Meta-analysis results do not reflect the real safety of biologics in psoriasis.

BACKGROUND: In reported systematic reviews and meta-analyses of randomized controlled trials (RCTs) assessing treatments for psoriasis, the proportion of serious adverse events (SAEs) did not differ between treatments and placebo. Including cases of psoriasis worsening as SAEs may explain the lack of difference. OBJECTIVES: This systematic review and meta-analysis aimed to explore this possibility. METHODS: Among the 140 RCTs included in the Living Network Cochrane Review (last search on 8 May 2019), we selected those comparing a biologic treatment against placebo. The primary outcome was the numbers of SAEs in the treatment and placebo arms after excluding cases of psoriasis worsening. Secondary outcomes were the number of adverse events (AEs) of special interest. The trial was registered on PROSPERO (CRD42019124495). RESULTS: We analysed 51 RCTs. Of these, 21 included at least one anti-tumour necrosis factor (TNF)-α arm, 15 one anti-interleukin (IL)-17 arm, 11 one anti-IL-23 arm and nine one anti-IL-12/23 arm. With cases of psoriasis worsening included, the risk of occurrence of SAEs between biologic treatments and placebo did not differ: risk ratio (RR) 1·09, 95% confidence interval (CI) 0·88-1·36. After excluding cases of psoriasis worsening, the RR became significant (RR 1·30, 95% CI 1·02-1·65). By drug class, the RRs were for anti-TNF-α, 1·68 (95% CI 1·11-2·54; no missing data); anti-IL-17, 1·28 (95% CI 0·88-1·85; no missing data); anti-IL-23, 0·95 (95% CI 0·59-1·52; no missing data) and anti-IL-12/23, 1·18 (95% CI 0·72-1·94; no missing data). We were unable to examine potential differences in AEs of special interest between biologic treatments and placebo arms because of the small number of events. CONCLUSIONS: On excluding cases of worsening psoriasis, the risk of occurrence of SAEs is higher in the biologic than in the placebo arm. Given the rare events, we could not highlight whether this higher risk of SAEs was related to AEs of special interest. Reporting of SAEs in clinical trials has to be changed to provide more transparency through the separate reporting of disease flares leading to hospital admission and other SAEs.

Interventions for chronic palmoplantar pustulosis: abridged Cochrane systematic review and GRADE assessments.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic inflammatory disease in which sterile and relapsing pustules appear on the palms and soles. OBJECTIVES: To assess the effects of interventions for chronic PPP to induce and maintain complete remission. METHODS: We searched for randomized controlled trials (RCTs), including people with PPP or chronic palmoplantar pustular psoriasis, in the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and eight trials registers up to July 2020. Study selection, data extraction and risk-of-bias assessment were carried out independently by two review authors. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. RESULTS: We included 37 RCTs (1663 participants, 76% women, mean age 50 years). Mean treatment duration was 11 weeks. Topical vitamin D derivative may be more effective than placebo in achieving clearance [risk ratio (RR) 7·83, 95% confidence interval (CI) 1·85-33·12; low-certainty evidence from two trials]. Concerning biological therapies, there was little or no difference between etanercept and placebo in achieving clearance (low-certainty evidence from one trial), ustekinumab is less effective than placebo in reducing severity (low-certainty evidence from one trial), and guselkumab (RR 2·88, 95% CI 1·24-6·69) and secukinumab (RR 1·55, 95% CI 1·02-2·35) are probably better in reducing disease severity (moderate-certainty evidence from two and one trial(s), respectively) but may cause more serious adverse events than placebo. CONCLUSIONS: Evidence is lacking for or against major chronic PPP treatments. Risk of bias and imprecision limit our confidence in the results.

Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing.

BACKGROUND: Acral lesions, mainly chilblains, are the most frequently reported cutaneous lesions associated with COVID-19. In more than 80% of patients tested, nasopharyngeal swabs were negative on reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 when performed, and serology was generally not performed. METHODS: A national survey was launched on 30 March 2020 by the French Society of Dermatology asking physicians to report cases of skin manifestations in patients with suspected or confirmed COVID-19 by using a standardized questionnaire. We report the results for acral manifestations. RESULTS: We collected 311 cases of acral manifestations [58.5% women, median age 25.7 years (range 18-39)]. The most frequent clinical presentation (65%) was typical chilblains. In total, 93 cases (30%) showed clinical suspicion of COVID-19, 67 (22%) had only less specific infectious symptoms and 151 (49%) had no clinical signs preceding or during the course of acral lesions. Histology of skin biopsies was consistent with chilblains. Overall, 12 patients showed significant immunological abnormalities. Of the 150 (48%) patients who were tested, 10 patients were positive. Seven of 121 (6%) RT-PCR-tested patients were positive for SARS-CoV-2, and five of 75 (7%) serology-tested patients had IgG anti-SARS-CoV-2. Tested/untested patients or those with/without confirmed COVID-19 did not differ in age, sex, history or acral lesion clinical characteristics. CONCLUSIONS: The results of this survey do not rule out that SARS-CoV-2 could be directly responsible for some cases of chilblains, but we found no evidence of SARS-CoV-2 infection in the large majority of patients with acral lesions during the COVID-19 lockdown period in France. What is already known about this topic? About 1000 cases of acral lesions, mainly chilblains, were reported during the COVID-19 outbreak. Chilblains were reported to occur in young people within 2 weeks of infectious signs, which were mild when present. Most cases did not have COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR), and few serology results were available. What does this study add? Among 311 patients with acral lesions, mainly chilblains, during the COVID-19 lockdown period in France, the majority of patients tested had no evidence of SARS-CoV-2 infection. Overall, 70 of 75 patients were seronegative for SARS-Cov-2 serology and 114 of 121 patients were negative for SARS-CoV-2 RT-PCR.

Individual- and hospital-level factors associated with epidermal necrolysis mortality: a nationwide multilevel study, France, 2012-2016.

BACKGROUND: Epidermal necrolysis (EN) is a rare and life-threatening condition. OBJECTIVES: To assess whether admitting hospital characteristics and interhospital transfer are associated with mortality due to EN. METHODS: We studied the French nationwide hospital discharge database (retrospective national cohort). All patients admitted during 2012-2016 with a code for EN in the International Classification of Diseases, 10th Revision, were eligible. We extracted data on the patients (age, sex, intensive care unit admission, comorbidities) and hospitals (private proprietary vs. public, nonteaching or teaching; and number of admissions for EN as a proxy for experience). Multivariable analysis was used to identify independent predictors of in-hospital mortality with mixed logistic regression. RESULTS: We identified 991 patients (467 male; mean age 52·7 ± 23 years). They were admitted to 300 different hospitals, including teaching hospitals (25% of hospitals) for around half of the patients. Overall, 597 patients (60%) had a diagnosis of Stevens-Johnson syndrome (SJS), 171 (17%) had SJS/toxic epidermal necrolysis (TEN) overlap and 223 (23%) had TEN. In total, 109 (11%) patients died: nine (2%) with SJS, 26 (15%) with SJS/TEN overlap and 74 (33%) with TEN. The in-hospital mortality rate was lower in centres with vs. without substantial EN experience - odds ratio for one supplemental EN admission in a department 0·5 (95% confidence interval 0·3-1·0); P = 0·05 - even after adjusting for potentially relevant individual risk factors. We found no significant association between mortality and interhospital transfer. CONCLUSIONS: Our findings highlight increased survival of patients with EN in centres with a high volume of EN procedures. If confirmed in other settings, these findings reinforce the importance of expertise in early diagnosis and management of this condition. What's already known about this topic? Epidermal necrolysis (EN) is a rare and life-threatening condition. At the individual level, risk factors for in-hospital mortality have been identified. Few studies have examined the association between hospital characteristics and EN mortality, with special attention to referral hospitals. What does this study add? Short-term mortality rates were lower for patients in centres with EN experience than in centres without EN experience, after adjusting for known risk factors. We found no association between interhospital transfer and survival. If confirmed in other settings, these findings support the early transfer of patients with suspected or diagnosed EN to centres with experience, where a multidisciplinary approach can be implemented by experienced healthcare professionals, to maximize short-term survival.

Interventions for erythema multiforme: a systematic review.

Treatment of erythema multiforme (EM) is not codified. We performed a systematic review of the effect of any topical or systemic treatment on time to healing and frequency of episodes with acute and chronic forms of EM in adults. Four databases (MEDLINE, CENTRAL, EMBASE and LILACS) and other sources were searched for articles published up to 20 March 2018. Randomized control trials (RCTs), observational studies and case series (n ≥ 10) were considered. From 1558 references, we included one RCT and six case series. The RCT (n = 20) showed a significant difference in complete remission of EM with continuous acyclovir vs. placebo over 6 months. One case series found a mean reduction in flare duration with thalidomide for recurrent EM (5.1 vs. 16.2 days; n = 20). Adverse events were poorly or not reported in included studies. Quality of life was never assessed. One limitation of our study is that we excluded the cases of isolated mucosal EM in order to prevent inclusion of Stevens-Johnson syndrome cases. In conclusion, there is low-level evidence for continuous acyclovir treatment for recurrent EM (one RCT). Evidence for other treatments is only based on retrospective case series. Results for thalidomide, in particular, encourage further research. Data concerning safety are insufficient. PROSPERO registration no. CRD42016053175.

Report from the kick-off meeting of the Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN).

A major obstacle of evidence-based clinical decision making is the use of nonstandardized, partly untested outcome measurement instruments. Core Outcome Sets (COSs) are currently developed in different medical fields to standardize and improve the selection of outcomes and outcome measurement instruments in clinical trials, in order to pool results of trials or to allow indirect comparison between interventions. A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The international, multidisciplinary Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN) aims to develop and implement COSs in dermatology, thus making trial evidence comparable and, herewith, more useful for clinical decision making. The inaugural meeting of CSG-COUSIN was held on 17-18 March 2015 in Dresden, Germany, as the exclusive theme of the Annual Cochrane Skin Group Meeting. In total, 29 individuals representing a broad mix of different stakeholder groups, professions, skills and perspectives attended. This report provides a description of existing COS initiatives in dermatology, highlights current methodological challenges in COS development, and presents the concept, aims and structure of CSG-COUSIN.

[Adult Kawasaki disease]. / Syndrome de Kawasaki de l'adulte.

BACKGROUND: Kawasaki disease is an acute vasculitis seen rarely in adults. Diagnosis is based on fever lasting at least 5 days and four or five major clinical criteria in the absence of any other potential pathological causes. CASE REPORT: A 50-year-old woman taking no new medications immediately beforehand was seen with a febrile maculopapular exanthema present for 3 days, as well as gradual onset of enanthema, cheilitis, odynophagia, adenopathy, peripheral oedema and bilateral conjunctivitis. Fever and markers of inflammation persisted despite 3 days of antibiotic therapy. The diagnosis of Kawasaki disease was made on the basis of the presence of all the major diagnostic criteria of Kawasaki disease. A favourable outcome was achieved 48 hours after the start of intravenous immunoglobulin and aspirin. DISCUSSION: Our case is of interest because of the presence of all the diagnostic clinical criteria as well as the favourable outcome achieved rapidly with treatment. In adults, the rarity of this disease, which frequently presents in the incomplete forms, with lack of specific clinical signs and the unavailability of diagnostic laboratory tests mean that diagnosis is usually delayed. It is recommended that treatment be initiated before the disease has progressed for 10 days.

Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors.

Toxic epidermal necrolysis (TEN) is a rare life-threatening adverse drug reaction characterized by a massive destruction of the epidermis. Immunohistological studies of skin biopsies of TEN showed infiltrates of predominantly CD8+ T lymphocytes even though other authors reported a prominent involvement of cells of the monocyte-macrophage lineage. The aim of this study was to characterize phenotypically and functionally the cells present in the cutaneous blister fluid of four patients with TEN. We first determined that lymphocytes were predominant in blister fluid obtained early, while monocytes/macrophages later became the most important population. We then showed that this lymphocyte population, mainly CD3+CD8+, corresponded to a peculiar cell subset as they expressed cutaneous leucocyte antigen, killer inhibitory receptors KIR/KAR and failed to express CD28 molecule. Functionally, we determined that blister T lymphocytes had a cytotoxic T lymphocyte (CTL)- and NK-like cytotoxicity. The role of this cytotoxic lymphocyte population present at the site of lesions during TEN remains to be understood.

[Hand-foot-mouth syndrome recurring during common variable deficiency]. / Syndrome "mains-pieds-bouche" récidivant au cours d'un déficit commun variable.

BACKGROUND: Common variable immunodeficiency is characterized by hypogammaglobulinemia and recurrent bacterial infections. More uncommonly, these patients develop chronic enterovirus infectious meningoencephalitis. Recurrent enterovirus skin infection has not been reported to date in subjects with common variable immunodeficiency. CASE REPORT: A 26-year-old man had suffered repeated episodes of otorhinolaryngological and pulmonary infections since childhood. He experienced three episodes of vesicular cutaneous eruption involving the palms of both hands, the plantar aspect of the feet and the buccal mucosa. The patient was hospitalized in March 1995 at the third episode. Temperature was 38 degrees C. He had maculopapulous and vesicular eruptions on the palm of the hands and plantar aspect of the feet with irritation in some areas. Petichial lesions were seen on the palate. PCR demonstrated viral DNA and cell cultures of a lesion biopsy were positive for enterovirus. Gammaglobulinemia was 4 g/l with low B cell count. DISCUSSION: Viral infections are uncommon in patients with common variable immunodeficiency as cellular immunity remains normal. Severe viral infections caused by enteroviruses have however been reported, generally associating chronic, and generally fatal, meningoencephalitis. Our case would be the first case of a recurrent hand, foot and mouth disease in such patients.