Pembrolizumab-induced Stevens-Johnson syndrome in advanced squamous cell carcinoma of the lung: A case report and review of literature

lNTRODUCTlON

Pembrolizumab is an anti-PD-1 (programmed death 1) humanized IgG4 monoclonal antibody that blocks the PD-1 receptor to enable T cell killing. Pembrolizumab, combined with chemotherapy, has shown improved efficacy in patients with advanced squamous cell carcinoma of the lung[1], with drugrelated adverse events reported in 64% of patients[2]. However, adverse events of grade 3 or higher were reported in less than 10% of patients and included cutaneous side-effect cases.

2.2 RT-PCR法检测ABCG2的mRNA表达结果 因方差不齐，故使用Dunnett’s T3方法，四组之间两两比较差异有统计学意义(P<0.05)。与对照组相比，阿霉素组ABCG2 mRNA表达上升，苦参素组和联合组ABCG2 mRNA表达下降。见表1。

CASE PRESENTATlON

Chief complaints

The patient was a 68-year-old female without a history of smoking. On October 1st, 2020, she was admitted due to repeated cough and breathlessness for 1 mo.

Immunotherapy, as a new treatment in the 2010s, has a definite effect on the treatment of advanced lung cancer. However, there remain many difficulties to be overcome in the treatment of serious adverse reactions related to immunotherapy. The combination of high-dose corticosteroid shock therapy, IVIG,cyclosporine, and best supportive care might reduce mortality in the treatment of SJS. The incidence of serious immune-related skin toxicity, such as SJS, is low, but the lethality is still very high. However,there is still a long way to go for immune-related adverse events, such as predictors for adverse events and ways to prevent them in advance. In future studies, we might focus more on the prediction,prevention, and treatment of irAEs, although immunotherapy is in full swing.

History of present illness

Systemic examinations, including chest computed tomography (CT), whole abdominal CT, brain magnetic resonance imaging (MRI), bone scintigraphy, and blood tests, were performed. The test results showed that the levels of tumor markers were clearly elevated, and CT indicated a lung mass in the right lobe, several bilateral nodules, multiple mediastinal lymph nodes, and a solitary liver metastasis.Squamous cell carcinoma of the lung was diagnosed through CT-guided percutaneous needle lung biopsy, and polymerase chain reaction (PCR) revealed no epidermal growth factor receptor, anaplastic lymphoma kinase, or receptor tyrosine kinase mutations. According to the American Joint Commission on Cancer 8edition staging system, she was clinically diagnosed with stage IVA lung squamous cell carcinoma (cT4N2M1b). According to the 2020 National Comprehensive Cancer Network guidelines,the combination of immunotherapy and chemotherapy is the best optional treatment for patients with advanced lung squamous cell carcinoma. On October 14, 2020, the patient was treated with one cycle of paclitaxel 270 mg d1 + cisplatin 120 mg d1 chemotherapy combined with pembrolizumab therapy. On November 4, 2021, which was nearly three weeks after one cycle of chemotherapy, the patient started with low fever, sore throat, and severe fatigue. Then, the patient was considered to be related to cold exposure. Penicillin treatment was used in the hospital nearby, but the patient's symptoms did not improve, which lasted for almost 5 d. On November 9, small papules and typical erythema,accompanied by severe itchiness and general discomfort, gradually appeared on the patient's skin and were mainly distributed in the anterior chest and face. Considering the severity of the patient's symptoms, the patient visited our hospital on November 12. The patient’s temperature was normal.The pain in her throat persisted. The physical examination of the patient showed that multiple erythematous papules could be detected on the patient’s head, neck, chest, and back (covering 30% of the total body skin) (Figure 1), most of which fused to form blisters. The patient reported that these papules felt mild itchiness but painful. Eyelid edema was obvious. There were some ulcers around the lip. The patient’s oral ulcers were too painful to allow her to eat anything.

History of past illness

There was no remarkable past medical history with no alcohol consumption or history of smoking.

Personal and family history

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Physical examination

Since the 21century, the introduction of immunotherapy treatments has dramatically revolutionized the treatment paradigm of non-small-cell lung cancer (NSCLC)[16]. However, immune checkpoint inhibition usually leads to systemic adverse reactions, which are immune-related adverse events,mainly encompassing rash, colitis, pneumonitis, hepatitis, and thyroiditis[17]. Dermatologic toxicities seem to be the most frequently reported adverse events. SJS is a rare and severe dermatologic toxicity with high mortality[4]. The first SJS case induced by pembrolizumab in NSCLC was reported in a Japanese case[14]. Our case report is the first Chinese case of pembrolizumab-associated SJS in NSCLC.

Laboratory examinations

She was admitted to our hospital, and the relevant blood tests after admission are shown in Table 1 below.

Imaging examinations

Chest and abdominal CT scans showed that the primary lung lesions and liver metastases were significantly reduced, and the overall response evaluation was PR according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

FlNAL DlAGNOSlS

We arranged an urgent consultation with a dermatologist. According to the skin and mucous membrane performance of the patient during these days, the rapid development of the disease, and history of PD-1 inhibitor use, pembrolizumab-induced SJS was diagnosed.

TREATMENT

由文献[4]关于剪力滞系数分析可知，箱梁截面总的剪力滞系数λ取决于偏心距，偏心距越小，箱梁截面总的剪力滞产生的剪力滞效应越接近于仅受到轴力作用的状态。本文仅施加预应力时，偏心距较小，所以截面剪力滞系数更接近于仅受轴向荷载作用下的弯矩。与文献[3]中所得出的跨中剪力滞系数相近，箱梁顶板的剪力滞系数峰值(正对腹板的上翼缘板处)均为1左右，进一步说明了本文的数值解是符合解析解的。

OUTCOME AND FOLLOW-UP

By referring to the opinions from the consultation, intravenous methylprednisolone 120 mg/d (2 mg/kg/d), gamma globulin 20 g/d, topical gentamicin, and diluted potassium permanganate were administered. Sepprayi 25 mg (recombinant human type II tumor necrosis factor receptor-antibody fusion protein, rhTNFR:Fc) was injected subcutaneously twice a week, and oral antihistamine was administered for pruritus. After a week of treatment, the dermatologic toxicities were gradually alleviated (Figure 4). Then, oral prednisone was gradually reduced, and topical drug administration continued. The treatment lasted for 3 mo, and the skin toxicity eventually disappeared (Figure 5). In terms of lung carcinoma, the pulmonary nodule was smaller than the baseline and remained stable during the 6-mo evaluation. In May 2021, the latest re-examination showed that although the patient didnot receive any antitumor treatment, the lesion remained stable.

DlSCUSSlON

A poor general condition, SCORTEN (severity-of-illness score for TEN) score of 4 points. Nikolsky’s sign was positive. Koebner phenomenon was negative. Erythematous papules could be detected on the patient’s head, neck, chest, and back (covering 30% of the total body skin) with mild itchy but painful symptoms. Eyelid edema was obvious. There were some ulcers around the lip. Her oral ulcers were too painful to allow her to eat anything. No other apparently positive signs were found.

At present, the exact mechanism of SJS remains undefined. The currently recognized theory is the T cell-mediated type IV delayed hypersensitivity reaction[18,19]. The drug triggering SJS binds the T cell receptor and MHC class I, and as a result, it leads to the massive replication of cytotoxic T cells, which directly kill keratinocytes, and the release of granulysin, which destroys cells in the skin and the mucous membrane[20]. Yun-Shiuan’s research showed that the blockade of PD-1/PD-L1 may contribute to the imbalance of the immune system, manifesting the enhancement of the T cell response and increasing the incidence of hypersensitivity[21]. During the treatment of SJS induced by ipilimumab and nivolumab in a melanoma patient[22], an increase in CD8+ T cells in the dermal epidermal junction and an increase in PD-L1 expression in keratinocytes were noted. Unfortunately, the biopsy analysis of our case has not been finished, and therefore, this viewpoint cannot be further confirmed. Overall, the mechanism of SJS caused by immunosuppressive drugs requires further research.

Cutaneous toxicities of immune checkpoint inhibitors might result in a longer PFS (progression-free survival) and a higher OS (overall survival) rate[23]. Bairavi and his colleagues demonstrated that NSCLC patients with one irAE and multisystem irAEs incrementally improved OS and PFS. Longer immune checkpoint inhibitor durations were an independent risk factor for the development of irAEs.In our case, it was rare that such severe AEs occurred after just one cycle of immunotherapy[24]. Susana also indicated that the median PFS was 9.49 mo in the group with irAEs1.99 mo in the group without irAEs (＜ 0.0001) in NSCLC treated with nivolumab[25]. In our case, the condition of the patient was stable for up to 6 mo just after one cycle of the treatment. Thus, we speculate that skin toxicities and delayed immunological effects both contributed to such a long progression-free survival time.

There is no standard treatment regimen for SJS[26], and multidisciplinary care, best supportive care,and corticosteroids are currently the most important components of its therapy[20]. By applying highdose corticosteroids early, we can rapidly arrest SJS, while the optimal cutoff time of corticosteroids remains controversial because of its adverse drug reaction[27]. From the author’s perspective, the appropriate duration of high-dose corticosteroids is within 4 wk. The combination of IVIG and steroids seems to bring better outcomes to patients with SJS[28].

Therefore, we immediately administered moderate- to high-potency topical steroids to treat the affected areas, oral antihistamines for pruritus and oral prednisone at 40 mg/d. After three days of treatment,the dermatologic toxicities were clearly aggravated. On November 18 (Figure 2), the rash began to spread to almost the entire body (covering more than 45% of the total body skin). The blisters were formed superficially in the epidermis with skin ulceration, and most of them had blood and fluid oozing. Part of the epidermis was peeled off from the surface of the body, exposing a moist, painful,flushed erosive surface. The oral ulcers continued to be aggravated. Both the itchiness and pain worsened, and the patient became severe (G3-4). At this point, we suspended immunotherapy,administered high potency topical steroids to the affected areas and prophylactically used antibiotics;additionally, we increased the prednisone dose to 100 mg. After three days of treatment, the cutaneous toxicities continued to worsen (Figure 3).

In addition to corticosteroids and IVIG, drugs that suppress the immune response or inflammatory factors are also being tried in the treatment of SJS. Over the last several years, several retrospective trials have advocated the benefits of cyclosporine in the treatment of SJS/TEN[29,30]. Cyclosporine inhibits the activation of CD4+ and CD8+ T cells in the early phase, subsequently inhibiting the secretion of granulysin, granzyme, and perforin[31]. Despite a lack of randomized control trials, cyclosporine has proven to have a mortality benefit in the treatment of SJS/TEN without a low risk of side effects. In our case, we did not use cyclosporine due to the lack of experience in the early phase of treatment for SJS. In the late phase, we used recombinant human tumor necrosis factor receptor type II-Fc fusion protein antibody as recommended by the dermatologist. The reason we used Sepprayi is that it can reduce the level of inflammatory factors, such as tumor necrosis factor-α (TNF-α), inhibiting the occurrence of hypersensitivity[32]. In our case, Sepprayi had a clear effect on the improvement of the patient's inflammatory response. However, more clinical practice and data support are needed due to limited trials.

CONCLUSlON

团结乡乡村旅游发展以及“美丽家园”建设是一个长期而艰巨的任务，在其后期的发展、建设过程中，仍需要进一步研究和实践。将PPP模式运用到美丽乡村旅游发展建设中，及对乡村旅游相关从业人员进行培训等，对促进云南乡村旅游的发展有着积极的作用。

FOOTNOTES

Wu JY and Kang K designed the study and performed the experiments; Yi J, Yang B, and Wu JY performed the experiments, analyzed the data, and wrote the manuscript; Wu JY and Kang K contributed to this article equally.

Consent was obtained from the patient for publication of this report.

The authors declare that they have no competing interests.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

Family and personal history were unremarkable. She had no significant medical history or drug allergy.

China

在高校之间，形成高校联盟，共同进行符合企业需求的人才联合定制培养，构建基于高校联盟的协同共享平台。建立人才联合培养的灵活机制，组建各种跨学校的研究中心、实验中心、教学中心，通过搭建多种形式的跨学科教育平台，组织不同高校、不同学科的教师一起突破学科壁垒，组成跨学科研究小组和教学小组，开设全校性的公共跨学科课程，以整体组合的课程替代严格的学科分类课程，同时大力推进全校范围内的选课制，尤其是跨学科专业的选课制度，以学院为主体，按学科群开设大量的跨学科选修课，鼓励学生跨学院跨专业选课，为学生带来不同的学科视野和综合化的知识结构，从而有效地促进人才培养。

具体到毕业设计的管理来说，面对新工科的要求，需要将毕业设计的总体目标分解成一系列任务，通过完成一系列的任务去实现社会岗位需求毕业生的人文素养、科技知识、实践技能、职业能力、伦理价值和行为规范的新工科目标。从选题到完成答辩的整个教学进程都应该在传统学科专业建设的基础上，重新审视培养方案、管理模式、教学平台建设的合理性,并提出对指导教师能力素质的新要求。

Jing-Yi Wu 0000-0003-1886-5697; Kai Kang 0000-0002-0429-0346; Jing Yi 0000-0001-8040-9516; Bin Yang 0000-0002-2249-2590.

Liu JH

A

实用性的核心是教师的直觉。教师应创建自己的课程内容。根据实际，选择合适的教学材料。教师自己构建课程内容，选取既有知识性又有时代感的材料，拓宽学生视野，使学生获得新的信息。

Liu JH