Journal Pre-proof

Immune checkpoint-mediated psoriasis: a multicentric European study of 115 patients

from European Network for Cutaneous ADverse Event to Oncologic drugs (ENCADO)
group.

Vasiliki Nikolaou, MD, Vincent Sibaud, MD, Davide Fattore, MD, Pietro Sollena, MD,
Ariadna Ortiz-Brugués, MD, Damien Giacchero, MD, Maria Concetta Romano, MD,
Julia Riganti, MD, Konstantinos Lallas, MD, Ketty Peris, MD, Dimitra Voudouri, MD,
Aimilios Lallas, MD, Gabriella Fabbrocini, MD, Elisabeth Lazaridou, MD, Cristina
Carrera, MD, Maria Carmela Annunziata, MD, Ernesto Rossi, MD, Angela Patri, MD,
Dimitrios Rigopoulos, MD, Alexander J. Stratigos, MD, Zoe Apalla, MD
PII: S0190-9622(20)33115-7
DOI: https://doi.org/10.1016/j.jaad.2020.08.137
Reference: YMJD 15460

To appear in: Journal of the American Academy of Dermatology

Received Date: 26 March 2020

Revised Date: 27 July 2020
Accepted Date: 20 August 2020

Please cite this article as: Nikolaou V, Sibaud V, Fattore D, Sollena P, Ortiz-Brugués A, Giacchero D,
Romano MC, Riganti J, Lallas K, Peris K, Voudouri D, Lallas A, Fabbrocini G, Lazaridou E, Carrera C,
Annunziata MC, Rossi E, Patri A, Rigopoulos D, Stratigos AJ, Apalla Z, Immune checkpoint-mediated
psoriasis: a multicentric European study of 115 patients from European Network for Cutaneous ADverse
Event to Oncologic drugs (ENCADO) group., Journal of the American Academy of Dermatology (2021),
doi: https://doi.org/10.1016/j.jaad.2020.08.137.

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© 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
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1 Article type: Original article

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3 Title: Immune checkpoint-mediated psoriasis: a multicentric European study of 115
4 patients from European Network for Cutaneous ADverse Event to Oncologic drugs
5 (ENCADO) group.
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7 Authors: Vasiliki Nikolaou, MD 1 Vincent Sibaud, MD 2 Davide Fattore, MD 3 Pietro
8 Sollena, MD 4 Ariadna Ortiz-Brugués, MD 5 Damien Giacchero, MD 6 Maria
9 Concetta Romano, MD 7 Julia Riganti, MD 8 Konstantinos Lallas, MD 9 Ketty Peris,
10 MD 4 Dimitra Voudouri, MD 1 Aimilios Lallas, MD 9 Gabriella Fabbrocini, MD 3
11 Elisabeth Lazaridou, MD 10 Cristina Carrera, MD 5 Maria Carmela Annunziata, MD 3
12 Ernesto Rossi, MD 11 Angela Patri, MD 3 Dimitrios Rigopoulos, MD 1 Alexander J.
Stratigos, MD 1 Zoe Apalla MD 10

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15 Affiliations:
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16 1st Department of Dermatology, “Andreas Sygros” Hospital for skin diseases,
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17 National & Kapodestrian University of Athens, Medical School, Athens, Greece.
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18 Institut Universitaire du cancer, Toulouse Oncopole, Toulouse, France
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19 Section of Dermatology, Department of Clinical Medicine and Surgery, University
20 of Naples Federico II, Naples, Italy
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21 Department of Dermatology, Università Cattolica del Sacro Cuore, Rome, Italy;
22 Fondazione Policlinico “A. Gemelli” IRCCS, Rome, Italy
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23 Hospital Clinic Barcelona, Spain
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24 Centre Antoine Lacassagne, Nice, France
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25 San Camillo Forlanini Hospital, Rome, Italy
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26 Hospital Italiano of Buenos Aires, Argentina
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27 First Dermatology Department, Medical School, Aristotle University of
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28 Thessaloniki, Greece
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29 Second Dermatology Department, Medical School, Aristotle University of
30 Thessaloniki, Greece
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31 Medical Oncology, Fondazione Policlinico “A. Gemelli” IRCCS, Rome, Italy
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34 Corresponding author: Dr Vasiliki Nikolaou
35 Cutaneous Toxicities Clinic, OncoDermatology Department
36 “Andreas Sygros” Hospital for skin diseases
37 5 I.Dragoumi str
38 12161 Athens , Greece
39 e-mail: drviknik@yahoo.com
40 tel: 0030-210-7265153
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42
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43 Manuscript word count: 2,716

44 Abstract word count: 200
45 Capsule summary word count: 48
46 References: 30
47 Tables: 3
48 Supplementary Tables: 1 (available at
49 https://data.mendeley.com/datasets/m7w8sszs6y/draft?preview=1)
50 Figures: 2
51 Funding sources: None
52 Conflicts of Interest: None declared

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53 Reprint requests: Vasiliki Nikolaou

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54 Keywords: immune checkpoint inhibitors, psoriasis, adverse events, nivolumab,
55 pembrolizumab, immunotherapy, skin toxicity
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77 Abstract

78 Background: Immune checkpoint inhibitors (ICIs)-mediated psoriasis poses

79 significant diagnostic and therapeutic challenges.

80 Objective: To report data on ICI-mediated psoriasis, emerging from the largest so far

81 cohort and to propose a step-by-step management algorithm.

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82 Μethods: The medical records of all patients with ICI-mediated psoriasis were

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83 retrospectively reviewed across nine institutions.
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84 Results: We included a cohort of 115 individuals. Grade-1, 2 and 3 disease severity
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85 was reported in 60/105 (57.1%, 10 missing data), 34/105 (32.4%) and 11/105
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86 (10.5%), respectively. The ratio between de novo and exacerbation cases of psoriasis
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87 was 21/90 (23.3%). The most common systemic therapy was acitretin (23 patients,
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88 20.1%), followed by systemic steroids (8 patients, 7%), apremilast (7 patients, 6.1%),

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89 methotrexate (5 patients, 4.3%) and biologics (4 patients, 3.6%). Overall, 29/112

90 patients (25.9%) interrupted and 20/111 (18%) permanently discontinued ICIs due to

91 psoriasis. BSA>10% at baseline had a 3.6 increased risk for ICIs treatment

92 modification (OR=3.64, CI 1.27-10.45, p=0.03) and a 6.4 increased risk for

93 permanent discontinuation (OR=6.41, CI 2.40-17.11, p<0.001). Guttate psoriasis and

94 grade2/3 disease were significant positive predictors for antitumor response of ICI

95 whereas pruritus was a negative predictor.

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97 Limitations: Retrospective design

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99 Conclusion: Acitretin, apremilast and methotrexate are safe and effective modalities

100 for ICI-mediated psoriasis. In most cases, ICI can be completed unhindered. A

101 therapeutic algorithm is proposed.

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119 Introduction

120 Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting cytotoxic T

121 lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1)

122 or programmed death ligand-1 (PD-L1). Their addition in our armamentarium has

123 radically transformed the therapeutic arena in oncology, providing the potential of

124 high-level and durable responses in a large number of diverse malignancies.

125 The introduction of ICIs has resulted in the recognition of a new spectrum of

126 immune-related adverse events’ (irAEs) that may occasionally limit their use [1]. The

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127 nature of irAEs has not been completely elucidated, however it is meaningful that

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128 they are mostly immune-mediated, resulting by the T-cell activation of cytotoxic

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CD4+/CD8+ [2]. Skin toxicities are the most prevalent irAEs related to
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130 immunotherapy. Lichenoid reactions, maculopapular rashes, vitiligo and other
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131 autoimmune skin diseases, including bullous disorders, have been reported in the
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132 literature [3,4,5].

133 Considering that the use of anti-PD-1 anti-PD-L1 antibodies is relatively new, our
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134 experience with the management of immune-triggered skin toxicity remains empirical
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135 and occasionally exploratory. In the current manuscript we present our experience

136 with immunotherapy-triggered psoriasis, focusing on disease phenotypic

137 characteristics and management.

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145 Patients and methods

146 This was a multi-centric retrospective study of psoriasis related to immunotherapy,

147 conducted in the name of ENCADO (European Network for Cutaneous ADverse

148 Event to Oncologic drugs) group. For the aims of the study we used the databases of 9

149 oncodermatology units from Greece, France, Italy, Spain and Argentina and searched

150 for psoriasis cases, developing through the treatment course with ICI until the end of

151 December 2019. Inclusion criteria were patients developing psoriasis after anti-PD-1

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152 or anti-PDL1 treatment with available data on sex, age, psoriasis type(s), type of

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153 immunotherapy, primary cancer and the number of ICI doses until the event. We also

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recorded and analyzed more parameters including personal/family history of the
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155 disease, psoriasis grading and pruritus , the need for interruption or ICI
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156 discontinuation, the therapeutic interventions, as well as the treatment outcomes. We

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157 recorded epidemiologic data of the patients including sex, age, primary cancer,

158 psoriasis subtype(s) and personal/family history of the disease. The severity of
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159 psoriasis as well as pruritus were classified using the Common Terminology Criteria
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160 for Adverse Events (CTCAE). Disease severity was classified as grade-1 (<10% Body

161 Surface Area [BSA], mild), grade-2 (10-30% BSA, moderate) and grade-3 (>30%

162 BSA, severe). The type of immunotherapy, the number of ICI doses until the event,

163 the need for interruption or ICI discontinuation, the therapeutic interventions, as well

164 as the treatment outcomes were also recorded. The therapeutic responses to psoriasis

165 treatment were evaluated based on the reduction of BSA and it was graded as no

166 response (<30% BSA reduction of the initial BSA involved), partial response (30%-

167 80% BSA reduction) and excellent response (>80% BSA reduction). Best oncologic
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168 response to immunotherapy was recorded and graded according to Response

169 Evaluation Criteria in Solid Tumors (RECIST) criteria [6].

170 Statistical analysis

171 For continuous variables, we conducted a descriptive analysis calculating the mean

172 and standard deviation and we checked for normality using Kolmogorov–Smirnov

173 test. Also, Mann–Whitney T-test and ANOVA Kruskal–Wallis were used for the

174 comparisons between them. Pairwise comparisons were also conducted. For

175 dichotomous and categorical variables, Pearson X2–test was used for the association

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176 between the variables. Crude and adjusted odds ratio and corresponding 95%

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177 Confidence Intervals (CI) were calculated from univariate and multivariate

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conditional logistic regression, respectively. A level of a=0.10 was used as a cutoff
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179 for variable removal in the automated model selection for multivariate logistic
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180 regression. A survival analysis with Kaplan – Meier method and Log – Rank test for
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181 the comparison of time to response to psoriatic treatment were also conducted. All the

182 statistical tests were two–sided and the level of significance was set at a=0.05. Data
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183 analysis was carried out using SPSS Statistics for Windows, version 25.0 (IBM-
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184 Corp).

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194 Results

195 ENCADO members provided data of 115 patients with anti-PD-1/PD-L1 induced

196 psoriasis that were included in the study. The mean (SD) follow-up period after

197 psoriasis diagnosis was 9.3 (7.09) months.

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198 Demographic characteristics of the study group are listed in Table-1. Thirty-three out

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199 of 115 (30.8%) patients had a personal history of psoriasis; in 20 out of 33 of them the

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201 history of psoriasis were available in only 93 patients and was positive in 32 of them
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202 (34.4%).

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204 (14.9). In patients with clinically present psoriasis upon ICI initiation, deterioration of
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205 the disease was recorded sooner compared to those with no active psoriatic at baseline
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206 (mean number of infusions 5.4 vs 12.2, p<0.05) (Table-2). No dosage differences

207 were noted among anti-PD-1 and anti-PDL1 agents or in regards with any other

208 specific drug of this group. Patients with non small cell lung cancer (NSCLC)

209 developed psoriasis sooner compared to those with melanoma (9.7 vs. 20.8 mean

210 number of infusions), but this was not statistically significant (Figure-1a). The

211 number of infusions until psoriasis development or deterioration was higher in

212 females compared to males (14.9 vs. 10.1, respectively, p=0.025).

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213 Thirty patients (30/107, 28%) developed additional cutaneous irAEs, namely macular

214 rash (8 patients), vitiligo (7 patients) and lichen planus (5 patients). Another 20.8%

215 (20/96) of cases were complicated with systemic irAEs.

216 Clinical characteristics

217 Plaque psoriasis was the most commonly diagnosed clinical form (49/115, 42.6%),

218 followed by the palmoplantar (14/115, 12.2%) (Table-1). Interestingly, 30/115

219 (26.1%) patients developed simultaneously or subsequently more than one clinical

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220 subtypes of psoriasis. Nail involvement was recorded in 37/115 cases (32.7%),

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221 whereas 8.1% reported symptoms of psoriatic arthritis. Pruritus was present in 67/115

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223 reactions. No differences were found regarding number of infusions and type of
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224 psoriatic lesion (Figure-1b). The mean (SD) BSA affected at visit one was 15.9

225 (17.22) and the worst mean BSA during follow-up was 16.3 (15.9). Figure 2
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226 illustrates representative cases of different psoriatic phenotypes at baseline.

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228 Psoriasis treatment and outcomes

229 Sixty-eight patients (68/115, 59.1%) were solely treated with topical agents, mainly

230 topical steroids (37 patients), followed by calcipotriol plus betamethasone (26

231 patients). Four patients underwent narrow band UVB phototherapy combined with

232 topical steroids (2 patients) or with calcipotriol plus betamethasone (2 patients) and

233 one patient with topical retinoids (tazarotene gel) plus topical steroids

234 Forty-seven patients (40.9%) were treated with both systemic and topical agents

235 (Suppl Table-1). The most common systemic therapy was acitretin monotherapy (21
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236 patients,10-25mg/day, 18.3 %), followed by systemic steroids (8 patients, 7 %),

237 apremilast (7 patients at standard dose, 6.1%), methotrexate (5 patients, 7.5-

238 20mg/week, 4.3%) and biologics (4 patients, 3.5%). Systemic steroids were

239 prescribed at an initial dose of 25-50 mg/day with a gradual decrease in a mean period

240 of 5.8 weeks. Acitretin was used in combination with topical corticosteroids or/and

241 calcipotriol (16 patients, 76.2%), or in combination with phototherapy (UVB-NB, 5

242 patients, 23.8%). Four patients were treated with biologic agents, including two with

243 anti-TNFa (adalimumab and infliximab), one with ustekinumab and one with the

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244 combination of acitretin and guselkumab. Eighteen out of 23 patients treated with

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245 acitretin showed either excellent response of psoriasis with complete clearance of the

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lesions (6/23, 26%) or partial response (12/23, 52.1%). A significant clinical
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247 improvement (excellent response or partial response) was also reported in all patients
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248 treated with apremilast. Interestingly, all patients treated with systemic steroids, also
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249 showed a positive clinical response. Regarding biologics, partial response was

250 observed in one patient in infliximab and in one patient in ustekinumab, whilst two
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251 individuals did not response to adalimumab and guselkumab. The first non responder
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252 had intolerable grade-2 disease presenting with plaques, inverse and guttate lesions

253 whereas palms, soles and nails were also involved. The second non responder had

254 grade-3 plaque psoriasis with nail and palmoplantar involvement also. The Median

255 time (CI) to response to psoriasis treatment was 8 (7.02 – 8.98) months for acitretin,

256 14 (1.16 – 26.8) for apremilast , 6 (4.30 – 7.69) for methotrexate , 3 (1.17 – 4.28) for

257 steroids. Patients treated with systemic steroids showed quicker response to psoriasis

258 treatment and this was the only statistically significant comparison (steroids vs other

259 therapies, Log – Rank test p= 0.01).

260 Impact on ICIs survival

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261 Overall, 29/112 patients (25.9%) interrupted ICI treatment due to psoriasis, whereas

262 20/111 patients (18%) permanently discontinued immunotherapy. Interestingly, no

263 differences regarding the need for oncological treatment discontinuation were

264 recorded between patients treated exclusively with topical regimens and patients

265 treated with systemic therapies (8 patients/12.5% with topical treatment only vs. 12

266 patients/26.7% with systemic treatment, p=0.128). Patients with psoriasis affecting

267 more than 10% of the BSA had 3.6 increased risk for treatment modification

268 (OR=3.64, CI 1.27-10.45, p=0.03) and 6.4 increased risk for treatment interruption

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269 (OR=6.41, CI 2.40-17.11, p<0.001). The presence of pustular psoriasis also increased

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270 the risk of treatment interruption (odds ratio: 4.9, CI 1.41-16.96, p<0.012).
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271 Antitumoral effect of ICI
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272 Overall, 67.7% of the treated patients improved after immunotherapy, by either

273 complete (19/99, 19.2%) or partial (48/99, 48.5%) response. From univariate
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274 regression, Guttate psoriasis and disease affecting >10 of BSA were found to be
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275 positive predictors leading to a 2.73-fold (p=0.05, C.I 0.98 – 7.55) and 2.55-fold
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276 (p=0.03, C.I 1.05 – 6.22) increased probability for response, respectively.

277 Contrariwise, patients with pruritus posed a decreased probability for response and

278 the relationship was statistical significant (OR=0.38, p=0.03, C.I 0.16 – 0.91). From

279 multivariate logistic regression, only severity (positive predictor for response to ICI,

280 OR=3.15, C.I. 1.18-8.41) and pruritus (negative predictor for response to ICI, OR=

281 0.35, C.I. 0.12-0.97) were statistically significant (Τable-3).

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289 Discussion

290 Psoriatic lesions have been reported in various ICI-treated case series

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291 [7,8,9,10,11,12]. Several studies report that the majority of these patients are

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292 complicated with psoriasis on the setting of exacerbation of a preexisting condition

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[10,13,14,15]. We present the largest to date series of cancer patients treated with
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294 ICIs, complicated with psoriasis. According to our analysis 70% of the cases were
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295 affected by psoriasis de novo with unique disease features. Based on our data, as well
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296 as current European guidelines [16,17,18], we propose an algorithmic approach

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297 regarding proper management of psoriasis in this setting.

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298 Our study supports that development of psoriasis occurs later than other skin

299 toxicities. According to recent literature, in patients treated with nivolumab, skin

300 irAEs presented after a median of 5 weeks, while similar results (6.4 weeks) were

301 reported in lung cancer studies [19,20]. Phillips et al, in a large study of 285 patients

302 with cutaneous adverse reactions also reported that psoriasiform rashes presented in a

303 median time of 61 days for 21/285 patients with recorded skin toxicities [21]. In our

304 population, the minimum period until psoriasis diagnosis was significantly longer

305 than the aforementioned (12 weeks). Nevertheless, there was a noticeable difference

306 between the group of patients with a prior psoriasis history vs. the de novo group,
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307 with the former being affected significantly earlier. For both groups, close skin

308 surveillance and early expert consultation should be part of standard care.

309 Regarding response to immunotherapy, our rates were quite positive reaching overall

310 response rates of 67.7%. Previous studies on melanoma and lung cancer patient have

311 supported that skin reactions are analogically related to therapeutic efficacy

312 [22,23]. Our study, mainly based on melanoma and lung cancer patients as well, is in

313 line with latter observation. Moreover, in our study the presence of guttate lesions, as

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314 well as psoriasis affecting >10% of body surface area were both associated with better

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315 response rates to immunotherapy in comparison with other types of psoriasis and mild

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symptomatology, respectively. On the contrary, the presence of pruritus was a

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negative predictor. However, larger prospective studies are needed in order to safely

318 confirm if these clinical signs could be viable prognostic factors.

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319 Apart from the epidemiological and disease characteristics, in our cohort we
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320 attempted to focus on therapeutic aspects of this novel type of irAE. The most
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321 common systemic agent administered was acitretin. Acitretin, opposed to many other
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322 anti-psoriatic drugs, does not harbor immunosuppressive properties, and in this

323 context it does not interfere with ICI treatment [24]. In our sample, response rates

324 were satisfactory and the treatment was well tolerated, with no unpredicted adverse

325 events and therefore, we recommend acitretin as one of the first-line options in ICI-

326 induced psoriasis.

327 Our study included 7 individuals with moderate to severe psoriasis successfully

328 managed with apremilast. All patients responded well, with 2 out of 7 achieving

329 excellent response and 5 achieving partial response. An important advantage of

330 apremilast is that, based on the summary of product characteristics (SmPC) of the
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331 drug, there is no contra-indication or specific warning in cancer patients. Likewise,

332 there is evidence of optimal outcomes in similar scenarios [25,26]. Without

333 overlooking the weaknesses of a small sample, we believe that apremilast may

334 represent a valuable therapeutic weapon against anti-PD1 induced psoriasis.

335 Methotrexate was administered in only 5 patients in our group with all of them

336 achieving excellent and partial responses. Recent psoriasis guidelines from the French

337 group reviewed the risk of cancer associated with systemic therapies and reported that

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338 there does not seem to be an increased risk for cancer in patients treated with

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339 methotrexate except for a possible increase of non-melanoma skin cancer [8].

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However, further studies are needed, to obtain solid evidence.
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341 The role of systemic steroids in the treatment of psoriasis is controversial. Ιn our daily
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342 clinical practice we avoid systemic steroids, since it is well-known that rapid

343 withdrawal of systemic steroids may lead to rebound phenomenon. To date, only one
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344 case report has been published, reporting a patient with pembrolizumab induced
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345 psoriatic dermatitis that was successfully treated with systemic steroids, without
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346 exacerbation after discontinuation [27]. In our cohort, 8 individuals were managed

347 with systemic steroids, resulting in satisfactory response. However, since systemic

348 steroids might intervene with ICI treatment, in 5 out of 8 cases immunotherapy was

349 discontinued. Despite our small sample, and based on the relatively large number of

350 available anti-psoriatic agents, we recommend that systemic steroids should be

351 preserved for cases resistant to other interventions.

352 Our experience with biologics was limited, since these agents are not recommended in

353 patients with active malignancies. However, a recent meta-analysis of nine studies,

354 assessing the risk of carcinogenesis or cancer recurrence in 11679 patients exposed
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355 either to anti-TNFa or to non-biologic disease-modifying antirheumatic drugs, did not

356 detect any increased risk for the former [28]. Moreover the “prophylactic”

357 administration of anti-TNFa concomitantly to ICI therapy has been reported to be

358 capable of resolving several shortcomings of the latter, while retaining its anti-tumor

359 efficacy [29]. Phillips et al. reported that IL-23a and IL-12/23 inhibition might be

360 beneficial in patients with steroid refractory irAEs, whereas antitumoral response was

361 maintained in two patients treated with guselkumab and ustekinumab respectively

362 [21]. On the other hand, Esfahani K et al, supported loss of anti-tumor efficacy in a

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363 patient with pembrolizumab-induced psoriasis treated with secukinumab [30]. In our

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364 study, four patients were treated with biological agents, of which two responded well

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366 despite clinical improvement. Given the increased disease severity, response rates
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367 were satisfying, however the decision for biological therapy should be always
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368 individualized.
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369 The effect of systemic immunomodulatory treatments on ICIs remains a controversy.

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370 Recent studies, in groups with pre-existing autoimmune disease, have shown that the

371 median progression free survival (PFS) was shorter in patients receiving

372 immunosuppressive therapy at ICI initiation [16]. Although there were differences

373 with our study, related to the initiation time of immunomodulators our results indicate

374 that coadministration of systemic treatment for psoriasis and ICI did not effect the

375 overall therapeutic effect of the latter. This indicates that treatment of psoriasis is of

376 great clinical value even by the use of systemic therapies, which do not seem to

377 compromise immunotherapy’s overall efficacy.

378 Some of the major limitations of our study are due to its retrospective nature.

379 Significant parameters, like PASI scores, cannot therefore be evaluated, resulting in
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380 missing data for a more accurate for patient’s categorization. Future prospective

381 studies, including pathology data, will advocate further analysis and better

382 understanding of this unique irAE.

383 In conclusion, we present the largest –to our knowledge– series of patients

384 complicated with psoriasis during anti-PD1/L1 treatment. The clinical characteristics

385 of this entity are highly diverse. Early diagnosis and adequate management with

386 agents that do not interfere with immunotherapy, or with the underlying malignancy,

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387 is crucial. In this context, we introduce a practical therapeutic algorithm that we

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388 consider useful for both, dermatologists and oncologists. In most cases, ICI treatment

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can be completed, as long as strict dermatological surveillance is present throughout
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409 Abstract
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410 Background: Immune checkpoint inhibitors (ICIs)-mediated psoriasis poses
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411 significant diagnostic and therapeutic challenges.
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Objective: To report data on ICI-mediated psoriasis, emerging from the largest so far

413 cohort and to propose a step-by-step management algorithm.

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414 Μethods: The medical records of all patients with ICI-mediated psoriasis were

415 retrospectively reviewed across nine institutions.

416 Results: We included a cohort of 115 individuals. Grade-1, 2 and 3 disease severity

417 was reported in 60/105 (57.1%, 10 missing data), 34/105 (32.4%) and 11/105

418 (10.5%), respectively. The ratio between de novo and exacerbation cases of psoriasis

419 was 21/90 (23.3%). The most common systemic therapy was acitretin (23 patients,

420 20.1%), followed by systemic steroids (8 patients, 7%), apremilast (7 patients, 6.1%),

421 methotrexate (5 patients, 4.3%) and biologics (4 patients, 3.6%). Overall, 29/112

422 patients (25.9%) interrupted and 20/111 (18%) permanently discontinued ICIs due to
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423 psoriasis. BSA>10% at baseline had a 3.6 increased risk for ICIs treatment

424 modification (OR=3.64, CI 1.27-10.45, p=0.03) and a 6.4 increased risk for

425 permanent discontinuation (OR=6.41, CI 2.40-17.11, p<0.001). Guttate psoriasis and

426 grade2/3 disease were significant positive predictors for antitumor response of ICI

427 whereas pruritus was a negative predictor.

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429 Limitations: Retrospective design

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431 Conclusion: Acitretin, apremilast and methotrexate are safe and effective modalities

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432 for ICI-mediated psoriasis. In most cases, ICI can be completed unhindered. A

433 therapeutic algorithm is proposed.

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456 Introduction

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457 Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting cytotoxic T

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lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1)
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459 or programmed death ligand-1 (PD-L1). Their addition in our armamentarium has
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460 radically transformed the therapeutic arena in oncology, providing the potential of
na

461 high-level and durable responses in a large number of diverse malignancies.

462 The introduction of ICIs has resulted in the recognition of a new spectrum of
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463 immune-related adverse events’ (irAEs) that may occasionally limit their use [1]. The
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464 nature of irAEs has not been completely elucidated, however it is meaningful that

465 they are mostly immune-mediated, resulting by the T-cell activation of cytotoxic

466 CD4+/CD8+ [2]. Skin toxicities are the most prevalent irAEs related to

467 immunotherapy. Lichenoid reactions, maculopapular rashes, vitiligo and other

468 autoimmune skin diseases, including bullous disorders, have been reported in the

469 literature [3,4,5].

470 Considering that the use of anti-PD-1 anti-PD-L1 antibodies is relatively new, our

471 experience with the management of immune-triggered skin toxicity remains empirical

472 and occasionally exploratory. In the current manuscript we present our experience
 20

473 with immunotherapy-triggered psoriasis, focusing on disease phenotypic

474 characteristics and management.

475

476

477

478

479

480

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481

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482 Patients and methods

483
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This was a multi-centric retrospective study of psoriasis related to immunotherapy,
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484 conducted in the name of ENCADO (European Network for Cutaneous ADverse
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485 Event to Oncologic drugs) group. For the aims of the study we used the databases of 9
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486 oncodermatology units from Greece, France, Italy, Spain and Argentina and searched

487 for psoriasis cases, developing through the treatment course with ICI until the end of
ur

488 December 2019. Inclusion criteria were patients developing psoriasis after anti-PD-1
Jo

489 or anti-PDL1 treatment with available data on sex, age, psoriasis type(s), type of

490 immunotherapy, primary cancer and the number of ICI doses until the event. We also

491 recorded and analyzed more parameters, including personal/family history of the

492 disease, psoriasis grading and pruritus , the need for interruption or ICI

493 discontinuation, the therapeutic interventions, as well as the treatment outcomes. The

494 severity of psoriasis as well as pruritus were classified using the Common

495 Terminology Criteria for Adverse Events (CTCAE). Disease severity was classified

496 as grade-1 (<10% Body Surface Area [BSA], mild), grade-2 (10-30% BSA,

497 moderate) and grade-3 (>30% BSA, severe). The type of immunotherapy, the number
 21

498 of ICI doses until the event, the need for interruption or ICI discontinuation, the

499 therapeutic interventions, as well as the treatment outcomes were also recorded. The

500 therapeutic responses to psoriasis treatment were evaluated based on the reduction of

501 BSA and it was graded as no response (<30% BSA reduction of the initial BSA

502 involved), partial response (30%-80% BSA reduction) and excellent response (>80%

503 BSA reduction). Best oncologic response to immunotherapy was recorded and graded

504 according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria [6].

505

of
506 Statistical analysis

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507 For continuous variables, we conducted a descriptive analysis calculating the mean

508
-p
and standard deviation and we checked for normality using Kolmogorov–Smirnov
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509 test. Also, Mann–Whitney T-test and ANOVA Kruskal–Wallis were used for the
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510 comparisons between them. Pairwise comparisons were also conducted. For
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511 dichotomous and categorical variables, Pearson X2–test was used for the association

512 between the variables. Crude and adjusted odds ratio and corresponding 95%
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513 Confidence Intervals (CI) were calculated from univariate and multivariate
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514 conditional logistic regression, respectively. A level of a=0.10 was used as a cutoff

515 for variable removal in the automated model selection for multivariate logistic

516 regression. A survival analysis with Kaplan – Meier method and Log – Rank test for

517 the comparison of time to response to psoriatic treatment were also conducted. All the

518 statistical tests were two–sided and the level of significance was set at a=0.05. Data

519 analysis was carried out using SPSS Statistics for Windows, version 25.0 (IBM-

520 Corp).

521

522
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523

524

525

526

527

528

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529

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530
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531 Results
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532 ENCADO members provided data of 115 patients with anti-PD-1/PD-L1 induced
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533 psoriasis that were included in the study. The mean (SD) follow-up period after

534 psoriasis diagnosis was 9.3 (7.09) months.

ur
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535 Demographic characteristics of the study group are listed in Table-1. Thirty-three out

536 of 115 (28.7%) patients had a personal history of psoriasis; in 20 out of 33 of them the

537 disease was active and clinically apparent upon ICI initiation. Data about family

538 history of psoriasis were available in only 93 patients and was positive in 32 of them

539 (34.4%).

540 The mean number (SD) )of drug dosages until psoriasis onset or exacerbation was

541 11.2 (14.9). In patients with clinically present psoriasis upon ICI initiation,

542 deterioration of the disease was recorded sooner compared to those with no active

543 psoriatic at baseline (mean number of infusions 5.4 vs 12.2, p=0.01 (Table-2). No

544 dosage differences were noted among anti-PD-1 and anti-PDL1 agents or in regards
 23

545 with any other specific drug of this group. Patients with non small cell lung cancer

546 (NSCLC) developed psoriasis sooner compared to those with melanoma (9.7 vs. 20.8

547 mean number of infusions), but this was not statistically significant (Figure-1a). The

548 number of infusions until psoriasis development or deterioration was higher in

549 females compared to males (14.9 vs. 10.1, respectively, p=0.025).

550 Thirty patients (30/107, 28%) developed additional cutaneous irAEs, namely macular

551 rash (8 patients), vitiligo (7 patients) and lichen planus (5 patients). Another 20.8%

of
552 (20/96) of cases were complicated with systemic irAEs.

ro
553 Clinical characteristics

554
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Plaque psoriasis was the most commonly diagnosed clinical form (49/115, 42.6%),
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555 followed by the palmoplantar (14/115, 12.2%) (Table-1). Interestingly, 30/115
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556 (26.1%) patients developed simultaneously or subsequently more than one clinical
na

557 subtypes of psoriasis. Nail involvement was recorded in 37/115 cases (32.7%),

558 whereas 8.1% reported symptoms of psoriatic arthritis. Pruritus was present in 67/115
ur

559 (58.3%) patients including 38 (33%) Grade 1, 21 (18.3%) grade 2 and 8 (7%) grade 3
Jo

560 reactions. No differences were found regarding number of infusions and type of

561 psoriatic lesion (Figure-1b). The mean (SD) BSA affected at visit one was 15.9 (7.22)

562 and the worst mean (SD) BSA during follow-up was 16.3 (15.9). Figure 2 illustrates

563 representative cases of different psoriatic phenotypes at baseline.

564

565 Psoriasis treatment and outcomes

566 Sixty-eight patients (68/115, 59.1%) were solely treated with topical agents, mainly

567 topical steroids (37 patients), followed by calcipotriol plus betamethasone (26
 24

568 patients). Four patients underwent narrow band UVB phototherapy combined with

569 topical steroids (2 patients) or with calcipotriol plus betamethasone (2 patients) and

570 one patient with topical retinoids (tazarotene gel) plus topical steroids.

571 Forty-seven patients (40.9%) were treated with both systemic and topical agents

572 (Suppl Table-1). The most common systemic therapy was acitretin monotherapy (21

573 patients,10-25mg/day, 18.3 %), followed by systemic steroids (8 patients, 7 %),

574 apremilast (7 patients at standard dose, 6.1%), methotrexate (5 patients, 7.5-

of
575 20mg/week, 4.3%) and biologics (4 patients, 3.5%). Systemic steroids were

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576 prescribed at an initial dose of 25-50 mg/day with a gradual decrease in a mean period

577 -p
of 5.8 weeks. Acitretin was used in combination with topical corticosteroids or/and

578
re
calcipotriol (16 patients, 76.2%), or in combination with phototherapy (UVB-NB, 5

579 patients, 23.8%). Four patients were treated with biologic agents, including two with
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580 anti-TNFa (adalimumab and infliximab), one with ustekinumab and one with the
na

581 combination of acitretin and guselkumab. Eighteen out of 23 patients treated with
ur

582 acitretin showed either excellent response of psoriasis with complete clearance of the
Jo

583 lesions (6/23, 26%) or partial response (12/23, 52.1%). A significant clinical

584 improvement (excellent response or partial response) was also reported in all patients

585 treated with apremilast. Interestingly, all patients treated with systemic steroids, also

586 showed a positive clinical response. Regarding biologics, partial response was

587 observed in one patient in infliximab and in one patient in ustekinumab, whilst two

588 individuals did not response to adalimumab and guselkumab. The first non responder

589 had intolerable grade-2 disease presenting with plaques, inverse and guttate lesions

590 whereas palms, soles and nails were also involved. The second non responder had

591 grade-3 plaque psoriasis with nail and palmoplantar involvement also. The median

592 time (CI) to response to psoriasis treatment was 8 (7.02 – 8.98) months for acitretin,
 25

593 14 (1.16 – 26.8) for apremilast, 6 (4.30 – 7.69) for methotrexate, 3 (1.17 – 4.28) for

594 steroids. Patients treated with systemic steroids showed quicker response to psoriasis

595 treatment and this was the only statistically significant comparison (steroids vs other

596 therapies, Log – Rank test p= 0.01).

597 Impact on ICIs survival

598 Overall, 29/112 patients (25.9%) interrupted ICI treatment due to psoriasis, whereas

599 20/111 patients (18%) permanently discontinued immunotherapy. Interestingly, no

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600 differences regarding the need for oncological treatment discontinuation were

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601 recorded between patients treated exclusively with topical regimens and patients

602
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treated with systemic therapies (8 patients/12.5% with topical treatment only vs. 12
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603 patients/26.7% with systemic treatment, p=0.128). Patients with psoriasis affecting
lP

604 more than 10% of the BSA had 3.6 increased risk for treatment modification

605 (OR=3.64, CI 1.27-10.45, p=0.03) and 6.4 increased risk for treatment interruption
na

606 (OR=6.41, CI 2.40-17.11, p<0.001). The presence of pustular psoriasis also increased
ur

607 the risk of treatment interruption (odds ratio: 4.9, CI 1.41-16.96, p<0.012).
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608 Antitumoral effect of ICI

609 Overall, 67.7% of the treated patients improved after immunotherapy, by either

610 complete (19/99, 19.2%) or partial (48/99, 48.5%) response. From univariate

611 regression, Guttate psoriasis and disease affecting >10 of BSA were found to be

612 positive predictors leading to a 2.73-fold (p=0.05, C.I 0.98 – 7.55) and 2.55-fold

613 (p=0.03, C.I 1.05 – 6.22) increased probability for response, respectively.

614 Contrariwise, patients with pruritus posed a decreased probability for response and

615 the relationship was statistical significant (OR=0.38, p=0.03 , C.I 0.16 – 0.91). From

616 multivariate logistic regression, only severity (positive predictor for response to ICI,
 26

617 OR=3.15, C.I. 1.18-8.41) and pruritus (negative predictor for response to ICI, OR=

618 0.35, C.I. 0.12-0.97) were statistically significant (Τable-3).

619

620

621

622

623

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624

625
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626
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627 Discussion
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628 Psoriatic lesions have been reported in various ICI-treated case series
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629 [7,8,9,10,11,12]. Several studies report that the majority of these patients are

630 complicated with psoriasis on the setting of exacerbation of a preexisting condition

631 [10,13,14,15]. We present the largest to date series of cancer patients treated with

632 ICIs, complicated with psoriasis. According to our analysis 70% of the cases were

633 affected by psoriasis de novo with unique disease features. Based on our data, as well

634 as current European guidelines [16,17,18], we propose an algorithmic approach

635 regarding proper management of psoriasis in this setting.

636 Psoriasis exacerbation and psoriasiform rashes have been reported in various case

637 series [7,8,9,10,11,12]. However, the precise clinical characteristics of this novel

638 toxicity and its effect on the overall course of immunotherapy are vastly unknown.
 27

639 We present the largest-to date-series of patients, developing psoriasis as an irAE. We

640 propose an algorithmic approach regarding proper management of psoriasis in this

641 setting, based upon our experience, as well as current European guidelines [13,14,15].

642 The safety of ICIs in individuals with pre-existing autoimmune diseases has gained

643 great attention. Previous studies report that the majority of patients treated with ICIs

644 are complicated with psoriasis on the setting of exacerbation of a preexisting

645 condition [10,16,17,18]. Our data significantly differ since approximately 70% of the

of
646 studied population was affected by psoriasis de novo. Given the retrospective nature

ro
647 of our study this fact should be evaluated accordingly, however, the increasing ratio

648 -p
of de novo cases, in combination with the unique disease phenotype, suggests that a
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649 multidisciplinary approach towards optimization of cutaneous toxicities management
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650 in oncologic patients should definitely include an experienced-in skin toxicities-

651 dermatologist.
na

652 Our study supports that development of psoriasis occurs later than other skin
ur

653 toxicities. According to recent literature, in patients treated with nivolumab, skin
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654 irAEs presented after a median of 5 weeks, while similar results (6.4 weeks) were

655 reported in lung cancer studies [19,20]. Phillips et al, in a large study of 285 patients

656 with cutaneous adverse reactions also reported that psoriasiform rashes presented in a

657 median time of 61 days for 21/285 patients with recorded skin toxicities [21]. In our

658 population, the minimum period until psoriasis diagnosis was significantly longer

659 than the aforementioned (12 weeks). Nevertheless, there was a noticeable difference

660 between the group of patients with a prior psoriasis history vs. the de novo group,

661 with the former being affected significantly earlier. For both groups, close skin

662 surveillance and early expert consultation should be part of standard care.
 28

663 Regarding response to immunotherapy, our rates were quite positive reaching overall

664 response rates of 67.7%. Previous studies on melanoma and lung cancer patient have

665 supported that skin reactions are analogically related to therapeutic efficacy

666 [22,23]. Our study, mainly based on melanoma and lung cancer patients as well, is in

667 line with latter observation. Moreover, in our study the presence of guttate lesions, as

668 well as psoriasis affecting >10% of body surface area were both associated with better

669 response rates to immunotherapy in comparison with other types of psoriasis and mild

670 symptomatology, respectively. On the contrary, the presence of pruritus was a

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671 negative predictor. However, larger prospective studies are needed in order to safely

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672 confirm if these clinical signs could be viable prognostic factors.
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673
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Apart from the epidemiological and disease characteristics, in our cohort we

674 attempted to focus on therapeutic aspects of this novel type of irAE. The most
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675 common systemic agent administered was acitretin. Acitretin, opposed to many other
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676 anti-psoriatic drugs, does not harbor immunosuppressive properties, and in this
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677 context it does not interfere with ICI treatment [24]. In our sample, response rates
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678 were satisfactory and the treatment was well tolerated, with no unpredicted adverse

679 events and therefore, we recommend acitretin as one of the first-line options in ICI-

680 induced psoriasis.

681 Our study included 7 individuals with moderate to severe psoriasis successfully

682 managed with apremilast. All patients responded well, with 2 out of 7 achieving

683 excellent response and 5 achieving partial response. An important advantage of

684 apremilast is that, based on the summary of product characteristics (SmPC) of the

685 drug, there is no contra-indication or specific warning in cancer patients. Likewise,

686 there is evidence of optimal outcomes in similar scenarios [25,26]. Without

 29

687 overlooking the weaknesses of a small sample, we believe that apremilast may

688 represent a valuable therapeutic weapon against anti-PD1 induced psoriasis.

689 Methotrexate was administered in only 5 patients in our group with all of them

690 achieving excellent and partial responses. Recent psoriasis guidelines from the French

691 group reviewed the risk of cancer associated with systemic therapies and reported that

692 there does not seem to be an increased risk for cancer in patients treated with

693 methotrexate except for a possible increase of non-melanoma skin cancer [8].

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694 However, further studies are needed, to obtain solid evidence.

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695 The role of systemic steroids in the treatment of psoriasis is controversial. Ιn our daily

696
-p
clinical practice we avoid systemic steroids, since it is well-known that rapid
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697 withdrawal of systemic steroids may lead to rebound phenomenon. To date, only one
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698 case report has been published, reporting a patient with pembrolizumab induced

699 psoriatic dermatitis that was successfully treated with systemic steroids, without
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700 exacerbation after discontinuation [27]. In our cohort, 8 individuals were managed
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701 with systemic steroids, resulting in satisfactory response. However, since systemic
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702 steroids might intervene with ICI treatment, in 5 out of 8 cases immunotherapy was

703 discontinued. Despite our small sample, and based on the relatively large number of

704 available anti-psoriatic agents, we recommend that systemic steroids should be

705 preserved for cases resistant to other interventions.

706 Our experience with biologics was limited, since these agents are not recommended in

707 patients with active malignancies. However, a recent meta-analysis of nine studies,

708 assessing the risk of carcinogenesis or cancer recurrence in 11679 patients exposed

709 either to anti-TNFa or to non-biologic disease-modifying antirheumatic drugs, did not

710 detect any increased risk for the former [28]. Moreover the “prophylactic”
 30

711 administration of anti-TNFa concomitantly to ICI therapy has been reported to be

712 capable of resolving several shortcomings of the latter, while retaining its anti-tumor

713 efficacy [29]. Phillips et al. reported that IL-23a and IL-12/23 inhibition might be

714 beneficial in patients with steroid refractory irAEs, whereas antitumoral response was

715 maintained in two patients treated with guselkumab and ustekinumab respectively

716 [21]. On the other hand, Esfahani K et al, supported loss of anti-tumor efficacy in a

717 patient with pembrolizumab-induced psoriasis treated with secukinumab [30]. In our

718 study, four patients were treated with biological agents, of which two responded well

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719 and the other two had to discontinue immunotherapy because of side effects and

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720 despite clinical improvement. Given the increased disease severity, response rates

721
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were satisfying, however the decision for biological therapy should be always
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722 individualized.
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723 The effect of systemic immunomodulatory treatments on ICIs remains a controversy.

na

724 Recent studies, in groups with pre-existing autoimmune disease, have shown that the
ur

725 median progression free survival (PFS) was shorter in patients receiving
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726 immunosuppressive therapy at ICI initiation [16]. Although there were differences

727 with our study, related to the initiation time of immunomodulators our results indicate

728 that coadministration of systemic treatment for psoriasis and ICI did not effect the

729 overall therapeutic effect of the latter. This indicates that treatment of psoriasis is of

730 great clinical value even by the use of systemic therapies, which do not seem to

731 compromise immunotherapy’s overall efficacy.

732 Some of the major limitations of our study are due to its retrospective nature.

733 Significant parameters, like PASI scores, cannot therefore be evaluated, resulting in

734 missing data for a more accurate for patient’s categorization. Future prospective
 31

735 studies, including pathology data, will advocate further analysis and better

736 understanding of this unique irAE.

737 In conclusion, we present the largest –to our knowledge– series of patients

738 complicated with psoriasis during anti-PD1/L1 treatment. The clinical characteristics

739 of this entity are highly diverse. Early diagnosis and adequate management with

740 agents that do not interfere with immunotherapy, or with the underlying malignancy,

741 is crucial. In this context, we introduce a practical therapeutic algorithm that we

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742 consider useful for both, dermatologists and oncologists. In most cases, ICI treatment

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743 can be completed, as long as strict dermatological surveillance is present throughout

744 treatment. -p
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745
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746
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747

748 Treatment algorithm for anti-PD-1/PD-L1 induced psoriasis

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749
Jo

Family history, Personal History of Psoriasis

750 and/or active mild to moderate psoriatic
lesions at ICI initiation?
751
752
yes
753
754 no
755 Follow-up on a regular basis.
Continue antipsoriatic treatment*
756 Psoriasis exacerbation?
757
Grade 2/3
758 no yes
yes (BSA >10)
759
760
yes no
761
762Grade 0/1
Stop ICI until
or tolerable Specific indications for systemic treatment?**
763Grade 2.
Discuss reintroduction Special indications for treatment
on a case764
by case basis. yes
withholding?*** yes
Reintroduce
765 ICI under no
systemic treatment no
766
767 Topical treatment ****
Topical treatment +
Phototherapy (UVB-NB) # no
Response?
yes
yes Response? no*****
 32

768
769
770
771
772
773
774
775
776
777
778
779
780
781

of
782
783

ro
784
785
786
787
-p
re
788
789
lP

790
791
792
na

793
794 #
Patients treated for melanoma are excluded
ur

795
796 * Patients with active psoriasis under systemic treatment can start ICI under close follow-up:
797 -Patients under Acitretin, Apremilast or Methotrexate can start ICI under close surveillance
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798 -Patients under cyclosporine should be referred to dermatology expert for treatment modification
799 -Patients under biologics should be discussed case by case in a multidisciplinary approach with oncologists
800
801
802
803 **Special indications for systemic treatment
804 - Involvement of sensitive areas such as face, hands, genitals, nails, scalp
805 - Disseminated lesions
806 - Mild to moderate psoriatic arthritis
807 - DLQI > 10
808 - Severe symptoms (eg itch, burning)
809 - Intolerable Grade 2
810
811 *** Special indications for ICI cessation or withholidng
812 Grade 3 (BSA >30)
813 Erythrodermic psoriasis: Consider introducing systemic corticosteroids (prednisolone 0.2-0.5 mg/kgr)
814 Generalized Pustular psoriasis: Consider introducing systemic corticosteroids (prednisolone 0.2-0.5 mg/kgr)
815 Severe symptoms (eg itch, burning)
816
817 **** Topical treatments
818 - Topical steroids
819 - Calcipotriol
820 - Tazarotene
821 - UVB-NB
822
823
824 ***** Discuss with cancer specialists on a case by case basis
 33

825
826
827
828
829
830
831
832
833
834
835
836
837
838

of
839
840

ro
841
842
843
844
-p
re
845
846
lP

847
848
849
na

850
851
ur

852 Table 1: Epidemiologic and clinical characteristics at baseline and therapeutic intervention
853
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854
Total number (n)=115 (%)
Sex
Male 88 (76.5)
Female 27 (23.5)
Mean age (SD)
Male 68.5 (9.3)
Female 63.7 (11.8)
Primary cancer
NSCLC 69 (60)
Melanoma 17 (14.8)
Head & Neck SCC 6 (5.2)
Renal Cell Carcinoma 6 (5.2)
Urothelial Carcinoma 6 (5.2)
Hodgkin’s Lymphoma 2 (1.7)
Merkel Cell Carcinoma 1 (0.9)
Hepatocellular Carcinoma 3 (2.6)
Gastric Cancer 2 (1.7)
Mesothelioma 1 (0.9)
Ovarian Cancer 1 (0.9)
Pulmonary Neuroendocrine Cancer 1 (0.9)
Immune Checkpoint Inhibitor
Anti-PD1: 99 (86.1)
 34

Nivolumab 68 (59.2)
Pembrolizumab 30 (26.1)
Spartalizumab 1 (0.8)
Anti-PDL1: 16 (13.9)
Durvalumab 6 (5.2)
Atezolizumab 9 (7.9)
Avelumab 1 (0.8)
Anti-PD-1/PD-L1 Monotherapy
Yes 100
No: 15
Ipilimumab 2
Cabozantinib 1
Pazopanib 1
Bevacizumab 1
Campetinib 1
Anti-LAG-3 1
Chemotherapy (Platinum base) 6
Dabrafenib 2

of
Psoriasis type
Plaque psoriasis 49 (42.6)

ro
Pustular psoriasis 8 (7)
Palmoplantar psoriasis 14 (12.2)
Guttate psoriasis 8 (7)
Nail psoriasis
Inverse psoriasis
-p2 (1.7)
1 (0.9)
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Erythrodermic psoriasis 3 (2.6)
> 1 type: 30 (26.1)
Plaque & palmoplantar psoriasis 11
lP

Plaque, palmoplantar & guttate 11

Plaque, palmoplantar & pustular 4
Inverse & palmoplantar 2
na

Pustular, palmoplantar & guttate 2

Grade (1st visit)
Grade 1 (<10% BSA, mild) 60 (57.1)
ur

Grade 2 (10-30% BSA, moderate) 34 (32.4)

Grade 3 (>30% BSA, severe) 11 (10.5)
Treatment
Jo

Topicals monotherapy 68 (59.1)

Acitretin 21 (18.3)
Apremilast 7 (14.8)
Methotrexate 5 (4.3)
Steroids 8 (7)
Anti-TNFa 2 (1.7)
Ustekinumab 1 (0.9)
Acitretin + Guselkumab 1 (0.9)
Acitretin followed by Methotrexate 1 (0.9)
Acitretin followed by Apremilast 1 (0.9)
855
856
857
858
859
860
861
862
863
864
 35

865
866
867
868
869
870
871
872
873
874
875
876
877
878

of
879
880

ro
881
882
883
884
-p
re
885
886
lP

887
888
889
na

890
891 Table 2: Number of infusions until psoriasis
ur

892
Number of infusions (Mean, SD) P- value ₸
Sex 0.025
Jo

Male 10.1 (13.7)

Female 14.9 (18.1)
Psoriasis type 0.09
Plaque psoriasis 10.3 (9.63)
Pustular psoriasis 17.8 (35.1)
Palmoplantar psoriasis 10.5 (8.33)
Guttate psoriasis 16.6 (17.9)
Nail psoriasis 23.5 (13.4)
Inverse psoriasis 10
Erythrodermic psoriasis 14 (17.3)
> 1 type 8.83 (15.8)
Personal history of psoriasis 0.076
No 11.5 (13.2)
Yes 9.82 (17.9)
ICI 0.615
Anti-PD1 11.3 (15.4)
Anti-PDL1 10.9 (12.0)
Active psoriasis at initiation 0.019
No 12.2 (15.8)
Yes 5.43 (3.87)
Family history 0.808
No 11.3 (13.6)
 36

Yes 11.9 (18.3)

Type of cancer 0.773
NSCLC 9.87 (10.4)
Melanoma 20.8 (29.3)
Head & Neck SCC 6.5 (5.24)
Renal Cell Carcinoma 7.33 (4.63)
Urothelial Carcinoma 15.3 (18.3)
Hodgkin’s Lymphoma 6.5 (0.70)
Merkel Cell Carcinoma 18
Hepatocellular Carcinoma 7 (5.00)
Gastric Cancer 5 (4.24)
Mesothelioma 5
Ovarian Cancer 9
Pulmonary Neuroendocrine 4
893
₸
894 : p-value for dichotomous variables (sex, ICI, etc.) based on Mann – Whitney t – test and for nominal
895 variables (type of psoriasis and cancer) based on ANOVA Kruskal – Wallis.

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896
897

ro
898
899
900
901
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902
903
lP

904
905
906
na

907
908
909
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Table 3. Possible predictors affecting the antitumoral effect of ICI

910
Response vs No – Response (stable or progressive disease)
Jo

Odds Ratio P-value Confidence Intervals

Univariate analysis
Guttate psoriasis 2.73 0.05 0.98 – 7.55
Pruritus 0.38 0.03 0.16 – 0.91
Severity 2.55 0.03 1.05 – 6.22
Systemic Therapy 1.42 0.39 0.62 – 3.26
Acitretin 1.20 0.71 0.42 – 3.42
Steroids 2.13 0.30 0.49 – 9.11
Treatment Modification 1.30 0.56 0.53 – 3.19
Multivariate analysis
Pruritus 0.35 0.04 0.12 – 0.97
Severity 3.15 0.02 1.18 – 8.41
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932 Abbreviations list

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934 BSA: Body Surface Area

935 CI: Confidence Intervals

936 CTCAE: Common Terminology Criteria for Adverse Events

937 CTLA-4: Cytotoxic T Lymphocyte-Associated Antigen-4

938 ENCADO: European Network for Cutaneous ADverse Event to Oncologic drugs

939 ICI : Immune Checkpoint Inhibitors

940 irAEs: immune-related Adverse Events

941 NSCLC: Non Small Cell Lung Cancer

942 PD-1: Programmed Cell Death Protein-1

943 PD-L1: Programmed Death Ligand-1

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944 PFS: Progression Free Survival

945 RECIST: Response Evaluation Criteria in Solid Tumors

946 UVB-NB: Narrowband UVB

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1
O'Reilly A, Hughes P, Mann J, et al. An immunotherapy survivor population:

health-related quality of life and toxicity in patients with metastatic melanoma treated

with immune checkpoint inhibitors. Support Care Cancer 2020;28:561-570.

2
Berner F, Bomze D, Diem S et al. Association of checkpoint inhibitor-induced toxic

effects with shared cancer and tissue antigens in non-small cell lung cancer. JAMA

Oncol 2019; 5:1043-1047.

3
Sibaud V, Meyer N, Lamant L, et al. Dermatologic complicaitons of anti-PD-1/PD-

L1 immune checkpoint antibodies. Curr Opin Oncol 2016;28:254-263.

4
Collins LK, Chapman MS, Carter JB, Samie FH. Cutaneous adverse effects of the

immune checkpoint inhibitors. Curr Probl Cancer 2017;41:125-128.

 39

5
Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicity

and immunotherapy. Am J Clin Dermatol 2018;19:345-361.

6
Schwartz LH, Litiere S, De Vries E et al. RECIST 1.1- Update and clarification:

from the RECIST committee. Eur J Cancer 2016; 62:132-137.

7
Bonigen J, Raynaud-Donzel C, Hureaux J et al. Anti-PD1-induced psoriasis. A

study of 21 patients. J Eur Acad Dermatol 2017; 31:e254-257.

8
Voudouri D, Nikolaou V, Laschos K, et al. Anti-PD1/PDL1 induced psoriasis. Curr

of
Probl Cnacer 2017; 41:407-412.

ro
9
Ruiz-Banobre J, Perez-Pampin E, Garcia-Gonzalea J et al. Development of psoriatic
-p
arthritis during nivolumab therapy for metastatic non-small cell lung cancer, clinical
re
outcome analysis and review of the literature. Lung Cancer 2017;108: 217-221.
lP

10
Guven DC, Kilickap S, Guner G, Taban H, Dizdar O. Development of de novo
na

psoriasis during nivolumab therapy in a patient with small cell lung cancer. J Oncol

Pharm Practice 2020; 26:256-258.

ur

11
Chujo S, Asahina A, Itoh Y, et al. New onset psoriasis during nivolumab treatment
Jo

for lung cancer. J Dermatol 2018; 45:e55-e56.

12
Coleman E, Ko C, Dai F, et al. Inflammatory eruptions associated with immune

checkpoint inhibitor therapy: a single-institution retrospective analysis with

stratification of reaction by toxicity and implications for management. J Am Acad

Dermatol 2019; 80:990-997.

13
DeBock M, Hulstaert E, Kruse V, Brochez L. Psoriasis vulgaris exacerbation

during treatment with a PD-1 checkpoint inhibitor: case report and literature review.

Case Rep Dermatol 2018;10:190-197.

 40

14
Scarfi F, Lacava R, Patrizi A, et al. Follicular psoriasis induced by pembrolizumab

in a patient with advanced non-small-cell lung cancer. Int J Dermatol 2019; 58:e151-

e152.
15
Matsumura N, Ohtsuka M, Kikuchi N, et al. Exacerbation of psoriasis during

nivolumab therapy for metastatic melanoma. Acta Derm Venereol 2016; 96:259-260.
16
Nast A, Gisondi P, Ormerod AD, et al. European S3-Guidelines on the systemic

treatment of psoriasis vulgaris-Update 2015;Short version-EDF in cooperation with

of
EADV and IPC. J Eur Acad Dermatol 2015; 29:2277-2294.

ro
17
Amatore F, Villani AP, Tauber M et al. French guidelines on the use of systemic

-p
treatments for moderate-to-severe psoriasis in adults. J Eur Acad Dermatol Venereol
re
2019; 33:464-483.
lP

18
Gisondi P, Altomare G, Ayala F et al. Italian guidelines on the systemic treatments

of moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol 2017; 31:774-

na

790.
ur

19
Weber JS, Hodi FS, Wolchock JD et al. Safety profile of nivolumab monotherapy:
Jo

a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017; 35:785-

792.
20
Aso M, Toi Y, Sugisaka J et al. Association between skin reaction and clinical

benefit in patients treated with anti-programmed cell death 1 monotherapy for

advanced non-small cell lung cancer. Oncologist 2019; 24:1-9.

21
Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune related

cutaneous adverse events. J Clin Oncol 2019; 37:2746-2758.

22
Min Lee CK, Li S, Tran DC et al. Characterization of dermatitis after PD-1/PD-L1

inhibitor therapy and association with multiple oncologic outcomes: a retrospective

case-control study. J Am Acad Dermatol 2018 79:1047-1052.

 41

23
Chan L, Hwang SJE, Byth K, et al Survival and prognosis of individuals receiving

programmed cell death 1 inhibitor with and without immunologv cutaneous adverse

events. J Am Acad Dermatol 2020; 82:311-316.

24
Rademaker M, Rubel DM, Agnew K, et al. Psoriasis and cancer. An

Australian/New Zealand narrative. Australas J Dermatol 2019; 60:12-18.

25
Fattore D, Annuziata MC, Panariello L, et al. Successful treatment of psoriasis

induced by immune checkpoint inhibitors with apremilast. Eur J Cancer 2019;

of
110:107-109.

ro
26
Apalla Z, Psarakis E, Lallas A, et al. Psoriasis in Patients With Active Lung
-p
Cancer: Is Apremilast a Safe Option? Dermatol Pract Concept 2019; 9: 300-1.
re
27
Suzuki M, Matsumoto S, Takeda Y, Sugiyama H. Systemic psoriasiform dermatitis
lP

appeared after the administration of pembrolizumab. Intern Med. 2019; Nov 29 [Epub

ahead of print]
na

28
Micic D, Komaki Y, Alavanja A, et al. Risk of cancer recurrence among
ur

individuals exposed to antitumor necrosis factor therapy: A systematic review and

Jo

meta-analysis of observational studies. J Clin Gastroenterol 2019; 53:e1-e11.

29
Alvarez M, Otano I, Minute L, et al. Impact of prophylactic TNF blockade in the

dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity. Cell Stress 2019;

3:236-239.
30
Esfahani K, Miller Jr WH. Reversal of autoimmune toxicity and loss of tumor

response by interleukin-17 blockade. N Engl J Med 2017; 376:1989-91.

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Figure legends
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Figure 1 a. Boxplot of Number of doses to Primary cancer. There was not a statistical
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significant difference between the number of doses for adverse event and the primary
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cancer (ANOVA p=0.77, pairwise comparisons p>0.05) b. Boxplot of Number of

doses to Type of psoriasis. There was not a statistical significant difference between

the number of doses for adverse event and the type of psoriasis (ANOVA p=0.09,

pairwise comparisons p>0.05)

Figure 2 a. Plaque type psoriasis b. Palmar psoriasis c. Nail psoriasis d. Guttate

psoriasis e. Pustular psoriasis f. Plantar pustulosis

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Capsule summary
• Cutaneous toxicities represent a crucial limitation for Immune Checkpoint
Inhibitors applicability.
• Psoriasis affecting more than 10% of the body surface area as well as pustular
psoriasis increase the risk of treatment modification/interruption. Guttate
psoriasis and grade2/3 disease may be significant positive prognostic
indicators for antitumoral effect of Immune Checkpoint Inhibitors

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