Melachrinou, Maria

Monastirli, Alexandra

Pasmatzi, Efi

Tsambaos, Dionysios

Tzouma, Anastasia

Hospital Chronicles (E-Journal)

CASE REPORTRosacea-Like Demodicosis Induced by Topical Pimecrolimus: Immunohistochemical Evaluation  of Inflammatory InfiltrateEfi Pasmatzi1, MD, Maria Melachrinou2, MD, Alexandra Monastirli1, MD, Anastasia Tzouma1, MD, Dionysios Tsambaos1, MD, PhDA B S T R A C TWe present a 48-year-old female patient who developed rosacea-like demodicosis af-ter seven days of topical application of 1% pimecrolimus cream. The inflammatory infiltrate in the lesions was mainly composed of T-cells with a CD4+/CD8+ ratio = 0.33; B-cells (CD20+) and NK-cells (CD56+) were not detected. Large numbers of (CD68+) histiocytes were demonstrated, whereas the number of Langerhans cells (CD1a+) revealed no significant alteration. The reduced CD4+:CD8+ ratio may have led to a modification of follicular microenvironment favouring the excessive prolifera-tion of Demodex mites, who triggered a presently unknown sequence of events leading to the development of pimecrolimus-induced rosacea-like demodicosis.I N T R O D U C T I O NDemodex folliculorum and Demodex brevis are obligatory ectoparasites in the fol-licular infundibulum and in the sebaceous ducts and meibomian glands, respectively. Demodex mites do not cause clinical manifestations in most infected individuals, unless local or systemic immune function of the host is impaired, follicular infesta-tion is heavy and the mites penetrate into the dermis1-3. Demodicosis is a term used to describe cutaneous disorders caused by Demodex mites including papulopustular rosacea, pustular folliculitis, perioral dermatitis, rosacea-like demodicosis, pityriasis folliculorum, demodicosis gravis, blepharitis and demodex granuloma4.We describe herein a patient with seborrheic dermatitis who developed a rosacea-like demodicosis with abundant Demodex mites subsequent to a 7-day topical application of 1% pimecrolimus cream.C A S E  R E P O R TA 48-year-old HIV negative female Caucasian patient with a 5-year history of facial seborrheic dermatitis presented with cutaneous lesions (accompanied by a burning sensation) that had suddenly developed after seven days of effective and well-toler-ated topical application of 1% pimecrolimus cream (Elidel, Novartis Hellas S.A., Departments of Dermatology1 and Pathology2, School of Medicine, University of Patras, GreeceKEY WORDS: Demodicosis, calcineurin inhibitors, rosacea, T-lymphocytesAddress for correspondence: E. Pasmatzi, M.D.Department of DermatologySchool of MedicineUniversity of PatrasP.O. Box 141326504 Rio-PatrasGreeceTel.: +30.2610.994 670Fax: +30.2610.993 951e-mail: PASMATZI@med.upatras.grSubmitted: 06-10-09 Accepted: 09-04-09HOSPITAL CHRONICLES 2009, 4(4): 172–174                  IMMUNOHISTOCHEMICAL STUDY IN DEMODICOSIS173Athens, Greece) prescribed by her dermatologist. She had previously been treated with topical antimycotics (ketocona-zole cream 2%; Fungoral, Janssen-Cilag, Athens, Greece) or steroids (dexamethasone 0.1 % cream, Thilodexine, Farmex S.A., Athens, Greece) with varying success; however, she had received no systemic or topical medications for treatment of the last exacerbation of her seborrheic dermatitis prior to the initiation of pimecrolimus. During pimecrolimus treatment she had not been exposed to sunlight, artificial UV-light or infrared radiation and had received no other topical or systemic medication. The patient denied any previous history of alcohol ingestion, rosacea, acne or perioral dermatitis. Physical examination revealed erythematous and edematous papules and plaques on the nasolabial folds, cheeks, perioral and periorbital areas (Fig. 1).Routine laboratory investigations including flow cytometry analysis of peripheral lymphocyte subpopulations revealed no abnormalities. Potassium hydroxide examination of skin scrapings showed numerous Demodex mites. Histopathologi-cal examination of a lesional skin biopsy revealed a dermal perivascular and diffuse predominantly lymphocytic infiltrate mixed with histiocytes. Lymphocytes, isolated and in small clusters, had penetrated into the slightly parakeratotic and spongiotic epidermis (Fig. 2A), whereas 3-5 Demodex mites were seen in hair follicles (Figs. 2B & 2C), suggesting a ro-sacea-like demodicosis. Immunohistochemical investigation performed for the first time in this study revealed that the lymphocytic infiltrate was mainly composed of T-cells (CD3+ and CD5+) with a predominance of CD8+ relative to CD4+ lymphocytes and a CD4+/CD8+ ratio = 0.33 (Figs. 2D & 2E); B-cells (CD20+) and NK-cells (CD56+) were not detected. Large numbers of (CD68+) histiocytes were demonstrated, whereas the number of Langerhans cells (CD1a+) revealed no significant alteration. After 4 weeks of treatment with 50 mg oral minocycline hydrochloride (Minocin caps 50 mg, Teofarma, Athens, Greece) twice daily, the patient revealed a complete resolution of her facial lesions.D I S C U S S I O NTopical pimecrolimus, a representative of macrolactam immunomodulators, is an effective and safe second-line mo-dality for the short-term and intermittent management of non-immunocompromised patients with atopic and seborrheic dermatitis and other dermatoses unresponsive to, or intoler-ant of other treatments5-7. Its side effects include transient local skin reactions (burning/tingling, erythema, pruritus), increased incidence of mostly viral cutaneous infections and lymphadenopathy5. The patient presented herein had received no systemic or topical medications for treatment of the last exacerbation of her seborrheic dermatitis prior to the initia-tion of pimecrolimus. Thus, in view of the morphology of the cutaneous manifestations, the identification of numerous Demodex mites in skin scrapings and in the hair follicles and FIGURE 1. Clinical aspect of pimecrolimus-induced rosacea-like demodicosis.FIGURE 2. A. Histopathological aspect of rosacea-like demodi-cosis, showing Demodex mites within hair follicles and dermal lymphocytic infiltrate (hematoxylinosin; original magnification x 200); B. & C. Intrafollicular mites at higher magnification (hematoxylin-eosin; original magnification x 400); Immunos-taining of dermal inflammatory infiltrate for CD4 (D; original magnification x 200) and CD8 (E; original magnification x 200), clearly showing the predominance of CD8+ cells.HOSPITAL CHRONICLES 4(4), 2009174of the temporal relationship between the occurrence of the skin lesions and the topical application of this compound, the diagnosis of pimecrolimus-induced rosacea-like demodicosis was established. To our knowledge, this is the fourth report of this disorder (Table 1) in patients with seborrheic or atopic dermatitis8-10. However, the potential to cause this rare compli-cation is also shared by tacrolimus and seems to be a common property of topical calcineurin inhibitors11.In the lesional skin of patients with either atopic or sebor-rheic dermatitis there is a numerical increase of Langerhans cells, as compared to healthy controls12,13. Furthermore, in contrast to the inflammatory infiltrate in the lesions of atopic and seborrheic dermatitis, in which T-lymphocytes are mostly of helper cell phenotype (CD4+)12,13, in the present case CD8+ cells predominated over CD4+ cells, although CD4+:CD8+ ratio in peripheral blood of the patient was within normal limits (2.17). It seems, therefore, reasonable to suggest that this distinct immunohistochemical profile may be due to the biological action of topical pimecrolimus. Indeed, it is well known that the latter mainly acts through inhibition of the calcineurin-dependent signal transduction pathway, which is required for activation of CD4+ T-lymphocytes14. Thus, the reduced CD4+:CD8+ ratio found in the lesional skin of our patient may be interpreted in terms of a pimecrolimus-induced downregulation of IL-2 synthesis and reduction in the numbers of CD4+ lymphocytes. The immunological alterations found in the present study support the hypothesis previously put forth by other groups8,10 according to which a pimecrolimus-induced local immunosuppressive effect may have led to a modifica-tion of follicular microenvironment favouring the excessive proliferation of Demodex mites, who triggered a presently unknown sequence of events leading to the development of pimecrolimus-induced rosacea-like demodicosis. Further studies are now warranted to define the incidence and the predisposing factors of this disorder and the role played by CD8+ cells in its pathogenetic mechanisms.TABLE 1. Reported cases of rosacea-like demodicosis after topical application of 1% pimecrolimus creamNo. Sex/age (years) Previous disease Onset time Treatment Reference1 Female/43 AD 3 days Doxycycline Lübbe et al (2003)2 Male/36 SD 4 days Minocycline Gorman & White (2005)3 Male/43 SD 7 days Minocycline Yoon et al (2007)4 Female/48 SD 7 days Minocycline Present caseAD = atopic dermatitis; SD = seborrheic dermatitisR E F E R E N C E S 1. Rufli T, Mumcuoglu Y. The hair follicle mites Demodex follicu-lorum and Demodex brevis: biology and medical importance. A review. Dermatologica 1981; 162:1-11. 2. Akilov O, Mumcuoglu Y. Immune response in demodicosis. JEADV 2004; 18:440-444. 3. Boutli F, Delli FS, Mourellou O. Demodicidosis as spinulosis of the face – a therapeutic challenge. J Eur Acad Dermatol Venereol 2007; 21:273-274. 4. Hsu C, Hsu M, Lee J. Demodicosis: A clinicopathological study. J Am Acad Dermatol 2009; 60:453-462. 5. Luger TA, Gollnick H, Schwennesen T, Bextermöller R et al. Safety and efficacy of pimecrolimus cream 1% in the daily practice: Results of a patient self-observation study in patients with atopic dermatitis. J Deutsch Derm Ges 2007; 10: 908-914. 6. Mensing CO, Mensing CH, Mensing H. Treatment with pimecro-limus cream 1% clears irritant dermatitis of the periocular region, face and neck. Pharmacol & Ther 2008; 47: 960-964. 7. Cook BA, Warshaw EM. Role of topical calcineurin inhibitors in the treatment of seborrheic dermatitis: a review of pathophysiol-ogy, safety and efficacy. Am J Clin Dermatol 2009; 10: 103-118. 8. Lόbbe J, Stucky L, Saurat JH. Rosaceiform dermatitis with follicular Demodex after treatment of facial atopic dermatitis with 1% pimecrolimus cream. Dermatology 2003; 207:205-207. 9. Gorman CR, White SW. Rosaceiform dermatitis as a complication of treatment of facial seborrheic dermatitis with 1% pimecrolimus cream. Arch Dermatol 2005; 141:1168. 10. Yoon TY, Kim HJ, Kim MK. Pimecrolimus-induced rosacea-like demodicosis. J Dermatol 2007;46:1103-1105. 11. Antille C, Saurat JH, Lubbe J. Induction of rosaceiform during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch Dermatol 2004; 140:457-460. 12. Bergbrant IM, Johansson S, Robbins D, Scheynius A et al. An immunological study in patients with seborrheic dermatitis. Clin Exp Dermatol 1991; 16:331-338. 13. Lugovic L, Lipozenocic J, Jakic-Razumovic J. Atopic dermatitis: immunophenotyping of inflammatory cells in skin lesions. Int J Dermatol 2001; 40:489-494. 14. Gupta AK, Chow M. Pimecrolimus: A review. JEADV 2003; 17:493-503.                     

Rosacea-Like Demodicosis Induced by Topical Pimecrolimus: Immunohistochemical Evaluation of Inflammatory Infiltrate

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Rosacea-Like Demodicosis Induced by Topical Pimecrolimus: Immunohistochemical Evaluation of Inflammatory Infiltrate

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