Dupilumab-induced psoriasiform dermatitis in two pediatric cardiac transplant patients.

Dupilumab is an interleukin-4 receptor antagonist important in the treatment of refractory atopic dermatitis (AD), particularly among pediatric patients. Two boys with a history of AD and cardiac transplant who developed psoriasiform dermatitis in response to dupilumab therapy are reported. These patients paradoxically developed an immune-mediated adverse drug reaction despite taking systemic immunosuppressive agents. While the literature suggests possible pathomechanisms for psoriasiform dermatitis despite immunosuppression, further research is necessary to better characterize this unique and unexpected phenomenon.

Disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia.

Fusarium is a polyphyletic genus of plant pathogens, members of which can cause opportunistic human infections with varying superficial and systemic presentations, including disseminated infections which typically occur in immunocompromised patients and have a poor prognosis. Treatment is challenging due to intrinsic resistance to many antifungal agents, and antifungal susceptibility testing is therefore essential. Early suspicion, isolation of the organism, and prompt initiation of management are crucial to improving survival. We present a case of disseminated Bisifusarium infection following toxic epidermal necrolysis in a child with B-cell acute lymphoblastic leukemia, successfully treated with liposomal amphotericin B, voriconazole, flucytosine, and terbinafine.

Concurrent acute generalized exanthematous pustulosis in siblings.

Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction triggered in most cases by drugs. It is characterized by abrupt onset and rapid evolution of fields of sterile pustules on an erythematous background. The role of genetic predisposition in this reactive disorder is being explored. We report the simultaneous occurrence of AGEP in two siblings after being exposed to the same drug.

Acute generalized exanthematous pustulosis complicated by cutaneous small vessel vasculitis: A case report and literature review.

Acute generalized exanthematous pustulosis (AGEP) is a rare skin eruption characterized by widespread erythematous lesions covered with numerous pustules. Leukocytoclastic vasculitis is now considered an uncommon but possible histopathological feature within the clinical and pathological spectrum of AGEP. Our report describes a rare case of AGEP overlapping with cutaneous small vessel vasculitis, a condition that has only been reported once in the literature.

The mixed spongiotic and interface reaction pattern: A study of clinical and histopathologic findings.

BACKGROUND: Categorization of biopsy specimens into inflammatory reaction patterns is central to dermatopathologic assessment. Mixed inflammatory patterns are poorly characterized and may represent clinicopathologic challenges. The purpose of this study was to identify clinical and histopathologic findings associated with the mixed spongiotic-interface dermatitis (SID) histopathologic pattern. METHODS: Fifty-one institutional biopsy specimens of SID were identified over a 2-year period by retrospective natural language search. Histopathologic and clinical features were identified. RESULTS: The most common histopathologic features associated with SID were mild spongiosis (51%), focal vacuolar interface change (72%), lymphocytic exocytosis (92%), and superficial-dermal lymphocytic infiltrate (94%) with variable eosinophils (61%). Clinically, 80% of subjects presented with a symmetric morbilliform eruption. Polypharmacy (94%), immunosuppression (47%), and history of malignancy (47%) were common. The most common diagnoses were drug reaction (37%), possible drug reaction (12%), and viral exanthem (12%). Drug reaction with eosinophilia and systemic symptoms represented 25% of all confirmed cutaneous adverse drug reactions (CADR). Average time from drug initiation to symptom initiation was 20 days (SD: 22.3, range: 0-90); median disease duration was 25.5 days. Spongiotic vesicles and Langerhans cells were less common in patients with a strong clinicopathologic diagnosis of drug reaction compared to non-drug eruptions (p = 0.04). CONCLUSIONS: The mixed SID pattern is commonly encountered in CADR but may represent a more subacute course, implying consideration for inciting medication(s) started before the typical 7- to 14-day window.

Lichen planus pemphigoides: A unique form of bullous and lichenoid eruptions secondary to nivolumab.

The widespread use of PD-1 inhibitors to treat various solid tumors has brought certain challenges for the clinician, including immune-related adverse events (irAEs). Cutaneous toxicities are among the most observed irAEs. Bullous and lichenoid dermatoses following PD-1 inhibitor therapy have been described. Here we report a novel case of lichen planus pemphigoides, featuring characteristics of both bullous pemphigoid and lichen planus, in a patient treated with nivolumab for renal cell carcinoma. We subsequently review all three cutaneous conditions which may arise in the context of PD-1 inhibitor therapy.

A striking presentation of pustular Sweet syndrome induced by trimethoprim-sulfamethoxazole.

We describe a strikingly robust presentation of trimethoprim-sulfamethoxazole (TMP-SMX)-induced pustular Sweet syndrome and discuss how to distinguish it from iododerma and other neutrophil-rich conditions. A review of the literature indicates that TMP-SMX-induced Sweet syndrome (SS) may have higher rates of neutrophilia and greater ocular, mucosal, and musculoskeletal involvement compared to SS from other drugs. Recognizing these features and identifying the offending agent are critical for correctly diagnosing TMP-SMX-induced SS in a timely manner.

Three cases of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) induced by proton-pump inhibitors.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), previously termed drug-related baboon syndrome, is an uncommon drug eruption. It is characterized by symmetrical erythema involving the gluteal and/or inguinal area in association with one other intertriginous area in the absence of systemic involvement. It typically develops a few hours to days after drug exposure. The diagnosis is based on clinical presentation and drug history. The treatment consists mainly of withdrawal of the causative agent; corticosteroids (topical or systemic) are prescribed to accelerate the resolution. We present three cases that appeared after proton-pump inhibitors (PPIs) intake.

The assessment of severe cutaneous adverse drug reactions.

Severe cutaneous adverse drug reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalised exanthematous pustulosis. These eruptions are a type of delayed hypersensitivity reaction and can be life-threatening. The assessment of a severe cutaneous drug reaction requires a detailed clinical history and examination to identify the culprit drug and evaluate the allergy. Allopurinol, antibiotics and anticonvulsants are often implicated. Patch testing and delayed intradermal testing can assist in determining if the reaction was allergic, however there is limited evidence about the sensitivity and specificity of skin testing in severe cutaneous adverse drug reactions. If the testing is non-conclusive or negative, it is recommended to avoid the suspected culprit drug and any structurally similar drug in future. Any decision to reintroduce a drug should be made after considering the harm-benefit ratio. Caution is also needed if considering a possibly cross-reactive drug in a patient with a history of severe cutaneous adverse drug reactions.

Purpuric drug eruptions induced by EGFR tyrosine kinase inhibitors are associated with IQGAP1-mediated increase in vascular permeability.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used as a treatment for non-small-cell lung cancer. There have been some reports of EGFR-TKIs being associated with vascular adverse events. We found that EGFR-TKIs decreased the proliferation of HMEC-1s (immortalized human dermal microvascular endothelial cells) and HMVECs (human dermal microvascular endothelial cells), and also inhibited the phosphorylation of EGFR and ERK. We examined the mRNA expression profile of erlotinib-treated HMEC-1s and identified IQ motif containing GTPase activating protein 1 (IQGAP1) as the most consistently up-regulated transcript and protein. IQGAP1 was also overexpressed and co-localized with endothelial cells in the lesional skin. Notably, increased IQGAP1 expression was associated with decreased transendothelial electrical resistance and increased vascular permeability in vitro. Erlotinib treatment enriched the staining of IQGAP1 and reduced the intensities of α-catenin at the sites of cell-cell contact. In conclusion, erlotinib induces adherens junction dysfunction by modulating the expression of IQGAP1 in dermal endothelial cells. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Duration of Oral Antibiotics Administration for Cetuximab-Induced Acneiform Eruption.

BACKGROUND: Acneiform eruption is the most common cutaneous adverse event associated with cetuximab. As it can affect quality of life and adversely affect chemotherapy schedule, additional medical care is required. OBJECTIVES: To investigate the adherence to and the duration of antibiotic administration to treat cetuximab-induced acneiform eruption. METHODS: Medical data of patients who were referred to the Department of Dermatology were reviewed from January 2013 to June 2018. Dermatologists assessed the severity of acneiform eruption and prescribed tetracycline-class antibiotics according to the severity every 2 or 4 weeks. We investigated the duration and amount of oral antibiotic administration and analyzed the factors that may affect the control of acneiform eruption statistically. RESULTS: A total of 207 of 267 patients referred to the Department of Dermatology showed acneiform eruption; 124 patients were treated with minocycline, 34 patients with doxycycline, 27 patients with both, and 22 patients with topical agents. The mean duration of oral antibiotic medication was 82.7 days. A statistical analysis of the factors that prolonged the use of antibiotics for more than 90 days showed that male and younger age were risk factors. Shorter time interval from starting cetuximab to starting antibiotics was associated with longer duration of antibiotic use, statistically. CONCLUSIONS: Cetuximab-induced acneiform eruption can be well controlled with tetracycline-class antibiotics in about 3 months. It can last longer in male and younger patients. The sooner and the more severe it appears, the longer it can last.

Severe Cutaneous Adverse Reactions to Drugs in Latin America: The RACGRAD Study.

BACKGROUND AND OBJECTIVE: Severe cutaneous adverse reactions to drugs (SCARs) are associated with high morbidity and mortality and with sequelae. Objective: To characterize patients with SCARs in 8 health care institutions in Latin America. METHODS: We performed a cross-sectional, descriptive, multicenter study of patients diagnosed with SCARs in Latin America between January 2009 and December 2018. The analysis was carried out using a database in BD Clinic. RESULTS: We collected 70 patients, of whom 42 (60%) were women. Mean age was 38.7 years. Forty-two patients (60%) had DRESS-DIHS, 12 (17.1%) TEN, 5 (7.1%) SJS, 6 (8.5%) AGEP, 4 (5.7%) other reactions not classified as SCARs, and 1 (1.4%) overlapping SJS-TEN. The main causative drugs were aromatic anticonvulsants in 31 cases (44.3%), ß-lactam antibiotics in 11 cases (15.7%), and non-ß-lactam antibiotics in 6 cases (8.6%). In all of the cases, the suspected drug was withdrawn at the first sign of a SCAR. Sixty-six patients (94.2%) received anti-inflammatory treatment, mostly systemic corticosteroids. Complications occurred in 53 cases (75.7%), and 3 patients died (4.3%). Thirteen patients (18.6%) had sequelae. CONCLUSIONS: This is the first multicenter report on SCARs in Latin America. DRESS-DIHS was the most frequently reported clinical entity, and anticonvulsants were the main triggers. Most of the patients received systemic corticosteroids. Complications were frequent, and 3 patients died.

Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: A guide for the dermatologist.

The new coronavirus, severe acute respiratory syndrome coronavirus 2, is associated with a wide variety of cutaneous manifestations. Although new skin manifestations caused by COVID-19 are continuously being described, other cutaneous entities should also be considered in the differential diagnosis, including adverse cutaneous reactions to drugs used in the treatment of COVID-19 infections. The aim of this review is to provide dermatologists with an overview of the cutaneous adverse effects associated with the most frequently prescribed drugs in patients with COVID-19. The skin reactions of antimalarials (chloroquine and hydroxychloroquine), antivirals (lopinavir/ritonavir, ribavirin with or without interferon, oseltamivir, remdesivir, favipiravir, and darunavir), and treatments for complications (imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine and low molecular weight heparins) are analyzed. Information regarding possible skin reactions, their frequency, management, and key points for differential diagnosis are presented.

Cutaneous side effects in a cohort of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: General description and further characterization, correlation with photoexposition and study of hypopigmentation as treatment's prognostic factor.

Cutaneous adverse effects (AE) related to tyrosine-kinase inhibitor (TKI) drugs have been mainly described as case reports. We have characterized their appearance and correlation with patient's photoexposition habits and, further, with treatment response, in 61 patients with chronic myelogenous leukemia (CML) treated with TKI drugs. We have found hypopigmentation in 49.2% of the cases and a statistically significant association with interferon (IFN) intake. Eyelid edema's frequency was 45.4%. Mean photo-exposure was 1.95 h/day and only 8.3% of the patients used sunscreen daily. 44.3% of the patients reported a lighter skin color with the treatment and a statistically significant relationship with conjunctival hemorrhage was also found. Concordance between patients and dermatologist was moderate (kappa index 0.41). We found xerosis (21.3%), eczematous eruptions (21.3%), melasma (4.9%) and other isolated skin problems (ie, granulomatous panniculitis) in up to 16.4% of cases. Appearance of hypopigmented macules is associated to vascular conjunctival fragility and these patients need a slightly longer time to reach a complete molecular response, but without additional changes in survival or relapse frequency. We have stablished a specific dermatologic diagnosis in all the cases and we have not found the previously published as maculopapular rashes. Hypopigmentation, the more frequent AE, was not perceived as a relevant side effect. Photosensitivity, in our cases, was not reported, although imatinib-treated patients avoided sun-exposure. In addition, we identified some nonpreviously described dermatologic conditions in patients taking TKI drugs, like granulomatous panniculitis tufted folliculitis or oral spindle cell lipoma.

Association between serum ferritin and the severity of drug eruptions.

BACKGROUND: Early recognition and treatment for severe drug eruption are important in improving clinical outcomes. A few studies have reported laboratory parameters to evaluate the severity of drug eruptions. This study aimed to determine the association between serum ferritin and the severity of drug eruptions. METHODS: We retrospectively reviewed patients diagnosed with drug eruptions in our hospital from 2013 to 2018. RESULTS: We identified 85 patients (mean age 53.4 years), 20 in the severe cutaneous adverse drug reactions (SCADRs) group and 65 in the non-SCADRs group. Serum ferritin level was higher in the SCADRs group compared with that in the CADRs group (P<.001). Serum ferritin was positively associated with peripheral white blood cell count, aspartate aminotransferase level, alanine aminotransferase level, blood glucose level, blood creatinine level, and body temperature. Receiver operating characteristic (ROC) analysis revealed a good diagnostic value of ferritin (area under the curve [AUC]:0.87, 95% confidence interval [CI]:0.78-0.96) with a sensitivity of 80% and a specificity of 87.7% at a cutoff value of 416.15 ng/mL. CONCLUSIONS: Serum ferritin is significantly associated with the severity of CADRs and hence might be potentially used to evaluate the severity of CADRs.

Glutathione S-transferase polymorphisms in patients with photosensitive and non-photosensitive drug eruptions.

BACKGROUND: Glutathione S-transferases (GSTs) play a critical role in cellular protection against oxidative damage. Polymorphisms in three major GST loci have been described. A number of studies have looked for an association between GSTs and skin diseases. PURPOSE: To ascertain the possibility that polymorphisms in the GSTM1, GSTT1, and GSTP1 genes may predict the development of photo-induced and non-photo-induced drug eruptions. METHODS: A cohort of 40 patients with drug eruptions, 10 of whom had developed a photo-induced drug reaction, and matched controls (116 for GSTM1 and GSTT1, 120 for GSTP1) were studied. Genotyping was conducted using direct sequencing and polymerase chain reaction. RESULTS: The GSTP1 Val/Val genotype was significantly associated with non-photosensitive drug eruptions (OR = 3.64, P value = 0.038), whereas associations observed between GSTP1, GSTM1, GSTT1 polymorphisms and photosensitive drug eruptions did not reach statistical significance. CONCLUSIONS: Variations in GSTP1 may affect the risk to develop non-photo-induced drug eruptions. These results warrant confirmatory studies in a larger patient sample.

Occupational allergic contact dermatitis caused by antibiotics in healthcare workers - relationship with non-immediate drug eruptions.

BACKGROUND: Occupational allergic contact dermatitis (ACD) in healthcare workers (HCWs) is common, but systemic antibiotics are rarely reported as the cause. OBJECTIVES: Characterize occupational ACD by handling systemic antibiotics. METHOD: A retrospective analysis was performed of ACD caused by systemic antibiotics among HCWs patch tested between 2010 and 2016 with a series of systemic antibiotics. RESULTS: We studied 4 female nurses aged 28-47 years who developed ACD while working in surgical departments. They had eczema of the hands, and forearms or face, and 1 patient, who previously had exanthema caused by flucloxacillin, also developed a generalized rash following airborne exposure to systemic antibiotics. Patch tests showed positive reactions to ampicillin and cefazolin in 1 patient, to cefotaxime and ceftriaxone in 2 patients, and to several penicillins in another patient. Three patients also reacted to rubber allergens, fragrances, and/or preservatives. All patients admitted having direct and sporadic exposure to systemic antibiotic solutions. Avoidance resulted in a significant improvement of ACD, but 1 patient had to change job. CONCLUSIONS: Occupational ACD caused by ß-lactam antibiotics, particularly cephalosporins, is significant in HCWs. Cross-reactions between ß-lactams are similar to those described in non-immediate drug eruptions. A relationship between systemic delayed drug hypersensitivity and ACD, as observed in one case, suggests that patients should avoid future use of the antibiotic to which they are sensitized.

[Severe skin reactions due to new medications]. / Schwere Hautreaktionen auf neue Medikamente.

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and a specific form of hypersensitivity syndrome which is nowadays called "drug reaction with eosinophilia and systemic symptoms" (DRESS) are severe, mainly drug-induced skin reactions. Whereas SJS/TEN is considered one reaction entity of different severity, DRESS has to be distinguished from SJS/TEN but also from other severe exanthems due to multiorgan involvement. Although SJS/TEN is generally referred to as drug reaction, in total only about three quarters of the cases are actually caused by drugs. After the clinical diagnosis is made, identification of the potential inducing factor is most important. In case medications are considered as causal, their withdrawal plays a key role in management. In order to identify and withdraw the inducing agent, a detailed and thorough medication history must be obtained. Agents identified or confirmed as inducers of SJS/TEN by pharmacoepidemiological studies are allopurinol, antibacterial sulfonamides, various antiepileptics, nevirapine and nonsteroidal anti-inflammatory drugs of the oxicam-type. Among drugs inducing DRESS are also various antiepileptics, but in addition allopurinol, sulfonamides and minocycline. Some cases of SJS/TEN and DRESS associated with the use of new medication, including targeted therapies and biologicals, have been observed.

An Epidemiological Study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis during 2010-2015 at Shahid Faghihi Hospital, Shiraz, Iran.

The Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two ends of the spectrum of severe immunobullous state characterized by keratinocyte apoptosis. The present study aimed to draw attention to various epidemiological features of SJS and TEN diseases such as causative drugs, underlying diseases, duration of hospitalization, and types of treatment. The records of all patients with the diagnosis of SJS, TEN, and SJS/TEN overlap during 2010-2015 were retrospectively reviewed. The records belonged to patients who were admitted to the Dermatology Tertiary Referral Center of Shahid Faghihi Hospital affiliated to the Shiraz University of Medical Sciences, Shiraz, Iran. From a total of 97 patients with such skin disorders, we identified SJS in 89 (91.8 %), TEN in 5 (5.1%), and SJS/TEN overlap in 3 (3.1%) patients. The most commonly consumed drug was Lamotrigine (21.6%) and the most common drug category was anticonvulsants (46.4%). In line with many studies, especially in Iran, Lamotrigine and anticonvulsant drugs were the most common causative drug and epilepsy was the most common underlying disease. Patients with SJS/TEN overlap or TEN were treated with combination therapy, whereas SJS patients received systemic corticosteroids.