As treatment with immune checkpoint inhibitors (CPIs) for cancer increases, so has the incidence of immune-related cutaneous adverse events (irCAEs). These toxicities can significantly impact quality of life and may be dose-limiting. Current guidelines for irCAEs offer only corticosteroids or CPI discontinuation. Evidence supports biologic immunomodulatory therapies when corticosteroids fail or need avoidance. A review of literature from 2010 to 2020 yielded 45 articles, resulting in 185 irCAEs, including bullous pemphigoid–like eruption (n = 55), psoriasis/psoriasiform dermatitis (n = 41), and maculopapular rash (n = 31). Treatments included immunomodulators, intravenous immunoglobulin, aprepitant, acitretin, tetracyclines, and biologic agents. Overall, 92.3% of patients saw improvement or resolution of their rash. Bullous pemphigoid–like eruptions were treated with a tetracycline +/− niacinamide (94.7% success [18/19]), omalizumab (100% success [7/7]), and rituximab (100% success [10/10]). Although prospective research is required, this review provides a comprehensive list of successful, non-corticosteroid treatment options for irCAEs to improve compliance with lifesaving cancer therapy.
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References
1.
SibaudV. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol, 2018; 19(3):345–361. doi:10.1007/s40257-017-0336-3.
2.
CurryJL, TetzlaffMT, NagarajanP, et al.Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol, 2017; 44(2):158–176. doi:10.1111/cup.12858.
3.
WeberJS, KählerKC, HauschildA. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol Off J Am Soc Clin Oncol, 2012; 30(21):2691–2697. doi:10.1200/JCO.2012.41.6750.
4.
WeberJS, HodiFS, WolchokJD, et al.Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol Off J Am Soc Clin Oncol, 2017; 35(7):785–792. doi:10.1200/JCO.2015.66.1389.
5.
EggermontAMM, Chiarion-SileniV, GrobJ-J, et al.Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol, 2015; 16(5):522–530. doi:10.1016/S1470-2045(15)70122-1.
6.
HodiFS, O'DaySJ, McDermottDF, et al.Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 2010; 363(8):711–723. doi:10.1056/NEJMoa1003466.
7.
WelbornM, KubickiSL, GargN, et al.Retrospective chart review of cutaneous adverse events associated with tremelimumab in 17 patients. Am J Clin Dermatol, 2018; 19(6):899–905. doi:10.1007/s40257-018-0376-3.
8.
PatelAB, PachaO. Skin reactions to immune checkpoint inhibitors. Adv Exp Med Biol, 2018; 995:117–129. doi:10.1007/978-3-030-02505-2_5.
9.
BrahmerJR, LacchettiC, SchneiderBJ, et al.Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol Off J Am Soc Clin Oncol, 2018; 36(17):1714–1768. doi:10.1200/JCO.2017.77.6385.
10.
RicciutiB, DahlbergSE, AdeniA, et al.Immune checkpoint inhibitor outcomes for patients with non–small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications. J Clin Oncol Off J Am Soc Clin Oncol, 2019; 37(22):1927–1934. doi:10.1200/JCO.19.00189.
11.
FajeAT, LawrenceD, FlahertyK, et al.High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer, 2018; 124(18):3706–3714. doi:10.1002/cncr.31629.
12.
Della CorteCM, MorgilloF. Early use of steroids affects immune cells and impairs immunotherapy efficacy. ESMO Open, 2019; 4(1):e000477. doi:10.1136/esmoopen-2018-000477.
13.
ArbourKC, MezquitaL, LongN, et al.Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non–small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol, 2018; 36(28):2872–2878. doi:10.1200/JCO.2018.79.0006.
14.
HorvatTZ, AdelNG, DangT-O, et al.Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol Off J Am Soc Clin Oncol, 2015; 33(28):3193–3198. doi:10.1200/JCO.2015.60.8448.
15.
MichotJM, BigenwaldC, ChampiatS, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer Oxf Engl 1990, 2016; 54:139–148. doi:10.1016/j.ejca.2015.11.016.
16.
SantiniFC, RizviH, PlodkowskiAJ, et al.Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res, 2018; 6(9):1093–1099. doi:10.1158/2326-6066.CIR-17-0755.
17.
MuntyanuA, NetchiporoukE, GersteinW, et al.Cutaneous immune-related adverse events (irAEs) to immune checkpoint inhibitors: a dermatology perspective on management. J Cutan Med Surg, 2021; 25(1):59–76. doi:10.1177/1203475420943260.
18.
PuzanovI, DiabA, AbdallahK, et al.Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer, 2017; 5(1):95. doi:10.1186/s40425-017-0300-z.
19.
SanlorenzoM, VujicI, DaudA, et al.Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol, 2015; 151(11):1206–1212. doi:10.1001/jamadermatol.2015.1916.
20.
PhillipsGS, WuJ, HellmannMD, et al.Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol Off J Am Soc Clin Oncol, 2019; 37(30):2746–2758. doi:10.1200/JCO.18.02141.
21.
KagoyaY, YoshimiA, KataokaK, et al.Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. J Clin Invest, 2014; 124(2):528–542. doi:10.1172/JCI68101.
22.
ZhouX, LiZ, ZhouJ. Tumor necrosis factor α in the onset and progression of leukemia. Exp Hematol, 2017; 45:17–26. doi:10.1016/j.exphem.2016.10.005.
23.
EsfahaniK, MillerWH. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N Engl J Med, 2017; 376(20):1989–1991. doi:10.1056/NEJMc1703047.
24.
BusseW, BuhlR, Fernandez VidaurreC, et al.Omalizumab and the risk of malignancy: results from a pooled analysis. J Allergy Clin Immunol, 2012; 129(4):983–989.e6. doi:10.1016/j.jaci.2012.01.033.
25.
ColemanE, KoC, DaiF, et al.Inflammatory eruptions associated with immune checkpoint inhibitor therapy: a single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. J Am Acad Dermatol, 2019; 80(4):990–997. doi:10.1016/j.jaad.2018.10.062.
26.
Law-Ping-ManS, MartinA, BriensE, et al.Psoriasis and psoriatic arthritis induced by nivolumab in a patient with advanced lung cancer. Rheumatol Oxf Engl, 2016; 55(11):2087–2089. doi:10.1093/rheumatology/kew281.
27.
ParakhS, NguyenR, OpieJM, et al.Late presentation of generalised bullous pemphigoid–like reaction in a patient treated with pembrolizumab for metastatic melanoma. Australas J Dermatol, 2017; 58(3):e109–e112. doi:10.1111/ajd.12488.
28.
BonigenJ, Raynaud-DonzelC, HureauxJ, et al.Anti–PD1-induced psoriasis: a study of 21 patients. J Eur Acad Dermatol Venereol JEADV, 2017; 31(5):e254–e257. doi:10.1111/jdv.14011.
29.
DamskyW, KoleL, TomaykoMM. Development of bullous pemphigoid during nivolumab therapy. JAAD Case Rep, 2016; 2(6):442–444. doi:10.1016/j.jdcr.2016.05.009.
30.
RofeO, Bar-SelaG, KeidarZ, et al.Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression. Clin Exp Dermatol, 2017; 42(3):309–312. doi:10.1111/ced.13042.
31.
BandinoJP, PerryDM, ClarkeCE, et al.Two cases of anti–programmed cell death 1–associated bullous pemphigoid–like disease and eruptive keratoacanthomas featuring combined histopathology. J Eur Acad Dermatol Venereol JEADV, 2017; 31(8):e378–e380. doi:10.1111/jdv.14179.
32.
SowerbyL, DewanAK, GranterS, et al.Rituximab treatment of nivolumab-induced bullous pemphigoid. JAMA Dermatol, 2017; 153(6):603–605. doi:10.1001/jamadermatol.2017.0091.
33.
ItoJ, FujimotoD, NakamuraA, et al.Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer Amst Neth, 2017; 109:58–61. doi:10.1016/j.lungcan.2017.04.020.
34.
BarbosaNS, WetterDA, WielandCN, et al.Scleroderma induced by pembrolizumab: a case series. Mayo Clin Proc, 2017; 92(7):1158–1163. doi:10.1016/j.mayocp.2017.03.016.
35.
TetzlaffMT, JazaeriAA, Torres-CabalaCA, et al.Erythema nodosum–like panniculitis mimicking disease recurrence: a novel toxicity from immune checkpoint blockade therapy—report of 2 patients. J Cutan Pathol, 2017; 44(12):1080–1086. doi:10.1111/cup.13044.
SundaresanS, NguyenKT, NelsonKC, et al.Erythema multiforme major in a patient with metastatic melanoma treated with nivolumab. Dermatol Online J, 2017; 23(9).
38.
UtsunomiyaA, OyamaN, IinoS, et al.A case of erythema multiforme major developed after sequential use of two immune checkpoint inhibitors, nivolumab and ipilimumab, for advanced melanoma: possible implication of synergistic and/or complementary immunomodulatory effects. Case Rep Dermatol, 2018; 10(1):1–6. doi:10.1159/000485910.
39.
RidpathAV, RzepkaPV, ShearerSM, et al.Novel use of combination therapeutic plasma exchange and rituximab in the treatment of nivolumab-induced bullous pemphigoid. Int J Dermatol, 2018; 57(11):1372–1374. doi:10.1111/ijd.13970.
40.
HaugV, BehleV, BenoitS, et al.Pembrolizumab-associated mucous membrane pemphigoid in a patient with Merkel cell carcinoma. Br J Dermatol, 2018; 179(4):993–994. doi:10.1111/bjd.16780.
41.
LopezAT, GeskinL. A case of nivolumab-induced bullous pemphigoid: review of dermatologic toxicity associated with programmed cell death protein-1/programmed death ligand-1 inhibitors and recommendations for diagnosis and management. Oncologist, 2018; 23(10):1119–1126. doi:10.1634/theoncologist.2018-0128.
42.
SiegelJ, TotonchyM, DamskyW, et al.Bullous disorders associated with anti–PD-1 and anti–PD-L1 therapy: a retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy. J Am Acad Dermatol, 2018; 79(6):1081–1088. doi:10.1016/j.jaad.2018.07.008.
43.
TomelleriA, CampochiaroC, De LucaG, et al.Anti–PD1 therapy–associated cutaneous leucocytoclastic vasculitis: a case series. Eur J Intern Med, 2018; 57:e11–e12. doi:10.1016/j.ejim.2018.07.023.
44.
ZumelzuC, AlexandreM, Le RouxC, et al.Mucous membrane pemphigoid, bullous pemphigoid, and anti–programmed death-1/programmed death-ligand 1: a case report of an elderly woman with mucous membrane pemphigoid developing after pembrolizumab therapy for metastatic melanoma and review of the literature. Front Med, 2018; 5:268. doi:10.3389/fmed.2018.00268.
45.
RiosA, CenP, DinhB, et al.Dramatic response of nivolumab-associated psoriasiform dermatitis to etoposide. Eur J Cancer Oxf Engl 1990, 2019; 107:97–99. doi:10.1016/j.ejca.2018.11.025.
46.
HorisbergerA, La RosaS, ZurcherJ-P, et al.A severe case of refractory esophageal stenosis induced by nivolumab and responding to tocilizumab therapy. J Immunother Cancer, 2018; 6(1):156. doi:10.1186/s40425-018-0481-0.
47.
GrimauxX, DelvaR, JadaudE, et al.Nivolumab-induced bullous pemphigoid after radiotherapy and abscopal effect. Australas J Dermatol, 2019; 60(3):e235–e236. doi:10.1111/ajd.12987.
48.
FixsenE, PatelJ, SelimMA, et al.Resolution of pembrolizumab-associated steroid-refractory lichenoid dermatitis with cyclosporine. Oncologist, 2019; 24(3):e103–e105. doi:10.1634/theoncologist.2018-0531.
49.
FattoreD, AnnunziataMC, PanarielloL, et al.Successful treatment of psoriasis induced by immune checkpoint inhibitors with apremilast. Eur J Cancer Oxf Engl 1990, 2019; 110:107–109. doi:10.1016/j.ejca.2019.01.010.
50.
JohnsonD, PatelAB, UemuraMI, et al.IL17A blockade successfully treated psoriasiform dermatologic toxicity from immunotherapy. Cancer Immunol Res, 2019; 7(6):860–865. doi:10.1158/2326-6066.CIR-18-0682.
51.
BezinelliLM, EduardoFP, MiglioratiCA, et al.A severe, refractory case of mucous membrane pemphigoid after treatment with pembrolizumab: brief communication. J Immunother Hagerstown Md 1997, 2019; 42(9):359–362. doi:10.1097/CJI.0000000000000280.
52.
KoscheC, StoutM, SosmanJ, et al.Dermatomyositis in a patient undergoing nivolumab therapy for metastatic melanoma: a case report and review of the literature. Melanoma Res, 2020; 30(3):313–316. doi:10.1097/CMR.0000000000000642.
53.
SingerS, NelsonCA, LianCG, et al.Nonbullous pemphigoid secondary to PD-1 inhibition. JAAD Case Rep, 2019; 5(10):898–903. doi:10.1016/j.jdcr.2019.07.015.
54.
KoscheC, OwenJL, SadowskyLM, et al.Bullous dermatoses secondary to anti–PD-L1 agents: a case report and review of the literature. Dermatol Online J, 2019; 25(10).
55.
KoscheC, OwenJL, ChoiJN. Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab. Dermatol Online J, 2019; 25(10).
56.
MonsourEP, PothenJ, BalaramanR. A novel approach to the treatment of pembrolizumab-induced psoriasis exacerbation: a case report. Cureus, 2019; 11(10):e5824. doi:10.7759/cureus.5824.
57.
KrammerS, KrammerC, SalzerS, et al.Recurrence of pemphigus vulgaris under nivolumab therapy. Front Med, 2019; 6:262. doi:10.3389/fmed.2019.00262.
58.
MorrisLM, LewisHA, CorneliusLA, et al.Neutrophil-predominant bullous pemphigoid induced by checkpoint inhibitors: a case series. J Cutan Pathol, 2020; 47(8):742–746. doi:10.1111/cup.13687.
59.
HiblerBP, MarkovaA. Treatment of severe cutaneous adverse reaction with tocilizumab. Br J Dermatol, 2020; 183(4):785–787. doi:10.1111/bjd.19129.
60.
SchwartzmanG, SimpsonMM, JonesR, et al.Anti-PD1 immune checkpoint inhibitor-induced bullous pemphigoid in metastatic melanoma and non–small cell lung cancer. Cutis, 2020; 105(6):E9–E12.
61.
CosimatiA, RossiL, DidonaD, et al.Bullous pemphigoid in elderly woman affected by non–small cell lung cancer treated with pembrolizumab: a case report and review of literature. J Oncol Pharm Pract Off Publ Int Soc Oncol Pharm Pract, 2021; 27(3):727–733. doi:10.1177/1078155220946370.
62.
BuiAN, HirnerJ, SingerSB, et al.De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy: clinicopathological correlation. Clin Exp Dermatol, 2021; 46(2):328–337. doi:10.1111/ced.14449.
63.
MesserA, DrozdB, GlitzaIC, et al.Dermatomyositis associated with nivolumab therapy for melanoma: a case report and review of the literature. Dermatol Online J, 2020; 26(8).
64.
HwangSJE, CarlosG, ChouS, et al.Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies. Melanoma Res, 2016; 26(4):413–416. doi:10.1097/CMR.0000000000000260.
65.
NayarN, BriscoeK, FernandezPenas P. Toxic epidermal necrolysis–like reaction with severe satellite cell necrosis associated with nivolumab in a patient with ipilimumab refractory metastatic melanoma. J Immunother Hagerstown Md 1997, 2016; 39(3):149–152. doi:10.1097/CJI.0000000000000112.
66.
TeulingsH-E, LimpensJ, JansenSN, et al.Vitiligo-like depigmentation in patients with stage III–IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol Off J Am Soc Clin Oncol, 2015; 33(7):773–781. doi:10.1200/JCO.2014.57.4756.
67.
HuaC, BoussemartL, MateusC, et al.Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol, 2016; 152(1):45–51. doi:10.1001/jamadermatol.2015.2707.
68.
Freeman-KellerM, KimY, CroninH, et al.Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res Off J Am Assoc Cancer Res, 2016; 22(4):886–894. doi:10.1158/1078-0432.CCR-15-1136.
69.
ZouW, RestifoNP. T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol, 2010; 10(4):248–256. doi:10.1038/nri2742.
70.
KryczekI, BanerjeeM, ChengP, et al.Phenotype, distribution, generation, and functional and clinical relevance of TH17 cells in the human tumor environments. Blood, 2009; 114(6):1141–1149. doi:10.1182/blood-2009-03-208249.
71.
KryczekI, WeiS, SzeligaW, et al.Endogenous IL-17 contributes to reduced tumor growth and metastasis. Blood, 2009; 114(2):357–359. doi:10.1182/blood-2008-09-177360.
72.
LopezAT, KhannaT, AntonovN, et al.A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. Int J Dermatol, 2018; 57(6):664–669. doi:10.1111/ijd.13984.
73.
PincA, SomasundaramR, WagnerC, et al.Targeting CD20 in melanoma patients at high risk of disease recurrence. Mol Ther J Am Soc Gene Ther, 2012; 20(5):1056–1062. doi:10.1038/mt.2012.27.
74.
KumakiN, OkamatsuC, TokudaY, et al.Breast cancer in patients of rheumatoid arthritis with methotrexate therapy mimicking histopathological changes after neoadjuvant chemotherapy. Tokai J Exp Clin Med, 2017; 42(2):104–108.
75.
WesselsJ a M, HuizingaTWJ, H-JGuchelaar. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatol Oxf Engl, 2008; 47(3):249–255. doi:10.1093/rheumatology/kem279.
76.
BöhmI. Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them. Biomed Pharmacother Biomedecine Pharmacother, 2004; 58(5):338–343. doi:10.1016/j.biopha.2004.04.010.
77.
BrodyM, BöhmI, BauerR. Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. Eur J Clin Chem Clin Biochem J Forum Eur Clin Chem Soc, 1993; 31(10):667–674. doi:10.1515/cclm.1993.31.10.667.
78.
SaniklidouAH, TighePJ, FaircloughLC, et al.IgE autoantibodies and their association with the disease activity and phenotype in bullous pemphigoid: a systematic review. Arch Dermatol Res, 2018; 310(1):11–28. doi:10.1007/s00403-017-1789-1.
79.
KremerN, SnastI, CohenES, et al.Rituximab and omalizumab for the treatment of bullous pemphigoid: a systematic review of the literature. Am J Clin Dermatol, 2019; 20(2):209–216. doi:10.1007/s40257-018-0401-6.
