Pembrolizumab-induced lichenoid dermatitis treated with dupilumab

Abstract

Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer treatment and are being increasingly used for many cancer subtypes. However, the development of cutaneous immune-related adverse events (cirAEs) can severely impact quality of life and result in discontinuation of ICI therapy. Lichenoid dermatitis is a cirAE that typically occurs due to anti–PD-1 and anti–programmed death receptor ligand 1 therapy and rarely with anti–cytotoxic T-lymphocyte-associate antigen 4 treatment, and, although pruritus is common, the clinical presentation can be broad.1Ellis S.R. Vierra A.T. Millsop J.W. Lacouture M.E. Kiuru M. Dermatologic toxicities to immune checkpoint inhibitor therapy: a review of histopathologic features.J Am Acad Dermatol. 2020; 83: 1130-1143https://doi.org/10.1016/j.jaad.2020.04.105Google Scholar In addition to systematically characterizing ICI-induced cirAEs,2Nadelmann E.R. Yeh J.E. Chen S.T. Management of cutaneous immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors: a systematic review.JAMA Oncol. 2022; 8: 130-138https://doi.org/10.1001/jamaoncol.2021.4318Google Scholar molecular phenotyping approaches, such as RNA in situ hybridization (RISH),3Wang A. Fogel A.L. Murphy M.J. et al.Cytokine RNA in situ hybridization permits individualized molecular phenotyping in biopsies of psoriasis and atopic dermatitis.JID Innov. 2021; 1100021https://doi.org/10.1016/j.xjidi.2021.100021Google Scholar have the potential to better personalize cirAE diagnosis and treatment selection. We report 2 cases of recalcitrant ICI-induced lichenoid dermatitis found to have type 2 inflammatory cytokine interleukin-13 (IL-13) on biopsy using RISH and successfully treated with dupilumab. Patient 1 is a 68-year-old woman with seropositive rheumatoid arthritis on adalimumab, hydroxychloroquine, and intermittent prednisone, in whom pancreatic adenocarcinoma developed and she was treated with PD-1 inhibitor pembrolizumab. Subsequently, an extensive pruritic rash developed in the patient. Physical examination demonstrated pink-violaceous, scaly papules coalescing into plaques scattered on the chest, back, arms, hands, and legs (Fig 1, A). Biopsies from the right side of the left thigh and dorsal aspect of the right hand showed a band of lichenoid infiltrate of lymphocytes with abundant eosinophils that obscures the dermoepidermal junction, which was consistent with anti–PD-1-induced lichenoid dermatitis (Fig 1, B). She was treated with acitretin 17.5 mg topical halobetasol and prednisone, but the rash and itch persisted. Pembrolizumab was held due to worsening rash. RISH staining results of the patient’s biopsy samples showed expression of the cytokine IL-13 (Fig 1, C). RISH staining for type 1 cytokine interferon gamma (IFN-γ), type 2 cytokine IL-4, and type 3 cytokine IL-17A were negative. She started receiving dupilumab, which resulted in sustained improvement of rash and itch (Fig 1, D), and the patient was able to restart her ICI therapy. She remains on pembrolizumab and dupilumab. Patient 2 is a 77-year-old man with metastatic clear cell renal cell carcinoma, in whom lichenoid dermatitis developed on pembrolizumab, resulting in discontinuation of ICI therapy. Physical examination demonstrated pink papules coalescing into large confluent plaques on flanks, abdomen, thighs, and buttocks (Fig 2, A). Biopsy from the abdomen showed a band-like infiltrate concerning for possible PD-1 induced lichenoid dermatitis (Fig 2, B) and RISH analysis results showed IL-13 staining (Fig 2, C). RISH staining for type 1 cytokine IFN-γ, type 2 cytokine IL-4, and type 3 cytokine IL-17A were negative. Past treatment with topical halobetasol daily and methotrexate 12.5 mg weekly was unsuccessful. He was started on dupilumab, and the rash cleared within 1 month (Fig 2, D) and pembrolizumab was reinstated. He remains on pembrolizumab and dupilumab. In this case series we describe the use of dupilumab, which is a IL-4 receptor α-antagonist that blocks both IL-4 and IL-13 signaling,4Beck L.A. Thaçi D. Hamilton J.D. et al.Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.N Engl J Med. 2014; 371: 130-139https://doi.org/10.1056/NEJMoa1314768Google Scholar for the treatment of lichenoid dermatitis in the setting of ICI therapy. Although there are substantial variability in the manifestation of skin-oriented toxicities based on factors including specific agent administered and underlying malignancy,5Nikolaou V.A. Apalla Z. Carrera C. et al.Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.Br J Dermatol. 2022; 187: 962-969https://doi.org/10.1111/bjd.21781Google Scholar lichenoid reactions are among the most common cirAEs and, when severe, cause interruption or discontinuation of immunotherapy treatment.2Nadelmann E.R. Yeh J.E. Chen S.T. Management of cutaneous immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors: a systematic review.JAMA Oncol. 2022; 8: 130-138https://doi.org/10.1001/jamaoncol.2021.4318Google Scholar,6Geisler A.N. Phillips G.S. Barrios D.M. et al.Immune checkpoint inhibitor-related dermatologic adverse events.J Am Acad Dermatol. 2020; 83: 1255-1268https://doi.org/10.1016/j.jaad.2020.03.132Google Scholar Therefore, there is a need to identify pathogenesis-based targets to expand the therapeutic armamentarium for patients with refractory cirAEs beyond steroids and ICI therapy discontinuation. Certain features may help distinguish ICI-induced lichenoid dermatitis from classic lichen planus, such as the presence of eosinophils,7Tetzlaff M.T. Nagarajan P. Chon S. et al.Lichenoid dermatologic toxicity from immune checkpoint blockade therapy: a detailed examination of the clinicopathologic features.Am J Dermatopathol. 2017; 39: 121-129https://doi.org/10.1097/DAD.0000000000000688Google Scholar but the precise underlying pathophysiology remains unclear,8Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168https://doi.org/10.1056/NEJMra1703481Google Scholar although one study has demonstrated phenotypic similarities between cutaneous acute graft versus host disease and anti–PD-1 interface cirAEs, suggesting potentially shared pathophysiologic mechanisms.9Almodovar Cruz G.E. Kaunitz G. Stein J.E. et al.Immune cell subsets in interface cutaneous immune-related adverse events associated with anti-PD-1 therapy resemble acute graft versus host disease more than lichen planus.J Cutan Pathol. 2022; 49: 701-708https://doi.org/10.1111/cup.14242Google Scholar We found that IL-13 is expressed in patient biopsies, suggesting that type 2 inflammation may play a role in the pathogenesis of ICI-induced lichenoid dermatitis and provides a molecular rationale for treatment with IL-4Rα antagonism. To our knowledge, this is the first report on the use of dupilumab for treatment of ICI-induced lichenoid dermatitis, demonstrating safe, rapid, and sustained improvement. Importantly, initiation of dupilumab therapy allowed for reinitiation of ICI cancer therapy. In classic cutaneous lichen planus, there are elevated levels of IFN-γ, IL-4, and IL-13 compared with psoriasis and a recent report of dupilumab treatment in a patient with cutaneous lichen planus.10Pietschke K. Holstein J. Meier K. et al.The inflammation in cutaneous lichen planus is dominated by IFN-γ and IL-21. A basis for therapeutic JAK1 inhibition.Exp Dermatol. 2021; 30: 262-270https://doi.org/10.1111/exd.14226Google Scholar,11Pousti B.T. Jin A. Sklovar L. et al.Dupilumab for the treatment of lichen planus.Cutis. 2021; 107: E8-E10https://doi.org/10.12788/cutis.0232Google Scholar In our 2 patients with pembrolizumab-induced lichenoid dermatitis, there was no RISH staining for IFN-γ, which may reflect potentially distinct mechanism of pathogenesis between classic cutaneous lichen planus and pembrolizumab-induced lichenoid dermatitis. However, more studies are needed to compare these overlapping, but distinct entities. Dupilumab has also been used with efficacy and tolerability in patients with classic bullous pemphigoid,12Abdat R. Waldman R.A. de Bedout V. et al.Dupilumab as a novel therapy for bullous pemphigoid: a multicenter case series.J Am Acad Dermatol. 2020; 83: 46-52https://doi.org/10.1016/j.jaad.2020.01.089Google Scholar indicating its relevance for use in other cirAE subtypes, including immunobullous. Altogether, these cases highlight the value of molecular phenotyping with technologies such as RISH to guide treatment selection, and suggest that dupilumab may be an effective therapeutic strategy for treating cirAEs without interrupting ICI therapy; however, further studies are necessary to validate these results. Dr Vesely’s spouse is an employee of Regeneron Pharmaceuticals, the maker of dupilumab. Dr Damsky is a consultant for Pfizer, Eli Lilly, and TWi Biotechnology, has received research funding from Pfizer, and receives licensing fees from EMD/Millipore/Sigma. Drs J. Park and E. Park have no conflicts of interest to declare.

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