Data mining of severe cutaneous adverse reactions related to immune checkpoint inhibitors in the FAERS / 中国药房

OBJECTIVE To mine and analyze severe cutaneous adverse reaction signals of 5 commonly used immune checkpoint inhibitors （ICIs）， and to provide reference for clinically safe use of drugs. METHODS Based on the FDA adverse events reporting system （FAERS） database，adverse drug events （ADEs） reports about severe cutaneous adverse reactions related to ipilimumab， nivolumab， pembrolizumab， atezolizumab and durvalumab were collected from listing in the United States to the fourth quarter of 2022. The ADE signals were mined and analyzed with reporting odds ratio （ROR） and Bayesian confidence propagation neural network （BCPNN）. RESULTS A total of 5 726 reports of severe cutaneous adverse reactions were collected， including 3 037 reports for nivolumab，1 465 reports for pembrolizumab， 130 reports for durvalumab， 429 reports for atezolizumab and 665 reports for ipilimumab. All 5 kinds of ICIs caused positive signals， the correlation degree of which was as follows： pembrolizumab＞atezolizumab＞nivolumab＞ipilimumab＞durvalumab. Stevens-Johnson syndrome（SJS） and toxic epidermal necrolysis （TEN） have been reported for all 5 ICIs， and the association was the strongest with pembrolizumab. CONCLUSIONS All 5 kinds of ICIs are associated with the risk of severe skin adverse reactions， and close attention should be paid to their clinical use， especially being cautious when using pembrolizumab. The combination of ICIs should be avoided as much as possible.

Acute generalized exanthematous pustulosis / Pustulosis exantemática generalizada aguda

Abstract Background: Acute generalized exanthematous pustulosis is a rare disease. Although it is usually related to drug intake, it is occasionally associated with infections, especially in the pediatric age. It is characterized by the sudden onset of sterile non-follicular pustules on an erythematous fundus, fever, and leukocytosis, with frequent and prompt spontaneous resolution. It mainly affects adults and is uncommon in childhood. Complications have been reported in approximately 20% of cases. Case report: We report the case of a 10-year-old female patient with a 5-day history of fever and dermatosis characterized by countless non-follicular pustules, predominantly on the trunk, inguinal folds, and proximal thighs but not involving palms, soles, and mucous membranes. The patient reported an incident of upper respiratory tract infection that occurred 7 days earlier. Histopathological examination confirmed the diagnosis of acute generalized exanthematous pustulosis. Spontaneous resolution occurred within 2 weeks. Conclusions: This disease is one of the severe cutaneous adverse reactions that usually have a self-limited and benign course within a few weeks. We propose that a previous respiratory infection triggered the acute generalized exanthematous pustulosis in this pediatric case. Knowledge of this pathology by the medical professionals, in general, and the pediatricians, in particular, will prevent an aggressive and inappropriate approach and management.

Resumen Introducción: La pustulosis exantemática generalizada aguda es una enfermedad rara. Aunque usualmente se relaciona con el consumo de drogas, ocasionalmente se asocia con infecciones, sobre todo en edad pediátrica. Se caracteriza por el inicio súbito de pústulas no foliculares estériles sobre un fondo eritematoso, fiebre y leucocitosis, con frecuente y pronta resolución espontánea. Afecta principalmente a los adultos, y no es frecuente en la niñez. Se han reportado complicaciones en cerca del 20% de casos. Caso clínico: Se presenta el caso de una paciente de 10 años con fiebre e historia de dermatosis de 5 días de evolución caracterizada por incontables pústulas no foliculares de predominio en tronco, pliegues inguinales y parte proximal de muslos, respetando palmas, plantas y mucosas. Refirió antecedente de infección respiratoria alta 7 días antes. El examen histopatológico confirmó el diagnóstico de pustulosis exantemática generalizada aguda. Presentó resolución espontánea en el transcurso de 2 semanas. Conclusiones: Esta enfermedad es una de las reacciones adversas cutáneas severas, que tiene un curso usualmente autolimitado y benigno en pocas semanas. Proponemos que la pustulosis exantemática generalizada aguda en este caso pediátrico fue desencadenada por la infección respiratoria previa. El conocimiento de esta patología por parte del gremio médico, en general, y del pediatra, en particular, evitará un abordaje y manejo agresivo e inapropiado.

Causative drugs for drug-induced cutaneous reactions in central China: a 608-case analysis

Abstract Background: Reports regarding the causative drugs of drug-induced cutaneous adverse reactions in China are indistinct, such that different regions have reported the spectrum of drugs differs substantially in different clinical conditions. Objective: To explore the causative drugs that led to cutaneous reactions. Methods: Adverse drug reaction reports from central China were collected and divided into cutaneous adverse reactions and severe cutaneous adverse reactions groups. Cases were reviewed retrospectively for causative drugs. Results: The male:female ratio was equal in both cutaneous adverse reactions and severe cutaneous adverse reactions. In cutaneous adverse reactions (n = 482), the highest incidence happened between 51 and 60 years of age and the top three causative drugs were antibiotics (48%), Chinese medicine (16%), and allopurinol (9%). In severe cutaneous adverse reactions (n = 126), the highest incidence happened between 41 and 50 years of age and the top three causative drugs were sedative-hypnotics and antiepileptics (39%), antibiotics (22%), and allopurinol (15%). Carbamazepine was the most frequently used single-drug (16/18) in sedative-hypnotics and antiepileptics. β-lactams were the most frequently used antibiotics that induced both cutaneous adverse reactions and severe cutaneous adverse reactions. Study limitations: The small sample size, retrospective design, collection of cutaneous adverse reactions and severe cutaneous adverse reactions at different time frames and locations, and exclusion of patients taking more than five medications are limitations of the study. Conclusions: Gender does not affect cutaneous adverse reactions and severe cutaneous adverse reactions. The top three drugs to induce cutaneous adverse reactions are antibiotics, Chinese medicine, and allopurinol, while those that triggered severe cutaneous adverse reactions are sedative-hypnotics and antiepileptics, antibiotics, and allopurinol. Carbamazepine is the most frequent single drug that induces severe cutaneous adverse reactions. β-lactams are the most frequently used antibiotics that induce both cutaneous adverse reactions and severe cutaneous adverse reactions.

Antiepileptic drug-induced severe cutaneous adverse reactions and HLA alleles: A report of five cases with lymphocyte activation test

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,

Clinical characteristics, culprit drugs and outcome of patients with Acute Generalised Exanthematous Pustulosis seen in Hospital Sultanah Aminah, Johor Bahru

Background: Acute generalised exanthematous pustulosis(AGEP) is a rare, cutaneous reaction characterised bysudden onset of numerous, non-follicular, sterile pustuleson oedematous erythematous skin, accompanied by feverand neutrophilia. AGEP is predominantly drug-induced. Skinlesions appear rapidly within 1-3 days of drug exposure andupon drug withdrawal, resolve rapidly within 15 days.Objective: To determine the clinical characteristics, culpritdrugs and outcome of patients with AGEP.Methods: A retrospective note review of all AGEP patientsseen from 2001-2015.Results: Among 21 AGEP patients, 76% were Malays, 9.5%Chinese, 9.5% Indians, and 5% Iban. Sixteen were femalesand 5 were males. Median age of patients was 40 years (IQR:26). The main culprit drug was amoxicillin (10 cases),followed by cloxacillin (three cases), phenytoin (two cases)and one case each of carbamazepine, sulphasalazine,allopurinol, cephalexin, ceftriaxone, celecoxib and herbalproduct. The median time from drug initiation to onset ofAGEP was 3 days (IQR: 5.5). Fever was documented in 52.4%, mucosal involvement 9.5%, purpura 4.7% and blisters4.7%. Neutrophilia was observed in 63.6% of patients andeosinophilia in 28.5%. While most patients requiredadmission (67%), all achieved complete recovery within 15days without any sequela.

An Epidemiological Study of Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) overlap in University Malaya Medical Centre

Introduction: Steven-Johnson syndrome and Toxic Epidermal Necrolysis are rare but life threatening severe cutaneous adverse reactions to drugs. To determine the epidemiology of SJS, TEN and SJS/TEN overlap in University Malaya Medical Centre (UMMC). Methods: All patients admitted to UMMC from year 2013-2015 for SJS, SJS/TEN, TEN were recruited. The classification of SJS, SJS/TEN overlap and TEN was made based on the criteria laid down by Bastuji et al.2 Results: A total of 32 patients were recorded to have SJS, SJS/TEN overlap and TEN from 2013 to 2015. Drugs (n=32, 86.49%) remained the most common aetiology of SJS and TEN. The top three commonest drugs are allopurinol (n=6), followed by carbamazepine (n=5) and bactrim (n=3). Conclusion: This study demonstrates that drugs were the most common cause of SJS/TEN. Antibiotics were the most common drug group that caused SJS/TEN. Awareness of the common etiology such as drug is important and high index of suspicion of SJS and TEN is needed if patients were on the above medications.

Validation of a Rapid, Robust, Inexpensive Screening Method for Detecting the HLA-B*58:01 Allele in the Prevention of Allopurinol-Induced Severe Cutaneous Adverse Reactions

The HLA B*58:01 allele has been worldwide reported as a pharmacogenetic susceptibility to allopurinol-induced severe cutaneous adverse reactions (SCARs). To prevent these life-threatening conditions, the American College of Rheumatology hingly recommended that the HLA-B*58:01 be screened prior to the initiation of allopurinol therapy. Therefore, we developed a rapid, robust, inexpensive screening method using SYBR® Green real time PCR to detect the HLA-B*58:01 allele. A total of 119 samples were tested. The assay has a sensitivity of 100% (95% CI: 69.15%-100%), a specificity of 100% (95% CI: 96.67%-100%), a positive predictive value of 100% (95% CI: 69.15%-100%) and a negative predictive value of 100% (95% CI: 96.67%-100%). HLA-B*58:01 genotyping results showed 100% agreement with those obtained from Luminex SSO/SBT/SSP. The lowest limit of detection of this method is 0.8 ng/µL of DNA. The unit cost of the test is only $3.8 USD. This novel screening test using SYBR® real time PCR would be appropriate to identify individuals with the HLA-B*58:01 allele for the prevention of allopurinol-induced SCARs.

Allopurinol-induced severe cutaneous adverse reactions: A report of three cases with the HLA-B*58:01 allele who underwent lymphocyte activation test

Allopurinol-induced severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome are reportedly associated with the HLA-B*58:01 genotype. Three patients who developed SCARs after allopurinol administration were subjected to HLA-B genotyping and lymphocyte activation test (LAT) to evaluate genetic risk and to detect the causative agent, respectively. All three patients given allopurinol to treat gout were diagnosed with DRESS syndrome. Symptom onset commenced 7-24 days after drug exposure; the patients took allopurinol (100–200 mg/d) for 2-30 days. HLA-B genotyping was performed using a polymerase chain reaction (PCR)-sequence-based typing (SBT) method. All patients had a single HLA-B*58:01 allele: HLA-B*13:02/*58:01 (a 63-year-old male), HLA-B*48:01/*58:01 (a 71-year-old female), and HLA-B*44:03/*58:01 (a 22-year-old male). Only the last patient yielded a positive LAT result, confirming that allopurinol was the causative agent. These findings suggest that patients with HLA-B*58:01 may develop SCARs upon allopurinol administration. Therefore, HLA-B genotyping could be helpful in preventing serious problems attributable to allopurinol treatment, although PCR-SBT HLA-B genotyping is time consuming. A simple genotyping test is required in practice. LAT may help to identify a causative agent.