J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

Journal website https://www.journalmc.org

Case Report

Volume 13, Number 9, September 2022, pages 449-455

Steven-Johnson Syndrome: A Rare but Serious Adverse Event of Nivolumab Use in a Patient With Metastatic Gastric Adenocarcinoma

Figure 1. (a) A confluent papular rash over both hands. (b) Erupted rash with vesicles and bullae over the right shoulder. (c) A maculopapular rash over the right upper extremity.

**Table 1.** Pertinent Laboratory Results on Admission
Blood test	Patient’s result	Reference result
Venous lactate	2.1 mmol/L	0.6 - 2.1 mmol/L
Serum bicarbonate	14.0 mmol/L	21.0 - 28.0 mmol/L
Serum anion gap	10.0 mmol/L	6.0 - 14.0 mmol/L
Serum creatinine	1.30 mg/dL	0.6 - 1.30 mg/dL
Serum sodium	130 mmol/L	133 - 144 mmol/L
Serum chloride	99 mmol/L	98 - 107 mmol/L
Serum potassium	4.6 mmol/L	3.5 - 5.2 mmol/L
Blood urea	23.0 mg/dL	8.6 - 25.0 mg/dL
Serum magnesium	1.4 mg/dL	1.5 - 2.6 mg/dL
Serum phosphate	4.1 mg/dL	2.5 - 4.5 mg/dL
Serum uric acid	6.9 mg/dL	4.4 - 7.6 mg/dL
Hemoglobin	9.5 g/dL	13.0 - 15.0 g/dL
Platelets	103 × 10³/mm³	150 - 450 × 10³/mm³
White blood cell	1.8 × 10³/mm³	4.0 - 11.0 × 10³/mm³
Serum albumin	3.8 g/dL	3.5 - 5.7 g/dL
Procalcitonin	0.60 ng/mL	0.20 - 0.49 ng/mL

Table 1. Pertinent Laboratory Results on Admission

Blood test

Patient’s result

Reference result

Venous lactate

2.1 mmol/L

0.6 - 2.1 mmol/L

Serum bicarbonate

14.0 mmol/L

21.0 - 28.0 mmol/L

Serum anion gap

10.0 mmol/L

6.0 - 14.0 mmol/L

Serum creatinine

1.30 mg/dL

0.6 - 1.30 mg/dL

Serum sodium

130 mmol/L

133 - 144 mmol/L

Serum chloride

99 mmol/L

98 - 107 mmol/L

Serum potassium

4.6 mmol/L

3.5 - 5.2 mmol/L

Blood urea

23.0 mg/dL

8.6 - 25.0 mg/dL

Serum magnesium

1.4 mg/dL

1.5 - 2.6 mg/dL

Serum phosphate

4.1 mg/dL

2.5 - 4.5 mg/dL

Serum uric acid

6.9 mg/dL

4.4 - 7.6 mg/dL

Hemoglobin

9.5 g/dL

13.0 - 15.0 g/dL

Platelets

103 × 10³/mm³

150 - 450 × 10³/mm³

White blood cell

1.8 × 10³/mm³

4.0 - 11.0 × 10³/mm³

Serum albumin

3.8 g/dL

3.5 - 5.7 g/dL

Procalcitonin

0.60 ng/mL

0.20 - 0.49 ng/mL

**Table 2.** Common Cutaneous irAEs Reported in 253 Patients^a Treated With Various Anti-PD-1 Agents per Review Conducted by Simonsen et al [1]
Cutaneous irAE	Patients number	Time to onset from the last cycle of anti-PD-1 agents (weeks)
^aSix patients had more than one specific skin reaction. irAEs: immune-related adverse effects; SJS: Steven-Johnson syndrome; TEN: toxic epidermal necrolysis; anti-PD-1: anti-programmed cell death receptor-1.
Pigmentation changes/vitiligo	58	1 - 36
Psoriasis	33	2 - 22
Bullous pemphigoid	31	3 - 84
Lichenoid dermatitis	30	< 1 - 92
Granulomatous reactions	10	4 - 40
Erythema multiforme/SJS/TEN	10	< 1 - 20
Lupus erythematosus-like rash	8	4 - 43

Table 2. Common Cutaneous irAEs Reported in 253 Patients^a Treated With Various Anti-PD-1 Agents per Review Conducted by Simonsen et al [1]

Cutaneous irAE

Patients number

Time to onset from the last cycle of anti-PD-1 agents (weeks)

^aSix patients had more than one specific skin reaction. irAEs: immune-related adverse effects; SJS: Steven-Johnson syndrome; TEN: toxic epidermal necrolysis; anti-PD-1: anti-programmed cell death receptor-1.

Pigmentation changes/vitiligo

1 - 36

Psoriasis

2 - 22

Bullous pemphigoid

3 - 84

Lichenoid dermatitis

< 1 - 92

Granulomatous reactions

4 - 40

Erythema multiforme/SJS/TEN

< 1 - 20

Lupus erythematosus-like rash

4 - 43

**Table 3.** A Literature Review of the Published Cases of Nivolumab-Induced SJS/TEN
Authors, year of publication	Patient’s age (years/gender	Underlying malignancy	Latency of onset of SJS/TEN symptoms	Management	Outcome of SJS/TEN
HCC: hepatocellular carcinoma; SCC: squamous cell carcinoma; NSCLC: non-small cell lung carcinoma; SJS: Steven-Johnson syndrome; TEN: toxic epidermal necrolysis; anti-PD-1: anti-programmed cell death receptor-1; ICU: intensive care unit.
Vivar et al, 2017 [12]	50/male	Metastatic malignant melanoma treated with dual anti-PD-1 agents (ipilimumab and nivolumab)	Initial clinical and pathological findings were consistent with a morbilliform drug rash which then progressed over 3 months to clinicopathological TEN. SCORTEN 5.	Poor response to infliximab and oral prednisone, followed by high-dose methylprednisolone and immunoglobulins	Lack of response of cutaneous lesions to immunosuppressive therapy with global clinical condition’s decline from polymicrobial sepsis. Death from multiorgan failure.
Kim et al, 2021 [13]	86/male	Metastatic HCC	Mucocutaneous lesions appeared after 14 days of the second cycle. Histology confirmed TEN. SCORTEN 3, mortality rate 35.5%.	Failure of oral prednisone. ICU admission with high-dose methylprednisolone and immunoglobulins	Initial re-epithelization of some skin lesions but overall clinical course deteriorated due to polymicrobial sepsis and advanced HCC. Death from multiorgan failure.
Dasanu, 2019 [14]	69/male	Metastatic HCC status post resection and recurrent tumor arterial embolization	Late onset of mucocutaneous lesions after 4 months (eight cycles) of nivolumab. Histology confirmed SJS.	Oral prednisone and supportive care	Complete resolution of mucocutaneous lesions within 3 weeks of treatment
Griffin et al, 2018 [15]	54/male	Recurrent follicular lymphoma	Mucocutaneous lesions appeared after 10 days of the first cycle. Histology confirmed TEN. SCORTEN 3, mortality rate 32%.	High-dose methylprednisolone followed by oral prednisone and supportive care	Initial rash improvement followed by TEN of respiratory mucosa, hospital-acquired cases of pneumonia leading to progressive respiratory failure and death
Garcia-Canzana et al, 2021 [16]	78/male	Metastatic SCC lung	Mucocutaneous lesions and constitutional symptoms 1 week after the second cycle. Histology confirmed SJS.	High-dose methylprednisolone followed by oral prednisone with tapering, and supportive care	Complete disappearance of mucocutaneous lesions after 1 month
Koshizuka et al, 2021 [17]	76/male	Metastatic SCC tongue status post resection and neck dissection, radiotherapy, and chemotherapy	Cutaneous lesions appeared after 27 days of the first cycle followed by the constitutional symptoms. Histology confirmed SJS. TEN was clinically diagnosed later in the second week of symptoms onset.	High-dose methylprednisolone followed by oral prednisone with gradual tapering and supportive care	Gradual improvement of rash with epithelization of the erupted lesions
Ito et al, 2017 [18]	76/female	Stage IV NSCLC	The unspecified onset of cutaneous lesions after the second cycle. SJS was complicated by refractory pruritis. Histology confirmed SJS.	Oral prednisone for 2 weeks and a topical steroid with supportive care	Complete disappearance of the rash but refractory pruritis that was, interestingly, aprepitant-responsive.
Salati et al, 2018 [19]	59/female	Metastatic NSCLC status post chemotherapy	Mucosal lesions and constitutional symptoms 1 week after the second cycle followed by a diffuse eruptive rash.	High-dose methylprednisolone and supportive care	Gradual rash improvement and skin healing
Shah et al, 2018 [20]	63/male	Stage IV SCC of uvula and soft palate status post neck dissection and local radiotherapy	Mucosal and cutaneous lesions appeared after 1 week after the first cycle. Skin rash distributed over recent radiation sites. Histology confirmed SJS.	Supportive care only	Good outcome of SJS rash
Rouyer et al, 2018 [21]	63/male	Recurrent pulmonary epidermoid carcinoma status post palliative radiotherapy and immunotherapy	Oral mucositis after 5 days from the second cycle and cutaneous lesions after 2 weeks, the rash appeared over previous radiation sites. Histology confirmed SJS with recall radiation dermatitis.	Unspecified	Unspecified
Nayar et al, 2016 [22]	64/female	Metastatic malignant melanoma refractory to ipilimumab therapy	Initial morbilliform rash that appeared after 2 weeks from the second cycle of nivolumab. The rash progressed into diffuse eruptive rash over 2 weeks with histology confirmed SJS.	High-dose methylprednisolone and immunoglobulins initially, followed by cyclosporin and oral prednisone taper	Gradual improvement of the skin rash.

Table 3. A Literature Review of the Published Cases of Nivolumab-Induced SJS/TEN

Authors, year of publication

Patient’s age (years/gender

Underlying malignancy

Latency of onset of SJS/TEN symptoms

Management

Outcome of SJS/TEN

HCC: hepatocellular carcinoma; SCC: squamous cell carcinoma; NSCLC: non-small cell lung carcinoma; SJS: Steven-Johnson syndrome; TEN: toxic epidermal necrolysis; anti-PD-1: anti-programmed cell death receptor-1; ICU: intensive care unit.

Vivar et al, 2017 [12]

50/male

Metastatic malignant melanoma treated with dual anti-PD-1 agents (ipilimumab and nivolumab)

Initial clinical and pathological findings were consistent with a morbilliform drug rash which then progressed over 3 months to clinicopathological TEN. SCORTEN 5.

Poor response to infliximab and oral prednisone, followed by high-dose methylprednisolone and immunoglobulins

Lack of response of cutaneous lesions to immunosuppressive therapy with global clinical condition’s decline from polymicrobial sepsis. Death from multiorgan failure.

Kim et al, 2021 [13]

86/male

Metastatic HCC

Mucocutaneous lesions appeared after 14 days of the second cycle. Histology confirmed TEN. SCORTEN 3, mortality rate 35.5%.

Failure of oral prednisone. ICU admission with high-dose methylprednisolone and immunoglobulins

Initial re-epithelization of some skin lesions but overall clinical course deteriorated due to polymicrobial sepsis and advanced HCC. Death from multiorgan failure.

Dasanu, 2019 [14]

69/male

Metastatic HCC status post resection and recurrent tumor arterial embolization

Late onset of mucocutaneous lesions after 4 months (eight cycles) of nivolumab. Histology confirmed SJS.

Oral prednisone and supportive care

Complete resolution of mucocutaneous lesions within 3 weeks of treatment

Griffin et al, 2018 [15]

54/male

Recurrent follicular lymphoma

Mucocutaneous lesions appeared after 10 days of the first cycle. Histology confirmed TEN. SCORTEN 3, mortality rate 32%.

High-dose methylprednisolone followed by oral prednisone and supportive care

Initial rash improvement followed by TEN of respiratory mucosa, hospital-acquired cases of pneumonia leading to progressive respiratory failure and death

Garcia-Canzana et al, 2021 [16]

78/male

Metastatic SCC lung

Mucocutaneous lesions and constitutional symptoms 1 week after the second cycle. Histology confirmed SJS.

High-dose methylprednisolone followed by oral prednisone with tapering, and supportive care

Complete disappearance of mucocutaneous lesions after 1 month

Koshizuka et al, 2021 [17]

76/male

Metastatic SCC tongue status post resection and neck dissection, radiotherapy, and chemotherapy

Cutaneous lesions appeared after 27 days of the first cycle followed by the constitutional symptoms. Histology confirmed SJS. TEN was clinically diagnosed later in the second week of symptoms onset.

High-dose methylprednisolone followed by oral prednisone with gradual tapering and supportive care

Gradual improvement of rash with epithelization of the erupted lesions

Ito et al, 2017 [18]

76/female

Stage IV NSCLC

The unspecified onset of cutaneous lesions after the second cycle. SJS was complicated by refractory pruritis. Histology confirmed SJS.

Oral prednisone for 2 weeks and a topical steroid with supportive care

Complete disappearance of the rash but refractory pruritis that was, interestingly, aprepitant-responsive.

Salati et al, 2018 [19]

59/female

Metastatic NSCLC status post chemotherapy

Mucosal lesions and constitutional symptoms 1 week after the second cycle followed by a diffuse eruptive rash.

High-dose methylprednisolone and supportive care

Gradual rash improvement and skin healing

Shah et al, 2018 [20]

63/male

Stage IV SCC of uvula and soft palate status post neck dissection and local radiotherapy

Mucosal and cutaneous lesions appeared after 1 week after the first cycle. Skin rash distributed over recent radiation sites. Histology confirmed SJS.

Supportive care only

Good outcome of SJS rash

Rouyer et al, 2018 [21]

63/male

Recurrent pulmonary epidermoid carcinoma status post palliative radiotherapy and immunotherapy

Oral mucositis after 5 days from the second cycle and cutaneous lesions after 2 weeks, the rash appeared over previous radiation sites. Histology confirmed SJS with recall radiation dermatitis.

Unspecified

Nayar et al, 2016 [22]

64/female

Metastatic malignant melanoma refractory to ipilimumab therapy

Initial morbilliform rash that appeared after 2 weeks from the second cycle of nivolumab. The rash progressed into diffuse eruptive rash over 2 weeks with histology confirmed SJS.

High-dose methylprednisolone and immunoglobulins initially, followed by cyclosporin and oral prednisone taper

Gradual improvement of the skin rash.

**Table 4.** Calculated Adverse Drug Reaction Probability Scale (Naranjo Algorithm) in Our Case [25]
Question	Yes	No	Do not know	Score
Total score ≥ 9: definite. 5 - 8: probable. 1 - 4: possible. ≤ 0: doubtful.
1. Are there previous conclusive reports on this reaction?	+1	0	0	+1
2. Did the adverse event appear after the suspected drug was administered?	+2	-1	0	+2
3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?	+1	0	0	+1
4. Did the adverse event reappear when the drug was re-administered?	+2	-1	0	0
5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?	-1	+2	0	+2
6. Did the reaction reappear when a placebo was given?	-1	+1	0	+1
7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
10. Was the adverse event confirmed by any objective evidence?	+1	0	0	0
Total score				+7

Table 4. Calculated Adverse Drug Reaction Probability Scale (Naranjo Algorithm) in Our Case [25]

Question

Yes

Do not know

Score

Total score ≥ 9: definite. 5 - 8: probable. 1 - 4: possible. ≤ 0: doubtful.

1. Are there previous conclusive reports on this reaction?

2. Did the adverse event appear after the suspected drug was administered?

-1

3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered?

4. Did the adverse event reappear when the drug was re-administered?

-1

5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?

-1

6. Did the reaction reappear when a placebo was given?

-1

7. Was the drug detected in blood (or other fluids) in concentrations known to be toxic?

8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

10. Was the adverse event confirmed by any objective evidence?

Total score