SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 48 BRIEF ARTICLE Demodicosis Mimicking Papulopustular Eruption in the Setting of Targeted Therapy Iulianna Taritsa, BA1, Shikha Walia, BS2, Jennifer N. Choi, MD1 1 Northwestern University Feinberg School of Medicine, Chicago, IL 2 Lake Erie College of Osteopathic Medicine, Erie, PA Here we discuss the dramatic cutaneous reactions of two patients receiving targeted therapies for cancer (one on a MEK inhibitor/BRAF inhibitor and the other receiving carfilzomib). A woman in her 50s receiving vemurafenib 480mg twice daily and trametinib 2mg daily for anaplastic astrocytoma presented to oncodermatology clinic with a 6-month history of persistent papulopustular eruption involving the face and scalp. Pink papules and pinpoint pustules were noted on the forehead, nose, cheeks, upper lip and chin one week after beginning targeted therapy (Figure 1a). Inflamed papules were scattered across the lateral and posterior neck and scalp. The lesions were not pruritic nor painful. She received doxycycline 100mg twice daily and triamcinolone 0.1% cream for the face and fluocinonide 0.05% solution for the scalp for suspected cutaneous reaction to MEK inhibitor/BRAF inhibitor (BRAFi/MEKi) therapy. Her eruption persisted over the next five months despite treatment with various oral antibiotics, topical antibiotics, and topical steroids. While mineral preparation of scrapings of active facial pustules did not reveal any organisms, the patient began treatment for presumed Demodex folliculorum folliculitis using ivermectin 15mg (two doses, 1 week apart). Remarkable improvement of the eruption was seen 10 days later. She then started a topical compounded cream including metronidazole 1%, ivermectin 1%, and azelaic acid 15% for daily use until complete resolution. One month later, her face was clear (Figure 1b). ABSTRACT Here we discuss the dramatic cutaneous reactions of two patients receiving targeted therapies for cancer (one on a MEK inhibitor/BRAF inhibitor and the other receiving carfilzomib). Demod icosis was the underlying cause in both cases, though the infection was mistaken for a reaction to the patients’ complex malignancy therapies. Given the prevalence of cutaneous side effects of chemotherapy and targeted cancer therapies and the protean nature of demodicosis, it follows that demodicosis may be easily mistaken as a drug reaction to a chemotherapeutic agent. Demodicosis in the setting of chemotherapy and immunosuppression must thus remain an important diagnostic consideration in patients undergoing cancer treatment to allow for appropriate diagnosis and management of cutaneous findings without discontinuation of essential chemotherapy. INTRODUCTION CASE REPORTS SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 49 Figure 1. Patient receiving vemurafenib and trametinib daily for anaplastic astrocytoma A) One week after starting targeted therapy. Pink papules and pinpoint pustules noted on the forehead, nose, cheeks, upper lip and chin B) Remarkable improvement of cutaneous events 10 days after starting ivermectin for demodicosis. A man in his 50s receiving proteasome inhibitor carfilzomib 54mg/m2 one dose every two weeks for multiple myeloma presented with a new onset facial rash consisting of 2-4 mm pink follicular papules on the face, neck, and scalp. The patient endorsed temporary improvement with 1g doses of methylprednisolone with every carfilzomib infusion. He initiated treatment with clobetasol 0.05% cream twice daily for 2 weeks with some improvement. Two months later, approximately two weeks after switching therapy to daratumumab, he was hospitalized for cancer-related complications and worsening pruritic facial eruption. His physical exam revealed excoriated, erythematous, folliculocentric papules, deep nodules, and pustules on the bilateral temples, cheeks, ears, scalp, forehead, and posterior neck (Figure 2a). Mineral scraping of pustules revealed no organisms. Punch biopsy showed deep suppurative inflammation with dermal neutrophilic infiltrate, and Demodex mites (Fig 3). He received 15mg of oral ivermectin (two doses, 1 week apart) for the treatment of demodicosis, achieving complete resolution at two-week follow-up (Fig 2b). Figure 2. Patient receiving carfilzomib, one dose every two weeks, then daratumumab for multiple myeloma A) Two weeks after starting daratumumab. Erythematous, folliculocentric papules, deep nodules, and pustules on the bilateral temples, cheeks, ears, scalp, forehead, and posterior neck B) Significant resolution seen two weeks after starting ivermectin for demodicosis. Demodex mites (Demodex folliculorum and brevis) are commensal organisms that colonize sebaceous areas. A range of facial inflammatory eruptions may be seen when the mites proliferate, including pustular folliculitis and conditions that mimic pityriasis folliculorum1, papulopustular rosacea, granulomatous rosacea, periorificial dermatitis, acne, blepharitis, and papulopustular scalp eruptions2. Infection incidence increases among the elderly or immunocompromised patients, including those with HIV and those receiving immunosuppression for cancer treatment3. Demodicosis has been associated with several immunomodulatory agents, including topical or systemic steroids, monoclonal antibody therapies like cetuximab and panitumumab4, and biologics like dupilumab5. These therapies are hypothesized to reduce the body’s defense against mite proliferation while simultaneously upregulating chemokines DISCUSSION SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 50 that recruit mast cells and macrophages, potentiating an inflammatory response4. Figure 3. Results of punch biopsy from the patient seen in Figure 2. Biopsy shows deep suppurative inflammation with dermal neutrophilic infiltrate, and Demodex mites. Our cases add to the literature of demodicosis following immunomodulatory therapy. The combination of BRAFi/MEKi has revealed distinct dermatologic toxicities, potentially due to BRAFi’s action on MAPK signaling and increased BRAF signaling6. The co-administration of a MEKi has been speculated to limit adverse effects by reducing MAPK/CRAF pathway activation7. However, patients on dual therapy still experience maculopapular eruptions, papulopustular eruption, epidermal hyperkeratosis in the form of verrucous keratoses8 and keratosis pilaris9, and keratoacanthomas. Proteasome inhibitors like carfilzomib have also been reported to cause cutaneous eruptions, including papulonodular eruptions, urticaria, cutaneous vasculitis8, and Sweet syndrome9. These exanthematous reactions are believed to be the result of cell-mediated delayed hypersensitivity10. To our knowledge, demodicosis mimicking papular eruptions associated with BRAFi/MEKi or proteasome inhibitors has previously been reported. The diagnosis of demodicosis can be made via skin scraping with mineral or KOH preparation or skin biopsy showing organisms within hair follicles (see Fig. 3)11. The diagnostic value of microscopic examination of sebaceous secretions versus standardized skin surface biopsy is debated. Treatment options include topical or oral ivermectin, topical permethrin, benzoyl benzoate, and metronidazole12. The long- term use of mid-potency or stronger topical corticosteroids on the face should be highly discouraged, as these have the potential to exacerbate this condition or can result in periorificial dermatitis which has a similar clinical presentation. Bacterial superinfection in the setting of Demodex infection has also been observed. Few reports exist that causally link BRAFi’s or proteosome inhibitors to Demodex infection. We suspect a potential relationship between the immunomodulatory effects of targeted therapy and susceptibility to Demodex, resulting in our patients’ cutaneous eruptions. Demodicosis in the setting of chemotherapy and immunomodulation must remain a diagnostic consideration in cancer patients to allow for appropriate management of cutaneous findings without discontinuation of essential cancer therapy. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Jennifer N. Choi, MD Northwestern University Feinberg School of Medicine Chicago, Illinois Email: jennifer.choi@northwestern.edu References: 1. Dominey A, Tschen J, Rosen T, Batres E, Stern JK. Pityriasis folliculorum revisited. J Am Acad CONCLUSION SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 51 Dermatol. Jul 1989;21(1):81-4. doi:10.1016/s0190-9622(89)70152-3 2. Hsu C-KMD, Hsu MM-LMD, Lee JY-YMD. Demodicosis: A clinicopathological study. Journal of the American Academy of Dermatology. 2008;60(3):453-462. doi:10.1016/j.jaad.2008.10.058 3. Ivy SP, Mackall CL, Gore L, Gress RE, Hartley AH. Demodicidosis in childhood acute lymphoblastic leukemia; an opportunistic infection occurring with immunosuppression. J Pediatr. Nov 1995;127(5):751-4. doi:10.1016/s0022- 3476(95)70168-0 4. Demodex inflammatory eruption due to EGFR inhibitor therapy. Journal of the American Academy of Dermatology. 2014;70(5):AB3-AB3. doi:10.1016/j.jaad.2014.01.012 5. Quint T, Brunner PM, Sinz C, et al. Dupilumab for the Treatment of Atopic Dermatitis in an Austrian Cohort-Real-Life Data Shows Rosacea-Like Folliculitis. J Clin Med. Apr 24 2020;9(4)doi:10.3390/jcm9041241 6. Su F, Viros A, Milagre C, et al. RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors. New England Journal of Medicine. 2012;366(3):207- 215. doi:10.1056/NEJMoa1105358 7. Dummer R, Rinderknecht J, Goldinger SM. Ultraviolet A and Photosensitivity during Vemurafenib Therapy. New England Journal of Medicine. 2012;366(5):480-481. doi:10.1056/NEJMc1113752 8. Ransohoff JD, Kwong BY. Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. Clin Lymphoma Myeloma Leuk. Dec 2017;17(12):834-851. doi:10.1016/j.clml.2017.07.005 9. Kim JS, Roh HS, Lee JW, Lee MW, Yu HJ. Distinct variant of Sweet’s syndrome: bortezomib‐ induced histiocytoid Sweet’s syndrome in a patient with multiple myeloma. International journal of dermatology. 2012;51(12):1491-1493. doi:10.1111/j.1365-4632.2011.05141.x 10. Wu KL, Heule F, Lam K, Sonneveld P. Pleomorphic presentation of cutaneous lesions associated with the proteasome inhibitor bortezomib in patients with multiple myeloma. J Am Acad Dermatol. Nov 2006;55(5):897-900. doi:10.1016/j.jaad.2006.06.030 11. Forton FM, De Maertelaer V. Two Consecutive Standardized Skin Surface Biopsies: An Improved Sampling Method to Evaluate Demodex Density as a Diagnostic Tool for Rosacea and Demodicosis. Acta Derm Venereol. Feb 8 2017;97(2):242-248. doi:10.2340/00015555-2528 12. Jacob S, VanDaele MA, Brown JN. Treatment of Demodex-associated inflammatory skin conditions: A systematic review. Dermatol Ther. Nov 2019;32(6):e13103. doi:10.1111/dth.13103