PracticalDermatology

Pembrolizumab falls within the immune checkpoint inhibitors (ICIs) class of cancer therapies and serves as a monoclonal antibody targeting the programmed cell death-1 (PD-1) receptor on T cells. When pembrolizumab binds to the PD-1 receptor, it prevents tumor cell PD-1 ligands, PD-L1, and PD-L2 from binding and inactivating the T cell. Thus, pembrolizumab allows for T-cell activation. Immune-checkpoint inhibitors are associated with immune-related adverse events (irAEs) caused by cytotoxic CD4+/CD8+ T cell activation.

Various irAEs include colitis, hepatitis, pneumonitis, and endocrinopathies.

Cutaneous irAEs (ircAEs) commonly manifest as maculopapular eruptions, some of which have an eczematous appearance clinically and spongiotic features histologically. The pathogenesis of an ICI-induced maculopapular rash remains unclear, but it is thought to involve the cross-recognition of antigens shared by the neoplastic cells and healthy skin by activated CD4+/CD8+ T cells. The eruptions are graded based on symptoms and severity, and the current treatment algorithm of a maculopapular eruption presenting after immune checkpoint inhibitor therapy involves topical corticosteroids for a grade 1 adverse event (AE), adding systemic corticosteroids for grade 2, and biologics (e.g., infliximab or tocilizumab) for grade 3+. Additional irAEs include pruritus, lichenoid reactions, psoriasis, vitiligo-like lesions, autoimmune skin diseases (e.g., bullous pemphigoid, dermatomyositis, vasculitis, Sjogren’s syndrome, alopecia areata), sarcoidosis, acneiform eruptions, nail changes, and oral mucosal toxicities.

Dupilumab is a monoclonal antibody targeting the interleukin-4 receptor alpha subunit (IL-4Ra), inhibiting IL-4 and IL-13 signaling. The IL-4 and IL-13 cytokines are components of the type 2 immune response. Dupilumab has been approved to treat atopic dermatitis in patients 6 months and older, asthma in patients 6 years of age and older, and chronic rhinosinusitis with nasal polyposis in patients 18 years of age and older. Dupilumab is effective for off-label use with bullous pemphigoid, prurigo nodularis, anal and genital pruritus, allergic contact dermatitis, and chronic spontaneous urticaria.

We report the use of dupilumab for a case of a pembrolizumab-induced irAE in a 64-year-old male characterized by maculopapular skin eruption, intense pruritus, and uncontrolled with topical and oral corticosteroids.

Case Report

A 64-year-old male presented with a pruritic maculopapular rash of the chest, abdomen, and back. Of note, the patient had a history of T2N1M0 squamous cell carcinoma to the right tonsil since 2013, which was initially treated with cisplatin and radiation and subsequently treated with neck dissection and radiation in 2016. Recurrence occurred approximately 4 years later, and it was not amendable for surgery due to the location of the mass. The patient elected to begin immunotherapy with pembrolizumab. The patient presented with a pruritic maculopapular rash of the chest, abdomen, and upper and lower back approximately 7 months after the initiation of pembrolizumab. The pruritus was constant and severe, interrupting sleep.

Physical examination demonstrated erythematous patches diffusely coalesced on the chest and back with multiple papules admixed with overlying excoriation (Figure 1A, B). Skin biopsy showed acute spongiotic dermatitis with intraepidermal vesicle and eosinophils. Lab tests did not demonstrate eosinophilia or transaminitis. DIF did not demonstrate findings suggestive of early bullous pemphigoid.

Figure 1 A, B: Erythematous patches with both follicular and non-follicular papules as well as superimposed excoriations.

The patient was repeatedly treated with various antihistamines, topical and intramuscular corticosteroids, and oral prednisone tapers, with the highest dose being 40mg (0.5mg/kg) daily. The patient experienced flares of the pruritic eruption when the taper reached 5mg. Pembrolizumab was eventually held secondary to the irAE, but the patient continued to experience flares upon cessation of the corticosteroid tapers. There was a significantly decreased quality of life due to excoriation, severe pruritus, and interrupted sleep.

About 11 months after the initial presentation of the eruption, the treatment taper was escalated to 1 week at 60mg, 2 weeks at 40mg, and then alternate day dosing once at 20mg daily for 2 weeks had been reached.

During the escalated taper, the patient reported a rash flare at 20mg of prednisone. The patient’s recent PET scan demonstrated findings concerning for recurrent malignancy. Due to the patient’s history of malignancies and the side effects of chronic corticosteroid use, the patient needed to stop corticosteroids and be bridged to a steroid-sparing agent or a more long-term solution. It was decided that the patient may benefit more from dupilumab, as it is an immunomodulator and would not cause as significant immunosuppression as with infliximab.

Dupilumab therapy was initiated with a loading dose of 600mg. Prednisone was titrated to 40mg during the bridge with a gradual taper to 5mg while waiting for the medicine to achieve a steady state. Approximately 1 month later, the patient’s eruption and pruritus were responsive to dupilumab. The patient continued once every 2-week dosing of 300mg of dupilumab, continued topical therapy (triamcinolone acetonide 0.1% ointment), and tapered and discontinued corticosteroids.

Discussion

Eczematous eruption (syn. maculopapular rash)

A maculopapular eruption is seen in approximately 20% of patients undergoing anti-PD-1/PD-L1 treatment. Maculopapular rash development has been reported to occur as early as a few days to weeks and as late as a few months after initiating an ICI. Current management of a maculopapular eruption presenting after immune checkpoint inhibitor therapy involves the following:

• Grade 1: moderate-to-high-potency topical corticosteroids twice a day
• Grade 2: moderate-to-high-potency topical corticosteroids twice a day or systemic corticosteroids such as prednisone 0.5-1mg/kg/day
• Grade 3+: Hold immune checkpoint inhibitor until grade 0-1 is reached; systemic corticosteroid (prednisone 0.5-1mg/kg/day with dose increase up to 2 mg/kg/day if no improvement) or biologics (infliximab or tocilizumab)

The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) defines a grade 2 maculopapular rash as “macules/papules covering 10-30% BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental ADL; rash covering >30% BSA with or without mild symptoms. A grade 3 maculopapular rash is defined as “macules/papules covering >30% BSA with moderate or severe symptoms; limiting self-care ADL.”

CTCAE defines grade 3 pruritus as “widespread and constant; limiting self-care ADL or sleep; systemic corticosteroid or immunosuppressive therapy indicated.” Treatment for grade 3 pruritus involves holding the immune checkpoint inhibitor until grade 0-1 is reached; oral antihistamines and GABA analogs; and omalizumab or dupilumab.

This patient’s ircAE was grade 2/3 due to body surface area and intense pruritus resulting in disruption of activities of daily living and sleep. A recent analysis reported using dupilumab in two cases to treat an ICI-induced eczematous eruption that was refractory or dependent on corticosteroids. A recent review stated that dupilumab could be used in a grade 3 rash setting. Our patient developed an ircAE, maculopapular rash, and pruritus, after being treated with an immune checkpoint inhibitor, pembrolizumab, in the setting of squamous cell carcinoma of the neck. The skin biopsy showed acute spongiotic dermatitis with intraepidermal vesicle and eosinophilia, suggestive of a drug reaction. The patient’s eruption was resistant to chronic steroid therapy and subsequently was treated with dupilumab with a successful response. The patient experienced a significant reduction in pruritus and improved skin disease within approximately 4 weeks.

This case presents a clinical scenario in which dupilumab may effectively treat an immune checkpoint inhibitor-induced maculopapular eruption. In summary, the case represents a new role for dupilumab in the treatment of ICI-induced cutaneous toxicities.

The authors have no relevant disclosures.

For Further Reading:

Hamid O, Robert C, Daud A, et al. Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. N Engl J Med. 2013;369(2):134-144. doi:10.1056/nejmoa1305133

Merck & Co. I. KEYTRUDA® (pembrolizumab): PD-1 Receptor Blockade. Accessed February 4, 2022. https://www.keytrudahcp.com/resources/mechanism-of-action/

Sibaud V. 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

Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. JAMA Oncol. 2016;2(10):1346-1353. doi:10.1001/jamaoncol.2016.1051

Apalla Z, Rapoport B, Sibaud V. Dermatologic immune-related adverse events: The toxicity spectrum and recommendations for management. Int J Women’s Dermatology. 2021;7(5):625-635. doi:10.1016/j.ijwd.2021.10.005

Flatz L, Berner F, Bomze D, et al. Association of Checkpoint Inhibitor-Induced Toxic Effects with Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer. JAMA Oncol. 2019;5(7):1043-1047. doi:10.1001/jamaoncol.2019.0402

Geisler AN, Phillips GS, Barrios DM, et al. Immune checkpoint inhibitor-related dermatologic adverse events. J Am Acad Dermatol. 2020;83(5):1255-1268. doi:10.1016/j.jaad.2020.03.132

Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. N Engl J Med. 2016;375(24):2335-2348. doi:10.1056/nejmoa1610020

Wynn TA. Type 2 cytokines: Mechanisms and therapeutic strategies. Nat Rev Immunol. 2015;15(5):271-282. doi:10.1038/nri3831

Sanofi and Regeneron Pharmaceuticals I. DUPIXENT. Accessed February 4, 2022. https://www.dupixent.com

Kaye A, Gordon SC, Deverapalli SC, Her MJ, Rosmarin D. Dupilumab for the Treatment of Recalcitrant Bullous Pemphigoid. JAMA Dermatology. 2018;154(10):1225-1226. doi:10.1001/jamadermatol.2018.2526

Seidman JS, Eichenfield DZ, Orme CM. Dupilumab for bullous pemphigoid with intractable pruritus. Dermatol Online J. 2019;25(11). doi:10.5070/d32511046147

Beck KM, Yang EJ, Sekhon S, Bhutani T, Liao W. Dupilumab Treatment for Generalized Prurigo Nodularis. JAMA Dermatology. 2019;155(1):118-120. doi:10.1001/jamadermatol.2018.3912

Mollanazar NK, Elgash M, Weaver L, Valdes-Rodriguez R, Hsu S. Reduced Itch Associated With Dupilumab Treatmentin 4 Patients With Prurigo Nodularis. JAMA Dermatology. 2019;155(1):121-122. doi:10.1001/jamadermatol.2018.3906

Yang EJ, Murase JE. Recalcitrant anal and genital pruritus treated with dupilumab. Int J Women’s Dermatology. 2018;4(4):223-226. doi:10.1016/j.ijwd.2018.08.010

Machler BC, Sung CT, Darwin E, Jacob SE. Dupilumab use in allergic contact dermatitis. J Am Acad Dermatol. 2019;80(1):280-281.e1. doi:10.1016/j.jaad.2018.07.043

Lee JK, Simpson RS. Dupilumab as a novel therapy for difficult-to-treat chronic spontaneous urticaria. J Allergy Clin Immunol Pract. 2019;7(5):1659-1661.e1. doi:10.1016/j.jaip.2018.11.018

Hendricks AJ, Yosipovitch G, Shi VY. Dupilumab use in dermatologic conditions beyond atopic dermatitis–a systematic review. J Dermatolog Treat. 2021;32(1):19-28. doi:10.1080/09546634.2019.1689227

Oetjen LK, Mack MR, Feng J, et al. Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell. 2017;171(1):217-228.e13. doi:10.1016/j.cell.2017.08.006

Yosipovitch G, Rosen JD, Hashimoto T. Itch: From mechanism to (novel) therapeutic approaches. J Allergy Clin Immunol. 2018;142(5):1375-1390. doi:10.1016/j.jaci.2018.09.005

Belum VR, Benhuri B, Postow M., et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor | Elsevier Enhanced Reader. European Journal of Cancer. Published 2016. Accessed February 1, 2022. https://reader.elsevier.com/reader/sd/pii/S0959804916001258?token=611FC9FB874B2EA4E64449F121B93F2FB4E3803B3AB2E1BEF82956DEBDAD3424A43DD852F6390C230BB262F6F0546007&originRegion=us-east-1&originCreation=20220202001219

Cancer Institute N. Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.; 2017. https://www.meddra.org/

Phillips GS, Wu J, Hellmann MD, et al. Treatment Outcomes of Immune-Related Cutaneous Adverse Events. J Clin Oncol. 2019;37:2746-2758. doi:10.1200/JCO.18