Elizabeth Phillips

Importance; Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN) are rare, potentially fatal adverse drug reactions. As the use of immune checkpoint inhibitors (ICIs) expands, their role as direct inducers or synergistic contributors to SJS/TEN remains incompletely characterized.

Objective: To determine whether ICIs are independent risk factors for SJS/TEN, evaluate their interactions with known culprit drugs, and assess their impact on latency and mortality.

Design: Cross-sectional analysis of adverse event reports submitted to the U.S. Food and Drug Administration Adverse Event Reporting System (FDA FAERS) between January 2013 and December 2023, sanitized and de-duplicated. Logistic regression and Cox models were used to assess predictors of SJS/TEN development, mortality, and latency.

Setting: Global pharmacovigilance reports submitted to FAERS.

Participants: A total of 17,495 unique and de-identified patients reported SJS/TEN, of 13,986,839 total reports.

Exposures: Suspected causative drugs, including ICIs.

Main Outcomes and Measures: Primary outcomes were the adjusted odds of developing SJS/TEN, time-to-event (TTE) of reaction/drug latency, and all-cause mortality. Depending on the analysis, covariates included age, sex, number of concomitant drugs, cancer diagnosis, and specific drug exposures.

Results: Of 17,495 SJS/TEN cases (median age 53 years, 37.6% male), 970 (5.5%) had ICI exposure and 653 (3.7%) listed an ICI as the primary suspect. ICI exposure was associated with developing SJS/TEN (adjusted OR, 6.69; 95% CI, 6.19-7.23) while controlling for age, exposure to strong and weak culprits, number of concomitant drugs, and cancer diagnosis. ICI increases SJS-TEN risk among patients exposed to allopurinol (OR, 4.35; 95% CI, 3.12-6.06) and TMP-SMX (OR, 5.68; 95% CI, 4.05-7.95) with the same covariates. Among patients with small-molecule-induced SJS/TEN, mortality was strongly associated with ICI exposure (particularly exposure to multiple ICI, OR, 7.31; 95% CI, 3.09-17.27). Among all SJS/TEN cases, ICI exposure was associated with delayed onset, compared to cancer patients not exposed to ICI and non-cancer patients (median 20 vs 14 vs 13 days; P < .0001).

Conclusions and Relevance: ICIs are associated with increased SJS/TEN risk, both independently and in combination with known culprit drugs, and may delay disease onset. These findings support increased vigilance in prescribing known culprits alongside ICI.

Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis.
To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA).
We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.
In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B*44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patients.
HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.
HLA alleles including HLA-B*13:01 and HLA-B*38:02 are risk factors for co-trimoxazole-induced SCAR in Asian populations. However, the generalizability of these associations to other global populations is unknown but critical for population-appropriate risk stratification and diagnosis.
HLA alleles with shared peptide binding specificities (SPBS) to Asian-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and South Africa.
HLA alleles previously associated with co-trimoxazole-induced SCAR do not identify risk across populations. However, HLA alleles with SPBS provide biological plausibility and strategies for global and population-appropriate clinical risk stratification and diagnosis of cotrimoxazole-induced SCAR.

This is one of the largest long-term studies following an SJS/TEN reaction that reports long-term survey-based sequelae and adds to the understanding of SJS/TEN as a condition with chronic complications long beyond the acute reaction. We report significant long-term life impacts among survivors of SJS/TEN in the USA. Additional follow-up and long-term care of this patient population is of the utmost importance.

Background
Co-trimoxazole is a leading global cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Co-trimoxazole-induced SCAR are associated with HLA class I alleles including HLA-B*13:01 and HLA-B*38:02 in Southeast Asian (SEA) populations. However, the global generalizability of these associations is unknown but critical for population-appropriate risk stratification and diagnosis.

Objective
To determine HLA risk factors associated with co-trimoxazole-induced SJS/TEN and DRESS in populations from the United States (US) and South Africa (SA).

Methods
We performed high-resolution HLA typing on dermatologist-adjudicated co-trimoxazole-induced SCAR patients in the US (n=63) and SA (n=26) compared to population controls. Peptide binding and docking analyses were performed using MHCcluster2.0 and CB-Dock2.

Results
In a multiple logistic regression model, HLA-B*44:03 (Pc<0.001, OR: 4.08), HLA-B*38:01 (Pc<0.001, OR: 5.66), and HLA-C*04:01 (Pc=0.003, OR: 2.50) were independently associated with co-trimoxazole-induced SJS/TEN in the US. HLA-B* 44:03 was also associated with co-trimoxazole-induced DRESS in SA (Pc=0.019, OR: 10.69). Distinct HLA-B variants with shared peptide binding specificities (SPBS) and HLA-C*04:01 identified 94% and 78% of co-trimoxazole-induced SJS/TEN and DRESS in the US, respectively. The SEA risk allele HLA-B*13:01, with SPBS to HLA-B*44:03, was identified in just 1/63 US SCAR patient.

Conclusion
HLA alleles with SPBS to SEA-related risk alleles including HLA-B*44:03 (SPBS with HLA-B*13:01) and HLA-B*38:01 (SPBS with HLA-B*38:02) but also HLA-C*04:01 predisposed to co-trimoxazole-induced SCAR in the US and SA. These findings provide biological plausibility and strategies for global risk prediction and diagnosis of co-trimoxazole-induced SCAR.

Inaccurate penicillin allergy labels (PALs) affect antimicrobial stewardship, health outcomes, and costs. More than 95% of PALs can be de-labeled when tested, but this rarely happens.
We sought to determine whether education and an electronic health record (EHR) tool kit to identify low-risk PALs would facilitate inpatient penicillin allergy de-labeling by pharmacists.
Pragmatic Removal of Penicillin Allergy Electronic Health Record Labels was a stepped-wedge, nonblinded, randomized, controlled, pragmatic clinical trial including 12 inpatient medical units. From November 2020 to November 2021, units entered intervention at 1-month stepped intervals in random order. Medically stable, nonpregnant adults with an her-documented PAL who were hospitalized on intervention units for 24 hours were included. The intervention included pharmacist and nursing education, a patient list for systematic identification of PALs, presentation of a risk-assessment tool, and an oral amoxicillin challenge order set. The primary outcome was removal of PAL by hospital discharge. Secondary outcomes included safety and implementation measures, longer-term continued label removal, and antibiotic use.
On 12 randomized units, 2,052 patients with a PAL presented during the 1-year trial. More intervention-exposed patients had EHR-documented penicillin allergy removal compared with controls (45 of 1,018 [4.4%] vs 31 of 1,034 [3%], respectively; adjusted odds ratio = 2.05; 95% CI, 1.08-3.91). More intervention-exposed patients received an EHR-documented penicillin allergy risk assessment than did controls (86 of 1,018 [8.4%] vs 27 of 1,034 [2.6%]; adjusted odds ratio = 6.42; 95% CI, 3.08-13.38). Moreover, 27 of 1,018 intervention patients (2.7%) received amoxicillin challenge compared with 21 of 1,034 control patients (2.0%). All amoxicillin challenges were tolerated.
Education and deployment of an inpatient EHR tool kit increased the rate of inpatient removal of inaccurate penicillin allergies before discharge.

Consensus guidelines outline the recommended management of delayed drug hypersensitivity reactions (DHRs), but clinical practices are largely expert-based and may vary significantly across populations and regions. This study evaluated the approach and management of health care specialists globally regarding DHRs, including severe cutaneous adverse reactions.
To assess the current practices, knowledge, and availability of allergy testing for DHRs, including severe cutaneous adverse reactions, among relevant health care professionals globally.
The Global AppRoAch for Severe Cutaneous Adverse Reactions Survey study is a prospective, web-based survey conducted using the Research Electronic Data Capture platform. The 10- to 15-minute survey was directed to 14 allergy/immunology and dermatology associations through international mailing lists across 48 countries.
Among the 8561 members contacted, answers from 130 health care providers practicing in all 6 continents were analyzed. Most respondents identified as White (88 of 130 [68%]) and female (79 of 130 [61%]), representing a range of age groups and clinical expertise. Most practiced in dermatology (69 of 130 [53%]), followed by allergy/immunology (46 of 130 [35.4%]), and were based in an urban setting (127 of 130 [98%]). Among the 45 respondents (34.6%) who managed severe cutaneous adverse reactions, 27 (60%) had access to multidisciplinary care. Practices varied widely by clinical phenotype; for example, for maculopapular exanthema, 63 respondents indicated treating through the reaction (63 of 130 [49%]), whereas 16 (16 of 130 [12%]) offered desensitization. Under patient education and follow-up, only 60 (60 of 130 [46.2%]) participants organized a follow-up with the implicated specialist.
Significant variability in the management of DHRs was observed among the respondents. The results highlight the need for evidence-based protocols to standardize guidelines for managing DHRs.

Immune checkpoint inhibitors (ICIs) are paradigm-shifting cancer treatments that are increasingly associated with Stevens-Johnson syndrome, toxic epidermal necrolysis (SJS/TEN) and other life-threatening cutaneous reactions. Differentiating ICI-induced true SJS/TEN from SJS/TEN-like reactions is difficult, the latter of which may be distinct lichenoid or bullous reactions.1-3 In some cases, ICI-related SJS/TEN-like reactions occur in association with human leukocyte antigen (HLA)–restricted drug culprits like allopurinol, suggesting a 2-hit mechanism.4 With increasing ICI use, a clearer understanding of their role in SJS/TEN is critical.

Methods
We analyzed 13 986 839 deduplicated Food and Drug Administration Adverse Event Reporting System (FAERS) reports (2013-2023), containing 17 495 patients with SJS/TEN. We assessed the impact of ICI using logistic regressions adjusted for age, sex, cancer, polypharmacy, and strong (lamotrigine, trimethoprim-sulfamethoxazole, phenytoin, allopurinol, carbamazepine) or weak (azithromycin, clarithromycin, erythromycin, ciprofloxacin, levofloxacin, moxifloxacin, and acyclovir) culprit exposure.

To assess latency patterns, we performed Cox proportional hazards analyses among patients with SJS/TEN with documented latency. In 1 model, we compared latency between ICI-attributed and non–ICI-attributed cases, classifying primary suspect (PS) by ICI mechanism. In another, we used time-dependent Cox regression with interval splitting to dynamically update exposure to programmed cell death 1 (PD-1) and its ligand (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), or lymphocyte-activation gene 3 (LAG-3) inhibitors. Both models incorporated the same covariates as the logistic regression. Additional eMethods are in Supplement 1.

Results
In a multivariable logistic regression (Table), ICI exposure was associated with increased risk of SJS/TEN (adjusted odds ratio [aOR], 9.14; 95% CI, 8.42-9.93; P < .001). Strong culprit drugs were the strongest independent predictors of SJS/TEN (aOR, 14.31; 95% CI, 13.77-14.87). Importantly, cancer diagnosis was inversely associated with SJS/TEN risk (aOR, 0.60; 95% CI, 0.58-0.63). Interaction terms revealed additive synergy between ICI exposure and culprit drugs. The ICI–strong culprit interaction yielded an attributable proportion (AP) of 0.38, indicating that 38% of the risk in co-exposed patients was attributable to interaction. For ICI-weak culprits, AP was even higher (0.52).

Importance Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) survivors experience substantial long-term sequelae. Research on physical symptoms experienced during acute hospitalization is well documented, but limited studies have been completed on the long-term biopsychosocial effects of SJS/TEN, particularly from the patient’s perspective.

Objective To increase the understanding of the long-term complications of SJS/TEN.

Design, Setting, and Participants This qualitative investigation was completed from within a community-based study, the SJS Survivors Study, using a semistructured, in-depth interview guide to query participants about their SJS/TEN experience postdischarge from the hospital. Interviews took place by phone from July 2021 through August 2023. This study included adults who experienced SJS/TEN within the United States.

Main Outcome and Measures A biopsychosocial theory-based framework and hierarchical coding system were utilized to understand the long-term life impacts of survivors of SJS/TEN.

Results The 29 participants, aged 26 to 76 years, were 66% female and 69% White and had experienced SJS/TEN from a wide range of drugs. Patients experienced support while in the hospital, but once discharged, felt isolated and without support to understand the potential sustained impacts of SJS/TEN in their lives and the lives of their family members. Patients experienced ongoing biological symptoms, such as skin issues, debilitating visual impairment, blindness, and lack of functional autonomy. Psychological impacts included symptoms of anxiety, obsessive thinking, flashbacks, and depression. Socially, some survivors expressed a sense of abandonment and described negative impacts on their careers. Survivors also expressed frustration and isolation with having to navigate posthospital care alone. There was a lack of preemptive discharge education and SJS/TEN-specific planning. Lack of physician knowledge about SJS/TEN was particularly noted and survivors turned to the internet for guidance instead of receiving direction from their physicians. Medical distrust among survivors was frequently noted.

Conclusions and Relevance The findings highlight the need for postdischarge care coordination among patients and their primary physicians, including mental health support. This care coordination should be arranged prior to discharge to ensure the availability of adequate support and optimal health outcomes. It is essential that clinicians and researchers prioritize the understanding of long-term sequelae of SJS/TEN and improve current discharge education and protocols for patients and their families.

Cytomegalovirus (CMV) establishes lifelong latency and is linked to immunosenescence in older and immunocompromised individuals. We hypothesize that CMV drives systemic and tissue-specific immune changes that may contribute to cardiovascular disease (CVD). Thoracic aorta, blood and perivascular mediastinal adipose tissue from cardiac surgery patients (n = 11) were processed within 30–60 min of excision. CMV IgG titres were quantified through ELISA to determine CMV status: CMV(−) (n = 4) and CMV(+) (n = 7). Immune profiling was performed using flow cytometry and single-cell RNA sequencing. Analyses included MiloR and differential gene expression. Participants (mean age 69.7 ± 8.4 years) were 80% male and 70% Caucasian. CMV(−) and CMV(+) participants had mean IgG titres of 0.038 and 13.55 IU ml−1, respectively. CD8+ T-cells expressing CD57+, GPR56+ and CX3CR1+ (CGC) were increased in the blood of CMV(+) participants. In the aorta of CMV(+) participants, CD8+ T cells and CD4+ T cells had decreased HLA-C expression and suppressed interferon-α pathways. In contrast, the TNF-α signalling pathway was increased. CMV infection shapes immune responses and in this pilot, we observed suppression of interferon-α signalling and increased TNF-α-associated pathways in the aorta. Larger studies are needed to define how CMV-driven immune remodelling contributes to CVD.

This article is part of the discussion meeting issue ‘The indirect effects of cytomegalovirus infection: mechanisms and consequences.’