Long-term Physical and Psychological Outcomes of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

Key Points

Question

What are the long-term physical and psychological sequelae noted in survivors of acute Stevens-Johnson syndrome/toxic epidermal necrolysis?

Findings

In this survey study that included 121 adult survivors of acute Stevens-Johnson syndrome/toxic epidermal necrolysis, the most common physical sequelae were cutaneous problems (84.3%), ocular problems (59.5%), and oral mucosal problems (50.8%). A total of 53.3% of the participants screened positive for depression, and 43.3% screened positive for anxiety.

Meaning

Results of this study suggest that awareness of the high rates of long-term physical sequelae, depression, and anxiety among survivors of acute Stevens-Johnson syndrome/toxic epidermal necrolysis may facilitate evaluation and access to health services.

Abstract

Importance

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is known to cause multiple end-organ complications in its acute phase, but less is known about the long-term association with patients’ mental health and quality of life.

Objective

To examine the chronic physical and psychological sequelae affecting patients with SJS/TEN.

Design, Setting, and Participants

A survey study conducted at 11 academic health centers in the US evaluated 121 adults diagnosed with SJS/TEN by inpatient consultive dermatologists between January 1, 2009, and September 30, 2019.

Interventions

Patients completed a survey that included the following validated questionnaires: Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Primary Care Post-Traumatic Stress Disorder Screen (PC-PTSD), and the 12-item Short Form Health Survey (SF-12). The survey also included questions created by the study team regarding fear, patient education, and long-term sequelae relevant to SJS/TEN.

Main Outcomes and Measures

Primary outcome measures were the percentage of patients reporting long-term physical sequelae; the percentage of patients with positive results on PHQ-9, GAD-7, and PC-PTSD screening; and the numeric score on the SF-12 (score of 50 defined as average physical and mental well-being).

Results

A total of 121 individuals (73 women [60.3%]; mean [SD] age, 52.5 [17.1] years) completed the survey (response rate, 29.2%). The most common long-term physical sequelae reported were cutaneous problems (102 of 121 [84.3%]), ocular problems (72 of 121 [59.5%]), and oral mucosal problems (61 of 120 [50.8%]). A total of 53.3% (64 of 120) of the respondents had results indicating depression on the PHQ-9, 43.3% (52 of 120) showed signs of anxiety on the GAD-7, and 19.5% had results indicating PTSD on the PC-PTSD. The mean (SD) SF-12 Physical Component Summary score was 42.4 (22.8), and the mean Mental Component Summary score was 46.1 (20.9). A total of 28.2% (33 of 117) of the respondents were unable to work, 68.1% (81 of 119) were fearful of taking new medications, and 30.0% (36 of 120) avoided taking prescribed medications for a diagnosed medical condition.

Conclusions and Relevance

This survey study found that long-term physical sequelae, depression, and anxiety appear to be common in patients with SJS/TEN, with implications for health and well-being. Improved awareness of these complications may assist health professionals in offering medical care, counseling, and support to patients with SJS/TEN.

This survey study examines long-term physical and mental sequelae in individuals after experiencing Stevens-Johnson syndrome/toxic epidermal necrolysis.

Introduction

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe, life-threatening drug-induced eruption that can cause multiple end-organ complications in the acute setting.¹ Earlier work has shown survivors of acute SJS/TEN may experience various long-term physical sequelae, including cutaneous and ophthalmologic scarring, dyspigmentation, dental complications, genitourinary symptoms, and pulmonary disease.¹ Although these physical complications of SJS/TEN have been documented, they have not been reported systematically. In addition, few studies have examined the psychological outcomes of SJS/TEN. Previous work has suggested that posttraumatic stress disorder (PTSD),² anxiety, depression,³ and decreased health-related quality of life⁴ are important issues, but these studies have been limited by small sample size. We evaluated the long-term physical sequelae, psychological distress, and quality of life in individuals who experienced SJS/TEN in a large, multicenter cohort of patients from the US.

Methods

This multicenter survey study included adults diagnosed with SJS/TEN by inpatient consultative dermatologists between January 1, 2009, and September 30, 2019. Potential participants were identified via electronic health records and contacted by telephone or mail depending on local institutional review board requirements. Validated questionnaires included the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), the Primary Care Post-Traumatic Stress Disorder Screen (PC-PTSD), and the 12-item Short Form Health Survey (SF-12). Primary outcome measures were the percentage of patients reporting long-term physical sequelae; the percentage of patients with positive results on PHQ-9, GAD-7, and PC-PTSD screening; and the numeric score on the SF-12 (score of 50 defined as average physical and mental well-being). Additional questions created by the study team regarding fear, patient education, and long-term sequelae relevant to SJS/TEN were also included. Patients completed the survey by mail, electronically, or by telephone depending on local institutional review board requirements. Data were collected in a deidentified manner using Research Electronic Data Capture (REDCap) and analyzed in Microsoft Excel, version 365 (Microsoft Corp). Descriptive statistics were used to summarize demographic characteristics and survey responses. This study was approved by the institutional review board of the University of Pennsylvania and by institutional review boards of the other participating institutions. A waiver of written documentation of informed consent was obtained because the research presented no more than minimal risk of harm and involved no procedures for which written consent is normally required. This study followed the American Association for Public Opinion Research (AAPOR) reporting guideline.

Results

A total of 121 individuals who had survived SJS/TEN from 11 academic health centers completed the survey (Table), a response rate of 29.2%. The most common long-term complications reported were cutaneous problems (84.3% [102 of 121]), ocular problems (59.5% [72 of 121]), and oral mucosal problems (50.8% [61 of 120]) (Figure). A total of 53.3% (64 of 120) of the respondents had a positive depression screen on the PHQ-9. In these individuals, depression was categorized as mild in 54.7% (35 of 64), moderate in 20.3% (13 of 64), moderately severe in 15.6% (10 of 64), and severe in 9.4% (6 of 64). In addition, 43.3% (52 of 120) of the participants screened positive for anxiety on the GAD-7. A total of 19.5% (23 of 118) had positive results of screening for PTSD on the PC-PTSD. Some participants sought psychological support after their severe drug eruption. A total of 25.0% (30 of 120) of the participants reported receiving treatment from a psychologist or counselor, 18.5% (22 of 119) reported seeing a psychiatrist, and 7.5% (9 of 120) attended group support or therapy. On the SF-12, the mean (SD) Physical Component Summary was 42.4 (22.8) (n = 111), and the mean Mental Component Summary was 46.1 (20.9) (n = 111), revealing below-average physical and mental well-being (average, 50).

Table. Characteristics of Respondents After Severe Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Characteristic	Respondents, No. (%)
Age, mean (SD), y	52.5 (17.1)
Sex
Male	47 (38.8)
Female	73 (60.3)
Nonbinary/other	1 (0.8)
Race/ethnicity
White	83 (68.6)
Black or African American	25 (20.7)
Asian	8 (6.6)
Native American	2 (1.7)
Other	3 (2.5)
Time since severe drug reaction, ya
<1	21 (17.4)
1-2	19 (15.7)
2-5	32 (26.4)
5-10	38 (31.4)
>10	11 (9.1)

^aThe overlap in ranges aligns with the actual survey question, which included the categories as shown in the Table.

Figure. Percentage of Patients With Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Reporting Long-term Sequelae.

Cutaneous sequelae comprise irregular pigmentation, eruptive nevi, abnormal nail regrowth, alopecia, chronic eczema, and pruritus. Ocular sequelae comprise dry eye, photophobia, ingrown eyelashes, chronic conjunctivitis, corneal scarring, and blindness. Oral mucosal sequelae comprise tongue dysmotility, scarring of oral mucosa, oral ulcers, and decayed or missing teeth. Genital mucosal sequelae comprise vaginal or penile mucosal scarring, pain during intercourse, infertility, menstrual abnormalities, and genital ulcers. Gastrointestinal sequelae comprise trouble swallowing, esophageal stricture or web, small-bowel obstruction, and ulcers. Pulmonary sequelae comprise chronic bronchitis, bronchiolitis obliterans organizing pneumonia, bronchiectasis, and chronic obstructive pulmonary disease. Renal sequelae comprise acute tubular necrosis, chronic renal insufficiency, and glomerulonephritis. PTSD indicates posttraumatic stress syndrome.

A total of 74.2% (89 of 120) of the participants were afraid to experience a severe drug eruption again, and 40.3% (48 of 119) feared that their friends or family members would also develop a severe drug reaction. In addition, 68.1% (81 of 119) of the respondents were fearful of taking new medications, and 30.0% (36 of 120) said they avoid taking prescribed medications for a diagnosed medical condition. A total of 35.8% (43 of 120) of the participants answered no when asked whether they received education about future medication avoidance, and 33.3% (39 of 117) reported having unanswered medical questions about their severe drug reaction. A total of 9.2% (11 of 120) of the respondents reported being rehospitalized for another severe drug reaction, 69.2% (81 of 117) took time off before returning to work, and 28.2% (33 of 117) were unable to work. The mean amount of time away from work by 68 participants was 27.6 weeks (range, 0.5-260 weeks).

Discussion

These results suggest long-term physical sequelae and depression are common in patients with SJS/TEN. Most of the previous publications describing long-term complications of SJS/TEN are small retrospective studies or case reports. Previous studies reported that the incidence of cutaneous sequelae ranged from 23% to 100%, and ocular sequelae ranged from 20% to 75%.⁵ Chronic oral complications, such as ulcers and depapillation of the tongue, were reported in up to 25% of patients.⁵ In the present study, 50.8% of the participants reported oral mucosal problems, suggesting that chronic oral sequelae may be more common than previously thought. A study of 17 patients found that most were followed up by a dermatologist, but few patients reporting ocular or genitourinary sequelae were followed up by an ophthalmologist or gynecologist.⁶

A previous study of 17 patients who survived SJS/TEN found that 29% of the patients developed depression³; in the present study, more than half (53.3%) of the respondents screened positive. During 2013-2016, the National Health and Nutrition Examination Survey reported that 8.1% of adults in the US had results indicating moderate or worse depression in a given 2-week period.⁷ In this study, 24.2% (29 of 120) of the participants with SJS/TEN had moderate or worse depression. Another study found that 23% (7 of 30) of patients were found to have PTSD 6 months after the acute phase of SJS/TEN.² Findings in our study were similar, with 19.5% of the participants screening positive for PTSD. In the US, the overall lifetime prevalence of PTSD is between 8% and 9%.⁸ These physical and psychological sequelae of SJS/TEN contributed to a substantial amount of lost work time and disability.

In a qualitative study, 14 individuals who survived SJS/TEN expressed frustration over unanswered questions about their severe drug reaction.⁹ Most patients also said they relied on internet sources for information.⁹ Similarly, 33.3% of participants in our study reported inadequate education and unanswered medical questions. These unanswered questions may have contributed to the reported fear of new medications (68.1%) as well as avoidance of prescribed medications (30.0%). Another qualitative study highlighted patient concerns about the heritability of severe drug reactions.¹⁰ Although our study did not specifically address the question of heritability, it noted that patients fear the possibility of friends or family members experiencing SJS/TEN, suggesting this fear is an important topic for clinicians to address with patients. Patients’ concerns could be related to the possibility of heritability or a newfound awareness of severe drug reactions.

Inadequate education regarding medication avoidance and the safety of taking new medications, along with insufficient access to disease-relevant information postdischarge, are practice gaps affecting patients with SJS/TEN. Greater awareness of the high rates of depression and anxiety among survivors of acute SJS/TEN may facilitate screening and provision of mental health services. Understanding these patient-centered needs may assist clinicians in offering medical care, counseling, and support. The high rates of long-term physical and psychological complications of SJS/TEN necessitate multidisciplinary follow-up. Dermatologists should evaluate patients for the development of long-term complications to facilitate appropriate follow-up care, including mental health services.

Limitations

Study limitations include a low survey response rate, which likely resulted from attempting to contact patients who survived a critical illness who (1) might no longer receive care at the reference center, (2) may have died or be experiencing chronic health issues that interfered with participation, and (3) were contacted years after the diagnosis of SJS/TEN, perhaps resulting in a decreased desire to participate. Recall bias, as well as variability in the length of time between SJS/TEN diagnosis and survey administration, are additional potential limitations. The deidentified nature of the survey responses prevented a fuller characterization of the cohort and analysis of responses in the context of patient medical records, which might inform the association between disease manifestations, severity, and long-term sequelae. Prolonged hospitalization or intensive care unit stays may be associated with sequelae that are not specific to SJS/TEN. Large sample size, use of validated questionnaires, and inclusion of patients from multiple institutions across the US may improve the reliability of results establishing the long-term physical and psychological outcomes of SJS/TEN.

Conclusions

This multicenter survey study suggests that long-term physical and psychological complications following SJS/TEN are common. Improved awareness of these complications among health care professionals may facilitate care delivery to survivors of acute SJS/TEN.