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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 38  |  Issue : 4  |  Page : 236-239

Stevens–Johnson syndrome and toxic epidermal necrolysis related to immune checkpoint inhibitors: Two cases and literature review


Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan

Date of Submission12-Aug-2019
Date of Decision04-Mar-2020
Date of Acceptance15-May-2020
Date of Web Publication16-Dec-2020

Correspondence Address:
Dr. Kwei-Lan Liu
No. 123, Dapi Rd., Niaosong District, Kaohsiung 83301
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ds.ds_24_20

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  Abstract 


Immune checkpoint inhibitor-related Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were rarely reported. We summarized the courses and the characteristics of two cases. The first case was a 74-year-old woman receiving pembrolizumab for Stage 2 urothelial cell carcinoma of the bladder. SJS developed 27 days after the first dose of pembrolizumab. The other case was a 67-year-old woman receiving atezolizumab for Stage 4 renal urothelial cell carcinoma. TEN developed after the eighth cycle of atezolizumab. Both patients were treated with low-dose corticosteroid and supportive management. Their wounds healed without dermatologic sequelae.

Keywords: Atezolizumab, immune checkpoint inhibitors, pembrolizumab, Stevens–Johnson syndrome, toxic epidermal necrolysis


How to cite this article:
Hsu TJ, Liu KL. Stevens–Johnson syndrome and toxic epidermal necrolysis related to immune checkpoint inhibitors: Two cases and literature review. Dermatol Sin 2020;38:236-9

How to cite this URL:
Hsu TJ, Liu KL. Stevens–Johnson syndrome and toxic epidermal necrolysis related to immune checkpoint inhibitors: Two cases and literature review. Dermatol Sin [serial online] 2020 [cited 2021 Aug 5];38:236-9. Available from: https://www.dermsinica.org/text.asp?2020/38/4/236/303695




  Introduction Top


Stevens–Johnson syndrome (SJS), SJS/toxic epidermal necrolysis (TEN) overlap syndrome, and TEN are rare but potentially fatal mucocutaneous adverse drug reactions. These entities are in a disease continuum, only different in the areas of involved body surfaces. Clinical prodromes include fever and influenza-like symptoms, followed by the eruption after a few days. Initial lesions are erythematous-to-dusky red macules or atypical target lesions. The lesions later coalesce and may evolve to bullae and then slough. Oral and genital mucosal erosions and ocular involvement are the frequent manifestations.[1]

SJS and TEN are mainly triggered by medications and less frequently by infections of the upper airway. Rapid withdrawal of the culprit drugs and the best supportive care are the mainstay of management in the acute stage. SJS and TEN are potentially fatal, and the most frequently used model for predicting mortality rate is a severity-of-illness score for TEN.[1]

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies targeting various checkpoint proteins, including cytotoxic T-lymphocyte antigen 4, programmed cell death-1, and programmed cell death-ligand 1. These drugs have significantly improved the treatment of a variety of cancers. Anti-cytotoxic T-lymphocyte antigen 4 antibody ipilimumab was approved for late-stage melanoma. Anti-programmed cell death-1 antibodies, pembrolizumab and nivolumab, are used in metastatic melanoma and nonsmall cell lung cancer. Pembrolizumab is also used in head-and-neck squamous cell carcinoma, classic Hodgkin's lymphoma, urothelial carcinoma, and many other cancers, as approved by the United States Food and Drug Administration. Anti-programmed cell death ligand-1 antibody, atezolizumab, is used for treating metastatic urothelial cell carcinoma and nonsmall cell lung cancer.[2]

Most side effects of ICIs are immune-related adverse events, which are notably mediated by triggering cytotoxic T-cells activity.[3] Dermatologic reactions are the most common immune-related side effects, which mainly manifest as maculopapular rashes and pruritus.[4] SJS and TEN are rare but potentially life-threatening complications.

We present two cases of ICI-related SJS and TEN.


  Case Reports Top


Case 1

A 74-year-old woman with end-stage renal disease, for which she had been on regular hemodialysis for years, had Stage II urothelial cell carcinoma of the bladder diagnosed in August 2017. She had received transurethral removal of bladder tumor and local radiotherapy. Tumor progression was noticed in follow-up computed tomography, revealing residual bladder cancer with suspicious local invasion to the cervix and possible lung metastasis. Because of the patient's reluctance to surgical treatment, pembrolizumab was used for salvage therapy.

On October 2, 2018, she received the first dose of 100-mg infused pembrolizumab. Ten days later, petechiae and purpura developed on the bilateral lower limbs. After another 11 days, she reported generalized painful skin lesions and painful oral ulcers. Dysuria was also noted. Physical examinations showed generalized round erythematous to purpuric patches, with coalescence on the face, trunk, and four limbs, including palms and soles. Some of the patches had central erosions with crust formation [Figure 1]a, [Figure 1]b, [Figure 1]c. Several oral ulcers and genital ulcers were also found [Figure 1]a. There was no conjunctivitis. The skin lesions progressed to several patches of sheet-like epidermal detachment during the following week, affecting about 10% of the body surface area [Figure 1]d. Serology tests were negative for immunoglobulin M (IgM) of herpes simplex virus (HSV) and Mycoplasma pneumoniae. The pathology report of the skin biopsy revealed interface dermatitis with full layer epidermal necrolysis [Figure 1]e. The clinical and pathological findings were compatible with SJS.
Figure 1: (a-c) Generalized round erythematous to purpuric patches with coalescence on the face, chest, abdomen, and four limbs, including the palms and soles, some of which had central erosions with crust formation. Several oral ulcers were also noted. (d) The skin lesions progressed to several patches of sheet-like epidermal detachment during the following week, affecting about 10% of the body surface area. (e) The pathology showed interface dermatitis with full layer epidermal necrolysis and sparse lymphocytic infiltration in superficial dermis

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With a thorough review of medications, history, and evaluation of algorithm of drug causality for epidermal necrolysis (ALDEN) score and Naranjo adverse drug reaction probability scale (Naranjo scale), pembrolizumab was identified as the culprit drug [Supplement 1].

We immediately stopped pembrolizumab therapy and treated the patient with methylprednisolone 20 mg daily in the acute stage and provided careful wound care. The skin lesions healed gradually without complications. Due to cancer progression with peritoneal carcinomatosis-related bowel obstruction and intra-abdominal infection, the patient decided to receive hospice care. She passed away several days later.

Case 2

A 67-year-old woman had hypertension and end-stage renal disease on hemodialysis. She had Stage IV right renal urothelial cell carcinoma, with peritoneal and neck lymphadenopathies. Atezolizumab had been regularly administered since August 6, 2018. Partial remission was evidenced by the shrinkage of the retroperitoneal lymph nodes in the follow-up imaging studies. The eighth cycle of atezolizumab was given on February 14, 2019.

In addition to cancer, she was also diagnosed with tuberculosis peritonitis and pulmonary tuberculosis in January 2019, which initially presented as fever and abdominal pain. We made the diagnoses based on serial positive sputum cultures and the omentum biopsy, which showed granulomatous infection with acid–fast bacilli. First-line anti-tuberculosis treatment with isoniazid, ethambutol, rifampin, and pyrazinamide had been given since January 23, 2019.

Generalized itchy skin rash started on February 18, 2019. During the next 2 weeks, the skin rash progressed to generalized erythematous to purpuric macules and patches [Figure 2]a, [Figure 2]b, [Figure 2]c. Bullae developed on erythematous patches, and some ruptured with erosions [Figure 2]d. Oral and genital ulcers and mild conjunctivitis were also noted on physical examination [Figure 2]a. The skin rash evolved to sheet-like epidermal detachment and epidermal necrosis involving nearly 80% of the body surface area [Figure 2]e and [Figure 2]f. The diagnosis of TEN was confirmed by skin biopsy [Figure 2]g and [Figure 2]h.
Figure 2: (a-c) Generalized erythematous to purpuric macules and patches. Oral ulcers were also noted. (d) Bullae developed on erythematous patches and some ruptured with erosions. (e and f) The skin rash evolved to sheet-like epidermal detachment and epidermal necrosis involving around 80% of the body surface area. (g and h) The pathology showed subepidermal cleft with full layer epidermal necrosis. Perivascular sparse inflammatory cell infiltration predominantly lymphocyte and some eosinophils were noted. Direct immunofluorescence was not performed

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After reviewing her medications and calculating the ALDEN score and the Naranjo scale, atezolizumab and anti-tuberculosis medications are the possible culprit drugs. Lymphocyte transformation tests were done for those possible culprit drugs, which showed mildly elevated granzyme B level to atezolizumab. Atezolizumab-related TEN was thus diagnosed. She was admitted to the surgical intensive care unit for optimal wound care and supportive management. Hydrocortisone 100 mg was given every 12 h for 9 days until the epidermal necrolysis reached the plateau and re-epithelization started. The skin lesions healed gradually without sequelae.

To continue the treatment for pulmonary tuberculosis and tuberculosis peritonitis, we re-challenged rifampicin and isoniazid after she recovered from TEN. None of the drugs provoked skin reactions, and she kept those medications.

She did not receive further treatment for cancer. Follow-up imaging study showed further regression of the right renal tumor and metastatic lymph nodes. She is currently regularly followed up at our oncology department.


  Discussion Top


Cutaneous side effects are the most prevalent side effects of ICIs, which occur in up to one-third of patients treated with ICIs. The manifestations are usually nonspecific maculopapular rash and pruritus, which are usually mild and self-limiting. Other cutaneous side effects include vitiligo-like lesions, lichenoid eruption, and drug eruptions. Severe drug eruptions such as drug eruptions with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, SJS, and TEN have been rarely reported.[4],[5]

In general, mild cutaneous adverse reactions can be managed with topical moisturizers, topical steroids, or oral antihistamines, and the ICIs therapy can be continued. In moderate diseases, low-dose corticosteroid may be needed. Delay in the ICI therapy should be considered if the side effects are intolerable. In severe or life-threatening cases, dose interruption or even permanent discontinuation of the ICI therapy should be considered prudently and high-dose steroid is necessary.[3],[5]

SJS and TEN are mainly triggered by medications. More than 100 medications have been reported to cause SJS and TEN. Allopurinol, antibiotics (especially, trimethoprim-sulfamethoxazole and penicillins, anticonvulsants), and nonsteroid anti-inflammatory drugs of oxicam type are the most common causes.[1],[6] Differential diagnoses include erythema multiforme major and autoimmune bullous dermatoses, such as bullous lupus erythematosus.[1]

In the first case, we measured IgM level of HSV and M. pneumonia for excluding possibilities of viral infection-related erythema multiforme or SJS. The final diagnosis was made clinically due to the temporal relation between the drug initiation and skin eruption and the successful remission of skin lesions after the discontinuation of pembrolizumab. In the second case, both anti-tuberculosis drugs and atezolizumab are possible causative agents. The utilization of lymphocyte transformation test raised suspicion of atezolizumab and provided rationales for re-challenging anti-tuberculosis drugs.

ALDEN score and the Naranjo scale have been used to assess the causality of individual drugs.[7],[8] Lymphocyte transformation test and lymphocyte function assay by measuring are also helpful in assessing drug causality but are used primarily in a research setting.[8] The assays are performed by isolation of the mononuclear cells from the peripheral blood, in vitro challenge of suspected drugs, measurement of lymphocyte proliferation, and drug-induced cytokine production including granulysin, granzyme B, and interferon-γ.

The pathogenesis of SJS and TEN is not well understood. It is thought to be a delayed type hypersensitivity reaction to drugs. Histopathologic findings show abundant cytotoxic T-cells and natural killer T-cells in early lesions, which suggest a cell-mediated cytotoxic reaction.[8] Granulysin is a key mediator in keratinocyte apoptosis, and serum granulysin level increases in early SJS and TEN.[6]

Typically, SJS and TEN clinically begin within 8 weeks after the administration of culprit drugs for the first time.[1] However, in the circumstances of ICIs-related SJS or TEN, the duration between the onset of drug exposure and the development of drug eruption is variable and can delay to several months or after several cycles of treatment.[9] Severe cases of delayed onset of SJS/TEN related to ICIs have been reported, and the longest interval is about 140 days, after the 15th course of pembrolizumab.[10],[11] This characteristic is also noted in our second case, in which TEN developed after the eighth cycle, the 210th day, of atezolizumab. This delay causes difficulty in the applications of ALDEN score, which would be lower if the patient has history of previous exposure to ICIs without severe drug eruption. The notoriety score of the ICIs is not well established, either. Therefore, it may be inappropriate to apply ALDEN score on cases of ICI-related SJS and TEN.

The principal treatment in the acute stage includes rapid withdrawal of the culprit drug and best supportive care. The use of corticosteroid is controversial for classic SJS and TEN in the acute stage. Some studies showed systemic corticosteroid may lower morbidity in early diseases, while other studies showed inconsistent results.[12],[13] In contrast, in cases of ICIs-related SJS or TEN, it is crucial to recognize and treat the side effects early, and the administration of a short course of immunosuppressive therapy, for 2 weeks–2 months, is sometimes necessary.


  Conclusion Top


ICI is a promising treatment for various advanced cancers. However, rare side effects such as SJS and TEN may be life-threatening. For SJS and TEN, early recognition and withdrawal of the offending drugs are the most important measures. Supportive care is the principle of treatment. Corticosteroid use is controversial in classic SJS/TEN, but high-dose corticosteroid should be considered for ICI-related SJS/TEN.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplement Top


Concurrent medications include: Darbepoetin alfa, hydroxocobalamin, thiamine, vitamin B complex, calcium acetate, calcium polystyrene sulfonate, raloxifene, topical flurbiprofen, acetaminophen, and tramadol for end-stage renal disease and chronic pain. All the above medications have been used for more than 2 months.







 
  References Top

1.
Harr T, French LE. Stevens-Johnson syndrome and toxic epidermal necrolysis. Chem Immunol Allergy 2012;97:149-66.  Back to cited text no. 1
    
2.
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and Anti-CTLA-4 therapies in cancer: Mechanisms of action, efficacy, and limitations. Front Oncol 2018;8:86.  Back to cited text no. 2
    
3.
Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA 2018;320:1702-3.  Back to cited text no. 3
    
4.
Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol 2016;28:254-63.  Back to cited text no. 4
    
5.
Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: Skin toxicities and immunotherapy. Am J Clin Dermatol 2018;19:345-61.  Back to cited text no. 5
    
6.
Harris V, Jackson C, Cooper A. Review of toxic epidermal necrolysis. Int J Mol Sci 2016;17. pii: E2135.  Back to cited text no. 6
    
7.
Sassolas B, Haddad C, Mockenhaupt M, Dunant A, Liss Y, Bork K, et al. ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: Comparison with case-control analysis. Clin Pharmacol Ther 2010;88:60-8.  Back to cited text no. 7
    
8.
Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current perspectives on Stevens-Johnson syndrome and toxic epidermal necrolysis. Clin Rev Allergy Immunol 2018;54:147-76.  Back to cited text no. 8
    
9.
Chen CB, Wu MY, Ng CY, Lu CW, Wu J, Kao PH, et al. Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies. Cancer Manag Res 2018;10:1259-73.  Back to cited text no. 9
    
10.
Saw S, Lee HY, Ng QS. Pembrolizumab-induced Stevens-Johnson syndrome in non-melanoma patients. Eur J Cancer 2017;81:237-9.  Back to cited text no. 10
    
11.
Hwang A, Iskandar A, Dasanu CA. Stevens-Johnson syndrome manifesting late in the course of pembrolizumab therapy. J Oncol Pharm Pract 2019;25:1520-2.  Back to cited text no. 11
    
12.
Creamer D, Walsh SA, Dziewulski P, Exton LS, Lee HY, Dart JK, et al. U.K. guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol 2016;174:1194-227.  Back to cited text no. 12
    
13.
Morita K, Matsui H, Michihata N, Fushimi K, Yasunaga H. Association of early systemic corticosteroid therapy with mortality in patients with Stevens-Johnson syndrome or toxic epidermal necrolysis: A retrospective cohort study using a nationwide claims database. Am J Clin Dermatol 2019;20:579-92.  Back to cited text no. 13
    


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