Pembrolizumab- induced subacute cutaneous lupus erythematosus in a patient with oropharyngeal squamous cell carcinoma: A case report and literature review

ABSTRACT

Considering the increasing use of immune checkpoint inhibitors in cancer treatment, our aim is to report a rare cutaneous immune-related adverse event induced by PD-1 inhibitor pembrolizumab and provide a brief overview of pembrolizumab-induced subacute cutaneous lupus erythematosus (SCLE) cases in the literature. We report a 67-year-old woman with oropharyngeal squamous cell carcinoma who developed SCLE during treatment with pembrolizumab. After 18 weeks (sixth cycle) of pembrolizumab immunotherapy, a widespread pruritic erythematous rash evaluated as grade 3 immune-related adverse event appeared primarily on the patient's limbs. Histopathological examination and direct immunofluorescence showed characteristic features of SCLE. The patient was treated with oral prednisone 40 mg daily and topical corticosteroids. In 2 weeks, her rash had cleared up significantly and her pruritus had disappeared. SCLE is an infrequent but recognized immune-related adverse event linked to pembrolizumab treatment.

Introduction

An important progress in cancer therapy has been made with the development of immune checkpoint inhibitors (ICIs) that are monoclonal antibodies which target programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). A humanized monoclonal anti-PD1 antibody named pembrolizumab (Keytruda) has been approved after extensive research in various malignancies including recurrent or metastatic head and neck squamous cell carcinoma.¹

Although it has numerous therapeutic advantages, because of its distinct mode of action, it is linked to various immune-related adverse events (irAEs).^2,3 Cutaneous lupus erythematosus (CLE) is an uncommon but recognized irAE linked to pembrolizumab use. Acute cutaneous lupus erythematosus (ACLE), subacute cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE) are three main categories into which cutaneous lupus is classified. To the best of our knowledge, this is the first case report of SCLE caused by pembrolizumab in which a patient with HNSCC is involved.

Materials and methods

Following a diagnosis of oropharyngeal squamous cell carcinoma (OPSCC) in a 67-year-old woman, chemoradiotherapy was initiated with cisplatin. Treatment was interrupted because the patient developed stomatitis after the second dose, necessitating supportive infusions. Consequently, the regimen was switched to carboplatin. After restaging in January 2024, palliative treatment with pembrolizumab, 5-fluorouracil and cisplatin every 21 days was initiated. About 12 weeks (fourth cycle) after initiation of the combined immunochemotherapy, the patient developed a pruritic rash on her extremities evaluated as grade 1 immune-related cutaneous adverse event (ircAE) and topical corticosteroids were added to her treatment. Given the positive tumor response to the drug regimen, combined immunochemotherapy was withheld, and she continued to receive pembrolizumab 200 mg i.v. alone. After 18 weeks (sixth cycle) of pembrolizumab immunotherapy, the patient experienced a widespread erythematous rash evaluated as grade 3 ircAE primarily affecting the limbs. She was referred to the dermatology clinic for pruritic, crusted and scaly red papules along with erosions and scaling (Figure 1a,b). Additionally, depigmentation on the upper extremities was seen. Antinuclear antibodies (ANA) tested negative during the initial workup. Histopathological examination revealed skin with mild epidermal hyperplasia and diffuse spongiosis, hyperkeratosis, mild acanthosis and vacuolar degeneration of the basal layer with few apoptotic cells. There was interface dermatitis with lymphocytic infiltrate along the dermo-epidermal junction and mild perivascular and periadnexal lymphocytic infiltrates. Staining with PAS showed thickening of the basement membrane, which was focally disrupted by the lymphocytic infiltrate. Direct immunofluorescence uncovered immunoglobulin G and complement C3 fragment deposition in a granular pattern along the basement membrane zone (Figure 2). The patient was started by oral prednisone 40 mg daily and topical corticosteroids after pembrolizumab treatment was declined due to the diagnosis of pembrolizumab-induced SCLE. Within 2 weeks, her rash had cleared up significantly and her pruritus had disappeared as well.

Figure 1a.

Figure 1b.

Clinical findings of the patient. Crusted and scaly red papules along with erosions and scaling primarily affecting her upper (a) and lower (b) extremities.

Figure 2.

Left upper extremity skin with hyperplastic epidermis with hyperkeratosis (#), diffuse spongiosis (*), lichenoid changes in the lower part of epidermis with lymphocytic infiltration, apoptotic cells (arrowhead) and disruption of the dermo-epidermal junction (arrow), thickening of the basement membrane (open arrow) with rough granular depositions of IgG and C3 detected by direct immunofluorescence. HE – hematoxylin and eosin; IgG, C3 – direct immunofluorescence; PAS – periodic acid Schiff; 200 × .

Discussion

This case report describes a 67-year-old woman who started treatment for OPSCC and later developed pembrolizumab-induced SCLE. A skin biopsy verified the diagnosis after she complained of a widespread pruritic erythematous rash, mostly affecting the limbs. Her symptoms significantly improved after corticosteroid treatment and cessation of pembrolizumab administration.

IrAEs are defined as adverse events associated with ICIs treatment.⁴ A pooled analysis of phase 3 clinical trials evaluating the safety profile of adjuvant pembrolizumab revealed that approximately 36.2% of patients receiving the drug experienced at least one irAE.⁵ The most prevalent were endocrinopathies, pneumonitis, colitis and cutaneous side effects.⁶ The majority of ircAEs associated with pembrolizumab therapy were mild or moderate and did not interfere with treatment continuation. Only 1.8% of treated patients developed severe skin reactions above the grade ≥3.⁵ Interestingly, some patients experiencing severe toxicities have achieved durable cancer responses, highlighting the significance of careful monitoring and treatment of irAEs.^7–9

Although there is a wide variety in clinical presentation, nonspecific maculopapular rashes are the most typical ircAE. Psoriasis, bullous dermatoses, and lichenoid reactions are a few autoimmune-like presentations that have been reported. Additionally, a recent case study discovered that patients with lung cancer treated with pembrolizumab may also develop palmoplantar keratoderma, a rare and uncommon cutaneous toxicity.³

Developing cutaneous lupus as an ircAE is rare, and to our knowledge, there are only nine reported cases of SCLE-induced pemrolizumab in patients with melanoma, non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma (SCLC) treated with immunotherapy since 2018 (Table 1). This is the first report of a patient receiving immunotherapy for OPSCC developing SCLE as a result of pembrolizumab administration. ICI-induced SCLE is comparable to idiopathic SCLE based on clinical and serological findings, but it is linked to drug exposure and resolves with drug withdrawal. The pathogenic mechanism of SCLE induced by pembrolizumab is not completely understood and it is currently unknown, whether it is caused by de novo skin toxicity or the reactivation of a preexisting illness.¹⁰ A “multi-hit hypothesis” has been released, where exposure to ICIs may act as an extra “hit” by inducing a stronger immunological response to a previously tolerated medicine.¹¹

Table 1.

Characteristics of patients who developed SCLE after receiving pembrolizumab therapy.

Patient	Reference	Age	Sex	Malignancy	SCLE onset after pembrolizumab start (weeks)	Histopathological characteristics	Direct immuno-fluorescence	Autoimmune serologies	Treatment	Immunotherapy management	SCLE response (weeks)
1	Andersson et al.	62	F	NSCLC	188	Interface dermatitis with Civatte bodies.	NR	ANA, anti-Ro, anti-La	HCQ, prednisolone, topical corticosteroid	withdrawal	resolved within 12 weeks
2	Blakeway et al.	79	F	melanoma	9	Vacuolar interface pattern with Colloid bodies in the spinous and basal layers and an upper dermal moderately dense perivascular infiltrate of lymphocytes.	granular deposition of C3c in the basement membrane zone	ANA negative	topical corticosteroid	withdrawal	resolved within 3 weeks
3	Blakeway et al.	75	M	melanoma	27	Vacuolar interface pattern with colloid bodies in the spinous and basal layers and an upper dermal perivascular mildly dense infiltrate of lymphocytes and increase in dermal mucin.	granular deposition of IgG, IgA and IgM in the basement membrane zone	ANA negative	topical corticosteroid	withdrawal	resolved within 3 weeks
4	Bui et al.	65	M	SCLC	12	Prominent interface dermatitis with focal vesicle formation and lichenoid infiltrate, prominent dyskeratotic keratinocytes with epidermal necrosis, follicular pllugging, superficial to mid-dermal perivascular, periadnexal lymphocytic infiltrate.	negative	ANA 1:320 speckled pattern, anti-Ro	HCQ, antihistamines, topical corticosteroid	withdrawal	resolved within 8 weeks
5	Gambichler et al.	52	M	NSCLC	6	Focal vaculoar interface dermatitis with only a sparse perivascular lymphocytic infiltrate in the upper dermis.	linear deposits of C3, IgM, IgG along the basement membrane zone	anti-Ro	HCQ, prednisolone	withdrawal	NR
6	Marano et al.	60	F	NSCLC	9	Interface dermatitis with adnexal involvement and increased dermal mucin.	IgG, IgA, IgM cytoid bodies, linear fibrin deposits at the basement membrane, granular IgG and C3	ANA 1:2560, anti-Ro, anti-La, anti-histone	prednisone, infliximab, topical corticosteroid	withdrawal	resolved within 4 weeks
7	Michot et al.	63	M	melanoma	22	Lichenoid dermatosis with staged apoptotic bodies in the epidermis. Peripheral inflammatory mononuclear infiltrate in the upper dermis. No mucin deposits in the dermis.	Positive for IgG: discontinuous low-intensity band and epidermal dermal junction. C3 positive: rough band	ANA >1280, anti-Ro, anti-La, ENA	HCQ, topical corticosteroid	withdrawal	resolved within 4 weeks
8	Ogawa et al.	80	M	melanoma	15	Dense infiltration of lymphocytes in the basement membrane zone, the superficial dermis and perivascular regions, absent melanocytes in the part of the basal cell layer, strong liquefaction degeneration and superficial dermal edema.	negative	anti-Ro	prednisolone, topical corticosteroid	withdrawal	resolved within 12 weeks
9	Shao et al.	54	M	melanoma	28	Interface reaction, with lymphocytes at the dermal-epidermal junction, occasional dyskeratotic keratinocytes, perivascular and perifollicular lymphocytic inflammation, rare eosinophils, sligh increase in mucin.	NR	NR	none	withdrawal	resolved within 4 weeks
10	Present case	67	F	OPSCC	12	Hyperplastic epidermis with hyperkeratosis, diffuse spongiosis, lichenoid changes in the lower part of epidermis with lymphocytic infiltration, apoptotic cells and disruption of the dermo-epidermal junction.	thickening of the basement membrane with rough granular depositions of IgG and C3	ANA negative	prednisone, topical corticosteroid	withdrawal	resolved within 2 weeks

SCLE: subacute cutaneous lupus erythematosus, F: female, M: male, NR: not reported, NSCLC: non-small-cell lung carcinoma,SCLC: small-cell-lung carcinoma, OPSCC: oropharyngeal squamous cell carcinoma, HCQ: hydroxychloroquine.

Several risk factors and biomarkers for irAEs have been discussed including high neutrophil–lymphocyte ratio, elevated C-reactive protein, use of PD-1 inhibitors, high PD-L1 expression, current or past smoking status.¹² However, these findings remain controversial and further investigation is needed to create accurate predictive tools for ICI-related toxicities in the future.

Calcium channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, terbinafine and TNF-alfa inhibitors should always be ruled out when considering medications related to SCLE.¹³ Depending on the clinical presentation, this can be enhanced by skin biopsy and more specialized testing. The biopsies taken from patients display histopathological characteristics such as interface dermatitis, vacuolar alteration at the basement membrane zone and perivascular lymphocytic infiltration that are similar to those seen in SCLE. Leukocytoclastic vasculitis, a hallmark of drug-induced SCLE, may be seen.¹⁴ Antibodies ANA and anti-Ro (SS-A) suggestive of SCLE are typically present but were negative in our patient.¹⁵ According to previous reports, the interval between the start of pembrolizumab immunotherapy and the occurrence of SCLE range between 6 and 188 weeks. In our case, the development of symptoms started about 12 weeks after initiation of the therapy. Pembrolizumab has a mean elimination half-life of 27 days; however, immunotherapy agents have a sustained effect which may affect the drug’s elimination.¹⁶ Based on recently published cases, the SCLE eruption is resolved relatively early, only a few weeks (between 3 and 12 weeks) after pembrolizumab discontinuation. In the present case, the rash cleared up within 2 weeks. A clinical practice guideline on the management of ICI-induced ircAEs was published by the European Society of Medical Oncology (ESMO).⁴ As per their recommendations, the severity of the disease and the grade of ircAEs will determine whether or not ICI therapy needs to be withheld. A combination of topical and oral corticosteroids and hydroxychloroquine has been shown to be effective in the treatment of pembrolizumab-induced SCLE in previously documented cases. In addition, stopping the ICI medication was necessary in the majority of instances.

In conclusion, this case report supports the evidence that SCLE should be considered as an ircAE induced by pembrolizumab. Considering the increasing use of ICIs in cancer treatment, we believe based on present and previous reported cases that PD-1 immunotherapies should be added to the list of medications that can induce lupus erythematosus.

Biography

Beata Mayer is a dermatology resident, PhD student and teaching assistant at the Department of Dermatovenerology, Comenius University in Bratislava, Slovakia. Her academic and clinical work is primarily focused on autoimmune diseases, with a special interest in cutaneous lupus erythematosus. Through her research and teaching, she is committed to advancing the understanding and treatment of dermatological conditions, particularly those with immune-related causes.

Funding Statement

The author(s) reported that there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethics statement

This study was conducted in compliance with the Declaration of Helsinki and applicable regulatory requirements. Before submitting the manuscript to the journal, the patient’s publication consent was obtained.