to our clinic with asymptomatic symmetric purple mottling on her upper extremities and thighs [Figures 1 and 2]. Her complaints were not related to ambient temperature, and she had no personal or family history of hypercoagulability, connective tissue disease, or vasculitis. A detailed laboratory work-up including complete blood count, coagulation profile, cryoproteins, lupus anticoagulant panel, acute phase reactants, and antibody panels for connective tissue diseases were performed and appeared within normal ranges. No disease that could be associated with LR was detected. Histopathological examination was not performed. Before starting fingolimod, she had previously been treated with pulse steroids, teriflunomide, and interferon-beta. Approximately 1 year after the discontinuation of interferon-beta, fingolimod 0,5 mg/day treatment was started, and LR was developed in the first months of the drug use. When LR developed, the patient was not using any medication other than fingolimod. The Naranjo scale, a standardized adverse drug event probability scale,[2] was applied to identify the causality of the drug reaction. According to the Naranjo scale, the case was classified as “probable” fingolimod-induced LR.

Figure 1.

Upper extremities having mottled, violaceous lacy reticular rash known as livedo reticularis

Figure 2.

Left hand with a net-like cyanotic pattern, closer view

Fingolimod is the first oral disease-modifying drug approved for MS. It is a sphingosin-1 phosphate (S1P) receptor antagonist, and it inhibits lymphocyte migration by causing a reversible lymphocyte sequestration in the lymph nodes.[3] Modulation of S1P receptors induces several biological responses, including endothelial cell adhesion, angiogenesis, and cardiovascular dysfunction.[4] Commonly known side effects include fatigue, headache, elevated liver enzymes, opportunistic infections, bradycardia, atrioventricular (AV) nodal block, progressive multifocal leukoencephalopathy, and macular edema.[5] In our case, we observed LR in association with fingolimod, and it can be explained by the potential vasoconstrictive effects of the drug. Sphingolipids and their metabolites are vasoactive compounds, and activation of the S1P-type-3 receptor on vascular smooth muscle cells results in vasoconstriction due to intracellular calcium release.[5] Literature review revealed one case of peripheral vascular side effects, including purplish blotches, tingling, itching, and edema of hands,[6] one case of reversible cerebral vasoconstriction syndrome,[7] rare cases of stroke and retinal arterial vasospasm.[8] Our case report suggests that fingolimod has the potential to cause rare vasoconstrictive effects and disturbances in cutaneous blood flow; therefore, livedo reticularis should be considered as a potential side effect.

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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that the name and initials will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.