Publications by authors named "Delphine Staumont-Salle"

32 Publications

Moderate-to-severe eosinophilia induced by treatment with immune checkpoint inhibitors: 37 cases from a national reference center for hypereosinophilic syndromes and the French pharmacovigilance database.

Oncoimmunology 2020 7;9(1):1722022. Epub 2020 Apr 7.

Univ. Lille, CHU Lille, Service de Médecine Interne Et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (Ceraino), Lille, France.

A better understanding of immune-related adverse events is essential for the early detection and appropriate management of these phenomena. We conducted an observational study of cases recorded at the French reference center for hypereosinophilic syndromes and in the French national pharmacovigilance database. Thirty-seven reports of eosinophilia induced by treatment with immune checkpoint inhibitors (ICIs) were included. The median [range] time to the absolute eosinophil count (AEC) peak was 15 [4─139] weeks. The median AEC was 2.7 [0.8─90.9] G/L. Eosinophil-related manifestations were reported in 21 of the 37 cases (57%). If administered, corticosteroids were always effective (n = 10 out of 10). Partial or complete remission of eosinophilia was obtained in some patients not treated with corticosteroids, after discontinuation (n = 12) or with continuation (n = 4) of the ICI. The AEC should be monitored in ICI-treated patients. If required by oncologic indications, continuation of ICI may be an option in asymptomatic hypereosinophilic patients, and in corticosteroid responders.
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http://dx.doi.org/10.1080/2162402X.2020.1722022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153834PMC
April 2020

Occupational purpuric contact dermatitis to methylchloroisothiazolinone / methylisothiazolinone.

Contact Dermatitis 2020 Jul 20;83(1):69-71. Epub 2020 Apr 20.

CHU de Lille, Service de dermatologie, Lille, France.

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http://dx.doi.org/10.1111/cod.13537DOI Listing
July 2020

"Idiopathic Eosinophilic Vasculitis": Another Side of Hypereosinophilic Syndrome? A Comprehensive Analysis of 117 Cases in Asthma-Free Patients.

J Allergy Clin Immunol Pract 2020 04 18;8(4):1329-1340.e3. Epub 2019 Dec 18.

Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), Lille, France; Hôpital Ambroise Paré, Service de Médecine Interne, Assistance Publique-Hôpitaux de Paris, Boulogne-Billancourt, France.

Background: The absence of asthma may rule out a diagnosis of eosinophilic granulomatosis with polyangiitis in patients with hypereosinophilic syndrome (HES) and features of vasculitis.

Objective: To describe eosinophilic vasculitis (EoV) as a possible manifestation of HES in asthma-free patients.

Methods: We screened our hospital database and the literature for patients with HES who met the following 4 criteria: (1) histopathological or clinical features of EoV (biopsy-proven vasculitis with predominant eosinophilic infiltration of the vessel wall and/or features of vasculitis with tissue and/or blood hypereosinophilia [absolute eosinophil count >1.5 G/L]); (2) no other obvious causes of reactive eosinophilia, organ damage, and vasculitis; (3) the absence of antineutrophil cytoplasmic antibodies; and (4) the absence of current asthma.

Results: Ten of our 83 (12%) asthma-free patients with HES and 107 additional cases in the literature met the criteria for EoV. After a critical analysis of the patients' clinical and laboratory characteristics and outcomes, we identified 41 cases of single-organ EoV (coronary arteritis, n = 29; temporal arteritis, n = 8; cerebral vasculitis, n = 4). Of the remaining 76 patients with EoV, the most frequent manifestations (>10%) were cutaneous vasculitis (56%), peripheral neuropathy (24%), thromboangiitis obliterans-like disease (16%), fever (13%), central nervous system involvement (13%), deep venous thrombosis (12%), and nonasthma lung manifestations (12%). Blood hypereosinophilia more than 1.5 G/L was observed in 79% of patients, and necrotizing vasculitis was observed in 44%.

Conclusions: Our results suggest that idiopathic EoV (HES-associated vasculitis) can be classified as an eosinophilic-rich, necrotizing, systemic form of vasculitis that affects vessels of various sizes in asthma-free patients.
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http://dx.doi.org/10.1016/j.jaip.2019.12.011DOI Listing
April 2020

Photodynamic Therapy Using a New Painless Light-Emitting Fabrics Device in the Treatment of Extramammary Paget Disease of the Vulva (the PAGETEX Study): Protocol for an Interventional Efficacy and Safety Trial.

JMIR Res Protoc 2019 Dec 3;8(12):e15026. Epub 2019 Dec 3.

U1189 - Image Assisted Laser Therapies for Oncology, Inserm, Centre Hospitalier et Universitaire de Lille, Université de Lille, Lille, France.

Background: Extramammary Paget disease of the vulva (EMPV) is a rare skin disorder commonly seen in postmenopausal Caucasian females that appears clinically as red, eczematous, pruriginous, and sometimes painful lesions. Although most cases are noninvasive, EMPV may be associated with an underlying or distant adenocarcinoma. EMPV has a chronic and relapsing course. The reference treatment is based on local surgical excision with negative margins. However, disease frequently extends far from the visible lesion, and surgical margins are frequently positive. Topical photodynamic therapy (PDT) is an established treatment modality for various dermatooncologic conditions. For example, red light irradiation with the Aktilite CL 128 and Metvixia (Galderma SA) as a photosensitizing molecule is a conventional protocol approved and widely used in Europe for PDT treatment of actinic keratosis, but this treatment is not yet widely used for EMPV because it has never clearly been demonstrated and is very painful.

Objective: The aim of the study is to investigate the efficacy and safety relating to the medical device PAGETEX as a new painless PDT device using Metvixia in the treatment of vulvar Paget disease. The primary end point is the disease control rate at 3 months in 30% of the patients included, defined as stability, partial response, or total response, considering the extent of the lesion. Secondary end points are the disease control rate at 6 months, patient quality of life, level of pain experienced by the patient at each PDT session, severity of erythema, presence of protoporphyrin IX in Paget cells after each PDT session, and overall satisfaction level of the patient.

Methods: The trial is an interventional, exploratory, simple group, nonrandomized, and single center (Lille University Hospital) study. Twenty-four patients will be included according to Simon's optimal plan. Therapeutic procedure is based on a cycle of two PDT sessions with the PAGETEX medical device at 15-day intervals (Metvixia incubation during 30 minutes and 635 nm red light illumination with a low irradiance for 2 hours and 30 minutes for a total fluence of 12 J/cm²). At the assessment session, 3 months after inclusion, if the control of the disease is partial or null, the patient will complete another cycle of two PDT sessions. A final evaluation will be performed in all patients at 6 months. Analyses will be performed using SAS version 9.4 software (SAS Institute Inc). The characteristics of the patients at baseline will be described; qualitative variables will be described by numbers and percentages, and quantitative variables will be described either by the mean and standard deviation for Gaussian distribution or by the median and interquartile range (ie, 25th and 75th percentiles). The normality of the distributions will be tested by a Shapiro-Wilk test and checked graphically by histograms.

Results: First patient was included in September 2019 and clinical investigations are planned until August 2022. The final results of this study are expected to be available in January 2023.

Conclusions: This clinical trial aims to evaluate the efficacy and safety of a new PDT protocol for the treatment of EMPV. The PAGETEX device could become the treatment of choice if it is effective, painless, and easy to implement and use in hospitals.

Trial Registration: ClinicalTrials.gov NCT03713203; https://clinicaltrials.gov/ct2/show/NCT03713203.

International Registered Report Identifier (irrid): PRR1-10.2196/15026.
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http://dx.doi.org/10.2196/15026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918208PMC
December 2019

Atopic dermatitis in elderly adults.

Eur J Dermatol 2019 Aug;29(4):371-374

Department of Dermatology, University Hospital of Lille, University of Lille, Lille, France.

Background: Atopic dermatitis (AD) in adults over 45 years of age (AD≥45) has been poorly studied.

Objectives: To determine whether the AD phenotype varies according to the pattern of AD onset in AD≥45 patients and whether response to cyclosporine A (CsA) is influenced by age.

Materials And Methods: This monocentric retrospective study was performed in a French university department of dermatology. We included 409 AD<45 patients (111 treated with CsA) and 124 AD≥45 patients (26 treated with CsA). Among AD≥45 patients, 20% were categorised into Subgroup 1 (persistence of AD since childhood), 52% into Subgroup 2 (recurrence of AD with a history of classic childhood AD), and 28% into Subgroup 3 (adult-onset AD).

Results: Gender, associated atopic comorbidities, a family history of atopy, and AD severity were similar regarding the different patterns of AD onset in AD≥45 patients. Skin lesions predominated on the face and neck in AD≥45 patients with AD since childhood (30% in Subgroups 1 and 2) compared to those with adult-onset AD (14% in Subgroup 3). The efficacy of CsA was similar between groups AD≥45 and AD<45, but 28% of AD≥45 patients versus 20% of AD<45 patients had increased serum creatinine levels under CsA.

Conclusion: No significant association seems to exist between the onset of AD and demographic or clinical characteristics in AD≥45 patients (except that head and neck involvement is rarer in adult-onset AD). Patient age does not influence response to CsA, but this drug appears to be less well tolerated in older patients.
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http://dx.doi.org/10.1684/ejd.2019.3609DOI Listing
August 2019

Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.

Cell 2019 05 25;177(5):1201-1216.e19. Epub 2019 Apr 25.

University of Lille, EGID, INSERM, CHU Lille, Institut Pasteur de Lille, U1011, 59019 Lille, France. Electronic address:

Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-like receptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatory signals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect the immune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DCs) are exacerbated by a high-fatty-acid (FA) metabolic environment. FAs suppress the TLR-induced hexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changes enhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded protein response (UPR), leading to a distinct transcriptomic signature with IL-23 as hallmark. Interestingly, chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response. Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23 expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innate immunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.
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http://dx.doi.org/10.1016/j.cell.2019.03.018DOI Listing
May 2019

A new phototherapy regimen during winter as an add-on therapy, coupled with oral vitamin D supplementation, for the long-term control of atopic dermatitis: study protocol for a multicentre, randomized, crossover, pragmatic trial - the PRADA trial.

Trials 2019 Mar 25;20(1):184. Epub 2019 Mar 25.

Univ Rennes, Rennes, France.

Background: Atopic dermatitis is a highly prevalent, chronic, relapsing disease in both adults and children. On the severity spectrum, lower-end patients benefit from small amounts of topical anti-inflammatory treatments (TAT), whereas higher-end patients need systemic immunosuppressants; in-between patients are treated with TAT and phototherapy. The major therapeutic challenge in this population is the long-term control of disease activity, and the current TAT-based pro-active strategy does not meet all their needs. Immunosuppressants are used as long-term control add-on treatments, but they are restricted to the most severely affected patients because of safety concerns. In addition, neither immunosuppressants nor other strategies have been properly evaluated in the long term despite long-term control having been acknowledged as one of the most important core outcome domains to be targeted in atopic dermatitis trials. Safe add-on therapies, rigorously evaluated for long-term control of the disease, are therefore needed. Phototherapy and vitamin D supplementation are both good candidates.

Methods: This is a multicenter, national, randomized, superiority, crossover trial testing add-on phototherapy (one winter under spaced sessions of phototherapy and one winter under observation) among subjects receiving standard care (i.e., TAT). On the same population, we will test the long-term control provided by oral supplementation of vitamin D versus placebo in a randomized, superiority, double-blind, parallel-group trial. The primary outcomes are (1) repeat measures of the PO-SCORAD severity score over 1 year and (2) cumulate consumption of TAT (number of tubes) during the winter. They will be tested following a hierarchical testing procedure. The secondary outcomes will be measures repeated over 2 years of investigator-based severity scores, patient-reported severity and quality of life scores, serum vitamin D levels, weeks during which the disease is well-controlled, inter-visit cumulate consumption of TAT, and synthetic patient-reported satisfaction at the end of each winter.

Discussion: This study includes two separate 2-year pragmatic trials designed to evaluate the efficacy of vitamin D supplementation and pro-active phototherapy for primary care atopic dermatitis patients receiving TAT on long-term control of disease activity. The experimental design enables the study of both interventions and exploration of the interaction between vitamin D and phototherapy. A pragmatic trial is particularly suited to the assessment of long-term control. This study explores the possibility of new and safe therapeutic strategies for the control of long-term atopic dermatitis, and is an example of efficacy research that is unlikely to be sponsored by industrialists. A potentially effective low-cost therapeutic strategy for long-term control is essential for patients and public health.

Trial Registration: ClinicalTrials.gov Identifier: NCT02537509 , first received: 1 September 2015.
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http://dx.doi.org/10.1186/s13063-019-3276-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434814PMC
March 2019

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

J Am Acad Dermatol 2019 Jul 27;81(1):143-151. Epub 2019 Feb 27.

CHU de Lille, Service de dermatologie, F-59000 Lille, France; Univ Lille, INSERM U995, Lille Inflammation Research International Center, F-59000, Lille, France. Electronic address:

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 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10). 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.
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http://dx.doi.org/10.1016/j.jaad.2019.02.053DOI Listing
July 2019

The burden of chronic spontaneous urticaria: unsatisfactory treatment and healthcare resource utilization in France (the ASSURE-CSU study).

Eur J Dermatol 2018 Dec;28(6):795-802

Hospices civils de Lyon, Claude-Bernard University, Lyon, France.

Data on the clinical burden of chronic spontaneous urticaria (CSU) and economic consequences are lacking in France. To characterize the clinical and economic burden of CSU in symptomatic patients despite treatment by analysing data of French patients from the ASSURE-CSU study. ASSURE-CSU was an international observational study that included CSU patients with symptoms that lasted for 12 months or more despite treatment. Disease characteristics and healthcare resource use were obtained from medical records. Data on disease history, health-related quality of life (HR-QoL), and work productivity were collected from a patient survey. A total of 101 patients were analysed (76.2% female; mean age: 48.9 years) with moderate to severe disease (UAS7 score ≥16) in 43.4% and angioedema in 72.3%. The mean (S.D.) total scores of Chronic Urticaria Quality of Life (CU-QoL) and Dermatology Life Quality Index (DLQI) were 37.7 (22.3) and 9.7 (6.9), respectively, thus indicating a significant impact of the disease on HR-QoL. Mean absenteeism and presenteeism were 6.4% and 20.8%, respectively, with a mean loss of work productivity estimated at 20.7%. The mean (S.D.) total direct cost of CSU was €2,397 per patient per year and was mainly driven by therapies (€1,435) and inpatient costs (€859). The indirect costs for four weeks were mainly presenteeism (€421) and loss of work productivity (€420). CSU significantly impairs HR-QoL, which increases with the severity of the disease. The direct and indirect costs for the management of symptomatic CSU are an important economic burden.
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http://dx.doi.org/10.1684/ejd.2018.3446DOI Listing
December 2018

C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis.

J Allergy Clin Immunol Pract 2019 Apr 11;7(4):1347-1351.e3. Epub 2018 Oct 11.

CHU Lille, Département de Médecine Interne et Immunologie Clinique, Centre de Référence des Maladies Auto-immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), University of Lille, Lille, France; Centre de Référence National des Syndromes Hyperéosinophiliques (CEREO), France; CHU Lille, Institut d'Immunologie, University of Lille, Lille, France; Inserm, CHU Lille, U995 - LIRIC - Lille Inflammation Research International Center, University of Lille, Lille, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.10.002DOI Listing
April 2019

Keratinocyte Expression of A20/TNFAIP3 Controls Skin Inflammation Associated with Atopic Dermatitis and Psoriasis.

J Invest Dermatol 2019 01 14;139(1):135-145. Epub 2018 Aug 14.

Université de Lille, INSERM, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France. Electronic address:

Keratinocytes are key players in chronic inflammatory skin diseases. A20 regulates NF-κB-dependent expression of proinflammatory genes and cell death, but the impact of its expression in keratinocytes on systemic inflammation and skin disorders has not been determined. Comparative transcriptomic analysis of microdissected epidermis showed that A20 is down-regulated in involved epidermis, but not in dermis, of psoriasis and atopic dermatitis patients, suggesting that loss of A20 expression in keratinocytes increases the vulnerability for psoriasis/atopic dermatitis induction. We have previously shown that epidermis-specific A20 knockout mice (A20) develop mild epidermal hyperplasia but no macroscopic skin inflammation. We now show that various cytokines and chemokines are up-regulated in A20 mouse skin. A20 mice also display systemic proinflammatory changes, even in the absence of skin immune cell infiltration, and an exacerbated disease severity upon induction of experimental psoriasis, atopic dermatitis, or skin barrier disruption. Keratinocytes showed increased proinflammatory gene expression in the absence of A20 in unstimulated and IL-17A-stimulated conditions, in part resulting from uncontrolled MyD88-dependent signaling. Our findings indicate that absence of A20 in keratinocytes leads to systemic inflammation at homeostatic conditions and is sufficient to exacerbate inflammatory skin disorders associated with different immune profiles by increasing cytokine and chemokine expression.
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http://dx.doi.org/10.1016/j.jid.2018.06.191DOI Listing
January 2019

Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma.

Melanoma Res 2018 10;28(5):451-457

Department of Dermatology, Claude Huriez Hospital, CHRU Lille.

Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.
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http://dx.doi.org/10.1097/CMR.0000000000000472DOI Listing
October 2018

Methotrexate Versus Cyclosporine in Adults with Moderate-to-Severe Atopic Dermatitis: A Phase III Randomized Noninferiority Trial.

J Allergy Clin Immunol Pract 2018 Mar - Apr;6(2):562-569.e3. Epub 2017 Sep 28.

Department of Allergology and Immunology, Clinical Research Unit, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, Université Lyon 1, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Inserm U1111, Lyon, France.

Background: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults.

Objective: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis.

Methods: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8 weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172).

Results: A total of 97 patients received methotrexate 15 mg (n = 50) or cyclosporine 2.5 mg (n = 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was -34% (-48% to -20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P < .0001).

Conclusions: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week 20.
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http://dx.doi.org/10.1016/j.jaip.2017.07.007DOI Listing
November 2019

Efficacy of combining pulse corticotherapy and methotrexate in alopecia areata: Real-life evaluation.

J Dermatol 2017 Dec 22;44(12):e319-e320. Epub 2017 Sep 22.

FHU Immune-Mediated Inflammatory Diseases and Targeted Therapies (IMMINeNT), Lille, France.

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http://dx.doi.org/10.1111/1346-8138.14013DOI Listing
December 2017

Patients with Crohn's Disease with High Body Mass Index Present More Frequent and Rapid Loss of Response to Infliximab.

Inflamm Bowel Dis 2017 10;23(10):1853-1859

*CHU Lille, Hepato-Gastroenterology Department, Claude Huriez Hospital, University of Lille 2, Lille, France; †CHU Lille, Dermatology Department, Claude Huriez Hospital, University of Lille 2, Lille, France; and ‡CHU Lille, Pharmacy Department, Claude Huriez Hospital, University of Lille 2, Lille, France.

Background: Infliximab (IFX) is effective in inducing and maintaining remission in patients with luminal and anoperineal Crohn's disease (CD). However, treatment failure within 12 months after initiating IFX is observed in a significant proportion of patients. The aim of the present study was to determine whether the body mass index (BMI) affects response to IFX during the first year of treatment in patients with CD.

Methods: All patients with luminal CD who began IFX between January 2010 and May 2014 were prospectively included. BMI was calculated before IFX treatment was begun, and patients were divided into 3 groups: normal BMI (BMI < 25 kg/m), overweight patients (BMI of 25.0-30 kg/m), and obese patients (BMI > 30.0 kg/m). The primary outcome was to evaluate the rate and delay of IFX optimization during the first year of treatment among normal weight, overweight, and obese patients.

Results: One hundred forty patients were included. Demographic and clinical characteristics at IFX initiation were comparable among the 3 groups. Within 12 months after the initiation of IFX, the rate of IFX optimization was significantly higher in overweight and obese patients than in the normal BMI group: 52%, 56%, and 20%, respectively (P = 0.0002). The median time until optimization of IFX was significantly shorter in overweight and obese patients than in the normal BMI group: 7, 7, and 10 months, respectively (P = 0.03). A BMI >25 kg/m was significantly associated with IFX optimization within 12 months on multivariate analysis.

Conclusion: This is the first study to show that optimization of IFX is more frequent and faster in obese and overweight patients with CD and occurs within 12 months after beginning IFX, suggesting that an induction regimen with higher doses of IFX and a tight control of IFX concentrations may be needed in these patients.
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http://dx.doi.org/10.1097/MIB.0000000000001179DOI Listing
October 2017

Tristetraprolin expression by keratinocytes controls local and systemic inflammation.

JCI Insight 2017 Jun 2;2(11). Epub 2017 Jun 2.

Walloon Excellence in Lifesciences and Biotechnology (WELBIO) and Institute for Medical Immunology, Université Libre de Bruxelles (ULB), Brussels, Belgium.

Tristetraprolin (TTP, encoded by the Zfp36 gene) regulates the mRNA stability of several important cytokines. Due to the critical role of this RNA-binding protein in the control of inflammation, TTP deficiency leads to the spontaneous development of a complex inflammatory syndrome. So far, this phenotype has been largely attributed to dysregulated production of TNF and IL‑23 by myeloid cells, such as macrophages or DCs. Here, we generated mice with conditional deletion of TTP in keratinocytes (Zfp36fl/flK14-Cre mice, referred to herein as Zfp36ΔEP mice). Unlike DC-restricted (CD11c-Cre) or myeloid cell-restricted (LysM-Cre) TTP ablation, these mice developed exacerbated inflammation in the imiquimod-induced psoriasis model. Furthermore, Zfp36ΔEP mice progressively developed a spontaneous pathology with systemic inflammation, psoriatic-like skin lesions, and dactylitis. Finally, we provide evidence that keratinocyte-derived TNF production drives these different pathological features. In summary, these findings expand current views on the initiation of psoriasis and related arthritis by revealing the keratinocyte-intrinsic role of TTP.
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http://dx.doi.org/10.1172/jci.insight.92979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453703PMC
June 2017

[Role of fractalkine/CX3CL1 and its receptor CX3CR1 in allergic diseases].

Med Sci (Paris) 2016 Mar 23;32(3):260-6. Epub 2016 Mar 23.

Université de Lille, Inserm, CHU Lille, European genomic institute of diabetes, institut Pasteur de Lille, U1011 - récepteurs nucléaires, maladies cardiovasculaires et diabète, 59000 Lille, France.

Allergic asthma and atopic dermatitis are diseases mainly resulting from the activation of Th2 cells, that produce cytokines favouring IgE production and eosinophilia but also of Th1 cells, that contribute to inflammation chronicity. Lymphocyte recruitment and retention of Th cells in target organs are 2 key events for asthma and atopic dermatitis pathogenesis. While lymphocyte migration is regulated by chemokines and lipid mediators such as leukotrienes and prostaglandins, factors involved in lymphocyte retention and survival within inflammatory tissues remain poorly understood. Recent works show that, in allergic diseases, there is an increased expression of fractalkine/CX3CL1 and its unique receptor CX3CR1 and that this chemokine does not act as chemoattractant. In allergic asthma, CX3CR1 expression regulates Th2 and Th1 cell survival in the inflammatory lung, while, in atopic dermatitis, it regulate Th2 and Th1 cell retention into the inflammatory site. Use of peptides blocking fractalkine binding to its receptor is currently tested in the treatment of asthma and atopic dermatitis.
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http://dx.doi.org/10.1051/medsci/20163203010DOI Listing
March 2016

CD3-CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder.

Haematologica 2015 Aug 14;100(8):1086-95. Epub 2015 Feb 14.

Institute of Immunology, French Eosinophil Network and Research Unit EA2686, Lille University Hospital, Université Lille Nord de France, Lille Department of Internal Medicine, Foch Hospital and Versailles-Saint-Quentin-en-Yvelines University, Suresnes, France.

The CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3(-)CD4(+) T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome. Atypical CD4(+) T cells lymphoid infiltrates were found in 10 of 12 CD3(-)CD4(+) L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3(-)CD4(+) T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3(-)CD4(+) T cells were CD2(hi) (n=9 of 14), CD5(hi) (n=12 of 14), and CD7(-)(n=4 of 14) or CD7(low) (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3(-)CD4(+) T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3(-)CD4(+) lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma.
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http://dx.doi.org/10.3324/haematol.2014.118042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004425PMC
August 2015

The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3-CD4+ aberrant T-cell phenotype.

Medicine (Baltimore) 2014 Oct;93(17):255-266

Institut d'Immunologie, Réseau Eosinophile, EA2686 (GL, FL, DL, ML, JT, JEK), Service d'Immunologie Clinique et de Médecine Interne, Centre de Référence Maladies Auto-Immunes Systémiques (GL, DL, LT, NLG, PYH), Institut de Pathologie (MCC), Service de Dermatologie (DSS), Service des Maladies du Sang (FM), Institut de Génétique Médicale, U837 Inserm (CRL), Réseau Eosinophile, U995 Inserm (MC), CHRU de Lille, Université Lille Nord de France, Lille; Service de Dermatologie (MAA, CL), CHU d'Angers, L'UNAM Université, Angers; Service de Dermatologie et Dermatologie Pédiatrique, Centre de Référence pour les Maladies Rares de la Peau, U1035 (AT), CHU de Bordeaux, Bordeaux; Service d'Hématologie (GS) and Service de Radiologie, CREATIS, UMR5220 CNRS, U1044 Inserm (FC), Hôpital Sud, Service de Pneumologie, Centre de Référence pour les Maladies Pulmonaires Rares (CK), Hospices Civils de Lyon, Université Claude Bernard Lyon I, Lyon; Service d'Onco-Hématologie (HM), Centre Hospitalier de La Roche-Sur-Yon, La Roche-Sur-Yon; Service d'Onco-Hématologie (KG), Centre Hospitalier de Beauvais, Beauvais; Service de Médecine Interne (FA), Hôpital Bicêtre, APHP, Université Paris Sud XI, Le Kremlin-Bicêtre; Service d'Hématologie et Immunologie Pédiatrique (AB), Hôpital Robert Debré, APHP, Université Paris Diderot and Service de Pneumologie A, Centre de Compétence Maladies Pulmonaires Rares (RB), Hôpital Bichat, APHP, Paris; Service de Médecine Interne (CMH), Centre Hospitalier d'Annecy, Annecy; Service de Médecine Interne, Hôpital Foch, Suresne; EA4340, Biomarqueurs en Cancérologie et en Onco-Hématologie, Université Versailles-Saint-Quentin-en-Yvelines (JEK), France.

The CD3-CD4+ aberrant T-cell phenotype is the most described in the lymphoid variant of hypereosinophilic syndrome (L-HES), a rare form of HES. Only a few cases have been reported, and data for these patients are scarce. To describe characteristics and outcome of CD3-CD4+ L-HES patients, we conducted a national multicentric retrospective study in the French Eosinophil Network. All patients who met the recent criteria of hypereosinophilia (HE) or HES and who had a persistent CD3-CD4+ T-cell subset on blood T-cell phenotyping were included. Clinical and laboratory data were retrospectively collected by chart review. CD3-CD4+ L-HES was diagnosed in 21 patients (13 females, median age 42 years [range, 5-75 yr]). Half (48%) had a history of atopic manifestations. Clinical manifestations were dermatologic (81%), superficial adenopathy (62%), rheumatologic (29%), gastrointestinal (24%), pulmonary (19%), neurologic (10%), and cardiovascular (5%). The median absolute CD3-CD4+ T-cell count was 0.35 G/L (range, 0.01-28.3), with a clonal TCRγδ rearrangement in 76% of patients. The mean follow-up duration after HES diagnosis was 6.9 ± 5.1 years. All patients treated with oral corticosteroids (CS) (n = 18) obtained remission, but 16 required CS-sparing treatments. One patient had a T-cell lymphoma 8 years after diagnosis, and 3 deaths occurred during follow-up.In conclusion, clinical manifestations related to CD3-CD4+ T cell-associated L-HES are not limited to skin, and can involve all tissue or organs affected in other types of HE. Contrary to FIP1L1-PDGFRA chronic eosinophilic leukemia patients, CS are always effective in these patients, but CS-sparing treatments are frequently needed. The occurrence of T-cell lymphoma, although rare in our cohort, remains a major concern during follow-up.
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http://dx.doi.org/10.1097/MD.0000000000000088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602413PMC
October 2014

CX₃CL1 (fractalkine) and its receptor CX₃CR1 regulate atopic dermatitis by controlling effector T cell retention in inflamed skin.

J Exp Med 2014 Jun 12;211(6):1185-96. Epub 2014 May 12.

Institut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, FranceInstitut National de la Santé et de la Recherche Médicale U1011, Institut Pasteur de Lille and Université Lille 2, 59019 Lille, France European Genomic Institute of Diabetes, 59045 Lille, France

Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1-CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.
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http://dx.doi.org/10.1084/jem.20121350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042636PMC
June 2014

Eosinophil-derived IFN-gamma induces airway hyperresponsiveness and lung inflammation in the absence of lymphocytes.

J Allergy Clin Immunol 2009 Sep 21;124(3):573-82, 582.e1-9. Epub 2009 Jun 21.

Inserm U547, Lille, France; Institut Pasteur de Lille, Lille, France.

Background: Eosinophils are key players in T(H)2-driven pathologies, such as allergic lung inflammation. After IL-5- and eotaxin-mediated tissue recruitment, they release several cytotoxic and inflammatory mediators. However, their exact contribution to asthma remains controversial. Indeed, in human subjects anti-IL-5 treatment inhibits eosinophilia but not antigen-induced airway hyperresponsiveness (AHR). Likewise, lung fibrosis is abrogated in 2 strains of eosinophil-deficient mice, whereas AHR is inhibited in only one of them. Finally, eosinophils have been shown to attract T(H)2 lymphocytes at the inflammatory site.

Objective: The ability of eosinophils to promote AHR and lung inflammation independently of lymphocytes was investigated.

Methods: Adoptive transfers of resting or activated eosinophils from IL-5 transgenic mice were performed into naive BALB/c mice, mice with severe combined immunodeficiency, and IFN-gamma-deficient BALB/c recipients.

Results: Adoptively transferred eosinophils induced lung inflammation, fibrosis, collagen deposition, and AHR not only in BALB/c mice but also in recipient mice with severe combined immunodeficiency. Surprisingly, IFN-gamma expression was increased in lungs from eosinophil-transferred animals. Furthermore, IFN-gamma neutralization in recipients partially inhibited eosinophil-induced AHR. Moreover, IFN-gamma-deficient eosinophils or eosinophils treated with a blocking anti-IFN-gamma receptor antibody failed to induce AHR in IFN-gamma-deficient recipients. Finally, in vitro and at low concentrations, IFN-gamma increased eosinophil peroxidase release, potentiated chemotaxis, and prolonged survival, suggesting the existence of an autocrine mechanism.

Conclusions: These results support the important and previously unsuspected contribution of eosinophils to lung inflammation independently of lymphocytes through production of IFN-gamma, the prototypical T(H)1 cytokine.
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http://dx.doi.org/10.1016/j.jaci.2009.04.031DOI Listing
September 2009

Fc(epsilon)RI and FcgammaRIII/CD16 differentially regulate atopic dermatitis in mice.

J Immunol 2009 May;182(10):6517-26

Institut National de la Santé et de la Recherche Médicale Unité 547, Institut Pasteur de Lille, and Université Lille 2, Lille, France.

The high-affinity IgE receptor Fc(epsilon)RI and, in some models, the low-affinity IgG receptor Fc(epsilon)RIIII/CD16 play an essential role in allergic diseases. In human skin, they are present on APCs and effector cells recruited into the inflamed dermis. FcRgamma is a subunit shared, among other FcRs, by Fc(epsilon)RI and CD16 and is essential to their assembly and signal transduction. Using an experimental model reproducing some features of human atopic dermatitis and specific FcR-deficient mice, we have herein delineated the respective contribution of Fc(epsilon)RIand Fc(epsilon)RIII/CD16 to the pathology. We demonstrate that symptoms of atopic dermatitis are completely absent in FcRgamma-deficient animals but only partially inhibited in either Fc(epsilon)RI- or FcgammaRIII/CD16-deficient animals. Absence or attenuation of the pathology is correlated to increased skin expression of regulatory IL-10 and Foxp3. While Fc(epsilon)RI controls both Th1 and Th2 skin response, mast cell recruitment into draining lymph nodes and IgE production, CD16 regulates only Th2 skin response, as well as T cell proliferation and IgG1 production. This isotype-specific regulation by the cognate FcR is associated to a differential regulation of IL-4 and IL-21 expression in the draining lymph nodes. Fc(epsilon)RIand CD16 thus contribute to atopic dermatitis but differentially regulate immune responses associated with the disease. Targeting both IgE/Fc(epsilon)RI and IgG/CD16 interactions might represent an efficient therapeutic strategy for allergic diseases.
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http://dx.doi.org/10.4049/jimmunol.0801055DOI Listing
May 2009

Peroxisome proliferator-activated receptor alpha regulates skin inflammation and humoral response in atopic dermatitis.

J Allergy Clin Immunol 2008 Apr 4;121(4):962-8.e6. Epub 2008 Feb 4.

Inserm U547, Lille, France.

Background: The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta, and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. In addition to their regulatory role on lipid and glucose metabolism, they exert anti-inflammatory properties. In skin both PPAR-alpha and PPAR-beta/delta regulate keratinocyte proliferation/differentiation and contribute to wound healing. The 3 PPAR isoforms are expressed by several cell types recruited into the dermis during inflammation.

Objective: We have investigated the role of PPAR-alpha in the regulation of atopic dermatitis (AD), a common skin inflammatory disease.

Methods: We chose a mouse model of inflammatory dermatosis with immunologic features of AD and used epicutaneous sensitization with ovalbumin in the absence of adjuvant, which mimics the human pathology.

Results: On antigen sensitization, PPAR-alpha-deficient mice display increased epidermal thickening, dermal recruitment of inflammatory cells, lung inflammation, airway hyperresponsiveness, and IgE and IgG2a production compared with their wild-type counterparts. Increased inflammation was correlated to an enhancement of TH2 and, to a greater extent, TH1 responses and to increased skin expression of nuclear factor kappaB. Interestingly, PPAR-alpha expression was decreased in eczematous skin from patients with AD compared with skin from nonatopic donors, suggesting that defective PPAR-alpha expression might contribute to the pathology. Topical application of WY14643, a specific PPAR-alpha agonist, significantly decreased antigen-induced skin inflammation in the AD model.

Conclusion: PPAR-alpha acts as a negative regulator of skin inflammation in AD.
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http://dx.doi.org/10.1016/j.jaci.2007.12.1165DOI Listing
April 2008

[Treatment of chronic lupus erythematosus with sulfasalazine in 18 patients: reappraisal].

Presse Med 2006 Jul-Aug;35(7-8):1138-42

Clinique dermatologique, Hôpital Claude-Huriez, Cedex, France.

Objective: To evaluate the efficacy and the tolerance of sulfasalazine in the treatment of chronic lupus erythematosus (CLE).

Patients And Methods: We prescribed sulfasalazine (2 g/d) for 18 patients with severe CLE, all of whom had contraindications for or treatment failure with antimalarial drugs and thalidomide. This study analyses their response to treatment, duration of therapy, reasons for stopping, adverse effects, and the influence of the N-acetyltransferase 2 (NAT2) phenotype.

Results: We observed 10 complete and 3 partial responses, and 4 patients maintained complete response for at least 7 years. Eight patients experienced adverse effects, and 2 needed to stop treatment (because of photosensitization and development of antinuclear antibodies). All side effects occurred in the first 3 months of treatment. None of the 18 patients developed systemic lupus erythematosus. Of the 10 complete responders, 9 were rapid acetylators (RA), while 4 of the 5 who failed to respond were slow acetylators (SA). Leukopenia and photosensitization were observed in SA patients, while different side effects occurred in RA patients (headaches, diarrhea, moderate increase in liver enzymes and antinuclear antibodies).

Conclusion: These findings confirm our earlier reports and demonstrate that sulfasalazine can be used successfully to treat severe CLE. NAT2 genotyping before initiating treatment helps to identify potential responders and avoid side effects. In RA patients, sulfasalazine can be an alternative to thalidomide after antimalarial drugs, whereas in SA patients, it should remain a third-line treatment, to be used only after antimalarials and thalidomide.
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http://dx.doi.org/10.1016/s0755-4982(06)74770-4DOI Listing
September 2006