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1
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Duan JL, Yang J, Zhang YL, Huang WT. Amelanotic primary cervical malignant melanoma: A case report and review of literature. World J Clin Oncol 2024; 15:953-960. [PMID: 39071457 PMCID: PMC11271727 DOI: 10.5306/wjco.v15.i7.953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/08/2024] [Accepted: 06/07/2024] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND Primary malignant melanoma of the cervix (PMMC) is an extremely rare disease that originates from primary cervical malignant melanoma and frequently represents a challenge in disease diagnosis due to unclarified clinical and histological presentations, particularly those without melanin. CASE SUMMARY Here, we report a case of amelanotic PMMC, with a history of breast cancer and thyroid carcinoma. The patient was finally diagnosed by immunohistochemical staining and staged as IB2 based on the International Federation of Gynecology and Obstetrics with reference to National Comprehensive Cancer Network guidelines and was treated with radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy. She then received combination therapy consisting of immunotherapy with tislelizumab and radiofrequency hyperthermia. She has remained free of disease for more than 1 year. CONCLUSION The differential diagnosis process reenforced the notion that immunohistochemical staining is the most reliable approach for amelanotic PMMC diagnosis. Due to the lack of established therapeutic guidelines, empirical information from limited available studies does not provide the rationale for treatment-decision making. By integrating 'omics' technologies and patient-derived xenografts or mini-patient-derived xenograft models this will help to identify selective therapeutic window(s) and screen the appropriate therapeutics for targeted therapies, immune checkpoint blockade or combination therapy strategies effectively and precisely that will ultimately improve patient survival.
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Affiliation(s)
- Jin-Lin Duan
- Department of Pathology, The Affiliated Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200332, China
| | - Jing Yang
- Department of Pathology, The Affiliated Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200332, China
| | - Yong-Long Zhang
- Laboratory of Targeted Therapy and Precision Medicine, Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Wen-Tao Huang
- Department of Pathology, The Affiliated Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200332, China
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2
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Pach JJ, Mbonu N, Bhullar S, Cohen JM, Leventhal JS. Immune Checkpoint Inhibitor-Induced Psoriasis: Diagnosis, Management, and a Review of Cases. Dermatol Clin 2024; 42:481-493. [PMID: 38796277 DOI: 10.1016/j.det.2024.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2024]
Abstract
Immune checkpoint inhibitors (ICIs) are effective antitumor agents but are associated with immune-related adverse events. ICI-induced psoriasis commonly presents in patients with a history of psoriasis but may occur de novo, and it has a significant physical and psychosocial impact. ICI-induced and non-ICI-induced psoriasis are likely mediated by similar cytokines, and similar treatments are employed. Topical treatment often suffices, and when needed, several systemic treatments appear to be effective without impacting antitumor response. Development of psoriasis may indicate a superior response to ICIs. Thus, recognition and management of ICI-induced psoriasis is essential to avoid ICI interruption and maximize therapeutic potential.
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Affiliation(s)
- Jolanta J Pach
- Department of Dermatology Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
| | - Nina Mbonu
- Meharry Medical College, 1005 Drive Db Todd Jr Boulevard, Nashville, TN 37208, USA
| | - Shaman Bhullar
- Department of Dermatology Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
| | - Jeffrey M Cohen
- Department of Dermatology Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA
| | - Jonathan S Leventhal
- Department of Dermatology Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
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3
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Tsiogkas SG, Mavropoulos A, Dardiotis E, Zafiriou E, Bogdanos DP. Biologics targeting IL-17 sharply reduce circulating T follicular helper and T peripheral helper cell sub-populations in psoriasis. Front Immunol 2024; 15:1325356. [PMID: 38835766 PMCID: PMC11148216 DOI: 10.3389/fimmu.2024.1325356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 05/07/2024] [Indexed: 06/06/2024] Open
Abstract
Introduction Circulating T follicular helper (cTfh) cells and circulating T peripheral helper (cTph) cells (which share common characteristics with the cTfh population) are implicated in the pathogenesis of immune-mediated and autoimmune diseases such as psoriasis (Ps). Their close interplay with the interleukin 17 (IL-17) axis and the ex vivo effect of IL-17-targeting biologic agents used to treat Ps on them are elusive. This study aimed to investigate the effect of biologics targeting IL-17 on cTfh and cTph cell subpopulations isolated from the blood of patients with Ps. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from patients with Ps at treatment initiation and three months later. Samples were also collected from controls. Cells were stained using monoclonal antibodies. Flow cytometry assessed the fraction of cTfh (CD3+CD4+CXCR5+) and cTph (CD3+CD4+CXCR5-PD-1hi) cells.. Results Flow cytometric analysis showed increased fractions of activated cTfh subsets including ICOS+ and ICOS+PD-1+ expressing cells, in patients compared to controls. Biologic blocking of IL-17A diminished the cTfh population. Furthermore, ICOS+ and ICOS+PD-1+ sub-populations were also inhibited. Finally, the cTph cell fraction significantly decreased after three months of successful treatment with biologics. Conclusion Early anti-IL-17-mediated clinical remission in Ps is associated with decreased cTfh and cTph cell subpopulations.
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Affiliation(s)
- Sotirios G. Tsiogkas
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Athanasios Mavropoulos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Efthimios Dardiotis
- Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Efterpi Zafiriou
- Department of Dermatology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - Dimitrios P. Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Thessaly, Larissa, Greece
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4
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Wan Z, Huang J, Ou X, Lou S, Wan J, Shen Z. Psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. An Bras Dermatol 2024; 99:425-432. [PMID: 38388337 PMCID: PMC11074622 DOI: 10.1016/j.abd.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 02/24/2024] Open
Abstract
PD-1 (programmed Death-1) immune checkpoint inhibitors have provided significant benefits to tumor patients. However, a considerable proportion of the patients develop immune-related adverse events (irAEs), of which cutaneous irAEs (cirAEs, e.g., psoriasis) occur relatively early. This review provides an overview of the current progress in psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. It not only describes the relevant influencing factors but also theoretically analyzes the immunological mechanisms that lead to the onset or exacerbation of psoriasis. Finally, the authors present guidelines for the treatment of psoriasis de novo or exacerbation by PD-1 checkpoint inhibitors. The review is intended to assist dermatologists in the early recognition and effective individualized management of such cirAE, which is helpful to continue or adjust the tumor-targeted immunotherapy on the basis of ensuring the quality of life of tumor patients.
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Affiliation(s)
- Zi Wan
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiangyuan Huang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaojie Ou
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Shuang Lou
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jianji Wan
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhu Shen
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
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5
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Morelli M, Carbone ML, Scaglione GL, Scarponi C, Di Francesco V, Pallotta S, De Galitiis F, Rahimi S, Madonna S, Failla CM, Albanesi C. Identification of immunological patterns characterizing immune-related psoriasis reactions in oncological patients in therapy with anti-PD-1 checkpoint inhibitors. Front Immunol 2024; 15:1346687. [PMID: 38495872 PMCID: PMC10940473 DOI: 10.3389/fimmu.2024.1346687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/14/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction Immunotherapy with biologics targeting programmed cell death protein-1 (PD-1) is highly effective in the treatment of various malignancies. Nevertheless, it is frequently responsible for unexpected cutaneous manifestations, including psoriasis-like dermatitis. The pathogenesis of anti-PD-1-induced psoriasis has yet to be clarified, even though it is plausible that some innate and adaptive immunity processes are in common with canonical psoriasis. The genetic predisposition to psoriasis of patients could also be a contributing factor. Here, we investigated the immunological and genetic profiles of two patients with metastatic melanoma and one patient affected by lung cancer, who developed severe psoriasis after receiving anti-PD-1 nivolumab therapy. Methods The immune patterns of the three patients were compared with those detectable in classical, chronic plaque-type psoriasis or paradoxical psoriasis induced by anti-TNF-α therapy, mostly sustained by adaptive and innate immunity processes, respectively. Therefore, immunohistochemistry and mRNA analyses of innate and adaptive immunity molecules were conducted on skin biopsy of patients. Genetic analysis of polymorphisms predisposing to psoriasis was carried out by NGS technology. Results We found that anti-PD-1-induced psoriasis showed immunological features similar to chronic psoriasis, characterized by the presence of cellular players of adaptive immunity, with abundant CD3+, CD8+ T cells and CD11c+ dendritic cells infiltrating skin lesions, and producing IL-23, IL-6, TNF-α, IFN-γ and IL-17. On the contrary, a lower number of innate immunity cells (BDCA2+ plasmacytoid dendritic cells, CD15+ neutrophils, CD117+ mast cells) and reduced IFN-α/β, lymphotoxin (LT)-α/β, were observed in anti-PD-1-induced psoriasis lesions, as compared with anti-TNF-α-induced paradoxical psoriasis. Importantly, the disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) psoriasis autoantigen was significantly upregulated in psoriasis lesions of anti-PD-1-treated patients, at levels comparable with chronic plaque-type psoriasis. Finally, NGS analysis revealed that all patients carried several allelic variants in psoriasis susceptibility genes, such as HLA-C, ERAP1 and other genes of the major psoriasis susceptibility PSORS1 locus. Discussion Our study showed that adaptive immunity predominates over innate immunity in anti-PD-1-induced psoriasis lesions, consistently with the local ADAMTSL5 overexpression. The presence of numerous SNPs in psoriasis susceptibility genes of the three patients also suggested their strong predisposition to the disease.
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Affiliation(s)
- Martina Morelli
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Maria Luigia Carbone
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Giovanni Luca Scaglione
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Claudia Scarponi
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Valentina Di Francesco
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Sabatino Pallotta
- Department of Dermatology, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Federica De Galitiis
- Department of Oncology, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Siavash Rahimi
- Anatomical Pathology Unit, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Stefania Madonna
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Cristina Maria Failla
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
| | - Cristina Albanesi
- Experimental Immunology Laboratory, Istituto Dermopatico dell’Immacolata (IDI-IRCCS), Rome, Italy
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Popa LG, Giurcaneanu C, Portelli MG, Mihai MM, Beiu C, Orzan OA, Ion A, Anghel TH. Perspectives on Psoriasiform Adverse Events from Immune Checkpoint Inhibitors: Lessons Learned from Our Practice. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:373. [PMID: 38541099 PMCID: PMC10972058 DOI: 10.3390/medicina60030373] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 10/24/2024]
Abstract
Background: New oncologic therapies, including immune checkpoint inhibitors (ICIs), have revolutionized the survival and prognosis of cancer patients. However, these therapies are often complicated by immune-related adverse effects (irAEs) that may impact quality of life and potentially limit their use. Among these adverse events are psoriasis and psoriatic arthritis that may develop de novo or flare under treatment with ICIs. Given the exceptional immune status of patients receiving ICIs, managing these conditions without interfering with the effect of the oncologic treatment may prove very challenging. Aim: To review the literature data on ICI-induced psoriasis exacerbation or development, to present our own experience, and to discuss the pathogenic mechanisms underlying this association and the optimal therapeutic approach for these patients. Case Reports: We report three cases of ICI-induced de novo psoriasis and two cases of ICI-induced psoriasis exacerbation that required systemic treatment. Oral acitretin treatment successfully controlled psoriasis lesions in three cases and allowed for the continuation of immunotherapy. Literature Review: We performed a medical literature search across several databases (PubMed, Medline, Google Scholar) using the search terms "immune checkpoint inhibitor-induced psoriasis/psoriasiform dermatitis/psoriasis arthritis". We identified and revised 80 relevant publications that reported 1102 patients with psoriasis and/or psoriasis arthritis induced or exacerbated by ICIs. We assessed the type of cancer, the therapeutic agent involved, the clinical form of psoriasis, the presence or absence of psoriatic arthritis, the personal and family history of psoriasis, the age, the gender, the time until onset or exacerbation of skin lesions, the specific treatment recommended, the need for ICI discontinuation, and the patient's outcome. Conclusions: As ICIs represent a fairly novel therapy, the association with several adverse effects is only now unraveling. Psoriasis exacerbation or onset following the initiation of immunotherapy is one such example, as more and more reports and case series are being published. Awareness of the relationship between psoriasis and treatment with ICIs, prompt recognition, and initiation of adequate skin-directed therapies are essential for the avoidance of skin lesions worsening, the need for systemic treatments that may interfere with ICIs' effects, or the discontinuation of the latter. In the absence of generally accepted guidelines, it is advisable to treat patients with severe, widespread psoriasis with drugs that do not impair the effects of immunotherapy and thus do not alter the patient's prognosis.
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Affiliation(s)
- Liliana Gabriela Popa
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Calin Giurcaneanu
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Mariana Georgiana Portelli
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Mara Mădălina Mihai
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Cristina Beiu
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Olguța Anca Orzan
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Ana Ion
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
| | - Teodora Hrista Anghel
- Faculty of Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania; (L.G.P.); (C.G.); (M.G.P.); (M.M.M.); (C.B.); (A.I.); (T.H.A.)
- Department of Dermatology, ‘Elias’ University Emergency Hospital, 011461 Bucharest, Romania
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Xu Z, Wang Y, Jiang C, Wang Z, Cheng Y, Fan M. The regulation of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriasis itch and itch sensitization in mouse. Mol Pain 2024; 20:17448069241252384. [PMID: 38631843 PMCID: PMC11069332 DOI: 10.1177/17448069241252384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 04/11/2024] [Accepted: 04/16/2024] [Indexed: 04/19/2024] Open
Abstract
PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.
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Affiliation(s)
- Zhehao Xu
- Department of Pharmacology, Clinic Medical College, Anhui Medical University, Hefei, China
| | - Yue Wang
- Department of Pharmacology, Clinic Medical College, Anhui Medical University, Hefei, China
- Department of Science and Education, Hefei BOE Hospital, Hefei, China
| | - Changcheng Jiang
- Department of Pharmacology, Clinic Medical College, Anhui Medical University, Hefei, China
| | - Zhengwei Wang
- Department of Pharmacology, Clinic Medical College, Anhui Medical University, Hefei, China
| | - YongFeng Cheng
- Department of Pharmacology, Clinic Medical College, Anhui Medical University, Hefei, China
| | - Manli Fan
- Department of Pharmacy, Fuyang Hospital, Anhui Medical University, Fuyang, China
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8
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Cao T, Zhou X, Wu X, Zou Y. Cutaneous immune-related adverse events to immune checkpoint inhibitors: from underlying immunological mechanisms to multi-omics prediction. Front Immunol 2023; 14:1207544. [PMID: 37497220 PMCID: PMC10368482 DOI: 10.3389/fimmu.2023.1207544] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/05/2023] [Indexed: 07/28/2023] Open
Abstract
The development of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of therapy for multiple malignancies, including urothelial carcinoma, non-small cell lung cancer, melanoma and gastric cancer. As part of their anti-tumor properties, ICIs can enhance susceptibility to inflammatory side effects known as immune-related adverse events (irAEs), in which the skin is one of the most commonly and rapidly affected organs. Although numerous questions still remain unanswered, multi-omics technologies have shed light into immunological mechanisms, as well as the correlation between ICI-induced activation of immune systems and the incidence of cirAE (cutaneous irAEs). Therefore, we reviewed integrated biological layers of omics studies combined with clinical data for the prediction biomarkers of cirAEs based on skin pathogenesis. Here, we provide an overview of a spectrum of dermatological irAEs, discuss the pathogenesis of this "off-tumor toxicity" during ICI treatment, and summarize recently investigated biomarkers that may have predictive value for cirAEs via multi-omics approach. Finally, we demonstrate the prognostic significance of cirAEs for immune checkpoint blockades.
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9
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Gargiulo L, Ibba L, Valenti M, Costanzo A, Narcisi A. Pembrolizumab-induced plaque psoriasis successfully treated with risankizumab in a patient with stage IV cutaneous melanoma. Melanoma Res 2023; 33:152-154. [PMID: 36728879 DOI: 10.1097/cmr.0000000000000875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Immune checkpoint inhibitors, such as pembrolizumab and nivolumab, are monoclonal antibodies that block programmed cell death 1 (PD-1) expressed on activated CD8+ T cells and play a crucial role in the treatment of advanced melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported, such as flares of plaque psoriasis, but no specific guidelines regarding the treatment are available. We present the case of a 28-year-old male diagnosed with stage IV non-BRAFV600E mutated melanoma in 2014. After the surgery and the failure of ipilimumab and IL-2, he started immunotherapy with pembrolizumab. One month after the start of the therapy, he came to our department showing a severe flare of plaque psoriasis with a body surface area of 40% and a Psoriasis Area and Severity Index (PASI) of 28. Given the severity of the clinical picture and the contraindications to conventional systemic therapy, we decided to start biological treatment with risankizumab, an anti-IL-23 inhibitor. After just the induction phase, he showed almost skin clearance obtaining a reduction of more than 90% of the baseline PASI. Our patient's rapid response to risankizumab enabled us to continue immunotherapy with pembrolizumab. The recognition of cutaneous signs of toxicity related to such drugs for advanced melanoma is of primary importance to start the correct treatment and continue the immunotherapy when possible.
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Affiliation(s)
- Luigi Gargiulo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Luciano Ibba
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Mario Valenti
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Antonio Costanzo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele
- Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
| | - Alessandra Narcisi
- Dermatology Unit, IRCCS Humanitas Research Hospital, Rozzano (MI), Italy
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10
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Sun X, Mei X, Liu Y. Exacerbation of psoriasis induced by Nivolumab in a patient with stage IIIc gastric adenocarcinoma: A case report and literature review. J Transl Autoimmun 2023; 6:100193. [PMID: 36852017 PMCID: PMC9958049 DOI: 10.1016/j.jtauto.2023.100193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 08/19/2022] [Indexed: 02/17/2023] Open
Abstract
Nivolumab, the programmed cell death 1 inhibitor, is a kind of immune checkpoint inhibitor commonly used to treat advanced cancers. Unfortunately, such drugs often induce various immune-related adverse events involving different body systems, with psoriasis being one of the skin toxicities. We report the clinical features of an exacerbated psoriasis induced by using nivolumab after three days in a patient with stage IIIc gastric adenocarcinoma. At the same time, we searched 27 case reports published from 2015 to 2021 over the world and systematically summarized the clinical manifestation of a total of 44 cases with psoriasis caused or exacerbated by Nivolumab. Commonly traditional treatment could be useful, and small molecule drugs such as apremilast are effective among some patients. However, more studies are needed to evaluate the efficacy and safety of biologics or small molecule drugs in treating psoriasis induced by nivolumab.
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Affiliation(s)
- Xiaojie Sun
- Clinical Trial and Cosmetics Testing Center, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, 210042, China
| | - Xiaole Mei
- Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, China.,Key Laboratory of Basic and Translational Research on Immunological Dermatology, Chinese Academy of Medical Sciences, Nanjing, Jiangsu, 210042, China
| | - Yi Liu
- Clinical Trial and Cosmetics Testing Center, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu, 210042, China
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11
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Yeh CY, Su SH, Tan YF, Tsai TF, Liang PH, Kelel M, Weng HJ, Hsiao YP, Lu CH, Tsai CH, Lee CH, Clausen BE, Liu FT, Lee YL. PD-L1 Enhanced by cis-Urocanic Acid on Langerhans Cells Inhibits Vγ4 + γδT17 Cells in Psoriatic Skin Inflammation. J Invest Dermatol 2023:S0022-202X(23)00161-6. [PMID: 36868499 DOI: 10.1016/j.jid.2023.02.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/31/2023] [Accepted: 02/07/2023] [Indexed: 03/05/2023]
Abstract
Psoriasis is an IL-23/IL-17-mediated inflammatory autoimmune dermatosis and ultraviolet B (UVB) may contribute to immunosuppression and ameliorate associated symptoms. One of the pathophysiology underlying UVB therapy is through the production of cis-urocanic acid (cis-UCA) from keratinocytes. However, the detailed mechanism is yet to be fully understood. In the current study, we found filaggrin expression and serum cis-UCA levels were significantly lower in psoriasis patients than in healthy controls. We also noted that cis-UCA application inhibited psoriasiform inflammation through the reduction of Vγ4+ γδT17 cells in murine skin and draining lymph nodes. Meanwhile, CCR6 was down-regulated on γδT17 cells, which would suppress the inflammatory reaction at a distal skin site. We revealed that 5-HT2A receptor (HTR2A), the known cis-UCA receptor, was highly expressed on Langerhans cells (LCs) in the skin. cis-UCA also inhibited IL-23 expression and induced PD-L1 on LCs, leading to the attenuated proliferation and migration of γδT cells. Compared to the isotype control, α-PD-L1 treatment in vivo could reverse the anti-psoriatic effects of cis-UCA. PD-L1 expression on LCs was sustained through cis-UCA-induced MAPK/ERK pathway. These findings uncover the cis-UCA-induced PD-L1-mediated immunosuppression on LCs, which facilitates the resolution of inflammatory dermatoses.
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Affiliation(s)
- Chen-Yun Yeh
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Sheng-Han Su
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yeh Fong Tan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan
| | - Tsen-Fang Tsai
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Pi-Hui Liang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Musin Kelel
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hao-Jui Weng
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Department of Dermatology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan; Department of Dermatology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Yu-Ping Hsiao
- Department of Dermatology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chun-Hao Lu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ching-Hui Tsai
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chih-Hung Lee
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung
| | - Björn E Clausen
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany
| | - Fu-Tong Liu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yungling Leo Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; College of Public Health, China Medical University, Taichung, Taiwan.
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12
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Watanabe T, Yamaguchi Y. Cutaneous manifestations associated with immune checkpoint inhibitors. Front Immunol 2023; 14:1071983. [PMID: 36891313 PMCID: PMC9986601 DOI: 10.3389/fimmu.2023.1071983] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.
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Affiliation(s)
| | - Yukie Yamaguchi
- Department of Environmental Immuno-Dermatology, Yokohama City University School of Medicine, Yokohama, Japan
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13
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Tanaka R, Ichimura Y, Kubota N, Konishi R, Nakamura Y, Mizuno S, Takahashi S, Fujimoto M, Nomura T, Okiyama N. The Role of PD-L1 on Langerhans Cells in the Regulation of Psoriasis. J Invest Dermatol 2022; 142:3167-3174.e9. [PMID: 35803322 DOI: 10.1016/j.jid.2022.06.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 01/05/2023]
Abstract
Langerhans cells (LCs) are skin-resident cells with potent antigen-presenting cell capabilities, which reportedly play some roles in the development of psoriasis, an inflammatory skin disease mediated by IL-17A‒producing cells, T helper 17 cells, and TCR-γδlow T cells. LCs in psoriatic skin lesions but not in normal skin express PD-L1, which binds to PD-1, an immune checkpoint molecule, to negatively regulate immune reactions. The aim of this study is to elucidate the regulatory role of LCs through the PD-1/PD-L1 axis in a murine model of imiquimod-induced psoriasis-like dermatitis. Imiquimod application on wild-type C57BL/6J mice induced PD-L1 expression on LCs both in the ear skin and skin-draining lymph nodes. To further identify the functional role of PD-L1 expressed on LCs, we generated conditional knockout mice lacking PD-L1 expression on LCs (Pd-l1-cKO mice). Pd-l1-cKO mice presented significantly more severe imiquimod-induced psoriasis-like dermatitis than their control littermates. Flow cytometric analysis showed that the frequency of activated IL-17A‒producing γδlow T cells was increased in the ear skin samples, and IL-17A production by CCR6+ migrating γδlow T cells increased in the skin-draining lymph nodes in imiquimod-applied Pd-l1-cKO mice than in control littermates. Collectively, LCs disrupt the exacerbation of psoriasis through PD-L1.
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Affiliation(s)
- Ryota Tanaka
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yuki Ichimura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Noriko Kubota
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Risa Konishi
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yoshiyuki Nakamura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Manabu Fujimoto
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Suita, Japan
| | - Toshifumi Nomura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Naoko Okiyama
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
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14
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Jfri A, Leung B, Said JT, Semenov Y, LeBoeuf NR. Prevalence of inverse psoriasis subtype with immune checkpoint inhibitors. IMMUNOTHERAPY ADVANCES 2022; 2:ltac016. [PMID: 36196370 PMCID: PMC9525015 DOI: 10.1093/immadv/ltac016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/16/2022] [Accepted: 09/20/2022] [Indexed: 11/14/2022] Open
Abstract
Background Cutaneous immune-related adverse events (irAEs) are the most common irAEs caused by immune-checkpoint inhibitors (ICI). Psoriasiform eruptions, both de novo and flares, may occur. Evidence is lacking on inverse psoriasis subtype. Methods A retrospective study was conducted at Dana-Farber Cancer Institute/Mass General Brigham through February 2020 using databases. Confirmed inverse psoriasis cases pre-/post-ICI initiation either independently or in conjunction with other psoriasis subtypes were included. Known psoriasis cases without flare post-ICI were excluded. Results A total of 262 (3%) individuals with any ICI-mediated psoriasiform cutaneous irAE were identified out of the 8683 DFCI ICI-treated patients. Of these, 13 (5% of psoriasis patients) had inverse psoriasis (mean age 68.7 years; 7/13 male sex). Median (range) time from ICI initiation to inverse psoriasis development or flare was 7 (4-12) and 3.5 (2-6) weeks, respectively. Pruritus occurred in 12/13 (92.30%) cases. 11 (85%) had inguinal involvement; other sites included gluteal cleft (6; 46%), inframammary (3; 23%), perianal (2; 15%), axilla (2; 15%), umbilicus (2; 15%), and infra-abdominal folds (1; 8%). Most (9/13) individuals had more than one site involved. The Common Terminology Criteria for Adverse Events severity was 1 in 10 (76.92%) individuals and 2 in 3 (15.38%) individuals. Six (46.15%) patients were treated initially by oncology with topical (nystatin, econazole, or clotrimazole) or systemic antifungals (fluconazole) for median (range) of 3.5 (1-7) months without improvement, for presumed candida intertrigo. Conclusion Patients on ICI may develop inverse psoriasis, which may be initially confused for fungal intertrigo. Delayed diagnosis can prolong symptoms, while patients are treated ineffectively with topical/systemic antifungals for presumed candida infection. Oncologist and dermatologist awareness is important to improve diagnosis of ICI-mediated inverse psoriasis, its management and affected patients' quality of life.
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Affiliation(s)
- Abdulhadi Jfri
- Dermatology Department, Harvard Medical School, Boston, MA, USA
- Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Division of Dermatology, King Abdulaziz Medical City, Jeddah, Saudi Arabia
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- Division of Dermatology, Department of Medicine, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
| | - Bonnie Leung
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
| | - Jordan T Said
- Dermatology Department, Harvard Medical School, Boston, MA, USA
- Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Yevgeniy Semenov
- Dermatology Department, Harvard Medical School, Boston, MA, USA
- Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
| | - Nicole R LeBoeuf
- Dermatology Department, Harvard Medical School, Boston, MA, USA
- Department of Dermatology, Brigham and Women’s Hospital, Boston, MA, USA
- Center for Cutaneous Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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15
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Minokawa Y, Sawada Y. Exacerbation of pre‐existence psoriasis following immune checkpoint inhibitor treatment. JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY 2022. [DOI: 10.1002/cia2.12244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Yoko Minokawa
- Department of Dermatology University of Occupational and Environmental Health Fukuoka Japan
| | - Yu Sawada
- Department of Dermatology University of Occupational and Environmental Health Fukuoka Japan
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16
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Yamamoto T. Skin Manifestation Induced by Immune Checkpoint Inhibitors. Clin Cosmet Investig Dermatol 2022; 15:829-841. [PMID: 35592732 PMCID: PMC9112343 DOI: 10.2147/ccid.s364243] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/21/2022] [Indexed: 11/23/2022]
Abstract
In accordance with recent therapeutic progress of immune checkpoint inhibitors for certain cancers, various disorders are induced as immune-related adverse events (irAEs) affecting the skin, gut, thyroid gland, lung, and liver. Among such irAEs, mucocutaneous manifestation is the most common. Cutaneous manifestations are categorized into several groups, ie, inflammatory reactions, immunobullous reactions, alterations of epidermal keratinocytes, and alterations of epidermal melanocytes; however, there are additionally various cutaneous toxicities, unclassified into those groups. Blocking of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PDL1) can lead to the induction of autoimmune reaction, via activation of cytotoxic T cells, inhibition of regulatory T cell function, and alteration of cytokine balance. Similarly, blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) reduces the suppressive function of regulatory T cells. Due to those mechanisms, various autoimmune conditions can be induced, in addition to nonspecific drug eruptions. Dermatologists should be aware of various types of those mucocutaneous manifestations, either common or rare, as well as the management of such conditions. Herein, various mucocutaneous manifestations of irAEs and cases involving Japanese patients have been described, based on a single institute's experience.
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Affiliation(s)
- Toshiyuki Yamamoto
- Department of Dermatology, Fukushima Medical University, Fukushima, Japan
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17
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Le TK, Kaul S, Cappelli LC, Naidoo J, Semenov YR, Kwatra SG. Cutaneous adverse events of immune checkpoint inhibitor therapy: incidence and types of reactive dermatoses. J DERMATOL TREAT 2022; 33:1691-1695. [PMID: 33656965 PMCID: PMC8458472 DOI: 10.1080/09546634.2021.1898529] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 02/26/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Dermatoses are common and potentially serious complications of programmed cell death receptor PD-1 immune checkpoint inhibitor (anti-PD-1 ICI) therapy. Understanding their incidence is necessary to support clinical awareness, diagnosis, and management. OBJECTIVE To examine the incidence and odds of reported non-cancerous dermatoses in the setting of anti-PD-1 ICI therapy. METHODS Cross-sectional study of anti-PD-1 (pembrolizumab or nivolumab) treated patients at a tertiary healthcare institution. Selected dermatologic events following immunotherapy were identified in the electronic medical record. Comparator arm were patients that developed these same dermatoses without receiving anti-PD-1 ICI therapy. RESULTS There were 13.7% (254/1857) patients that developed one of 28 dermatoses. Compared with the general population, patients treated with anti-PD-1 had a greater risk for development of mucositis (OR 65.7, 95% CI 35.0-123.3), xerostomia (OR 11.9, 95% CI 8.4-16.8), pruritus (11.3, 95% CI 8.9-14.3), and lichen planus/lichenoid dermatitis (OR 10.7, 95% CI 5.6-20.7). CONCLUSIONS We report the frequency of dermatoses encountered in the setting of ICI therapy, both common (pruritus, rash, vitiligo) and uncommon (scleroderma, urticaria).
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Affiliation(s)
- Thomas K. Le
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Subuhi Kaul
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura C. Cappelli
- Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jarushka Naidoo
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD, USA
| | | | - Shawn G. Kwatra
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD, USA
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18
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Chen CH, Yu HS, Yu S. Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article. Curr Oncol 2022; 29:2871-2886. [PMID: 35448208 PMCID: PMC9032875 DOI: 10.3390/curroncol29040234] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/15/2022] [Accepted: 04/15/2022] [Indexed: 12/19/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients.
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Affiliation(s)
- Chieh-Hsun Chen
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Hsin-Su Yu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
| | - Sebastian Yu
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan;
- Department of Dermatology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Correspondence: ; Tel.: +886-7-3121101 (ext. 6103)
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19
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Okiyama N, Tanaka R. Immune-related adverse events in various organs caused by immune checkpoint inhibitors. Allergol Int 2022; 71:169-178. [PMID: 35101349 DOI: 10.1016/j.alit.2022.01.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Indexed: 02/08/2023] Open
Abstract
Current cancer immunotherapies target immune checkpoint molecules such as the inhibitory receptor programmed cell death-1 (PD-1), one of its ligands, programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), a competitive ligand for CD28 binding to stimulatory receptors CD80 and CD86. Multiple biological drugs use monoclonal antibodies targeting PD-1, PD-L1 and CTLA-4 as cancer immunotherapies. These are termed immune checkpoint inhibitors (ICIs). However, activation of the immune system by ICIs can induce the development of immune-related adverse events (irAEs), which can affect multiple organ systems. The most frequent irAEs are cutaneous and mimic various types of spontaneous skin disorders. Most irAEs are classified as autoimmune conditions mediated by ICI-activated CD8+ cytotoxic T cells, some of which are also related to activated B cells and production of pathogenic antibodies. Interestingly, blockade of CTLA-4 mainly induces activation of T cells and inhibition of Treg cells. On the other hand, the mechanisms underlying anti-PD-1/PD-L1 ICI-induced irAEs are more complicated. PD-1 is a receptor expressed on T and B cells, which binds not only PD-L1, but also PD-L2. The role of PD-L1 is dominant in Th1 and Th17 immunity, while PD-L2 works mainly in Th2 immunity. Better understanding of the mechanisms underlying irAEs will allow for better management of irAEs and improve outcomes and quality of life in cancer patients.
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20
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Bhardwaj M, Chiu MN, Pilkhwal Sah S. Adverse cutaneous toxicities by PD-1/PD-L1 immune checkpoint inhibitors: Pathogenesis, Treatment, and Surveillance. Cutan Ocul Toxicol 2022; 41:73-90. [PMID: 35107396 DOI: 10.1080/15569527.2022.2034842] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Introduction-The therapeutic use of humanized monoclonal programmed cell death 1 (PD-1) (pembrolizumab, and nivolumab) and programmed cell death ligand-1 (PD-L1) (atezolizumab, avelumab, durvalumab) immune checkpoint inhibitors (ICPi) as potent anticancer therapies is rapidly increasing. The mechanism of signaling of anti-PD-1/PD-L1 involves triggering cytotoxic CD4+/CD8 + T cell activation and subsequent abolition of cancer cells which induces specific immunologic adverse events that are specific to these therapies. These drugs can cause numerous cutaneous reactions and are characterized as the most frequent immune-related adverse events (irAEs). Majority of cutaneous irAEs range from nonspecific eruptions to detectible skin manifestations, which may be self-limiting and present acceptable skin toxicity profiles, while some may produce life-threatening complications.Objective-.This review aims to illuminate the associated cutaneous irAEs related to drugs used in oncology along with the relevant mechanism(s) and management.Areas covered-Literature was searched using various databases including Pub-Med, Google Scholar, and Medline. The search mainly involved research articles, retrospective studies, case reports, and clinicopathological findings. With this review article, an overview of the cutaneous irAEs with anti-PD-1/PD-L1 therapy, as well as suggestions, have been provided, so that their recognition at early stages could help in better management and would prevent treatment discontinuation.Article highlightsCutaneous adverse effects are the most prevalent immune-related adverse events induced by anti-PD-1/PD-L1 immune-checkpoint antibodies.Cutaneous toxicities mainly manifest in the form of maculopapular rash and pruritus.More specific cutaneous complications can also occur, including vitiligo, worsened psoriasis, lichenoid dermatitis, mucosal involvement (e.g., oral lichenoid reaction), dermatomyositis, lupus erythematosus.Cutaneous manifestations can be life-threatening including Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN).Dermatologic toxicities are usually mild, readily manageable, and rarely result in significant morbidity.Adequate management of the cutaneous adverse event and recognition in early stages could lead to the prevention of worsening of the lesions and limit treatment disruption.
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Affiliation(s)
- Maitry Bhardwaj
- Faculty of Pharmaceutical Sciences, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Mei Nee Chiu
- Faculty of Pharmaceutical Sciences, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
| | - Sangeeta Pilkhwal Sah
- Faculty of Pharmaceutical Sciences, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India
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21
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Seervai RNH, Heberton M, Cho WC, Gill P, Murphy MB, Aung PP, Nagarajan P, Torres-Cabala CA, Patel AB, Ruiz-Bañobre J, Om A, Yamamoto T, Nikolaou V, Curry JL. Severe de novo pustular psoriasiform immune-related adverse event associated with nivolumab treatment for metastatic esophageal adenocarcinoma. J Cutan Pathol 2021; 49:472-481. [PMID: 34888886 DOI: 10.1111/cup.14185] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/15/2021] [Accepted: 12/06/2021] [Indexed: 12/12/2022]
Abstract
Breakthrough targeted therapies have produced significant improvements in survival for cancer patients, but have a propensity to cause cutaneous immune-related adverse events (irAEs). Psoriasiform irAEs, representing about 4% of dermatologic toxicities associated with immune checkpoint inhibitor (ICI) therapy, are usually mild, occur in older patients and present as an exacerbation of existing psoriasis after several doses of ICI therapy. We report a case of a 58-year-old woman with metastatic esophageal adenocarcinoma and no prior history of psoriasis who developed a pustular psoriasiform irAE, beginning 3 days after initiation of nivolumab and progressing to confluent erythroderma with pustules over 2 weeks despite topical steroid use. She had concurrent acrodermatitis enteropathica, clinically diagnosed and confirmed with a low serum zinc level, that improved with supplementation. Her psoriasiform irAE was refractory to systemic steroids and acitretin, prompting discontinuation of nivolumab and treatment with ustekinumab and concomitant slow taper of acitretin and prednisone. Pustular psoriasiform irAE is a rare but severe dermatologic toxicity resulting from ICI therapy. Given the diverse morphologic types of cutaneous irAEs that can occur during ICI therapy, a clinical and histopathologic examination of dermatologic toxicities is critical to identify patients who may benefit from biologic therapy.
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Affiliation(s)
- Riyad N H Seervai
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA.,Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.,Department of Dermatology, Baylor College of Medicine, Houston, Texas, USA
| | - Meghan Heberton
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Woo Cheal Cho
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Pavandeep Gill
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mariela B Murphy
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Phyu P Aung
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Carlos A Torres-Cabala
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Anisha B Patel
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Juan Ruiz-Bañobre
- Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, CIBERONC, Santiago de Compostela, Santiago, Spain
| | - Amit Om
- Department of Dermatology, Florida State University, Tallahassee, Florida, USA
| | - Toshiyuki Yamamoto
- Dermartment of Dermatology, Fukushima Medical University, Fukushima, Japan
| | - Vasiliki Nikolaou
- Cutaneous Toxicities Clinic, Oncodermatology Department, "Andreas Sygros" Hospital for Skin Diseases, Athens, Greece
| | - Jonathan L Curry
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.,Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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22
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Nadelmann ER, Yeh JE, Chen ST. Management of Cutaneous Immune-Related Adverse Events in Patients With Cancer Treated With Immune Checkpoint Inhibitors: A Systematic Review. JAMA Oncol 2021; 8:130-138. [PMID: 34709352 DOI: 10.1001/jamaoncol.2021.4318] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Importance There exists a paucity of literature that summarizes the effective management of cutaneous immune-related adverse events (cirAEs) in patients with cancer who are receiving immune checkpoint inhibitors (ICIs). Most published articles are small case series from a single institution. To our knowledge, the spectrum of possible treatments has not been systematically reviewed to highlight the breadth of options when caring for patients with cirAEs. Objective To further characterize the development of subtypes of cirAEs in patients with cancer treated with ICIs and provide recommendations on optimal treatment regimens based on the current literature. Evidence Review A search was performed in PubMed, Embase European, Web of Science, and Google Scholar on June 26, 2020, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, limited to the years 2010 to 2020. Articles that met predetermined inclusion criteria (published between January 1, 2010, and June 1, 2020; written in the English language; and original articles, brief reports, case reports, and research letters that reported primarily on cirAE management) were selected, and data were abstracted. Articles that met the scope of the review were also added from reference lists. When possible, the results of studies that addressed a similar question were combined quantitatively. Findings In total, 138 studies (87 from the aforementioned literature search and 51 additional studies pulled from the reference lists of included articles) were included that reported on 879 cirAEs. The subtypes of cirAEs included maculopapular, pruritus, lichenoid, immunobullous, psoriasiform, granulomatous, erythema multiforme or Stevens Johnson Syndrome, drug rash with eosinophilia and systemic symptoms, connective tissue disease, hair, oral, and miscellaneous. Treatments for cirAEs included a combination of topical corticosteroids, systemic corticosteroids, steroid-sparing agents, and discontinuation or cessation of immunotherapy. Conclusions and Relevance This systematic review found that treatment with ICIs was associated with many types of skin toxic effects, each with unique treatment options beyond current published guidelines. Further research into key differences between subtypes is critical to improve the care provided to patients with cancer.
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Affiliation(s)
- Emily R Nadelmann
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston
| | - Jennifer E Yeh
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston
| | - Steven T Chen
- Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston
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23
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Vinaixa Aranzazu A, Morillas-Lahuerta V, Blanco De Tord M, Carrascosa Carrillo JM. Ixekizumab for the treatment of erythrodermic psoriasis triggered by durvalumab-tremelimumab in a cancer patient. Eur J Dermatol 2021; 31:ejd.2021.4087. [PMID: 34463279 PMCID: PMC8572685 DOI: 10.1684/ejd.2021.4087] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Arrieta Vinaixa Aranzazu
- Dermatology department, Hospital Universitario Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, 08916 Barcelona, Spain
| | - Víctor Morillas-Lahuerta
- Dermatology department, Hospital Universitario Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, 08916 Barcelona, Spain
| | - María Blanco De Tord
- Dermatology department, Hospital Universitario Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, 08916 Barcelona, Spain
| | - José-Manuel Carrascosa Carrillo
- Dermatology department, Hospital Universitario Germans Trias i Pujol, Carretera de Canyet, s/n, Badalona, 08916 Barcelona, Spain
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24
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Tanaka R, Ichimura Y, Kubota N, Saito A, Nakamura Y, Ishitsuka Y, Watanabe R, Fujisawa Y, Mizuno S, Takahashi S, Fujimoto M, Okiyama N. Differential Involvement of Programmed Cell Death Ligands in Skin Immune Responses. J Invest Dermatol 2021; 142:145-154.e8. [PMID: 34310947 DOI: 10.1016/j.jid.2021.06.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 05/27/2021] [Accepted: 06/09/2021] [Indexed: 12/18/2022]
Abstract
PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γ‒mediated T helper type (Th)1-, IL-4‒mediated Th2-, and IL-17A‒mediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1‒deficient mice than in wild-type or Pd-l2‒deficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2‒deficient mice were more severe than that in wild-type or Pd-l1‒deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity.
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Affiliation(s)
- Ryota Tanaka
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yuki Ichimura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Noriko Kubota
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Akimasa Saito
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yoshiyuki Nakamura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yosuke Ishitsuka
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Laboratory of Cutaneous Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Rei Watanabe
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Laboratory of Cutaneous Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
| | - Yasuhiro Fujisawa
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Manabu Fujimoto
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Dermatology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Suita, Japan
| | - Naoko Okiyama
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
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25
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Mullangi S, Ponnam S, Lekkala MR, Koya S. A Case of De Novo Psoriasis Secondary to Nivolumab in a Patient With Metastatic Renal Cell Carcinoma. Cureus 2021; 13:e15703. [PMID: 34290912 PMCID: PMC8288591 DOI: 10.7759/cureus.15703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2021] [Indexed: 01/05/2023] Open
Abstract
Immune-mediated adverse events are commonly seen with immune checkpoint inhibitors like nivolumab. Oncology specialists usually have to screen patients for risk factors for autoimmune diseases, since immune checkpoint inhibitors can potentially exacerbate these events. Some of the immune-mediated side effects include polyneuropathies, colitis, and cutaneous adverse effects. Non-specific maculopapular rash, pruritus, lichenoid reactions, eczema, and vitiligo are the most common dermatologic side effects. It is thought that these adverse events are due to the blocking of the programmed cell death protein-1 (PD-1) pathway and are mediated by the cytotoxic T cells. Psoriasis has been previously reported as a side effect in a few case reports and most commonly presented as an exacerbation of preexisting psoriasis. However, de novo psoriasis occurrence as a result of nivolumab is a rare entity, especially in a non-melanoma patient. Here, we present a case of renal cell carcinoma treated with immunotherapy with nivolumab, who developed de novo psoriasis with palmoplantar involvement.
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Affiliation(s)
| | - Sreeja Ponnam
- Neurosurgery, Oklahoma Surgical Hospital, Tulsa, USA
| | | | - Supriya Koya
- Hematology and Oncology, Hillcrest Medical Center, Tulsa, USA
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26
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Skin Reactions to Immune Checkpoint Inhibitors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1342:319-330. [DOI: 10.1007/978-3-030-79308-1_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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27
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Muntyanu A, Netchiporouk E, Gerstein W, Gniadecki R, Litvinov IV. Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management. J Cutan Med Surg 2021; 25:59-76. [PMID: 32746624 DOI: 10.1177/1203475420943260] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors have proven to be efficacious for a broad spectrum of solid organ malignancies. These monoclonal antibodies lead to cytotoxic T-cell activation and subsequent elimination of cancer cells. However, they can also lead to immune intolerance and immune-related adverse event (irAEs) that are new and specific to these therapies. Cutaneous irAEs are the most common, arising in up to 34% of patients on PD-1 inhibitors and 43% to 45% on CTLA-4 inhibitors. The most common skin manifestations include maculopapular eruption, pruritus, and vitiligo-like lesions. A grading system has been proposed, which guides management of cutaneous manifestations based on the percent body surface area (BSA) involved. Cutaneous irAEs may prompt clinicians to reduce drug doses, add systemic steroids to the regiment, and/or discontinue lifesaving immunotherapy. Thus, the goal is for early identification and concurrent management to minimize treatment interruptions. We emphasize here that the severity of the reaction should not be graded based on BSA involvement alone, but rather on the nature of the primary cutaneous pathology. For instance, maculopapular eruptions rarely affect <30% BSA and can often be managed conservatively with skin-directed therapies, while Stevens-Johnson syndrome (SJS) affecting even 5% BSA should be managed aggressively and the immunotherapy should be discontinued at once. There is limited literature available on the management of the cutaneous irAEs and most studies present anecdotal evidence. We review the management strategies and provide recommendations for psoriatic, immunobullous, maculopapular, lichenoid, acantholytic eruptions, vitiligo, alopecias, vasculitides, SJS/toxic epidermal necrolysis, and other related skin toxicities.
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Affiliation(s)
- Anastasiya Muntyanu
- 54473507266 Division of Dermatology, McGill University, Montreal, QC, Canada
| | - Elena Netchiporouk
- 54473507266 Division of Dermatology, McGill University, Montreal, QC, Canada
| | - William Gerstein
- 54473507266 Division of Dermatology, McGill University, Montreal, QC, Canada
| | - Robert Gniadecki
- 3158 Division of Dermatology, University of Alberta, Edmonton, AB, Canada
| | - Ivan V Litvinov
- 54473507266 Division of Dermatology, McGill University, Montreal, QC, Canada
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28
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Foti C, Tucci M, Stingeni L, Hansel K, Lospalluti L, Frisario R, Giuffrida R, Romita P. Successful treatment with apremilast of severe psoriasis exacerbation during nivolumab therapy for metastatic melanoma. Dermatol Ther 2020; 34:e14653. [PMID: 33301205 DOI: 10.1111/dth.14653] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 11/23/2020] [Indexed: 11/27/2022]
Affiliation(s)
- Caterina Foti
- Department of Biomedical Science and Human Oncology. Dermatological Clinic, University of Bari, Bari, Italy
| | - Marco Tucci
- Section of Medical Oncology, Department of Biomedical Sciences and Clinical Oncology (DIMO), University of Bari 'Aldo Moro', Bari, Italy
| | - Luca Stingeni
- Dermatology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | - Katharina Hansel
- Dermatology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | - Lucia Lospalluti
- Department of Biomedical Science and Human Oncology. Dermatological Clinic, University of Bari, Bari, Italy
| | - Rosa Frisario
- Department of Biomedical Science and Human Oncology. Dermatological Clinic, University of Bari, Bari, Italy
| | - Roberta Giuffrida
- Dermatology Section, Department of Clinical & Experimental Medicine, University of Messina, Messina, Italy
| | - Paolo Romita
- Department of Biomedical Science and Human Oncology. Dermatological Clinic, University of Bari, Bari, Italy
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29
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Tanaka R, Ichimura Y, Kubota N, Saito A, Nakamura Y, Ishitsuka Y, Watanabe R, Fujisawa Y, Kanzaki M, Mizuno S, Takahashi S, Fujimoto M, Okiyama N. Activation of CD8 T cells accelerates anti-PD-1 antibody-induced psoriasis-like dermatitis through IL-6. Commun Biol 2020; 3:571. [PMID: 33060784 PMCID: PMC7567105 DOI: 10.1038/s42003-020-01308-2] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis. Tanaka et al investigate the mechanism by which psoriasis-like dermatitis may occur following PD-1 antibody treatment for melanoma. They find that PD-1 loss in CD8 T-cells accelerates dermatitis in a manner depending on IL-6 signaling, suggesting IL-6 as a potential therapeutic target.
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Affiliation(s)
- Ryota Tanaka
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yuki Ichimura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Noriko Kubota
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Akimasa Saito
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yoshiyuki Nakamura
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Yosuke Ishitsuka
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Rei Watanabe
- Department of Dermatology, Graduate School of Medicine Faculty of Medicine, Osaka University, Osaka, Japan
| | - Yasuhiro Fujisawa
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Mirei Kanzaki
- Department of Dermatology, Mito Saiseikai General Hospital, Ibaraki, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Manabu Fujimoto
- Department of Dermatology, Graduate School of Medicine Faculty of Medicine, Osaka University, Osaka, Japan
| | - Naoko Okiyama
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
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30
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George A, George R. Nivolumab (PD-1 Inhibitor) Induced Exacerbation of Psoriasis. Indian Dermatol Online J 2020; 11:261-262. [PMID: 32477996 PMCID: PMC7247661 DOI: 10.4103/idoj.idoj_47_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Anju George
- Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Renu George
- Department of Dermatology, Christian Medical College, Vellore, Tamil Nadu, India
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31
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Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol 2020; 83:1255-1268. [PMID: 32454097 DOI: 10.1016/j.jaad.2020.03.132] [Citation(s) in RCA: 276] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/17/2022]
Abstract
Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D3 analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.
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32
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Ellis SR, Vierra AT, Millsop JW, Lacouture ME, Kiuru M. Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features. J Am Acad Dermatol 2020; 83:1130-1143. [PMID: 32360716 DOI: 10.1016/j.jaad.2020.04.105] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 04/03/2020] [Accepted: 04/20/2020] [Indexed: 02/08/2023]
Abstract
Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.
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Affiliation(s)
- Samantha R Ellis
- Department of Dermatology, University of California, Davis, Sacramento, California; PotozkinMD Skincare Center, Danville, California
| | - Aren T Vierra
- Department of Dermatology, University of California, Davis, Sacramento, California
| | - Jillian W Millsop
- Department of Dermatology, Vacaville Medical Center, The Permanente Medical Group, Vacaville, California
| | - Mario E Lacouture
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maija Kiuru
- Department of Dermatology, University of California, Davis, Sacramento, California; Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California.
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33
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Simonsen AB, Kaae J, Ellebaek E, Svane IM, Zachariae C. Cutaneous adverse reactions to anti-PD-1 treatment-A systematic review. J Am Acad Dermatol 2020; 83:1415-1424. [PMID: 32320766 DOI: 10.1016/j.jaad.2020.04.058] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 02/06/2023]
Abstract
The use of the humanized monoclonal anti-programmed cell death 1 antibodies pembrolizumab and nivolumab as potent anticancer therapies is rapidly increasing. However, since their approval, numerous cases of cutaneous reactions have been reported. Cutaneous adverse reactions to these agents have yet to be fully characterized and range from nonspecific eruptions to recognizable skin manifestations, which may be localized and vary from mild to life threatening. This systematic review article provides an overview of the various adverse cutaneous reactions to pembrolizumab and nivolumab therapy and offers suggestions for their management.
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Affiliation(s)
- Anne Birgitte Simonsen
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
| | - Jeanette Kaae
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Eva Ellebaek
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Inge Marie Svane
- Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Claus Zachariae
- Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
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Abstract
OPINION STATEMENT The treatment of advanced melanoma has undergone a dramatic transformation over the last decade with the advent of targeted and immunomodulatory therapies. This transition from cytotoxic chemotherapy has yielded improvements in both survival and quality of life; yet despite their therapeutic advantages, these treatments have been associated with a diverse range of cutaneous adverse events (AEs). These range from relatively benign eczematous conditions to more severe inflammatory and bullous disorders, and can include induction of second malignancies. AEs can result in serious morbidity and risk of mortality if not recognised and managed early. As a consequence of their novelty, and rapid uptake, these agents have been subject to intense scrutiny and there is a general understanding that cutaneous AEs should be anticipated in treatment plans. Dermatologists should be integrated into management teams to assist in the development of treatment protocols for anticipated common AEs and to provide expert management of more severe, rare or unusual AEs. Our experience has shown a reduction in treatment interruptions, more rapid recognition of unusual AEs and improved management pathways for patients suffering cutaneous AEs.
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35
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Shazib MA, Woo S, Sroussi H, Carvo I, Treister N, Farag A, Schoenfeld J, Haddad R, LeBoeuf N, Villa A. Oral immune‐related adverse events associated with PD‐1 inhibitor therapy: A case series. Oral Dis 2020; 26:325-333. [DOI: 10.1111/odi.13218] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 10/01/2019] [Accepted: 10/18/2019] [Indexed: 12/30/2022]
Affiliation(s)
- Muhammad Ali Shazib
- Department of Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine Boston MA USA
- Division of Oral Medicine and Dentistry Brigham and Women’s Hospital and Dana‐Farber Cancer Institute Boston MA USA
| | - Sook‐Bin Woo
- Department of Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine Boston MA USA
- Division of Oral Medicine and Dentistry Brigham and Women’s Hospital and Dana‐Farber Cancer Institute Boston MA USA
| | - Hervé Sroussi
- Department of Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine Boston MA USA
- Division of Oral Medicine and Dentistry Brigham and Women’s Hospital and Dana‐Farber Cancer Institute Boston MA USA
| | - Ingrid Carvo
- Department of Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine Boston MA USA
| | - Nathaniel Treister
- Department of Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine Boston MA USA
- Division of Oral Medicine and Dentistry Brigham and Women’s Hospital and Dana‐Farber Cancer Institute Boston MA USA
| | - Arwa Farag
- Department of Oral Diagnostic Sciences Faculty of Dentistry King Abdul Aziz University Jeddah Saudi Arabia
- Division of Oral Medicine Tufts University School of Dental Medicine Boston MA USA
| | - Jonathan Schoenfeld
- Department of Radiation Oncology Dana‐ Farber Cancer Institute Boston MA USA
| | - Robert Haddad
- Department of Medical Oncology Dana‐Farber Cancer Institute Boston MA USA
| | - Nicole LeBoeuf
- Department of Dermatology Brigham and Women’s Hospital Boston MA USA
| | - Alessandro Villa
- Department of Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine Boston MA USA
- Division of Oral Medicine and Dentistry Brigham and Women’s Hospital and Dana‐Farber Cancer Institute Boston MA USA
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36
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C Guven D, Kilickap S, Guner G, Taban H, Dizdar O. Development of de novo psoriasis during nivolumab therapy in a patient with small cell lung cancer. J Oncol Pharm Pract 2020; 26:256-258. [PMID: 31566114 DOI: 10.1177/1078155219877234] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION The immune checkpoint inhibitors recently entered to small cell lung cancer (SCLC) stage, firstly in the third and recently in the first lines of therapy. This efficacy comes at the expense of many toxicities including skin toxicity. This toxicity is usually in the form of rash and pruritis; however, rare reactions like psoriasis can also be seen. CASE REPORT Herein, we report an SCLC case who developed de novo psoriasis while treated with nivolumab as the third-line treatment for SCLC. MANAGEMENT AND OUTCOME The psoriatic plaques were regressed with the topical highly potent steroid therapy, and immunotherapy was continued without further complications. DISCUSSION We think that rare adverse events like de novo psoriasis are important considering the expanding role of these agents; their timely recognition and treatment are important in the management of cancer patients.
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Affiliation(s)
- Deniz C Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Saadettin Kilickap
- Department of Preventive Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Gurkan Guner
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Hakan Taban
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Omer Dizdar
- Department of Preventive Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
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Skin Reactions to Immune Checkpoint Inhibitors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1244:235-246. [DOI: 10.1007/978-3-030-41008-7_11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Melanoma and Vitiligo: In Good Company. Int J Mol Sci 2019; 20:ijms20225731. [PMID: 31731645 PMCID: PMC6888090 DOI: 10.3390/ijms20225731] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/10/2019] [Accepted: 11/13/2019] [Indexed: 12/24/2022] Open
Abstract
Cutaneous melanoma represents the most aggressive form of skin cancer, whereas vitiligo is an autoimmune disorder that leads to progressive destruction of skin melanocytes. However, vitiligo has been associated with cutaneous melanoma since the 1970s. Most of the antigens recognized by the immune system are expressed by both melanoma cells and normal melanocytes, explaining why the autoimmune response against melanocytes that led to vitiligo could be also present in melanoma patients. Leukoderma has been also observed as a side effect of melanoma immunotherapy and has always been associated with a favorable prognosis. In this review, we discuss several characteristics of the immune system responses shared by melanoma and vitiligo patients, as well as the significance of occurrence of leukoderma during immunotherapy, with special attention to check-point inhibitors.
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Abstract
Drug eruptions are among the great masqueraders that sometimes cause diagnostic challenges in clinical practice. Pharmacologic agents may induce skin changes, sharing the same pathophysiologic mechanisms of specific dermatoses, or inducing drug eruptions with different pathologic mechanisms that have similar clinical presentations. The former conditions are usually called drug-induced skin diseases, whereas the latter conditions are termed "dermatosis-like drug eruptions." Both types are great imitators in dermatologic practice and can be easily misdiagnosed as other diseases or lead to unrecognized causative agents.
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Affiliation(s)
- Chia-Yu Chu
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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40
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Stotts MJ, Adjapong O, Kaplan DE. A Psoriasiform Drug Eruption Secondary to Nivolumab for Hepatocellular Carcinoma: A Case Report. Hepatology 2019; 70:1477-1479. [PMID: 31004512 DOI: 10.1002/hep.30659] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/08/2019] [Indexed: 01/22/2023]
Affiliation(s)
- Matthew J Stotts
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Opaku Adjapong
- Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA
| | - David E Kaplan
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.,Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA
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Nikfarjam A, Ransohoff JD, Callahan A, Jones E, Loew B, Kwong BY, Sarin KY, Shah NH. Early Detection of Adverse Drug Reactions in Social Health Networks: A Natural Language Processing Pipeline for Signal Detection. JMIR Public Health Surveill 2019; 5:e11264. [PMID: 31162134 PMCID: PMC6684218 DOI: 10.2196/11264] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 02/27/2019] [Accepted: 04/04/2019] [Indexed: 12/31/2022] Open
Abstract
Background Adverse drug reactions (ADRs) occur in nearly all patients on chemotherapy, causing morbidity and therapy disruptions. Detection of such ADRs is limited in clinical trials, which are underpowered to detect rare events. Early recognition of ADRs in the postmarketing phase could substantially reduce morbidity and decrease societal costs. Internet community health forums provide a mechanism for individuals to discuss real-time health concerns and can enable computational detection of ADRs. Objective The goal of this study is to identify cutaneous ADR signals in social health networks and compare the frequency and timing of these ADRs to clinical reports in the literature. Methods We present a natural language processing-based, ADR signal-generation pipeline based on patient posts on Internet social health networks. We identified user posts from the Inspire health forums related to two chemotherapy classes: erlotinib, an epidermal growth factor receptor inhibitor, and nivolumab and pembrolizumab, immune checkpoint inhibitors. We extracted mentions of ADRs from unstructured content of patient posts. We then performed population-level association analyses and time-to-detection analyses. Results Our system detected cutaneous ADRs from patient reports with high precision (0.90) and at frequencies comparable to those documented in the literature but an average of 7 months ahead of their literature reporting. Known ADRs were associated with higher proportional reporting ratios compared to negative controls, demonstrating the robustness of our analyses. Our named entity recognition system achieved a 0.738 microaveraged F-measure in detecting ADR entities, not limited to cutaneous ADRs, in health forum posts. Additionally, we discovered the novel ADR of hypohidrosis reported by 23 patients in erlotinib-related posts; this ADR was absent from 15 years of literature on this medication and we recently reported the finding in a clinical oncology journal. Conclusions Several hundred million patients report health concerns in social health networks, yet this information is markedly underutilized for pharmacosurveillance. We demonstrated the ability of a natural language processing-based signal-generation pipeline to accurately detect patient reports of ADRs months in advance of literature reporting and the robustness of statistical analyses to validate system detections. Our findings suggest the important contributions that social health network data can play in contributing to more comprehensive and timely pharmacovigilance.
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Affiliation(s)
- Azadeh Nikfarjam
- Stanford Center for Biomedical Informatics Research, Stanford Department of Medicine, Stanford, CA, United States
| | - Julia D Ransohoff
- Stanford Center for Biomedical Informatics Research, Stanford Department of Medicine, Stanford, CA, United States
| | - Alison Callahan
- Stanford Center for Biomedical Informatics Research, Stanford Department of Medicine, Stanford, CA, United States
| | | | | | - Bernice Y Kwong
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States
| | - Kavita Y Sarin
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA, United States
| | - Nigam H Shah
- Stanford Center for Biomedical Informatics Research, Stanford Department of Medicine, Stanford, CA, United States
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Heinzerling L, de Toni EN, Schett G, Hundorfean G, Zimmer L. Checkpoint Inhibitors. DEUTSCHES ARZTEBLATT INTERNATIONAL 2019; 116:119-126. [PMID: 30940340 PMCID: PMC6454802 DOI: 10.3238/arztebl.2019.0119] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 05/05/2018] [Accepted: 12/06/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening. METHODS This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry. RESULTS Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors. CONCLUSION The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.
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Affiliation(s)
| | - Enrico N. de Toni
- Department of Internal Medicine II, University Hospital, Ludwig-Maximilians-University (LMU) Munich
| | - Georg Schett
- Department of Medicine 3, University Hospital Erlangen-Nürnberg
| | | | - Lisa Zimmer
- Clinic for Dermatology, Essen University Hospital, University of Duisburg-Essen
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Abstract
Inflammatory skin diseases encompass a vast array of conditions. The field continues to expand and evolve with resurgence of conditions, through newly recognized medication adverse effects, and via more detailed descriptions of known dermatoses. The importance of clinicopathologic correlation and an up to date knowledge of dermatologic conditions cannot be overstated. This review focuses on an array of recent important developments in the histologic diagnosis of inflammatory conditions that affect the skin.
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De Novo Psoriasis Vulgaris Diagnosed after Nivolumab Treatment for Refractory Hodgkin's Lymphoma, Completely Resolved after Autologous Hematopoietic Stem Cell Transplantation. Case Rep Hematol 2018; 2018:6215958. [PMID: 30410803 PMCID: PMC6206568 DOI: 10.1155/2018/6215958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 09/09/2018] [Accepted: 09/24/2018] [Indexed: 11/17/2022] Open
Abstract
The programmed cell death protein-1 (PD-1) inhibitor nivolumab has been recently approved as an effective and safe treatment for patients with refractory/relapsed Hodgkin's lymphomas. Dermatological adverse events, mainly skin rash, have been reported in 1–5% of patients. We describe a case of de novo psoriasis vulgaris (PsV), diagnosed after nivolumab treatment for refractory Hodgkin's lymphoma. After administration of 6 cycles, skin lesions appeared in the right tibia, forearms, and dorsum of hands, and biopsy confirmed the diagnosis of PsV. The lesions completely resolved after autologous stem cell transplantation (ASCT) which was performed in the context of the treatment for the primary disease. PsV is an inflammatory skin disease, and it is considered to be mediated through cytotoxic T-cells. PD-1 blockage may lead to expansion of such T-cells, resulting thus in PsV appearance. The early published studies showed that nivolumab represents a safe treatment approach. PsV occurrence has not been reported so far in patients treated with nivolumab for hematological diseases, and it seems that long-term follow-up is necessary to fully clarify the entirety of PD-1 inhibitors' skin adverse events. Additionally, this clinical observation provides an evidence for a potential exploitation of ASCT in refractory and severe forms of PsV.
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De Bock 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. [PMID: 30186132 PMCID: PMC6120403 DOI: 10.1159/000491572] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 06/27/2018] [Indexed: 12/11/2022] Open
Abstract
Objective The incidence of immune-related adverse events is growing as the use of checkpoint inhibitors is exponentially increasing. Cutaneous adverse events are among the most frequent immune-related adverse events. The purpose of this case report and literature review is to highlight psoriasis as a potential adverse event with need for early recognition. Case Report and Literature Review We describe the case of a 65-year-old woman with psoriasis exacerbation while treated with nivolumab (anti-PD-1) for a stage IV melanoma. She had a history of scalp psoriasis but she presented with psoriatic lesions on both lower and upper limbs. Our patient was treated with topical steroids. So far, 34 other cases with an exacerbation of psoriasis during treatment with anti-PDL-1 or PD-1 therapy have been reported in the literature. A broad range of therapies are described, without any available guidelines for this particular condition. Conclusion Psoriasis exacerbation is an established side effect of PD-1/PDL-1 checkpoint inhibitors with 35 reported cases. Early recognition and management are challenging as there are no clear guidelines available. A close collaboration between oncologist and dermatologist is mandatory to manage this immune-related adverse event.
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Affiliation(s)
- Marlies De Bock
- Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
| | - Eva Hulstaert
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Vibeke Kruse
- Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
| | - Lieve Brochez
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
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Boada A, Carrera C, Segura S, Collgros H, Pasquali P, Bodet D, Puig S, Malvehy J. Cutaneous toxicities of new treatments for melanoma. Clin Transl Oncol 2018; 20:1373-1384. [PMID: 29799097 DOI: 10.1007/s12094-018-1891-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/09/2018] [Indexed: 12/13/2022]
Abstract
New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients' quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy.
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Affiliation(s)
- A Boada
- Dermatology Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Crta/Canyet s/n., Badalona, 08016, Barcelona, Spain.
| | - C Carrera
- Melanoma Unit, Dermatology Department, Hospital Clinic, Institut d'investigacions biomèdiques August Pi i Sunyer (IDIBAPS), CIBERER, Universitat de Barcelona, Barcelona, Spain
| | - S Segura
- Dermatology Department, Hospital del Mar, Parc de Salut Mar, Fundació Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
| | - H Collgros
- Sydney Melanoma Diagnostic Centre, Royal Prince Alfred Hospital, Sidney, Australia
| | - P Pasquali
- Dermatology Department, Pius Hospital Valls, Institut d'Investigació Sanitària Pere Virgili Valls, Tarragona, Spain
| | - D Bodet
- Dermatology Department, Hospital Universitari Vall d'Hebron, VHIR, Barcelona, Spain
| | - S Puig
- Melanoma Unit, Dermatology Department, Hospital Clinic, Institut d'investigacions biomèdiques August Pi i Sunyer (IDIBAPS), CIBERER, Universitat de Barcelona, Barcelona, Spain
| | - J Malvehy
- Melanoma Unit, Dermatology Department, Hospital Clinic, Institut d'investigacions biomèdiques August Pi i Sunyer (IDIBAPS), CIBERER, Universitat de Barcelona, Barcelona, Spain
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Safe Administration of Ipilimumab, Pembrolizumab, and Nivolumab in a Patient with Metastatic Melanoma, Psoriasis, and a Previous Guillain-Barré Syndrome. Case Rep Oncol Med 2018; 2018:2783917. [PMID: 29707397 PMCID: PMC5863341 DOI: 10.1155/2018/2783917] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 01/10/2018] [Indexed: 12/26/2022] Open
Abstract
Background Patients with autoimmune diseases were not evaluated in clinical trials with immune checkpoint inhibitors (ICIs), since a history of immune disorders, such as Guillain–Barré syndrome (GBS) and psoriasis, is one of the major risk factors for the development of immune-related adverse events (irAEs). This risk cannot be defined; therefore, physicians are called to manage these patients in clinical practice. Case Report We report the case of a 62-year-old male patient affected by metastatic melanoma, with a history of GBS and psoriasis, and treated with sequential ipilimumab, pembrolizumab, and nivolumab, without significant toxicities. Conclusion This case report supports that although a history of immune disorders is one of the major risk factors for development of irAEs, in some patients, it could be possible to safely administer sequential treatments with ICIs. A proper decision should be made, considering therapeutic options, disease-related risks, and those related to a recurrence of preexisting autoimmune disorders.
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Om A, Cardon B, Cohen G. Psoriasiform eruption on the face and extremities associated with nivolumab therapy. JAAD Case Rep 2018; 4:373-375. [PMID: 29693074 PMCID: PMC5911810 DOI: 10.1016/j.jdcr.2017.11.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Affiliation(s)
- Amit Om
- Florida State University Division of Dermatology, Tallahassee, Florida
| | - Brandon Cardon
- Florida State University College of Medicine, Tallahassee, Florida
| | - George Cohen
- Florida State University Division of Dermatology, Tallahassee, Florida
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Abstract
INTRODUCTION The prognosis of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC) after failure of first line chemotherapy is dismal. Until the publication of the results of CheckMate 141, not a single agent provided any survival benefit as a second line treatment for R/M HNSCC. Areas covered: A comprehensive review of the literature was conducted on the role of nivolumab in HNSCC. Expert commentary: Nivolumab is approved by the Food and Drug Administration for the treatment of patients based on the results of CheckMate 141 showing an overall survival benefit as compared to standard care (single agent docetaxel, methotrexate, or cetuximab). Of particular interest are immune-related adverse events which should be managed according to published guidelines.
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Affiliation(s)
- Pol Specenier
- a Department of Oncology , Antwerp University Hospital , Edegem , Belgium
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50
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Patel AB, Pacha O. Skin Reactions to Immune Checkpoint Inhibitors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 995:117-129. [DOI: 10.1007/978-3-030-02505-2_5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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