Factors associated with early relapse of infantile haemangioma in children treated for at least six months with oral propranolol: A case-control study using the 2014-2021 French Ouest DataHub.

BACKGROUND: The factors associated with early relapse of infantile haemangioma (IH) after a first course of treatment with oral propranolol for at least six months (initiated after the marketing authorization had been granted) have not previously been investigated. OBJECTIVES: To identify factors associated with the risk of early relapse in children with IH treated with oral propranolol according to the current prescribing guidelines. METHODS: We performed a multicentre, retrospective, case-control study, using the Ouest Data Hub database. All children treated for at least 6 months with oral propranolol for IH between 31 June 2014 and 31 December 2021, and with a follow-up visit at least three months after treatment discontinuation were included. A case was defined as relapse of IH within three months of treatment discontinuation; each case was matched for age at treatment initiation and for centre, with four (relapse-free) controls. The association between relapse and treatment or IH characteristics was expressed as an odds ratio (OR) from univariate and multivariate conditional logistic regressions. RESULTS: A total of 225 children were included. Of these, 36 (16%) relapsed early. In a multivariate analysis, a deep IH component was a risk factor for early relapse [OR = 8.93; 95%CI: 1.0-78.9, p = 0.05]. A propranolol dosage level of less than 3 mg/kg/day protected against early relapse [OR = 0.11; 95%CI: 0.02-0.7, p = 0.02]. Tapering before propranolol discontinuation was not associated with a lower risk of early relapse. CONCLUSION: The risk factors for late and early relapse are probably different. Investigation of the risk factors for early vs. late IH relapse is now warranted.

Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice.

BACKGROUND: Dupilumab is the first biotherapy available for the treatment of moderate-to-severe childhood atopic dermatitis (AD). OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of dupilumab in daily practice. METHODS: Patients aged 6-11, who had received a first dose of dupilumab, were included in this multicentre retrospective cohort study. The primary endpoint was change in SCORAD after 3 months of treatment. Secondary endpoints were change in IGA score at 3 months, proportion of patients with SCORAD50 and SCORAD75, description of adverse events and proportion of children in our cohort who would be excluded from pivotal phase 3 clinical trial. RESULTS: Eighty patients were included. After 3 months of treatment, there was a significant decrease in SCORAD (mean: 21.8 ± 13.8 vs 53.9 ± 18.5; P < 0.0001) and IGA (1.3 ± 0.8 vs 3.5 ± 0.7; P < 0.0001). Conjunctivitis was observed in 11.3% (n = 9/80); three patients experienced dupilumab facial redness (DFR); 17.5% (n = 14/80) reported injection site reactions; 6.3% (n = 5/80) discontinued treatment. 61.2% (n = 49/80) children were ineligible in the phase 3 trial. LIMITATIONS: There is no control group. Because it was a real life study based on information from patient medical records in a French multicentre cohort, we cannot rule out the presence of reporting bias generated by the use of patient reported characteristics and missing information. CONCLUSION: These real-life data confirm the efficacy and safety of dupilumab in children with moderate to severe AD extended to dyshidrosis and atopic prurigo, but it also revealed a lower frequency of DFR and conjunctivitis. However, administration in injectable form may be a barrier in this age group.

Risk of systemic infections requiring hospitalization in children with atopic dermatitis: a Danish retrospective nationwide cohort study.

BACKGROUND: Infections can trigger worsening of atopic dermatitis (AD). OBJECTIVES: To examine whether hospital-managed paediatric AD is associated with increased risk of extracutaneous infections requiring hospitalization in childhood. METHODS: A nationwide-based cohort study using Danish registries was done. Children aged < 18 years with a hospital diagnosis of AD and children without a hospital diagnosis of AD were sex- and age-matched at date of AD diagnosis. Study outcomes were extracutaneous infections that led to hospitalization. AD severity was defined according to prescriptions for treatments. RESULTS: Of 19 415 children with AD [median follow-up 7·4 years; interquartile range (IQR) 3·3-13.3] and 194 150 without AD (median follow-up 7·7 years; IQR 3·6-13·5), 56% were boys and 50% were aged < 2 years. Children with AD had an increased rate of lower respiratory [LRTI; adjusted hazard ratio (aHR) 1·79, 95% confidence interval (CI) 1·65-1·94)], upper respiratory (URTI; aHR 1·59, 95% CI 1·34-1·88), urinary tract (UTI; aHR 1·34, 95% CI 1·16-1·54), musculoskeletal (MSSI; aHR 1·33, 95% CI 1·06-1·66) and gastrointestinal infections (GITIs; aHR 1·24, 95% CI 1·14-1·35) vs. children without AD. Associations did not clearly vary with AD severity. Absolute risk difference per 10 000 person-years was 26·4 (95% CI 23·0-29·8) for LRTIs, 3·1 (95% CI 1·6-4·7) for URTIs, 3·6 (95% CI 1·8-5·4) for UTIs, 0·9 (95% CI 0·2-2·0) for MSSIs and 8·7 (95% CI 5·7-11·7) for GITIs. CONCLUSIONS: Children with hospital-managed AD have an increased risk of systemic infections that lead to hospitalization; absolute risk is generally low.

The cardiovascular safety of oral alitretinoin: a population-based cohort study involving 19 513 patients exposed to oral alitretinoin.

BACKGROUND: Oral alitretinoin is a retinoid used for severe chronic hand eczema. Although caution is recommended for patients with uncontrolled dyslipidaemia or cardiovascular risk factors, the actual atherothrombotic risk has not been investigated thus far. OBJECTIVES: To detect any excess of atherothrombotic events among patients exposed to alitretinoin, during treatment or in the 2 years following initiation. METHODS: Using the French Health Insurance database, we compared the number of patients who had an atherothrombotic event (coronary artery disease, ischaemic stroke or peripheral artery disease requiring revascularization) in the population exposed to oral alitretinoin vs. the general population of the same age, sex and baseline cardiovascular risk, using standardized morbidity ratios (SMRs). RESULTS: Between 2009 and 2017, 19 513 patients were exposed to oral alitretinoin in France. Sixty-four (0·3%) patients had an atherothrombotic event while on alitretinoin. Patients receiving alitretinoin experienced no more atherothrombotic events than the general population: patients without cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·65 [95% confidence interval (CI) 0·26-1·34] during alitretinoin treatment, and 1·21 (95% CI 0·90-1·59) in the 2 years following initiation; patients with cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·82 (95% CI 0·60-1·08) during alitretinoin treatment and 0·95 (95% CI 0·82-1·09) in the 2 years following initiation. Taken separately, SMRs for each outcome did not increase either. CONCLUSIONS: These data from an exhaustive nationwide population-based study do not support an increase in the incidence of atherothrombotic events with alitretinoin use, regardless of the baseline cardiovascular risk of the patient.

Association between hospital-diagnosed atopic dermatitis and psychiatric disorders and medication use in childhood.

BACKGROUND: While adult atopic dermatitis (AD) is associated with anxiety and depression, and paediatric AD is linked to attention deficit hyperactivity disorder (ADHD), the relationship between AD in childhood and other psychiatric disorders is largely unknown. OBJECTIVES: To determine the relationship between AD and diagnosis and treatment of psychiatric disorders in children. METHODS: All Danish children born between 1 January 1995 and 31 December 2012 with a hospital diagnosis of AD (n = 14 283) were matched 1 : 10 with children without a hospital diagnosis of AD. Endpoints were psychotropic medication use, hospital diagnoses of depression, anxiety, ADHD, or self-harming behaviour, accidental/suicidal death, and consultation with a psychiatrist or psychologist. RESULTS: Significant associations were observed between hospital-diagnosed AD and antidepressant [adjusted hazard ratio (aHR) 1·19, 95% confidence interval (CI) 1·04-1·36], anxiolytic (aHR 1·72, 95% CI 1·57-1·90), and centrally acting sympathomimetic (aHR 1·29, 95% CI 1·18-1·42) medication use. Consultation with a psychiatrist (aHR 1·33, 95% CI 1·16-1·52) or psychologist (aHR 1·25, 95% CI 1·11-1·41) was also associated with AD. No association with a hospital diagnosis of depression (aHR 0·58, 95% CI 0·21-1·56), anxiety (aHR 1·47, 95% CI 0·98-2·22) or self-harming behaviour (aHR 0·88, 95% CI 0·27-2·88) was observed, but a diagnosis of ADHD (aHR 1·91, 95% CI 1·56-2·32) was significantly associated with AD. The absolute risks were generally low. CONCLUSIONS: The increased risk of treatment, but not of a hospital diagnosis of psychiatric disorders in children with hospital-diagnosed AD, suggests that psychiatric issues in children with AD could be of a transient, reversible or mild-moderate nature.

Isotretinoin and risk factors for suicide attempt: a population-based comprehensive case series and nested case-control study using 2010-2014 French Health Insurance Data.

BACKGROUND: Although the causal role of isotretinoin in suicidal behaviour is controversial, suicide attempts (SA) do occur among patients taking isotretinoin. OBJECTIVES: To describe patient profiles and the management of isotretinoin among patients who committed or attempted suicide under treatment. To assess the risk factors for SA under isotretinoin. METHODS: We performed a comprehensive case series of suicides and SAs under isotretinoin, and a case-control study, using Nationwide French Health Insurance database. The main analysis compared cases (subjects with a SA during a course of isotretinoin) to controls, individually matched for age, gender and rank of the current course; controls were to be exposed to isotretinoin at the index date (date of SA for the corresponding cases). The patients' psychiatric history at isotretinoin initiation was studied. In a secondary analysis, patients who continued their isotretinoin treatment after their SA were compared to patients who discontinued it. RESULTS: In all, 328 018 subjects started a course of isotretinoin between 1 January 2010 and 31 December 2014 and 184 patients were hospitalized for a SA; half of them had a psychiatric history at initiation. In the multivariate analysis, psychiatric history and history of anxiety alone were risk factors for SA [Odds ratio (OR), 18.21; 95% confidence interval (CI), 9.96-33.30 and 4.78; 95% CI, 2.44-9.33, respectively]. Among 176 cases of SA with sufficient follow-up, 103 (58.5%) carried on with their treatment after their SA. Treatment initiation by a dermatologist was inversely associated with the continuation of the treatment after a SA (OR, 0.38; 95% CI, 0.18-0.80). CONCLUSIONS: Suicide attempts under isotretinoin are rare events, and our results suggest that most of the patients concerned have a risk-prone profile detectable at the time of treatment initiation. The risk-benefit ratio of continuing isotretinoin after a SA warrants further careful evaluation.

[Facial skin cancers: Comparison of opinions in French multidisciplinary team meetings]. / Cancers cutanés de la face : avis comparés de réunions de concertation pluridisciplinaire françaises.

BACKGROUND: The aim of our study was to evaluate the diversity, or homogeneity, of recommendations made in multidisciplinary team meetings (MTM) concerning the management of facial skin cancers in France, and to analyze the determinants thereof. PATIENTS AND METHODS: We contacted a panel of dermatology and ENT multidisciplinary teams (MDT) and collected their recommendations made at meetings regarding 3 clinical cases: squamous cell carcinoma in a renal transplant patient with an incomplete excision margin (case 1), locally advanced basal cell carcinoma (case 2), and lentigo maligna (case 3). The responses were analyzed globally and then based on 2 subgroups defined by the presence or absence of a dermatologist in the MTM. The effect of the makeup of the MTM (based on the presence of a dermatologist, a plastic surgeon, an oncologist and an ENT specialist) was evaluated for the main therapeutic proposals. RESULTS: The opinions of the 45 MDMs that responded to the survey were mixed for the three cases as regards important elements such as the indication of surgical revision for case 1, the proposal of an alternative treatment to surgery for case 2, and monitoring arrangements for case 3. Certain proposals were associated with the presence of a dermatologist in the MTM, such as discussion of adaptation of immunosuppressive treatment and details of the surgical margins to be applied for case 1, as well as simple monitoring and details of monitoring arrangements in case 3. CONCLUSION: It is important to maintain dermatologists in MTMs on account of their expertise in all therapeutic areas concerning skin cancers.

Biological treatments for paediatric psoriasis : a retrospective observational study on biological drug survival in daily practice in childhood psoriasis.

BACKGROUND: Three biotherapies - etanercept, adalimumab and ustekinumab - are licensed in childhood psoriasis. The few data available on their efficacy and tolerance are mainly derived from industry trials. However, biological drug survival impacts long-term performance in real-life settings. OBJECTIVE: The objective of this study was to evaluate the survival rates of biological therapies in children with psoriasis in real-life conditions. Secondary objectives were to evaluate the factors associated with the choice of the biological therapy and to report severe adverse events. MATERIALS AND METHODS: This study was an observational retrospective study. Data were extracted from the clinical records of 134 children. Kaplan-Meier estimates were used to analyse drug survival overall and in subgroups of plaque psoriasis, bio-naïve and non-naïve patients. RESULTS: We analysed 184 treatment courses: 70 with etanercept, 68 with adalimumab and 46 with ustekinumab. Factors associated with the choice of first-line biological agent were age at initiation (younger for adalimumab, P < 0.0001), age at onset of psoriasis (younger for adalimumab and etanercept, P = 0.03) and baseline Psoriasis Assessment Severity Index and Physician global assessment (both higher for adalimumab, P < 0.001). Drug survival rates were higher for ustekinumab than for adalimumab and etanercept (P < 0.0001) for all treatment and all psoriasis types, plaque-type psoriasis (P = 0.0003), patients naïve for biological agents (P = 0.0007) and non-naïve patients (P = 0.007). We reported eight serious adverse events (SAEs): severe infections (n = 3), significant weight gain (n = 2), psoriasis flare (n = 1) and malaise (n = 1). Biological therapy was discontinued in three children (one with psoriasis flare and two with weight gain). Only the two cases of weight gain resulted in an unfavourable outcome. CONCLUSIONS: Our real-life comparative study found that ustekinumab had the best drug survival outcome. The profile of SAEs in children was comparable to that in adults. These results will assist dermatologists in the decision-making process when choosing treatment options for children with psoriasis in daily practice.

Skin manifestations among GATA2-deficient patients.

GATA2 mutations have been identified in various diseases, such as MonoMAC syndrome, Emberger syndrome, familial myelodysplastic syndrome, acute myeloid leukaemia and dendritic cell, monocyte, B-cell and natural killer-cell deficiency. These syndromes present a wide range of clinical features, dominated by severe infections and haematological disorders such as myelodysplastic syndrome. Up to 70% of patients with GATA2 mutations have dermatological features, mainly genital or extragenital warts, panniculitis or erythema nodosum and lymphoedema. We report three patients presenting with common dermatological and haematological features leading to the diagnosis of GATA2 deficiency, but also with skin manifestations that have not been previously described: gingival hypertrophy, macroglossitis and glossitis and granulomatous lupoid facial lesions. Dermatologists can encounter patients with GATA2 mutations and should recognize this disorder.

Clinical and haemodynamic risk factors associated with discrepancies in lower limb length with capillary malformations: data from the national paediatric French cohort CONAPE.

BACKGROUND: Genetics discoveries have allowed for a better understanding of capillary malformations (CMs) associated with overgrowth syndrome. However, molecular analyses are still not easy to perform or interpret. Other analytical methods are needed. OBJECTIVES: To identify clinical and haemodynamic factors associated with leg length discrepancy (LLD) in children with CMs of the lower limbs. METHODS: Data were obtained from the multicentre French national cohort CONAPE (COhorte Nationale d'enfants atteints d'Angiome Plan de membrE inférieur), from children aged 2-12 years old with CMs of the lower limbs. Clinical characteristics were prospectively collected. Haemodynamic factors were measured by an sonographer who calculated the arterial blood flow (ABF) in both lower limbs. An ABF difference ≥ 50% between the two lower limbs was considered relevant. LLD ≥ 2% was determined by the same radiologist on centralized radiographs. RESULTS: We analysed data at baseline for 96 children. The mean ± SD age was 5·6 ± 3·1 years; 49 (51%) were male; and 14 (15%) showed LLD. In total, 32 patients (33%) had venous anomalies, 13 (14%) lymphatic anomalies and in one child a diagnosis of Parkes Weber syndrome was made. Only an increased circumference above the knee was more frequent with than without LLD (43% vs. 13%, P = 0·02). In all, 10/79 patients (13%) showed a difference in ABF ≥ 50%: four had LLD. The frequency of differences in ABF ≥ 50% was greater with than without LLD [33% (n = 4/12) vs. 9% (n = 6/67), P = 0·04]. CONCLUSIONS: ABF measured by Duplex ultrasonography is a simple, low-cost and noninvasive complementary examination for help in detecting LLD, with a difference of ≥ 50% possibly associated.

Drug survival and postdrug survival of first-line immunosuppressive treatments for atopic dermatitis: comparison between methotrexate and cyclosporine.

INTRODUCTION: Cyclosporine and methotrexate are the two preferred first-line immunosuppressive treatments in atopic dermatitis. The aim of this study was to compare the treatment profiles of methotrexate and cyclosporine in daily practice as the first-line immunosuppressive treatment in atopic dermatitis, using two survival analyses, 'drug survival' (time on the drug) and 'postdrug survival' (time between two drugs). METHODS: Retrospective study including patients with moderate-to-severe atopic dermatitis treated with methotrexate or cyclosporine as the first-line immunosuppressive treatment. The reasons for discontinuation of treatment were collected as follows: controlled disease, treatment failure, side event pregnancy and non-compliance. 'Drug survival' and 'postdrug survival' analyses were performed using the Kaplan-Meier method and predictive factors were analysed using uni- and multivariate Cox regression analyses. RESULTS: Fifty-six patients, among whom 25 patients treated with cyclosporine and 31 with methotrexate (median age: 34 ± 15 years), were included between 2007 and 2016. Reasons for discontinuation were not significantly different between 'controlled disease' and other reasons (P = 0.11). The median 'drug survival' was significantly longer for methotrexate (23 months) than for cyclosporine (8 months) (P < 0.0001). Six months from baseline, 93% of patients treated with methotrexate were still being treated vs 63% among patients treated with cyclosporine. The median of 'postdrug survival' was significantly longer for methotrexate (12 months) than for cyclosporine (2 months). Only treatment with CYC was a predictive factor for decreased 'drug survival' and 'postdrug survival'. CONCLUSION: This is the first direct comparison between methotrexate and cyclosporine as first-line immunosuppressive treatments for moderate-to-severe atopic dermatitis in daily practice. We evidenced two different treatment profiles: the duration of methotrexate administration is longer than that of cyclosporine. 'Postdrug survival' could be a new tool to assess the maintenance of effect of a drug after withdrawal in atopic dermatitis, and more broadly in chronic skin disease.

[Shifting cellulitis in a patient with X-linked hypogammaglobulinemia]. / Dermo-hypodermite bactérienne « à bascule ¼ chez un patient atteint d'hypogammaglobulinémie liée à l'X.

BACKGROUND: In cases of immunodeficiency, a systemic infection may be revealed by atypical symptoms, particularly those involving the skin. PATIENTS AND METHODS: The present case describes a 19-year-old male with X-linked hypogammaglobulinemia, or Bruton agammaglobulinemia, treated with intravenous immunoglobulin G antibodies. Over a 6-week period, the patient developed recurrent plaques in both legs, first on one and then on the other, without fever. Blood cultures were repeated and the fifth pair proved positive for Campylobacter jejuni. An abdominal scan showed appendicitis without intestinal signs. The patient was treated with azithromycin for 2 weeks, which resulted in full recovery from the skin lesions. DISCUSSION: Campylobacter bacteremia infections are severe and carry a 15% mortality rate at 30 days. The majority of affected patients present humoral immunodeficiency. The literature contains reports of 10 patients with C. jejuni-associated cellulitis, of whom 6 presented hypogammaglobulinemia. We postulate that the cutaneous manifestations were caused by septic metastases. The immunoglobulin replacement therapy mainly comprised IgG antibodies; IgA and IgM antibodies appear to play a key role in the response to C. jejuni infection, which could explain the susceptibility observed. The American guidelines recommend blood and skin cultures in patients with cellular immune defects. We suggest that this recommendation be extended to patients with humoral immunodeficiency.