key: cord-0983069-5w765j87
authors: Frings, Verena Gerlinde; Grän, Franziska; Machado, Álvaro; Lesort, Cécile; Vilas Boas, Pedro; Arianayagam, Sanju
title: Journal Club
date: 2021-05-14
journal: Eur J Dermatol
DOI: 10.1684/ejd.2021.3979
sha: 6442afe2e7a14c3126d9740a0c46338a92615329
doc_id: 983069
cord_uid: 5w765j87

nan

In light of the upcoming European Medicines Agency approval for JAK inhibitors for the treatment of atopic dermatitis, clarity about drug class safety considerations is important. In this context, Bieber et al. [1] reported pooled safety data for baricitinib, an oral, reversible, selective inhibitor of JAK1/JAK2, that is already approved for the treatment of rheumatoid arthritis and severe alopecia areata, and is in late-stage development for adult patients with moderate-to-severe atopic dermatitis (AD). In completed Phase 2 and 3 clinical trials, baricitinib as monotherapy and in combination with topical steroids improved signs and symptoms of AD [2, 3] . The analysis of the report by Bieber and colleagues included patient-level safety data from six double-blinded, randomized, placebo-controlled studies (one Phase 2 and five Phase 3), one double-blinded, randomized, long-term extension (LTE) study and one open-label LTE study, based on three data sets: placebocontrolled, 2-mg to 4-mg extended and All-bari AD. The All-bari AD data set provided estimates for incidence rates (IRs) of all adverse events (AEs) and assessment for less common types, as it included data for all patients who received at least one dose of baricitinib from any of the eight clinical trials at any time. Safety outcomes include treatment-emergent adverse events (TEAEs), AEs of special interest and abnormal laboratory changes. Altogether, data were collected for 2,531 patients who were given baricitinib for a median duration of 310 days. The frequency of serious infections, opportunistic infections and conjunctival disorders was low and similar between placebo-controlled treatment groups. The most common TEAEs in the baricitinib groups were nasopharyngitis, mild and short headaches, diarrhoea and creatine phosphokinase elevation without muscle-related symptoms or rhabdomyolysis. The most common serious infections were eczema herpeticum (n = 11, IR = 0.5), cellulitis (n = 6, IR = 0.3) and pneumonia (n = 3, IR = 0.1). Eczema herpeticum infections appear to be correlated with extent of AD disease severity in the baricitinib AD data set and may indicate that initial increases in eczema herpeticum eruptions with baricitinib 4-mg are offset with prolonged therapy by improvements in AD lesions. No increase in bacterial skin infections, malignancies, gastrointestinal perforations, positively adjudicated cardiovascular events or tuberculosis were reported. In the All-bari AD data set, there were two positively adjudicated major cardiovascular adverse events: two venous thrombosis events and one death. However, severe and predominantly active AD is independently associated with an increased risk of cardiovascular events [4] . Nevertheless, thromboembolic events are a recognized adverse drug reaction associated with JAK inhibitors [5] . This integrated safety analysis in patients with moderate-to-severe AD confirms the established safety profile of baricitinib and suggests that baricitinib may represent a reasonable treatment option for patients who experience eye symptoms with dupilumab. However, it also reminds us that we have to extend our anamnesis, to keep a close eye on lab results and select our patients for treatment with baracitinib wisely. Epidermal necrolysis, the unified denomination for Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS-TEN overlap, is a rare severe cutaneous drug reaction, certainly one of the true dermatological emergencies, which calls for rapid assessment of mortality. The long-time reference standard Score of TEN (SCORTEN) [6] and the recently published ABCD-10 score (age, bicarbonate, cancer, dialysis, 10% body surface area [BSA]) [7] , were compared in a single-centre retrospective study by Koh et al. [8] The ABCD-10 score not only consists of fewer parameters, but also introduces a new variable: dialysis before admission. The scores for SCORTEN and ABCD-10 depend on two factors: calibration and ability to discriminate (to stratify patients by mortality risk). In the study, 196 reported that the discrimination of ABCD-10 was similar to that of SCORTEN (ABCD-10, 0.78; 95% CI: 0.72-0.85; vs SCORTEN, 0.77; 95% CI: 0.69-0.84; p = 0.53; equal discrimination for patients treated with supportive care alone or immunomodulatory drugs). However, dialysis before admission, the most heavily weighted factor in ABCD-10, performed weaker in this cohort (odds ratio: 3.7; 95% CI: 1.0-13.2, p = 0.04). Additionally, the calibration of SCORTEN appears superior, although at higher score ranges, mortality may be overestimated. A limitation of this study was the scores from an Asian population, as the European and North American cohorts were used to develop SCORTEN and ABCD-10, respectively. Future studies may consider revising the existing SCORTEN, given its current good discrimination. Nevertheless, the most pressing need in EN clinical research is understanding whether immunomodulatory therapies can alter the disease's course. The current SARS-CoV-2 pandemic keeps us all busy and reminds us repeatedly that some diseases come with a multifacetted range of cutaneous manifestations. The timing of eruptions in the disease course and potential associations between morphological subtypes and outcome of the disease remain unclear. However, identification and characterization of COVID-19 skin lesions is important to prompt suspicion of SARS-CoV-2 infection [9] . Thus, dermatologists at Harvard Medical School and Massachusetts General Hospital created the COVID-19 Dermatology Registry and, in collaboration with the American Academy of Dermatology (AAD) and International League of Dermatologic Societies (ILDS), invited health care workers globally to submit data for possible cutaneous manifestations of confirmed or suspected COVID-19 [10] . Freeman et al. [11] analysed this data aiming to characterize internationally representative cutaneous manifestations of confirmed/suspected SARS-COV-2 infection and to gain insight into the pathophysiological course of COVID-19. The registry collected 716 cases of new-onset dermatological symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, whereas fixed livedo racemosa, retiform purpura, and true acral ischaemia appeared in critically ill patients, corroborating others' findings [12] . This suggests that thrombotic disease in critically ill patients with COVID-19 may extend to the skin in patients with livedo racemosa/retiform purpura/acro-ischaemia, with a morphology distinct from pernio [12] . Previously, Suchonwanit et al. [13] proposed that cutaneous manifestations of COVID-19 might present as two mechanistic patterns: clinical features similar to viral exanthemas and cutaneous eruptions secondary to COVID-19 systemic symptoms, especially vasculitis and thrombotic vasculopathy. Although this proposed dichotomy is a loose framework, it may provide a good starting point to consider further findings. Although the study by Freeman and colleagues [11] has obvious limitations (a case series, reliance on the providers -only half of whom were dermatologists -judgment in entering data, only 25% of patients with laboratory-confirmed disease), it highlights the wide variety of cutaneous manifestations of COVID-19 reported and should prompt further investigations. As a last point, I'd like to thank the members of the EJD's Residents' Board of the last two years: Sanju Arianayagam, Pedro Vilas Boas, Franziska Grän, Cécile Lesort and Álvaro Machado. They made an outstanding team of dedicated, enthusiastic and well-versed colleagues and contributed excellently to the Residents' Corner-in addition to their demanding specialist training.

Disclosure. Financial support: none. Conflicts of interest: none.

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials

Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a Phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy Phase III trials

Severe and predominantly active atopic eczema in adulthood and long term risk of cardiovascular disease: population based cohort study

Thromboembolism with Janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk?

SCORTEN: a severity-of-illness score for toxic epidermal necrolysis

Development and validation of a risk prediction model for in-hospital mortality among patients with Stevens-Johnson syndrome/toxic epidermal necrolysis-ABCD-10

Assessment and comparison of performance of ABCD-10 and SCORTEN in prognostication of epidermal necrolysis

Chilblains are a common cutaneous finding during the COVID-19 pandemic: a retrospective nationwide study from France

The AAD COVID-19 registry: crowdsourcing dermatology in the age of COVID-19

The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Cutaneous manifestations in COVID-19: lessons learned from current evidence