Use of cyclosporine in the treatment of patients with possible neurogenic rosacea presenting as persistent facial edema with burning sensation: A case series

Dear Editor, Persistent facial erythema and edema with burning sensation is an enigmatic condition under different names, especially neurogenic rosacea. Different from typical rosacea, papules, pustules, and phymatous changes are absent in this group of patients. Thus, it is not recognized as a distinct entity according to the global Rosacea Consensus 2019 panel.[1] In 2011, Scharschmidt et al. reported neurogenic rosacea as a new type, characterized by severe neurological symptoms such as burning or stinging sensation, in addition to facial redness and poor response to conventional treatments.[2,3] Facial erythrodysaesthesia may be a similar or closely related condition. Patients with neurogenic rosacea have a higher risk of neurological and neuropsychiatric conditions.[2] Previous case series has demonstrated treatment effectiveness with neuroleptic agents (gabapentin and pregabalin), duloxetine, tricyclic antidepressants, and memantine.[2] Nevertheless, the optimal treatment modalities of neurogenic rosacea are not well established. Along with dysregulation of the innate immune system, impaired adaptive immunity also contributed to the etiology of rosacea.[4] Therefore, immunosuppressants leading to inhibition of T-cell activation may also play a role in the treatment of the disease. Herein, we reported the use of oral cyclosporine in three cases of neurogenic rosacea with success after failure of multiple conventional treatments. The demographic data, disease course, and treatment responses of each patient are summarized in Supplementary Table 1. The clinical pictures before and after cyclosporine treatment of the three cases are illustrated in Figure 1 and Supplementary Figures 1 and 2, respectively. Among the three cases, the case number 2 had received a skin biopsy, showing perivascular and focal perifollicular lymphohistiocytes infiltration in the upper dermis, consistent with rosacea clinically. The patients’ cutaneous inflammation and treatment failure with common agents led us to consider cyclosporine as a treatment option. All three cases response significantly to oral cyclosporine within weeks. The consecutive treatment period for each patient was <1 year, and satisfactory results were achieved. Patient 1 had a follow-up duration of 3 years and experienced a relapse after being symptom-free off therapy for more than a year, but the condition improved significantly after adding back cyclosporine. Patient 2 reached long-term resolution off therapy with a follow-up period of 4 years, while patient 3 is currently under satisfactory control with regular cyclosporine 50 mg daily and had a follow-up duration of 2 years. During follow-up, none of the patients presented with decreased renal function or elevated blood pressure.Supplementary Table 1: Demographic data, disease course, and treatment responses of each patientFigure 1: Clinical pictures prior to (a and b) and after (c and d) cyclosporine treatment – Case 1.Supplementary Figure 1: Clinical pictures prior to (a and b) and after (c and d) cyclosporine treatment – Case 2.Supplementary Figure 2: Clinical pictures prior to (a and b) and after (c and d) cyclosporine treatment – Case 3.All of the patients we investigated were middle-aged females, consistent with the age and gender propensity reportedly by a recent Korean study.[3] Diagnosis of neurologic rosacea is usually made clinically. The differential diagnosis included sensitive skin syndrome, trigeminal neuralgia, and erythromelagia.[3] Neurogenic rosacea has additional characteristics compared to erythematotelangiectatic rosacea, such as rare papules and pustules, improved alleviation by cold stimuli and erythema mainly distributed on bilateral lateral cheeks to mandibular angles, sparing the nose, forehead, and central chin. Conversely, erythematotelangiectatic rosacea patients are more likely to develop erythema on the nose and medial cheeks.[4] Another common feature for patients with neurogenic rosacea is the constant use of a portable electric fan when the patients appear in the clinic. The use of oral cyclosporine in neurogenic rosacea has several merits. Pro-inflammatory cytokines can induce the expression of inducible nitric oxide synthase (iNOS), known potent vessel dilators implicating in the pathogenesis of rosacea.[5] Previous in vitro studies had validated that calcineurin inhibitors may play a role in inhibiting iNOS expression and nitric oxide (NO) production by destabilizing mRNA in a concentration-dependent manner.[6] Inhibitions of this pathway can reduce the vasodilatations caused by NO and relieving the facial erythema clinically.[7] Cyclosporine is a potent immunosuppressant. Recent studies had demonstrated that T-cells within facial biopsy specimens from patients with rosacea exhibited a Th1/Th17 T-cell polarization profile, and that IL-17 appears to enhance angiogenesis through vascular endothelial growth factor and affect the expression of LL-37 in keratinocytes.[4] LL-37 is an antimicrobial peptide known in the pathophysiology of rosacea, causing inflammation and angiogenesis.[4,8] Finally, patients with neurogenic rosacea often have very sensitive skin. The use of oral cyclosporine obviates exposure of any topical agents, including the atrophogenic corticosteroid and irritating topical calcineurin inhibitors. In conclusion, while not currently considered a standard therapy, oral cyclosporine may be a viable alternative for the cases of neurogenic rosacea that do not respond to conventional rosacea treatments, neuroleptic agents, or antidepressants. Further high-quality studies with larger patient populations are needed to assess the long-term efficacy and safety of this treatment. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Data availability statement All data generated or analyzed during this study are included in this published article and its supplementary information files. Financial support and sponsorship Nil. Conflicts of interest I-Heng Chiu has no conflict of interest to disclose. Tsen-Fang Tsai has conducted clinical trials or received honoraria for serving as a consultant for Abbvie, AnaptysBio, Boehringer Ingelheim, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli-Lilly, Galderma, GlaxoSmithKline, Janssen-Cilag, Leo pharmaceuticals, Merck Sharp and Dohme, Novartis, PharmaEssentia, Pfizer Inc., Sanofi-Aventis, and Tanabe. Tsen-Fang Tsai, also an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article.