Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Allergic contact dermatitis from essential oil in consumer products: Mode of uses and value of patch tests with an essential oil series. Results of a French study of the DAG (Dermato-Allergology group of the French Society of Dermatology).

OBJECTIVE: To analyse the clinical characteristics and sensitivity of an essential oil patch test series (EOS) in patients sensitized to their own essential oils (EOs). METHOD: We analysed the clinical data and patch test results obtained with the European baseline series (BSE) and an EOS, as well as the mode of use of EOs, through a questionnaire included in the patient file. RESULTS: The study included 42 patients (79% women, average age 50 years) with allergic contact dermatitis (ACD), 8 patients required hospitalization. All patients were sensitized to the EO they used, primarily lavender (Lavandula augustifolia, 8000-28-0), tea tree (Melaleuca alternifolia leaf oil, 68647-73-4), ravintsara (Cinnamomum camphora oil, 92201-50-8), and 2 cases were attributed to helichrysum (helichrysum italicum flower absolute, 90045-56-0). 71% had positive patch tests to fragrance mix I or II, 9 only to the EOS and 4 only with their personal EO. Interestingly, 40% of patients did not spontaneously mention the use of EOs, and only 33% received advice on their use at the time of purchase. CONCLUSION: Patch tests with the BSE, limonene and linalool HP, and oxidized tea tree oil is sufficient to detect most EO-sensitized patients. The most important is to test the patient's own used EOs.

Hand eczema in glove-wearing patients.

BACKGROUND: Allergic contact dermatitis to gloves is mostly induced by rubber accelerators. The European baseline series (EBS) appears insufficient to detect glove allergy. Since 2017, it is recommended to use the European rubber series (ERS) and to test the patients' own gloves. OBJECTIVES: To investigate the clinical profile of glove-wearing patients with hand eczema (HE) and to evaluate their sensitisation profile to glove allergens and the value of testing the patients' own gloves. METHODS: We conducted a French multicentre study of patients evaluated for HE between 2018 and 2020 and tested with the EBS, the ERS and their own gloves in patch tests and semi-open (SO) tests. RESULTS: A total of 279 patients were included; 32.6% of patients had positive tests to their own gloves or to glove allergens. Almost 45% of the sensitisations to glove allergens were detected only by the ERS. Among the patients tested both in patch tests and SO tests with their own gloves with positive results, 28% had positive SO tests only. Polyvinylchloride (PVC) gloves were positive in four patients. CONCLUSION: Our series confirms the need to test the ERS. All the patients' gloves must also be tested including PVC gloves. SO tests with gloves are useful as a complement to patch tests.

Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort.

BACKGROUND: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. OBJECTIVE: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort. METHODS: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up. RESULTS: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10-9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10-9, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm3) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10-6). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs. LIMITATIONS: No control group, missing data. CONCLUSION: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia.

DRESS and AGEP Reactions to Iodinated Contrast Media: A French Case Series.

BACKGROUND: Drug reactions with eosinophilia and systemic symptoms (DRESSs) and acute generalized exanthematous pustulosis (AGEP) are potentially severe cutaneous adverse drug reactions. OBJECTIVE: To describe the clinical findings and sensitization profiles of DRESS and AGEP patients who had been administered iodinated contrast media (ICM). METHODS: All adult patients in the dermatologist's French Investigators for Skin Adverse Reactions to Drugs (FISARD) network diagnosed with a DRESS or AGEP highly suspected to have been caused by an ICM were included retrospectively. RESULTS: Thirteen DRESS patients and 19 AGEP patients who had been administered ICM were included, and the median delay in DRESS and AGEP occurrence after ICM administration was short, 4 and 1 days, respectively. Five AGEP patients had systemic involvement. A high cosensitization rate (46%) was observed among the DRESS patients, mainly with beta-lactam antibiotics. Overall, 77% of our patients were sensitized to several ICM. Patch tests identified the suspected ICM for 21 cases (72%). The retrospective nature, the limited number of subjects, the absence of a control group of healthy individuals, and the lack of detailed information on previous exposure to sensitizing drugs are limitations of this study. CONCLUSIONS: We report a large series of DRESSs and AGEPs related to ICM administration. Skin tests appear useful for diagnosis and potentially to identify alternative ICM.

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.

The clinical spectrum and therapeutic management of hypocomplementemic urticarial vasculitis: data from a French nationwide study of fifty-seven patients.

OBJECTIVE: Hypocomplementemic urticarial vasculitis (HUV) is an uncommon vasculitis of unknown etiology that is rarely described in the literature. We undertook this study to analyze the clinical spectrum and the therapeutic management of patients with HUV. METHODS: We conducted a French nationwide retrospective study that included 57 patients with chronic urticaria, histologic leukocytoclastic vasculitis, and hypocomplementemia. We assessed clinical and laboratory data and evaluated the patients' cutaneous and immunologic responses to therapy. We evaluated treatment efficacy by measuring the time to treatment failure. RESULTS: Urticarial lesions were typically more pruritic than painful and were associated with angioedema in 51% of patients, purpura in 35%, and livedo reticularis in 14%. Extracutaneous manifestations included constitutional symptoms (in 56% of patients) as well as musculoskeletal involvement (in 82%), ocular involvement (in 56%), pulmonary involvement (in 19%), gastrointestinal involvement (in 18%), and kidney involvement (in 14%). Patients with HUV typically presented with low C1q levels and normal C1 inhibitor levels, in association with anti-C1q antibodies in 55% of patients. Hydroxychloroquine or colchicine seemed to be as effective as corticosteroids as first-line therapy. In patients with relapsing and/or refractory disease, rates of cutaneous and immunologic response to therapy seemed to be higher with conventional immunosuppressive agents, in particular, azathioprine, mycophenolate mofetil, or cyclophosphamide, while a rituximab-based regimen tended to have higher efficacy. Finally, a cutaneous response to therapy was strongly associated with an immunologic response to therapy. CONCLUSION: HUV represents an uncommon systemic and relapsing vasculitis with various manifestations, mainly, musculoskeletal and ocular involvement associated with anti-C1q antibodies, which were found in approximately half of the patients. The best strategy for treating HUV has yet to be defined.

Long-term effects of light damage on the retina of albino and pigmented rats.

PURPOSE: To observe the morphology and physiology of the retina in rats 11 weeks after a constant (24-hour) but moderate (500-lux) illumination for 1 week. METHODS: Levels of aspartate, gamma-aminobutyric acid (GABA), glutamate, glutamine, and taurine were measured by high-pressure liquid chromatography (HPLC) in the retina and vitreous humor of albino (Wistar) and pigmented (Long-Evans) rats. Semithin sections were used to determine retinal morphology. The TUNEL method was used to detect cells degenerating by apoptosis. Because the GABAergic system has been shown to be particularly sensitive to the loss of photoreceptors, an additional immunohistochemical study using anti-GABA, anti-glutamate decarboxylase (GAD)(67) and anti-GAD(65) antibodies was performed. RESULTS: No apparent morphologic changes were found in the retina of pigmented rats after constant illumination, whereas in albino rats disappearance of photoreceptors (except in the extreme retinal periphery) and cell bodies was observed. A significant number of TUNEL-positive nuclei also occurred in the remaining nuclear and ganglion cell layers. However, no change in the distribution of GABA, GAD(67), and GAD(65) immunoreactivities was found in either strain under constant illumination compared with control animals. Constant illumination affected the retinal levels of aspartate, glutamate, glutamine, glycine in both strains, whereas GABA contents did not change and taurine was decreased only in albino rats. A significant increase of vitreal glutamate levels was also found in both strains and of taurine levels only in albino rats. CONCLUSIONS: Phototoxicity can provoke durable retinal alterations beyond the period of lighting, suggesting progressive and probably continuous modifications of retinal physiology, even in pigmented animals in which the retina seems morphologically normal.