Severe cutaneous adverse reactions associated with the immune checkpoint inhibitors: A case/non-case analysis using the Food and Drug Administration Adverse Event Reporting System.

BACKGROUND/OBJECTIVES: The immune checkpoint inhibitors (ICIs) have been increasingly associated with severe cutaneous adverse reactions (SCARs). These reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) are uncommon but potentially lethal. Despite the severity of these reactions and growing association with the ICIs, their specific risk and mortality rates have been largely unexplored. METHODS: A case/non-case analysis was performed using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to examine the reporting odds ratios (RORs) for ICI-associated SCARs cases under two conditions: (1) ICIs compared with all drugs in FAERS and (2) ICIs compared with a reference group of pooled anticancer drugs to control for underlying malignancy. RESULTS: A statistically significant ROR for SJS (ROR: 5.44), TEN (ROR: 5.81) and DRESS (ROR: 1.38) were identified under Condition 1. Under Condition 2, this significance was maintained for SJS (ROR: 7.31), TEN (ROR: 7.40) and DRESS (ROR: 3.90), and mild significance was identified for AGEP (ROR: 1.89). Mortality rates for the ICIs were increased compared with the anticancer medications (28.5% vs. 24.5% for SJS, 55.3% vs. 46% for TEN, 3.0% vs. 2.1% for AGEP and 7.1% vs. 6.1% for DRESS). CONCLUSIONS: Our results suggest an association between SCARs and the ICIs independent of cancer status.

Case Report: Kawasaki disease associated with acute generalized exanthematous pustulosis secondary to carbocysteine.

Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption characterized by sterile pustules on an erythematous background, which is usually associated with drugs. AGEP is described as a self-limiting disease with favorable prognosis. We reported a case of Kawasaki Disease (KD) following AGEP. A 3-year-old male, who was admitted with pustules and five days of fever at our hospital, was diagnosed with AGEP. Despite the skin lesions and fever improving drastically after prednisolone therapy, the fever recurred on hospitalization day 5. The following symptoms suggestive of KD also appeared: bulbar conjunctival hyperemia, cervical lymphadenopathy, erythema of the lips, eruption on his trunk, and erythema and edema of the hands and feet. He was diagnosed with KD and treated with intravenous immunoglobulin. He was discharged on the thirteenth day of hospitalization without cardiac complications. Drug-induced lymphocyte stimulation test revealed carbocysteine as the suspected cause of AGEP, which consequently triggered KD. Because a mucosal lesion is uncommon in AGEP, bulbar conjunctival hyperemia suggested that KD sequentially occurred after AGEP. Since AGEP is benign and self-limited in most cases, it is necessary to differentiate other diseases, including KD, when recurrent fever or rash occurs in the course of AGEP.

Icodextrin-induced acute generalized exanthematous pustulosis in a patient with peritoneal dialysis.

Icodextrin has been widely prescribed for peritoneal dialysis (PD) patients with inadequate ultrafiltration, but icodextrin induced acute generalized exanthematous pustulosis (AGEP) has been not well recognized in clinical practice. We described a young-aged female with IgA nephropathy and end stage kidney disease under continuous automated peritoneal dialysis. She developed skin erythema with exfoliation over the groin 7th day after initiation of icodextrin based PD dialysate. Initially, her scaling skin lesion with pinhead-sized pustules affected the bilateral inguinal folds, and then it extended to general trunk accompanied by pruritus. She was admitted because of deterioration of skin lesion on 14th day of icodextrin exposure. She was afebrile and physical examination was notable for widespread erythematous papules with pruritus extending over her groins and trunk. Pertinent laboratory examination showed leukocytosis of 18 970 cells/µL with neutrophile count of 17 642 cells/µL (92.3%), and c-reactive-protein: 3.39 mg/dL. Skin biopsy revealed multifocal sub corneal abscess with papillary dermal edema, and upper-dermal neutrophilia with perivascular accentuation, consistent with the diagnosis of AGEP. After discontinuation of PD, she underwent temporary high-flux haemodialysis with treatment of steroid and antihistamine. Her dermatologic lesion resolved without any skin sequalae completely within 4 days, and she underwent icodextrin-free peritoneal dialysis at 17th day. This case highlighted the fact that icodextrin-induced AGEP should be early recognized to avoid inappropriate management.

Local injection of micro-dose guselkumab for palmoplantar pustulosis after partial failure of systemic ixekizumab treatment.

We present a palmoplantar pustulosis case partially resistant to systemic IL-17A inhibitor (ixekizumab) treatment, and then receiving a local injection of 0.1 mL micro-dose (1 mg) IL-23 inhibitor (guselkumab) every 4 weeks for four times. The paradoxical lesion disappeared rapidly following local injection and there was no recurrence after 8 weeks of drug withdrawal. This is the first clinical report on the treatment of palmoplantar pustulosis by local injection of micro-dose guselkumab.

308-nm excimer light is effective for palmoplantar pustulosis regardless of the presence or absence of focal infection: Single-center real-world experience of treatment for palmoplantar pustulosis.

Palmoplantar pustulosis (PPP) is relatively rare and recognition of PPP is different in different countries. Therefore, real-world data are limited. Local phototherapy for the palms and the soles is commonly used to treat PPP due to tolerable safety. However, data on the effectiveness of 308-nm excimer light are limited. In our study, we retrospectively investigated the effectiveness of treatments for PPP, especially phototherapy (308-nm excimer light), in our department. In addition, we examined whether smoking status and focal infection affected responsiveness to treatment of PPP. Patients who were diagnosed with PPP by board-certified dermatologists and visited our hospital from April 2015 to August 2018 were analyzed in this study. We collected data on PPP area severity index (PPPASI) before treatment. We also collected data on PPPASI in May to August 2018 as "after treatment" from all patients. Patients who received any treatment for less than 3 months were excluded. Nineteen patients (16 women and three men) were analyzed in this study. In patients treated with phototherapy (n = 12), PPPASI significantly decreased from a mean ± SD of 16.5 ± 10.3 to 4.5 ± 3.6 (p = 0.004), whereas it did not in patients treated without phototherapy (n = 7). Patients who quit smoking showed a significant decrease in PPPASI after treatment (16.8 ± 12.7 to 2.4 ± 2.9, p = 0.008). Regarding focal infection, in patients treated without phototherapy, the reduction rate of PPPASI was significantly lower in patients with focal infection than in those without focal infection (17.7 ± 21.5%, 71.1 ± 19.3%, p = 0.035), indicating that focal infection is associated with intractability. Meanwhile, in patients treated with phototherapy, PPPASI decreased regardless of the presence or absence of focal infection. In conclusion, our study demonstrated the effectiveness of local phototherapy consisting of 308-nm excimer light, regardless of focal infection. Patients who quit smoking were responsive to any treatment, indicating the importance of smoking cessation.

Severe cutaneous adverse reactions in a tertiary care center in Jamaica.

Background: Severe cutaneous adverse reactions (SCARs) are associated with morbidity and mortality. Objective: The aim was to determine the different types of SCARs, their morphology, common offending drugs, interventions, and outcomes. Methods: A retrospective cohort study was conducted of all patients admitted to the dermatology service at the University Hospital of the West Indies with Stevens-Johnson syndrome (SJS), SJS/toxic epidermal necrolysis overlap (TEN), TEN, drug reaction with eosinophilia and systemic symptoms and acute generalized exanthematous pustulosis between January 1, 2012 to June 1, 2022. Results: Fifty-one cases (51) met the inclusion criteria for SCAR. SJS, SJS/TEN overlap and TEN together accounted for 71.2% of cases. SCARs were most frequent in the fourth, fifth and 6th decades of life and there was a female preponderance. Antibiotics (31%) and anticonvulsants (29%) were the most common causative agents for SCARs. Most patients had at least 1 complication. The liver was the most common extracutaneous organ affected. Mortality was 7.8%. The main cause of death was sepsis. Limitations: Results were not generalizable. There were missing data and loss to follow-up. Conclusion: Judicious use of antimicrobials and corticosteroids may be beneficial in treatment of severe cutaneous drug reactions.

Treatment Patterns and Negative Health Outcomes in Palmoplantar Pustulosis Patients in Germany and the US.

INTRODUCTION: Limited information exists on the epidemiology, treatment, and burden of palmoplantar pustulosis (PPP) and defining the optimal course of treatment remains challenging without approved targeted treatments in most countries. Here, we describe the clinical and demographic characteristics, treatments received, and negative health outcomes experienced among patients with PPP in the United States (US) and Germany. METHODS: Retrospective cohort study between 2016 and 2021 using data from the US Merative™ MarketScan® Research Database and IQVIA™ German Disease Analyzer. Adult patients with PPP (ICD-10-CM L40.3) were followed from the date of their first qualifying PPP diagnosis and continued until the earlier of disenrollment or end date of database, during which treatment patterns and incidence rates of negative health outcomes were assessed. Treatment patterns included adherence, non-persistence, discontinuation, re-initiation, switching, and combination therapy. RESULTS: The prevalence of PPP was 0.005% and 0.065% in the MarketScan database and German Disease Analyzer, respectively, with 1629 and 3866 patients meeting the inclusion criteria. Most patients were female (71.3%, 67.8%), with mean (SD) age of 54.1 (11.7) and 56.9 (14.3) years, respectively. One year post index, most patients received topical treatment (77.4%, 65.3%), but non-persistence and discontinuation were high. Oral and biologic treatments displayed higher levels of adherence, particularly apremilast and tofacitinib among oral treatments and TNF inhibitors and IL-23 inhibitors among biologics. Rates of negative health outcomes were higher among patients not receiving treatment post-index compared with those receiving treatment post-index across both databases, regardless of prior treatment history. CONCLUSIONS: Establishing treatment guidelines remains an unmet need for patients with PPP and could improve quality of life by reducing the occurrence of negative health outcomes. The findings from this study may provide insight into the effectiveness of current treatment options for patients with PPP and can be leveraged to support the development of treatment guidelines.

A statistical symptomatic evaluation on SAPHO syndrome from 56 cases of confirmed diagnosis and 352 cases of non-SAPHO involvement.

OBJECTIVE: To report a statistical evaluation of symptomatology based on 56 cases of SAPHO syndrome and 352 non-SAPHO involvement cases, to propose a symptomatic scoring system in consideration of early warning for SAPHO syndrome. METHODS: A cohort comprising 56 subjects diagnosed with SAPHO syndrome was reported, as well as 352 non-SAPHO involvement cases, including their chief complaints, skin manifestations, radiological findings, and laboratory tests. We systematically reviewed previous published five representative huge cohorts from different countries to conclude several specific features of SAPHO by comparing with our case series. The score of each specific index is based on respective incidence and comparison of two cohorts was performed. RESULT: In terms of complaint rates, all subjects of two cohorts suffered from osseous pain, which appeared in the anterior chest wall, spine, and limb which were calculated. In respect to dermatological lesions, SAPHO patients suffered from severe acne, and other patients (82.14%) accompanied with palmoplantar pustulosis. Having received radiological examinations, most SAPHO subjects rather than non-SAPHO involvement cases showed abnormal osteoarticular lesions under CT scanning and more detailed information under whole-body bone scintigraphy. Differences also emerged in elevation of inflammation values and rheumatic markers like HLA-B27. Based on our cases and huge cohorts documented, the early warning standard is set to be 5 scores. CONCLUSIONS: SAPHO syndrome case series with 56 subjects were reported and an accumulative scoring system for the early reminder on SAPHO syndrome was proposed. The threshold of this system is set to be 5 points. Key Points • Fifty-six patients diagnosed by SAPHO syndrome with detailed symptoms and radiological findings were reported. • Comparison was made between the 56 SAPHO patients and 352 non-SAPHO involvement cases. • An accumulative scoring system for the early reminder on SAPHO syndrome was proposed and the threshold of this system is set to be five points.

Characterization and Management of Amicrobial Pustulosis of the Folds, Aseptic Abscess Syndrome, Behçet Disease, Neutrophilic Eccrine Hidradenitis, and Pyostomatitis Vegetans-Pyodermatitis Vegetans.

Neutrophilic dermatoses are a broadly heterogeneous group of inflammatory skin disorders. This article reviews 5 conditions: amicrobial pustulosis of the folds, aseptic abscess syndrome, Behçet disease, neutrophilic eccrine hidradenitis, and pyostomatitis vegetans-pyodermatitis vegetans.The authors include up-to-date information about their epidemiology, pathogenesis, clinicopathologic features, diagnosis, and management.

Generalized Pustular Psoriasis, Acute Generalized Exanthematous Pustulosis, and Other Pustular Reactions: A Clinical Review.

Generalized pustular rashes have various etiologies and can be challenging to diagnose and manage at first presentation. The authors provide an in-depth analysis of common pustular skin eruptions including generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis, focusing on their pathophysiology, triggers, clinical presentation, diagnostic challenges, and management strategies. The article also highlights recent advances in genetic research and biologic therapies for GPP and the future directions in personalized medicine and prevention strategies.

Efficacy of anti-interleukin-17A biological agents for palmoplantar psoriasis and palmoplantar pustulosis: A network meta-analysis.

BACKGROUND: The comparative efficacy of anti-IL (interleukin)-17A biological agents in palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP) are not well established. OBJECTIVE: To investigate the efficacy of different dosage regimens of anti-IL-17A biological agents compared with placebo in PP and PPP. METHODS: A literature search was conducted in PubMed, clinicaltrials.gov, and Embase. Meta-analysis was performed for all outcomes of randomized controlled trials, while network meta-analysis was only performed for the primary outcome. RESULTS: In total, 21 articles exploring the efficacy of 5 treatment options were included, 4 cohort studies were also reviewed. Meta-analysis demonstrated a statistically significant difference favoring anti-IL-17A biological agents versus placebo (OR = 6.84, 95 %[CI] [5.34, 8.76]). On-label secukinumab was identified as the most effective treatment option for patients with PP (OR = 33.50, 95 %[CI] [4.37,256.86]). PPP treated with secukinumab 300 mg showed benefit in terms of PPPASI 75 responses over 52 weeks. CONCLUSION: IL-17A biological agents had better PP disease clearance compared with placebo and on-label secukinumab was identified as the most effective treatment option for PP patients. Secukinumab 300 mg showed benefit for PPP patients.

Stellate ganglion block in the treatment of SAPHO syndrome: a case report.

Synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare and refractory autoinflammatory disease, and there is no consensus on its treatment. Stellate ganglion block (SGB) blocks sympathetic nerves, ameliorates immune dysfunction, and alleviates stress response, which has been used to treat various chronic pain syndromes, arrhythmias, and post-traumatic stress disorder (PTSD). Also, the SGB has been reported to be successfully used to treat certain skin diseases, autoinflammatory diseases, and menopausal symptoms. In this study, over 3 years of follow-up, we found that SGB successfully intervened the symptoms of SAPHO syndrome, including sternoclavicular joint arthritis and palmoplantar pustulosis.

Medication Associations With Severe Cutaneous Adverse Reactions: A Case/Non-Case Analysis Using the FDA Adverse Event Reporting System.

BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) are potentially life-threatening severe cutaneous adverse reactions (SCARs). Although the classical causal agents of SCARs (antibiotics, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol) are well characterized, there has been little update to this list to account for newly marketed medications. OBJECTIVE: To provide an updated and stratified list of medications with significant reporting odds ratios (RORs) of SCARs. METHODS: A case/non-case analysis using the United States FDA Adverse Event Reporting System was performed. RESULTS: As expected, the prototypical medication classes made up the majority of reported cases of SJS, TEN, AGEP, and DRESS (77%, 64%, 75%, and 72%, respectively). In addition, several infrequently or previously undescribed classes/medications implicated in SCARs were identified to have significant ROR signals, including acetylcysteine, anticoagulants, diuretics, immunotherapies, proton pump inhibitors, antivirals, and antifungals. Among these reported for SJS were acetylcysteine (ROR: 64.38) and fluconazole (ROR: 17.13). For TEN, we identified furosemide (ROR: 26.32), spironolactone (ROR: 14.45), fluconazole (ROR: 30.21), amphotericin B (39.06), and acetylcysteine (ROR: 93.12). For AGEP, we identified acyclovir (ROR: 61.72), valacyclovir (ROR: 30.76), and enoxaparin (ROR: 27.37). For DRESS, we identified vemurafenib (ROR: 17.35), acyclovir (ROR: 30.63), abacavir (ROR: 26.62), raltegravir (ROR: 23.27), and valacyclovir (ROR: 21.77) to have strong reporting odds. CONCLUSION: Our analysis provides an updated tool for physicians to reference when identifying suspected SCARs and a basis for future studies to investigate atypical medication causality.