Immune checkpoint inhibitor induced lichenoid reactions: A systematic review of characteristics and treatment outcomes

To the Editor: The use of immune checkpoint inhibitors (ICIs) as a method of cancer management has increased due to the efficacy; with the increased use of ICIs, there have been increased reports of immune-related adverse events. Lichenoid reactions (LRs) have been reported as specific cutaneous immune-related adverse events of ICIs.1Cruz M.J. Duarte A.F. Baudrier T. Cunha A.P. Barreto F. Azevedo F. Lichenoid drug eruption induced by misoprostol.Contact Dermatitis. 2009; 61: 240-242https://doi.org/10.1111/j.1600-0536.2009.01616.xCrossref PubMed Scopus (8) Google Scholar LRs are uncommon skin rashes that share many features with idiopathic lichen planus.2Lage D. Juliano P.B. Metze K. de Souza E.M. Cintra M.L. Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study.Int J Dermatol. 2012; 51: 1199-1205https://doi.org/10.1111/j.1365-4632.2011.05113.xCrossref PubMed Scopus (42) Google Scholar This systematic review aimed to summarize reports of ICI-induced LRs, offending drugs, and treatment outcomes.EMBASE and MEDLINE databases were searched on April 16, 2021, per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the key words “Lichen∗” along with “PD-1∗” or “PD-L1∗” or “CTLA-4∗.” In total, 83 studies were included (64 case reports, 11 case series, 6 retrospective cohort studies, and 2 prospective cohort studies), representing 194 patients (mean age, 64.7 years; male, 52.1%) and 4 drug classes (Fig 1). Drug classes included PD-1 inhibitors (85.1%, n = 165/194), PD-L1 inhibitors (6.7%, n = 13/194), CTLA-4 inhibitors (2.6%, n = 5/194), and combination therapy (5.7%, n = 11/194). Nivolumab (61.3%, n = 119/194), a PD-1 inhibitor, was the most prescribed ICI resulting in LR (Table I).Table ISummary of case reports of lichenoid reactions as a checkpoint inhibitor therapy adverse drug reaction∗Additional details regarding patient demographics and comorbidities are listed in Supplementary Table II (available via Mendeley at https://doi.org/10.17632/w7x25j7f5f.1).Drug classDrug name (specific drug cases/total cases in review)IndicationMean latency period, mo (n)Drug discontinuation (n)ResolutionTreatmentMean resolution period, d (n)Medications prescribed for the original indicationRecurrence of LR?Naranjo score (interpretation)PD-1 inhibitor (165)Nivolumab: 72% (119/165)Melanoma: 41% (49/119)Renal cell carcinoma: 23% (27/119)Non–small cell lung cancer: 16% (19/119)Lung cancer: 7% (8/119)Squamous cell carcinoma: 5% (6/119)Breast cancer: 2% (2/119)Glioblastoma: 2% (2/119)Lymphoma: 2% (2/119)Bladder cancer: 1% (1/119)Gastric cancer: 1% (1/119)Multiple myeloma: 1% (1/119)Pancreatic cancer: 1% (1/119)5.6 (104)Y: 23% (27/119)N: 35% (42/119)NR: 42% (50/119)CoR: 43% (51/119)Corticosteroids: 49% (25/51)Withdrawal and corticosteroids: 31% (16/51)Withdrawal only: 8% (4/51)Calcineurin inhibitor: 4% (2/51)Phototherapy: 4% (2/51)Retinoid: 2% (1/51)No treatment: 2% (1/51)61.8 (23)Unchanged: 23% (27/119)Methotrexate: 1% (1/119)Dabrafenib and trametinib: 1% (1/119)Docetaxel: 1% (1/119)NR: 75% (89/119)Y: 2% (2/119)N: 13% (15/119)NR: 86% (102/119)5.1 (probable)PR: 7% (8/119)Corticosteroids: 38% (3/8)Withdrawal and corticosteroids: 25% (2/8)No treatment: 25% (2/8)NR: 13% (1/8)14 (1)NoR: 2% (2/119)Withdrawal and corticosteroids: 50% (1/2)Withdrawal and Retinoid: 50% (1/2)NANR: 49% (58/119)Corticosteroids: 2% (1/58)NR: 98% (57/58)NAPembrolizumab: 28% (46/165)Melanoma: 54% (25/46)Non–small cell lung cancer: 22% (10/46)Breast cancer: 7% (3/46)Squamous cell carcinoma: 7% (3/46)Urothelial carcinoma: 4% (2/46)Invasive thymoma: 2% (1/46)Merkel cell carcinoma: 2% (1/46)Metastasis of unknown primary: 2% (1/46)3.7 (19)Y: 41% (19/46)N: 35% (16/46)NR: 24% (11/46)CoR: 67% (31/46)Withdrawal and corticosteroids: 42% (13/31)Corticosteroids: 42% (13/31)Withdrawal with retinoid: 6% (2/31)No treatment: 3% (1/31)Methotrexate: 3% (1/31)Withdrawal with methotrexate: 3% (1/31)100.1 (23)Unchanged: 35% (16/30)Discontinued treatment: 11% (5/30)Ipilimumab + nivolumab combination: 2% (1/31)Dabrafenib and trametinib: 2% (1/30)NR: 48% (22/30)Y: 4% (2/46)N: 31% (14/46)NR: 65% (30/46)5.4 (probable)PR: 9% (4/46)Withdrawal and corticosteroids: 25% (1/4)Corticosteroids: 75% (3/4)NR (4)NoR: 7% (3/46)Withdrawal and corticosteroids: 67% (2/3)Methotrexate: 33% (1/3)NANR: 17% (8/46)NR: 100% (8/8)NAPD-L1 inhibitor (13)Atezolizumab: 62% (8/13)Renal cell carcinoma: 50% (4/8)Non–small cell lung cancer: 38% (3/8)Adenocarcinoma of the esophagus: 13% (1/8)5.3 (8)Y: 38% (3/8)N: 38% (3/8)NR: 25% (2/8)CoR: 75% (6/8)Withdrawal and corticosteroids: 50% (3/6)Corticosteroids: 50% (3/6)150 (1)NR: 100% (8/8)N: 13% (1/8)NR: 88% (7/8)4.75 (possible)NoR: 13% (1/8)Corticosteroids: 100% (1/1)NANR: 13% (1/8)NR: 100% (1/1)NAAvelumab: 23% (3/13)Merkel cell carcinoma: 33% (1/3)Renal cell carcinoma: 33% (1/3)Urothelial carcinoma: 33% (1/3)2.5 (3)N: 100% (3/3)CoR: 33% (1/3)Corticosteroids: 100% (1/3)21 (1)Unchanged: 66.7% (2/3)NR: 33.3% (1/3)Y: 66.7% (2/3)NR: 33.3% (1/3)5 (probable)PR: 33% (1/3)Cryotherapy: 100% (1/3)NR (1)NR: 33% (1/3)Corticosteroids: 100% (1/3)NADurvalumab: 15% (2/13)Squamous cell carcinoma: 50% (1/2)Non–small cell lung cancer: 50% (1/2)15 (2)Y: 50% (1/2)NR: 50% (1/2)CoR: 100% (2/2)Withdrawal and corticosteroids: 100% (1/2)Corticosteroids: 100% (1/2)NR (2)NR: 100% (2/2)NR: 100% (2/2)6.5 (probable)CTLA-4 inhibitor (5)Ipilimumab: 80% (4/5)Melanoma: 100% (4/4)3.5 (4)Y: 25% (1/4)N: 50% (2/4)NR: 25% (1/4)CoR: 50% (2/4)Withdrawal and corticosteroids: 50% (1/2)Corticosteroids: 50% (1/2)NR (2)Unchanged: 25% (1/4)NR: 75% (3/4)N: 25% (1/4)NR: 75% (3/4)4 (possible)NR: 50% (2/4)NR: 100% (2/2)NATremelimumab: 20% (1/5)Renal cell carcinoma: 100% (1/1)NR (1)N: 100% (1/1)NoR: 100% (1/1)Corticosteroids: 100% (1/1)NAUnchanged: 100% (1/1)NR: 100% (1/1)3 (possible)Combination therapy (11)Nivolumab and ipilimumab: 45% (5/11)Melanoma: 60% (3/5)Non–small cell lung cancer: 40% (2/5)2.6 (5)N: 80% (4/5)NR: 20% (1/5)CoR: 80% (4/5)Corticosteroids: 100% (4/4)NR (1)Unchanged: 80% (4/5)NR: 20% (1/5)NR: 100% (5/5)4.6 (possible)NR: 20% (1/5)NR: 100% (1/1)NR (1)Ipilimumab and pembrolizumab: 18% (2/11)Melanoma: 100% (2/2)0.9 (2)NR: 100% (2/2)CoR: 50% (1/2)Corticosteroids: 100% (1/1)NR (1)Unchanged: 50% (1/2)NR: 50% (1/2)N: 100% (2/2)4 (possible)PR: 50% (1/2)Corticosteroids: 100% (1/1)NR (1)Nivolumab and bevacizumab: 9% (1/11)Non–small cell lung cancer: 100% (1/1)1.5 (1)N: 100% (1/1)CoR: 100% (1/1)Corticosteroids: 100% (1/1)NR (1)Unchanged: 100% (1/1)NR: 100% (2/2)4 (possible)Nivolumab and mogamulizaumab: 9% (1/11)Non–small cell lung cancer: 100% (1/1)3.3 (1)NR: 100% (1/1)NR: 100% (1/1)NR: 100% (1/1)NR (1)NR: 100% (1/1)NR: 100% (1/1)7 (probable)Nivolumab and Pembrolizumab: 9% (1/11)Melanoma: 100% (1/1)4.7 (1)NR: 100% (1/1)NR: 100% (1/1)NR: 100% (1/1)NR (1)NR: 100% (1/1)NR: 100% (1/1)4 (possible)Tislelizumab and sitravatinib: 9% (1/11)Non–small cell lung cancer: 100% (1/1)1.5 (1)NR: 100% (1/1)CoR: 100% (1/1)Corticosteroids: 100% (1/1)14 (1)NR: 100% (1/1)NR: 100% (1/1)4 (possible)CoR, Complete resolution; LR, lichenoid reaction; N, no; NA, not applicable; NoR, no response; NR, not reported; PR, partial resolution; Y, yes.∗ Additional details regarding patient demographics and comorbidities are listed in Supplementary Table II (available via Mendeley at https://doi.org/10.17632/w7x25j7f5f.1). Open table in a new tab Data showed that the mean onset of LR for nivolumab was 5.6 months (n = 104), and 51 (43%) of the 119 patients receiving treatment with nivolumab achieved complete resolution (CoR) within 61.8 days (n = 23). Of these 51 patients, CoR was achieved with corticosteroids in 25 (49%) patients, drug withdrawal with corticosteroids in 16 (31.0%), and drug withdrawal alone in 4 (8.0%); other treatment modalities were used in 8 patients (Table I). The mean onset of LR for pembrolizumab (23.7%, n = 46/194) was 3.7 months, and 31 (67%) of the 46 patients achieved CoR within 100.1 days. Of these 31 patients, CoR was achieved with corticosteroids in 13 (42%) patients and drug withdrawal with corticosteroids in 13 (42%) patients; other treatment modalities were used in 5 patients (Table I). The mean onset of LR for atezolizumab (4.1%, n = 8/194) was 161 days (n = 8), and 6 (75%) of the 8 patients achieved CoR, with a mean resolution period of 150 days. Of these 6 patients, CoR was achieved with corticosteroids in 3 (50%) patients and drug withdrawal with corticosteroids in 3 (50%) patients.The relationship between LRs and classic lichen planus remains unclear. Both share common histologic features, including subepidermal band-like cytotoxic lymphocyte infiltration and apoptosis of basal keratinocytes; to distinguish between them, clinical and histologic correlation is recommended.2Lage D. Juliano P.B. Metze K. de Souza E.M. Cintra M.L. Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study.Int J Dermatol. 2012; 51: 1199-1205https://doi.org/10.1111/j.1365-4632.2011.05113.xCrossref PubMed Scopus (42) Google Scholar Although mechanisms of LRs remain unclear, it is believed that T cells, dendritic cells, keratinocytes, and endothelial cells trigger an inflammatory reaction cascade (eg, L-selectin, major histocompatibility complex class II, intercellular adhesion molecules) that ultimately leads to LRs.3Yawalkar N. Pichler W.J. Mechanisms of cutaneous drug reactions. Article in German.J Dtsch Dermatol Ges. 2004; 2: 1013-1023 [quiz: 1024-1026]https://doi.org/10.1046/j.1439-0353.2004.04524.xCrossref PubMed Scopus (13) Google Scholar This is reinforced by observations that PD-1 inhibitors, due to unclear causes, frequently cause adverse cutaneous reactions, supporting claims that PD-1/PD-L1 interaction is necessary to preserve epidermal integrity during inflammatory skin reactions.4Goldinger S.M. Stieger P. Meier B. et al.Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy.Clin Cancer Res. 2016; 22: 4023-4029https://doi.org/10.1158/1078-0432.CCR-15-2872Crossref PubMed Scopus (124) Google ScholarLimitations of this systematic review include the small sample sizes, lack of high-quality randomized controlled trials, and lack of follow-up data. Additionally, the confirmation of ICI-induced LR in all included cases is challenging to determine. However, LR histology was confirmed by biopsy in 124 (63.9%) of the 194 patients. In addition, the mean Naranjo score was 5, which suggests a “probable” association between the suspected drug and LRs.5Naranjo C.A. Busto U. Sellers E.M. et al.A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther. 1981; 30: 239-245https://doi.org/10.1038/clpt.1981.154Crossref PubMed Scopus (8233) Google Scholar Despite these limitations, our findings provide essential conclusions to guide LR management, showing that 99 (51%) of the 194 patients with ICI-induced LR achieved CoR with drug withdrawal and corticosteroids (topical or oral) or corticosteroids (topical or oral) alone. To the Editor: The use of immune checkpoint inhibitors (ICIs) as a method of cancer management has increased due to the efficacy; with the increased use of ICIs, there have been increased reports of immune-related adverse events. Lichenoid reactions (LRs) have been reported as specific cutaneous immune-related adverse events of ICIs.1Cruz M.J. Duarte A.F. Baudrier T. Cunha A.P. Barreto F. Azevedo F. Lichenoid drug eruption induced by misoprostol.Contact Dermatitis. 2009; 61: 240-242https://doi.org/10.1111/j.1600-0536.2009.01616.xCrossref PubMed Scopus (8) Google Scholar LRs are uncommon skin rashes that share many features with idiopathic lichen planus.2Lage D. Juliano P.B. Metze K. de Souza E.M. Cintra M.L. Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study.Int J Dermatol. 2012; 51: 1199-1205https://doi.org/10.1111/j.1365-4632.2011.05113.xCrossref PubMed Scopus (42) Google Scholar This systematic review aimed to summarize reports of ICI-induced LRs, offending drugs, and treatment outcomes. EMBASE and MEDLINE databases were searched on April 16, 2021, per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the key words “Lichen∗” along with “PD-1∗” or “PD-L1∗” or “CTLA-4∗.” In total, 83 studies were included (64 case reports, 11 case series, 6 retrospective cohort studies, and 2 prospective cohort studies), representing 194 patients (mean age, 64.7 years; male, 52.1%) and 4 drug classes (Fig 1). Drug classes included PD-1 inhibitors (85.1%, n = 165/194), PD-L1 inhibitors (6.7%, n = 13/194), CTLA-4 inhibitors (2.6%, n = 5/194), and combination therapy (5.7%, n = 11/194). Nivolumab (61.3%, n = 119/194), a PD-1 inhibitor, was the most prescribed ICI resulting in LR (Table I). CoR, Complete resolution; LR, lichenoid reaction; N, no; NA, not applicable; NoR, no response; NR, not reported; PR, partial resolution; Y, yes. Data showed that the mean onset of LR for nivolumab was 5.6 months (n = 104), and 51 (43%) of the 119 patients receiving treatment with nivolumab achieved complete resolution (CoR) within 61.8 days (n = 23). Of these 51 patients, CoR was achieved with corticosteroids in 25 (49%) patients, drug withdrawal with corticosteroids in 16 (31.0%), and drug withdrawal alone in 4 (8.0%); other treatment modalities were used in 8 patients (Table I). The mean onset of LR for pembrolizumab (23.7%, n = 46/194) was 3.7 months, and 31 (67%) of the 46 patients achieved CoR within 100.1 days. Of these 31 patients, CoR was achieved with corticosteroids in 13 (42%) patients and drug withdrawal with corticosteroids in 13 (42%) patients; other treatment modalities were used in 5 patients (Table I). The mean onset of LR for atezolizumab (4.1%, n = 8/194) was 161 days (n = 8), and 6 (75%) of the 8 patients achieved CoR, with a mean resolution period of 150 days. Of these 6 patients, CoR was achieved with corticosteroids in 3 (50%) patients and drug withdrawal with corticosteroids in 3 (50%) patients. The relationship between LRs and classic lichen planus remains unclear. Both share common histologic features, including subepidermal band-like cytotoxic lymphocyte infiltration and apoptosis of basal keratinocytes; to distinguish between them, clinical and histologic correlation is recommended.2Lage D. Juliano P.B. Metze K. de Souza E.M. Cintra M.L. Lichen planus and lichenoid drug-induced eruption: a histological and immunohistochemical study.Int J Dermatol. 2012; 51: 1199-1205https://doi.org/10.1111/j.1365-4632.2011.05113.xCrossref PubMed Scopus (42) Google Scholar Although mechanisms of LRs remain unclear, it is believed that T cells, dendritic cells, keratinocytes, and endothelial cells trigger an inflammatory reaction cascade (eg, L-selectin, major histocompatibility complex class II, intercellular adhesion molecules) that ultimately leads to LRs.3Yawalkar N. Pichler W.J. Mechanisms of cutaneous drug reactions. Article in German.J Dtsch Dermatol Ges. 2004; 2: 1013-1023 [quiz: 1024-1026]https://doi.org/10.1046/j.1439-0353.2004.04524.xCrossref PubMed Scopus (13) Google Scholar This is reinforced by observations that PD-1 inhibitors, due to unclear causes, frequently cause adverse cutaneous reactions, supporting claims that PD-1/PD-L1 interaction is necessary to preserve epidermal integrity during inflammatory skin reactions.4Goldinger S.M. Stieger P. Meier B. et al.Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy.Clin Cancer Res. 2016; 22: 4023-4029https://doi.org/10.1158/1078-0432.CCR-15-2872Crossref PubMed Scopus (124) Google Scholar Limitations of this systematic review include the small sample sizes, lack of high-quality randomized controlled trials, and lack of follow-up data. Additionally, the confirmation of ICI-induced LR in all included cases is challenging to determine. However, LR histology was confirmed by biopsy in 124 (63.9%) of the 194 patients. In addition, the mean Naranjo score was 5, which suggests a “probable” association between the suspected drug and LRs.5Naranjo C.A. Busto U. Sellers E.M. et al.A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther. 1981; 30: 239-245https://doi.org/10.1038/clpt.1981.154Crossref PubMed Scopus (8233) Google Scholar Despite these limitations, our findings provide essential conclusions to guide LR management, showing that 99 (51%) of the 194 patients with ICI-induced LR achieved CoR with drug withdrawal and corticosteroids (topical or oral) or corticosteroids (topical or oral) alone. None disclosed.

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