Skin Testing and Drug Provocation Tests in Epidermal Necrolysis: A French Experience.

BACKGROUND: There are limited data on the use of skin testing, other than patch testing, and challenges in the evaluation of epidermal necrolysis (EN), including Stevens-Johnson syndrome and toxic epidermal necrolysis. OBJECTIVE: To report a French multicenter experience in skin testing and challenges in EN, and investigate the factors associated with tests' positivity. METHODS: All patients who were evaluated by patch tests (PTs), skin prick tests, intradermal tests (IDTs), or drug provocation tests (DPTs) for EN between 2010 and 2020 were retrospectively included through 2 French drug reaction networks. RESULTS: In total, 113 patients were included from 8 centers. Median (interquartile range) time from EN to hypersensitivity workup was 7.9 months (5.1-15 months). All patients had PTs, 17 (15%) had skin prick tests or IDTs with delayed readings and 32 (28.3%) had DPTs. One mild reaction occurred after a DPT. Overall, 22 patients (19.5%) had positive PTs, and the only factors associated with positivity were Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score and drug class. Only 1 IDT was positive but considered irrelevant. The DPTs were never performed to prove responsibility of a highly suspected drug but were used to confirm current tolerance of needed medications. CONCLUSIONS: Allergological workup in EN, performed by specialists involved in EN, seems safe. Skin tests, although of limited sensitivity, can be helpful for considering the reintroduction of essential drugs according to a benefit-to-risk decision. We propose an algorithm for approaching hypersensitivity testing in patients with EN, to be adapted to each patient.

Neurofibromatosis 1 French national guidelines based on an extensive literature review since 1966.

Neurofibromatosis type 1 is a relatively common genetic disease, with a prevalence ranging between 1/3000 and 1/6000 people worldwide. The disease affects multiple systems with cutaneous, neurologic, and orthopedic as major manifestations which lead to significant morbidity or mortality. Indeed, NF1 patients are at an increased risk of malignancy and have a life expectancy about 10-15 years shorter than the general population. The mainstay of management of NF1 is a patient-centered longitudinal care with age-specific monitoring of clinical manifestations, aiming at the early recognition and symptomatic treatment of complications as they occur. Protocole national de diagnostic et de soins (PNDS) are mandatory French clinical practice guidelines for rare diseases required by the French national plan for rare diseases. Their purpose is to provide health care professionals with guidance regarding the optimal diagnostic and therapeutic management of patients affected with a rare disease; and thus, harmonizing their management nationwide. PNDS are usually developed through a critical literature review and a multidisciplinary expert consensus. The purpose of this article is to present the French guidelines on NF1, making them even more available to the international medical community. We further dwelled on the emerging new evidence that might have therapeutic potential or a strong impact on NF1 management in the coming feature. Given the complexity of the disease, the management of children and adults with NF1 entails the full complement healthcare providers and communication among the various specialties.

Higher Frequency of Dipeptidyl Peptidase-4 Inhibitor Intake in Bullous Pemphigoid Patients than in the French General Population.

Dipeptidyl peptidase-4 inhibitors have been suspected to induce bullous pemphigoid (BP). The objective of this study was to compare the observed frequency of gliptin intake in a large sample of 1,787 BP patients diagnosed between 2012 and 2015 in France, with the expected frequency after indirect age standardization on 225,412 individuals extracted from the database of the National Healthcare Insurance Agency. The secondary objective was to assess the clinical characteristics and the course of gliptin-associated BP, depending on whether gliptin was continued or stopped. The observed frequencies of intake of the whole gliptin class and that of vildagliptin in the BP population were higher than those in the general population after age standardization (whole gliptin class: 6.0%; 95% confidence interval = 4.9-7.1% vs. 3.6%, observed-to-expected drug intake ratio = 1.7; 95% confidence interval = 1.4-2.0; P < 0.0001; vildagliptin = 3.3%; 95% confidence interval = 2.5-4.1% vs. 0.7%, ratio = 4.4; 95% confidence interval = 3.5-5.7; P < 0.0001). The association of any gliptin+metformin was also higher than in the general population, ratio = 1.8 (95% confidence interval = 1.3-2.4; P < 0.0001). Gliptin-associated BP had no specific clinical characteristics. Gliptin was stopped in 48 (45.3%) cases. Median duration to achieve disease control, rate, and delay of relapse were not different whether gliptin was stopped or continued. This study strongly supports the association between gliptin intake, particularly vildagliptin, and the onset of BP.

Patch testing in non-immediate cutaneous adverse drug reactions: value of extemporaneous patch tests.

BACKGROUND: Patch testing following a standardized protocol is reliable for identifying the culprit drug in cutaneous adverse drug reactions (CADRs). However, these patch tests (PTs) require pharmaceutical material and staff, which are not always easily available. OBJECTIVES: To evaluate an extemporaneous PT method in CADRs. METHODS: We retrospectively analysed data for all patients referred to our department between March 2009 and June 2013 for patch testing after a non-immediate CADR. The patients who supplied their own suspected drugs were tested both with extemporaneous PTs and with conventional PTs. Extemporaneous PTs involved a nurse crushing and diluting the drug in pet. in a ratio of approximately one-third to two-thirds. Standardized PTs were performed according to guidelines, with commercial drugs diluted to 30% or with active ingredients diluted to 10%. We analysed the data for the two PT methods in terms of the number of positive test reactions, drugs tested, and type of CADR for patients in whom the two PT methods were used. RESULTS: In total, 75 of 156 patients underwent the two PT procedures, including 91 double tests. Overall, 21 tests gave positive reactions with the two methods, and 69 other tests gave negative results with the two methods. CONCLUSION: Our series yielded results similar to those of published series concerning the types of CADR and the drugs responsible. Our results suggest that, for CADRs, if a patient supplies a suspected drug but if the pharmaceutical material and staff are not available for conventional PTs, extemporaneous PTs performed by the nurse with the commercial drug used by the patient can be useful and reliable.

Severe cutaneous adverse reactions to drugs.

During the past decade, major advances have been made in the accurate diagnosis of severe cutaneous adverse reactions (SCARs) to drugs, management of their manifestations, and identification of their pathogenetic mechanisms and at-risk populations. Early recognition and diagnosis of SCARs are key in the identification of culprit drugs. SCARS are potentially life threatening, and associated with various clinical patterns and morbidity during the acute stage of Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms, and acute generalised exanthematous pustulosis. Early drug withdrawal is mandatory in all SCARs. Physicians' knowledge is essential to the improvement of diagnosis and management, and in the limitation and prevention of long-term sequelae. This Seminar provides the tools to help physicians in their clinical approach and investigations of SCARs.

Acute Liver Failure/Injury Related to Drug Reaction With Eosinophilia and Systemic Symptoms: Outcomes and Prognostic Factors.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare severe adverse drug-induced reaction with multiorgan involvement. The outcome and prediction of those patients who develop severe acute liver injury (sALI) or acute liver failure (ALF) remain little known. METHODS: A multicenter retrospective study of patients admitted with a diagnosis of DRESS-related sALI or ALF. Histological review was performed on liver core biopsies from native livers. RESULTS: Sixteen patients (11 women, 5 men; mean age, 39±17.2 years) were classified as having definite (n=13) or probable (n=3) DRESS. At admission, 3 patients had hepatic encephalopathy; median levels of prothrombin time, INR, and total bilirubin were, respectively, 33% (Q1-Q3, 21-41), 2.74 (1.98-4.50), and 94 µmol/L (Q1-Q3, 39.5-243.5). Nine patients received corticosteroid therapy. Overall, 9 patients improved spontaneously and 7 worsened (liver transplantation [LT] (n=5), deceased (n=2)). Transplantation-free and post-LT survival was 56% and 60%, respectively. After LT, DRESS recurrence was observed in 3 of 5 patients. Systemic corticosteroid therapy was not significantly associated with a clinical improvement. In the multivariate analysis, factor V level less than 40% at day 0 and factor V levels of 40% or greater at admission but decreasing at day 2 were associated with worse outcome. Pathological findings (n=7) revealed atypical lymphoid infiltrates, Kupffer cell hyperplasia with erythrophagocytosis, and an inconstant presence of eosinophils. CONCLUSIONS: The spontaneous prognosis of patients with sALI/ALF due to DRESS is poor and was not improved by corticosteroid therapy. Histology is helpful to establish diagnosis. Dynamic variables regarding factor V values are predictive of a poor outcome.

Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Early diagnosis and prognosis monitoring for Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) still remain a challenge. This study aims to explore any cytokine/chemokine with prognostic potential in Stevens-Johnson syndrome/TEN. Through screening a panel of 28 serological factors, IL-6, IL-8, IL-15, tumor necrosis factor-α, and granulysin were upregulated in patients with Stevens-Johnson syndrome/TEN and selected for the further validation in total 155 patients with Stevens-Johnson syndrome/TEN, including 77 from Taiwan and 78 from the Registry of Severe Cutaneous Adverse Reactions. Among these factors evaluated, the levels of IL-15 (r = 0.401; P < 0.001) and granulysin (r = 0.223; P = 0.026) were significantly correlated with the disease severity in 112 samples after excluding patients with insufficient data to calculate the score of TEN. In addition, IL-15 was also associated with mortality (P = 0.002; odds ratio, 1.09; 95% confidence interval, 1.03-1.14; P = 0.001; adjusted odds ratio, 1.10; 95% confidence interval, 1.04-1.16). Consistent results were obtained after the exclusion of Taiwanese patients with sepsis to rule out possible confounders. Moreover, IL-15 was shown to enhance cytotoxicity of cultured natural killer cells and blister cells from patients with TEN. Our findings highlight a usefulness of IL-15 in prognosis monitoring and therapeutic intervention of this devastating condition.

AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production.

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.

Metabolic Tumour Burden Measured by 18F-FDG PET/CT Predicts Malignant Transformation in Patients with Neurofibromatosis Type-1.

BACKGROUND: To investigate the diagnostic and prognostic performances of 18F-FDG PET/CT measures of metabolic tumour burden in patients with neurofibromatosis type-1 (NF1), suspect of malignant transformation. METHODS: This retrospective study included 49 patients (15-60 years old, 30 women) with a diagnosis of NF1, followed in our Reference Centre for Rare Neuromuscular Diseases, who presented clinical signs of tumour progression (pain, neurological deficit, tumour growth). Quantitative metabolic parameters were measured on 149 tumoral targets, using semi-automatic software and the best cut off values to predict transformation was assessed by Receiver Operating Characteristics (ROC) analysis. Prognostic value of PET/CT metabolic parameters was assessed by Kaplan-Meier estimates of overall survival. RESULTS: Lesions were histologically documented in 40 patients: a sarcomatous transformation was found in 16, a dysplastic neurofibroma (NF) in 7, and a benign NF in 17; in the remaining 9 patients, a minimal follow-up of 12 mo (median 59 mo) confirmed the absence of transformation. The optimal cut off values for detection of malignant transformation were, in decreasing order of area under the ROC curves, a tumour-to-liver (T/L) ratio >2.5, SUVmax > 4.5, total lesion glycolysis (TLG) > 377, total metabolic tumour volume (TMTV) > 88 cm3, and heterogeneity index (HIsuv) > 1.69. The best prognostic marker was the TLG: the 4-y estimates of survival were 97% [95% CI, 90% - 100%] in patients with TLG ≤ 377 vs. 27% [95% CI, 5% - 49%] in patients with TLG > 377 (P < 0.0001; χ2 27.85; hazard ratio 13.27 [95% CI, 3.72-47.35]). T/L ratio, SUVmax and TMTV demonstrated slightly lower performance to predict survival, with χ2 ranging 14.41-19.12. The HIsuv index was not predictive of survival. CONCLUSION: Our study demonstrates that TLG and TMTV, as PET/CT measures of metabolic tumour burden, may be used clinically to identify sarcomatous transformation in patients with NF1 and predict overall survival, with a higher specificity for the TLG. Conventional measures such as the SUVmax, and T/L ratio also demonstrate high prognostic value.

Facial Scars following Toxic Epidermal Necrolysis: Role of Adnexal Involvement?

Toxic epidermal necrolysis (TEN) is a severe cutaneous adverse drug reaction leading to extensive sloughing of the skin. Late cutaneous complications such as pigmentation disorders are frequently reported. In this report, we present particular facial cutaneous sequelae with histological analysis after TEN. Two young patients who had survived TEN presented permanent multiple hypopigmented papules on the face affecting their quality of life. Histological analysis revealed areas of scarring, dystrophic microcalcifications and sebaceous hyperplasia. Late cutaneous sequelae are well documented; however, the physiopathological mechanisms leading to different clinical presentations remain unknown. We suggest that the destruction of the hair follicle by necrolysis leads to secondary dermal microcalcifications, scarring and sebaceous hyperplasia. Further studies are needed for a better understanding of these findings.

[DRUG INDUCED EXANTHEMA AND SEVERE CUTANEOUS DRUG REACTIONS]. / Exanthèmes médicamenteux et toxidermies sévères Signes généraux et muqueux imposent l'arrêt immédiat du médicament.

Cutaneous adverse drug reactions (CADR) are delayed hypersensivities. Their clinical presentation and severity are very diverse ranging from the frequent and benign exanthemas to the rare but severe CADR involving deep organs in the case of drug reaction with eosinophilia and systemic symptoms (DRESS) or leading to skin bulla and epidermal detachment in toxic epidermal necrolysis. The main differential diagnoses are infections, especially viral ones, which could give clinical symptoms identical to those occurring in CADR.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An Update.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous reactions, predominantly drug induced. The mortality rates for SJS and TEN are as high as 30 %, and short- and long-term morbidities are very common. SJS/TEN is one of the few dermatological diseases that constitute a true medical emergency. Early recognition and prompt and appropriate management can be lifesaving. In recent years, our understanding of the pathogenesis, clinical presentation, and management of SJS/TEN has improved. Nevertheless, in 2015, there are still no internationally accepted management guidelines. This review summarizes up-to-date insights on SJS/TEN and describes a protocol for assessment and treatment. We hope these suggested guidelines serve as a practical clinical tool in the management of SJS/TEN. The classic manifestation of SJS/TEN consists of initial "flu-like" symptoms (malaise, fever, anorexia) in the prodromal phase, followed by cutaneous and mucous membrane (ocular, oral, and genital) inflammation and pain, and other systemic involvement. Symptoms usually begin 4-28 days after the onset of drug intake. Treatment is multidisciplinary and includes identification and withdrawal of the culprit drug, transfer to a specialist unit, supportive care, medical treatment, communication, and provision of appropriate information and emotional support.

Prognostic factors in necrotizing soft-tissue infections (NSTI): A cohort study.

BACKGROUND: Necrotizing soft-tissue infection (NSTI) is uncommon but life-threatening. A recent meta-analysis estimated the overall mortality at 23.5%. OBJECTIVE: We sought to identify risk factors associated with mortality in a cohort of patients with NSTI in a tertiary care center. METHODS: We identified 512 patients with NSTI between 1996 and 2012 in the national hospital database Program for Medicalization of Information Systems and examined risk factors of mortality with NSTI by univariate and multivariate analysis. RESULTS: We included 109 patients with a confirmed diagnosis of NSTI; 31 (28%) died at a median follow-up of 274 days (range 2-6135 days). On multivariate analysis, independent risk factors of mortality were age older than 75 years (hazard ratio [HR] 4.4, 95% confidence interval [CI] 1.8-10.3), multifocal NSTI (HR 5.9, 95% CI 1.9-18.5), severe peripheral vascular disease (HR 5.1, 95% CI 1.5-17.0), hospital-acquired infection (HR 3.9, 95% CI 1.4-10.7), severe sepsis (HR 7.4, 95% CI 1.7-33.1), and septic shock on hospital admission (HR 13.9, 95% CI 3.8-50.4). LIMITATIONS: This was a retrospective cohort, which disallows a precise record of the delay between diagnosis and surgery. CONCLUSION: Our findings for this robust cohort of patients with a definite diagnosis of NSTI could help clinicians stratify NSTI severity at clinical course onset.

Fatal toxic epidermal necrolysis in a patient on teriflunomide treatment for relapsing multiple sclerosis.

We report a case of toxic epidermal necrolysis in a 46-year-old woman on teriflunomide treatment. Such a severe adverse cutaneous drug reaction with this new therapy for relapsing forms of multiple sclerosis should be early recognized in order to ensure the rapid withdrawal of the drug.

Treatment of neurofibromas with a carbon dioxide laser: a retrospective cross-sectional study of 106 patients.

BACKGROUND: Few studies have evaluated the efficacy of carbon dioxide (CO2) laser ablation for treating neurofibromatosis type 1 (NF1). OBJECTIVE: To evaluate laser treatment safety and patient satisfaction at the French National Referral Centre for Neurofibromatosis. METHODS: Retrospective survey with a specific questionnaire. The principal outcome measures included pain evaluation and assessments of treatment safety. RESULTS: We included 106 patients, 70% of whom had more than 50 neurofibromas. Laser treatment was performed mostly for aesthetic reasons, or due to pain, recurrent local trauma or familial influence, under a local anaesthetic, during outpatient visits. The mean pain score was 4.0 ± 2.7 during the administration of local anaesthesia, 2.4 ± 2.1 during laser treatment and <2 48 h after treatment in 56% of cases. The mean satisfaction score for the treatment was 4.6 ± 3.4 and was not associated with disease phenotype. CONCLUSIONS: CO2 laser treatment for NF could be considered more frequently and might help to decrease the social impact of the disease.

Stevens-Johnson syndrome and toxic epidermal necrolysis: ear, nose, and throat description at acute stage and after remission.

IMPORTANCE: Ear, nose, and throat (ENT) lesions are frequently involved in Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), although a detailed description is lacking in the literature. OBJECTIVES: To describe ENT lesions at the acute stage and follow-up in a large series of patients with SJS/TEN and identify factors associated with the severe ENT form. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of 49 patients with SJS/TEN hospitalized in a referral care center from 2005 to 2010. Patients who underwent a full ENT workup including examination and a nasal fiberoptic endoscopy by an otorhinolaryngologist in the acute phase and during follow-up at 2 and 12 months were included in the study. MAIN OUTCOMES AND MEASURES: Recorded variables included maximal body surface area (BSA) detachment, SCORTEN (Score of Toxic Epidermal Necrosis [a severity of illness score]), sites and type of ENT mucosal lesions, intensive care unit transfer, pulmonary infection, and mortality. "Severe ENT form" was defined by the occurrence of laryngeal lesions with the risk of airways obstruction. Clinical characteristics associated with severe ENT form were analyzed in univariate and multivariable analysis. RESULTS: Of the 49 patients who underwent a full ENT workup (female to male ratio, 1.1:1), ENT symptoms (eg, odynophagia, dysphagia, dysphonia, dyspnea, earache, nasal obstruction) occurred in 48 (98%). Dyspnea or dysphonia were significantly associated with severe ENT form (21% [P = .03] and 50% [P < .001], respectively). Topographic frequencies of lesions were as followed: lips and oral cavity (n = 46 [93%]) and pharynx and vestibule of the nose (n = 26 [53%]). Fourteen patients (29%) had severe ENT form. Findings for other recorded variables for those with vs without ENT examination are as follows: maximal BSA detachment (20% [0%-95%] vs 5.5% [0%-95%]; P = .004), SCORTEN (1 [0-5] vs 1 [0-5]; P = .54), intensive care unit transfer (10 [20%] vs 9 [19%]; P = .80), pulmonary infection (9 [18%] vs 6 [13%]; P = .10), and mortality (3 [6%] vs 5 [10%]; P = .70). In multivariable analysis, pulmonary infection was significantly associated with severe ENT form (odds ratio, 5.9 [95% CI, 1.1-32.8] [P = .04]). After remission of SJS/TEN, a complete ENT mucosal healing occurred in 36 patients (74%) at 2 months and in nearly all patients (n = 48 [98%]) at 1 year of follow-up. CONCLUSIONS AND RELEVANCE: Severe ENT form is associated with pulmonary infection and is easily detected by nasal fiberoptic endoscopy. ENT evaluation should be suggested when dysphonia or dyspnea is observed at the acute stage of SJS/TEN.