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.

Childhood epidermal necrolysis and erythema multiforme major: a multicentre French cohort study of 62 patients.

INTRODUCTION: The distinction between epidermal necrolysis [EN; including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and overlap syndrome] and erythema multiforme major (EMM) in children is confusing. We aimed to better describe and compare these entities. MATERIALS AND METHODS: This French retrospective multicentre study included children ≤18 years old referred for EN or EMM between 1 January 2008 and 1 March 2019. According to pictures, children were reclassified into TEN/overlap, SJS or EMM/unclassified (SJS/EMM) groups and compared for epidemiological and clinical data, triggers, histology and follow-up. RESULTS: We included 62 children [43 boys, median age 10 years (range 3-18)]: 16 with TEN/overlap, 11 SJS and 35 EMM. The main aetiologies were drugs in EN and infections (especially Mycoplasma pneumoniae) in EMM (P < 0.001), but 35% of cases remained idiopathic (TEN/overlap, 47%; SJS, 24%; EMM, 34%). The typical target lesions predominated in EMM (P < 0.001), the trunk was more often affected in EN (P < 0.001), and the body surface area involved was more extensive in EN (P < 0.001). Mucosal involvement did not differ between the groups. Two patients with idiopathic TEN died. Histology of EMM and EN showed similar features. The recurrence rate was 42% with EMM, 7% with TEN/overlap and 0 with SJS (P < 0.001). Sequelae occurred in 75% of EN but involved 55% of EMM. CONCLUSION: Clinical features of EN and EMM appeared well demarcated, with few overlapping cases. Idiopathic forms were frequent, especially for EN, meaning that a wide and thorough infectious screening, repeated if needed, is indicated for all paediatric cases of EN/EMM without any trigger drug. We propose a comprehensive panel of investigations which could be a standard work-up in such situation. Sequelae affected both EN and EMM.

Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients.

BACKGROUND: Identification of myositis-specific autoantibodies (MSAs) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype. OBJECTIVE: We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA. METHODS: A 3.5-year multicentre prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSAs and the presence of cancer, ILD and calcinosis. RESULTS: MSAs were detected in 47.1% of 117 included patients. Patients with antimelanoma differentiation-associated protein-5 antibodies (13.7%) had significantly more palmar violaceous macules/papules [odds ratio (OR) 9.9], mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), articular involvement (OR 15.2) and a higher risk of ILD (OR 25.3). Patients with antitranscriptional intermediary factor-1 antibodies (11.1%), antinuclear matrix protein-2 antibodies (6.8%) and antiaminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8) and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1). CONCLUSION: Recognition of the adult DM phenotype associated with MSAs would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.

Hereditary angioedema with normal C1 inhibitor and factor XII mutation: a series of 57 patients from the French National Center of Reference for Angioedema.

Hereditary angioedema (HAE) is a rare disease associated with either a quantitative or qualitative deficiency in C1-inhibitor (C1-INH) or normal C1-INH. HAE with normal C1-INH is associated in 20% of cases with mutations in the gene for factor XII (FXII) or FXII-HAE. A recent review described 41 families, including 14 German and 15 Spanish families. We have constructed a register of French patients and their characteristics. A national survey was launched through the French National Center of Reference for Angioedema (CREAK) to study the clinical, biological and therapeutic characteristics of patients with HAE linked to a mutation of FXII gene. Fifty-seven patients were identified from 24 different families. In most cases they were young women (mean age at diagnosis: 31 years, mean age at first symptom: 21 years, female/male ratio: 76%). Twenty-one per cent of the patients experienced angioedema attacks only during pregnancy or when on oestrogen contraception. Sixty-three per cent had attacks at all times, but they were more severe during these same periods. Male carriers of the mutation were more frequently asymptomatic than females (P = 0·003). C1-INH concentrate and icatibant were both effective for treating attacks. The prophylactic use of tranexamic acid led to a 64% decrease in the number of attacks. This is one of the largest series reported of HAE patients with FXII mutation. The therapeutic management appeared to be identical to that of HAE with C1-INH deficiency.

[Innovative therapies for metastatic melanoma in elderly patients]. / Place des traitements innovants du mélanome métastatique chez le sujet âgé.

The mortality rate for malignant melanoma is higher in elderly patients aged 75 years or more, with over 25% of melanomas being diagnosed in this population. This poorer prognosis might perhaps be improved by emerging targeted therapies and immunotherapy, although these agents must be prescribed with care in this rather fragile population. The purpose of our review of the literature concerning phase-2 and -3 published trials of these innovative molecules was to examine their optimal use in elderly patients presenting metastatic malignant melanoma. Most of the trials examined included elderly patients and some were analyzed by age sub-groups. In conclusion, elderly patients with ECOG 0/1 status can be given ipilimumab or vemurafenib as first-line therapy depending on tumoral BRaf mutation status. The benefit of combined targeted therapies does not seem to apply consistently in elderly patients and their use must be discussed. Further specific data must be collected in elderly patients concerning anti-PD1 molecules. For more fragile patients, risk scales or scores should enable more accurate use of innovative therapies in metastatic melanoma. Moreover, physicians must be aware of the common drug interactions with targeted therapies, since elderly patients are often taking several concomitant drugs.

[Inducible urticaria and chronic spontaneous urticaria]. / Urticaires inductibles et urticaires chroniques spontanées.

In the recently published 2013 revision of the guidelines of urticaria, chronic urticaria (CU) gathers chronic spontaneous urticaria (CSU) and inducible urticaria (IU), and excludes pseudourticarial rashes with more than 24h-lasting rash or more than 72h-lasting angiœdema. Activity and psychosocial impact of the disease must be measured with validated scores such as Urticaria and Angioedema Activity Scores, Urticaria Control Test, CU-Q2OL, AE-QOL. Although an allergic cause is generaly absent in CU, pathomecanisms remain elusive even since the well-known role of mast cell degranulation and the presence of autoantibodies anti-FcRεI or anti-IgE. Coagulation pathways may be involved, at least as an amplifying phenomenon. Mean duration of CU is 1 to 4 years, but many patients still have symptoms after 10 years, some predictive factors being known as severity, angioedema, a positive autologous serum test, inducible urticaria. Recommended routine diagnosic tests are validated provocation tests for IU (and cryoproteins for cold urticaria), blood cell count and CRP for CSU, since a thorough history and a normal detailed physical examination should avoid unnecessary tests. Management of CU has been improved by the off-label use of increased dosages of second generation anti- H1 antihistamines, but a subsequent therapeutic intensification may be necessary in some cases. Educational program may prevent this intensification. Independent studies evaluating available molecules are needed, along with more fundamental research studies.

[Dupilumab-related blepharoconjunctivitis: Recommendations of the CEDRE group. Atopic dermatitis, conjunctivitis and dupilumab: Which management approach?] / Blépharo-conjonctivites sous dupilumab : recommandations du groupe CEDRE. Dermatite atopique, conjonctivites et dupilumab : quelle prise en charge ?

Dupilumab is a recombinant monoclonal IgG4 type antibody which inhibits IL4 and IL13 signaling. It is indicated in moderate to severe atopic dermatitis (AD) in adults and adolescents over 12 years of age. Its side effects include conjunctivitis and blepharoconjunctivitis, affecting between 4.7% and 28% of patients depending on the study. The incidence of conjunctivitis in patients treated with dupilumab for AD appears to be higher than placebo in clinical studies. This increase was not observed in patients treated with dupilumab for asthma or sinonasal polyposis. The risk factors for conjunctivitis in patients with AD are disease severity, pre-existence of conjunctivitis and low concentrations of dupilumab, but the pathophysiology of this disease is poorly understood. A literature search carried out in April and May 2020 showed an increase in the number of publications on the subject, but there are currently no official joint dermatologist-ophthalmologist recommendations for prevention and management. The objective of this article is to provide an overview of the status of this subject, to address the main questions raised by this type of conjunctivitis and to suggest a course of action for starting and continuing treatment with dupilumab in patients with AD, according to the recommendations of the French Ophthalmologist/Dermatologist group CEDRE.

Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study.

BACKGROUND: The interest of long-term superpotent topical steroids (STS) in bullous pemphigoid (BP) has been supported by randomized controlled trials. However, inadequate compliance, poor cutaneous tolerance and nursing difficulties are potential drawbacks. Open-label studies on limited series of patients suggested that low-dose methotrexate (MTX) may be useful, permitting long-term maintenance of a clinical remission obtained by initial, short-term STS. OBJECTIVES: Open, clinical records-based retrospective analysis of a multicentre series of patients receiving a combined regimen of initial, short-term STS and MTX followed by long-term MTX alone. The primary objective was evaluation of the clinical efficiency of this strategy based on initial clinical remission and subsequent clinical maintenance. The secondary objective was evaluation of the tolerance (type and rating of adverse events) of this combined regimen. METHODS: Seventy patients with BP (mean age 82·7 years) were included. Treatment consisted of an initial combination of STS and MTX for a mean duration of 12·3 weeks followed by long-term MTX alone for a mean duration of 8·48 months with a mean and median MTX dosage of 10 mg per week. RESULTS: One hundred per cent of the patients showed an initial, complete clinical remission after a mean time interval of 21·9 days. The overall rate of long-term disease control was 76%, whereas 24% of patients experienced at least one relapse during subsequent treatment with MTX alone. Drug-related adverse effects were mainly haematological and gastrointestinal and resulted in treatment discontinuation in 11 patients (16%). Six patients (9%) died during the follow-up period with one death (1%) most likely to be related to treatment. CONCLUSIONS: Long-term low-dose MTX combined with short-term STS may result in protracted control of BP in carefully selected patients. These results should prompt randomized controlled trials comparing this treatment with the more usual regimen of long-term STS alone.

Interest of (18)F-FDG PET-CT scanning for staging and management of merkel cell carcinoma: a retrospective study of 15 patients.

BACKGROUND: The additional benefit of 18FDG-Positron Emission Tomography-Computed Tomography (FDG PET-CT) compared with conventional imaging is still a controversial issue in MCC. OBJECTIVES: This study was designed to evaluate the ability of FDG PET-CT to detect secondary lesions clinically inconspicuous and not shown by conventional imaging. METHODS: Clinical records of 15 MCC patients were retrospectively reviewed to investigate the specific interest of FDG PET-CT compared with X-computed tomography (CT). The main endpoint was the ability of FDG PET-CT to detect secondary lesions and the possible resulting changes in disease staging and management compared with pre-FDG PET-CT data including clinical examination, sentinel lymph node biopsy (SLNB), and diagnostic CT. RESULTS: FDG PET-CT was relevant with a single false negative result and led to significant changes in disease staging and management in 46% of patients compared with clinical examination alone. However, additional secondary lesions not detected by CT were evidenced during follow-up in a single patient with an already known metastatic disease, data which did not result in any change in staging and treatment. Sensitivity, specificity, positive predictive value and negative predictive value were respectively 0.66, 1, 1 and 0.8 for SLNB, 0.89, 1, 1 and 0.93 for CT and 0.89, 1, 1 and 0.93 for FDG PET-CT. No additional neoplasm was detected by FDG PET-CT. CONCLUSION: Although FDG PET-CT is of questionable value in MCC management when used in parallel with CT, it may be considered as a valuable option as a single whole-body survey procedure.

[Acquired angioedema due to C1-inhibitor deficiency: CREAK recommendations for diagnosis and treatment]. / Angiœdèmes par déficit acquis en C1-inhibiteur : recommandations du CREAK pour le diagnostic et la prise en charge.

Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy. The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients. The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.