Bousquet, Emilie

Chevreau, Christine

Lacouture, Mario E

Mazieres, Julien

Sibaud, Vincent

Tournier, Emilie

Zarbo, Allison

English

Henry Ford Health System Scholarly Commons

Henry Ford Health System Henry Ford Health System Scholarly Commons Dermatology Articles Dermatology 4-6-2017 Development of Papulopustular Rosacea during Nivolumab Therapy for Metastatic Cancer. Emilie Bousquet Allison Zarbo Emilie Tournier Christine Chevreau Julien Mazieres See next page for additional authors Follow this and additional works at: https://scholarlycommons.henryford.com/dermatology_articles Authors Emilie Bousquet, Allison Zarbo, Emilie Tournier, Christine Chevreau, Julien Mazieres, Mario E. Lacouture, and Vincent Sibaud ActaDVActaDVAdvances in dermatology and venereologyActa Dermato-VenereologicaSHORT COMMUNICATIONActa Derm Venereol 2017; 97: 539–540This is an open access article under the CC BY-NC license. www.medicaljournals.se/actaJournal Compilation © 2017 Acta Dermato-Venereologica.doi: 10.2340/00015555-2566539Dermatological toxicities represent the most frequent immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (1, 2). Safety profiles for anti-CTLA-4 inhibitors (ipilimumab) and agents targeting the programmed cell death (PD-1) receptor (nivolumab, pembrolizumab) appear to be very similar, yet a lower frequency is observed with the latter (2). A non-specific maculopapular rash represents the most frequent cutaneous toxicity of anti-PD-1 inhibitors, with a calculated all-grade incidence of 14.3% and 16.7% for nivolumab and pembrolizumab, respectively (3). These lesions mostly remain mild/moderate, self-limiting, and manageable with topical and/or oral steroids. Other dermatological complications can also occur, including pruritus, xerosis, alopecia, mucosal involvement, autoim-mune disorders and vitiligo, the latter being exclusively described in patients treated for melanoma (1–3). More recently, additional skin adverse events have been descri-bed, including lichenoid reactions, blistering disorders or occurrence and exacerbation of psoriasis (1–4). We report here 6 patients who developed a mid-facial rash sugges-tive of papulopustular rosacea, triggered or exacerbated by nivolumab therapy, which has not been reported so far in association with anti-PD-1 therapy.CASE REPORTSAll patients (5 men, 1 woman) were treated for different types of metastatic solid cancers (Table I). Lesions oc-curred after 1–19 cycles of nivolumab therapy (3 mg/kg every 2 weeks). They were mostly localized on the medial part of the face, with a characteristic combina-tion of papules and pustules on an underlying erythema, consistent with papulopustular rosacea. Symptoms were of mild intensity in all cases (grade 1 papulopustular rash) (Fig. 1a) except for one patient, who presented with an intolerable grade 2 toxicity (Fig. 1b). Lesions were easily managed with symptomatic treatment (to-pical metrodinazole and/or oral doxycycline), leading to a significant improvement in all cases. Nivolumab therapy was delayed in one patient and resumed after one cycle. Cutaneous biopsy was performed on the patient with grade 2 toxicity, which demonstrated characteristic histopathological features of papulopustular rosacea, with a predominant perivascular and perifollicular CD3+ T-cell infiltrate, associated with small and superficial di-lated blood vessels. In addition, PD-L1 immunostaining revealed a strong positivity in the perifollicular infiltrate cells (60%) (Fig. 2). Close examination of the patients’ history suggested pre-existing erythematotelangiectatic rosacea in 3 patients.DISCUSSIONDevelopment or exacerbation of papulopustular ro-sacea with anti-PD-1 therapy has not been described previously. We cannot, however, rule out the possibility that this event is under-reported during its development Development of Papulopustular Rosacea during Nivolumab Therapy for Metastatic CancerEmilie BOUSQUET1, Allison ZARBO2, Emilie TOURNIER3, Christine CHEVREAU4, Julien MAZIERES1, Mario E. LACOUTURE5 and Vincent SIBAUD6*1Pulmonary Medicine Unit, Hôpital Larrey, Centre Hospitalier Universitaire Toulouse, Université de Toulouse III, Toulouse, France, 2Department of Dermatology, Henry Ford Hospital Detroit, Michigan, USA, 3Department of Pathology, Institut Universitaire du Cancer, Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, 4Department of Medical Oncology, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse Oncopole, Toulouse, France, 5Dermatology Service, Memorial Sloan Kettering Cancer Center New York, NY, USA, and 6Departments of Oncodermatology and Clinical Research, Institut Claudius Regaud, Institut Universitaire du Cancer, Toulouse Oncopole, 1 rue Irene Joliot-Curie, FR-31059 Toulouse cedex, France. *E-mail: sibaud.vincent@iuct-oncopole.fr Accepted Nov 8, 2016; Epub ahead of print Nov 9, 2016Table I. Clinical description of reported patientsCase No./Sex/Age, yearsUnderlying malignancies TreatmentTime to onsetClinical gradinga Management OutcomePre-existing rosaceab1/F/48 Melanoma Nivolumab 19 cycles Grade 1 Topical metronidazole Regression No2/M/83 Renal cell carcinoma Nivolumab 1 cycle Grade 1 Topical metronidazole Regression Yes3/M/68 Tonsillar carcinoma Nivolumab 4 cycles Grade 1 Topical metronidazole Regression No4/M/70 Lung cancer Nivolumab 16 cycles Grade 2 (intolerable)Temporary discontinuation, topical metronidazole, oral doxycycline (100 mg/day)Regression Yes5/M/58 Renal cell carcinoma 2 cycles of nivolumab+ipilimumab, followed by nivolumab in monotherapy8 cycles Grade 1 Topical metronidazole Complete resolutionc Yes6/M/66 Melanoma 4 cycles of nivolumab+ipilimumab, followed by nivolumab in monotherapy15 cycles Grade 1 Topical metronidazole, oral doxycycline (100 mg/day)Complete resolutionc NoaFollowing National Cancer Institute CTCae V4.02. berythemato-telangiectatic rosacea. c4 and 8 weeks after the last dose of nivolumab, respectively.ActaDVActaDVAdvances in dermatology and venereologyActa Dermato-VenereologicaShort communication540www.medicaljournals.se/actabecause of unperformed complete skin examination by investigators. Moreover, acneiform rash has been infrequently reported with anti-PD-1 agents, but only by non-dermatologist investigators (5). This so-called “acneiform” rash could potentially correspond, at least in part, to a papulopustular rosacea. The pathophysio-logy of rosacea remains poorly understood, involving complex dysregulation of the innate immune, vascular and nervous systems (6). However, it has been postulated that the adaptive immune system, involving CD4+ Th1/Th17 cell activities, plays a significant role in the deve-lopment of all subtypes of rosacea (6, 7). In addition, it has been demonstrated that blockade of the PD-1 receptor may promote Th1/Th17 pathways (8). We therefore can speculate that anti-PD-1 monoclonal antibodies may favour the development of either psoriasis (4) or rosacea in predisposed patients. Clinicians should be aware of this new dermatological adverse event, which remains, in our experience, self-limiting, but may lead to temporary interruption. Early recognition and appropriate manage-ment also appear crucial to prevent a negative impact on patients’ quality of life.ACKNOWLEDGEMENTSConflicts of interest: VS has a speaking, consultant or advisory role with Roche, GlaxoSmithKline, Pierre Fabre, Merck, Bristol-Myers Squibb, Bayer and Boehringer Ingelheim. MEL receives research support from Roche/Genentech, Berg, the NIH/NCI Cancer Center Support Grant P20 CA008748; consulting fees from Boehringer Ingelheim, Galderma, Amgen, Roche/Genentech. JM has a speaking, consultant or advisory role with Roche, Bristol-Myers Squibb, PUMA, Pfizer, Novartis, Astra Zeneca and Boehringer Ingelheim. EB, ET, CC and AZ declare no conflicts of interest.REFERENCES1. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti PD-1 therapy. Eur J Cancer 2016; 60: 190–209.2. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016; 28: 254–263.3. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016; 60: 12–25.4. Matsumura N, Ohtsuka M, Kikuchi N, Yamamoto T. Exacer-bation of psoriasis during nivolumab therapy for metastatic melanoma. Acta Derm Venereol 2016; 96: 259–260.5. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372: 2018–2028. 6. Melnik B. Rosacea: the blessing of the celts -An approach to pathogenesis through translational research. Acta Dermatol Venereol 2016; 96: 147–156.7. Buhl T, Sulk M, Nowak P, Buddenkotte J, McDonald I, Aubert J, et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol 2015; 135: 2198–2208.8. Dulos J, Carven GJ, van Boxtel SJ, Buddenkotte J, McDonald I, Aubert J, et al. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer. J Immunother 2012; 35: 169–178. Fig. 2. PD-L1 immunostaining individualizing a strong positivity in the lympho-histiocytic infiltrate, associated with exocytosis into the pilosebaceous follicle (×50 magnification Ventana Ultraview DAB Detection Kit; Antigen retrieval was a standard automated process on the Ventana BenchMark XT clone SP142, Spring Bioscience, Pleasanton, CA, USA). Fig. 1. Clinical examples of nivolumab-induced rosacea. (a) Grade 1 papulopustular rosacea in case 2 and (b) intolerable grade 2 papulopustular rosacea in case 4 induced by nivolumab therapy.

Development of Papulopustular Rosacea during Nivolumab Therapy for Metastatic Cancer

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Development of Papulopustular Rosacea during Nivolumab Therapy for Metastatic Cancer

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