Summary
Background
The antimalarials (AMs) hydroxychloroquine (HCQ) and chloroquine (CQ) have demonstrated variable cutaneous response rates in cutaneous lupus erythematosus (CLE).
Objectives
We ...sought to assess the global cutaneous response rates to HCQ and CQ, with respect to CLE subtypes, based on previously published studies.
Methods
We performed a systematic review and meta‐analysis of studies published in MEDLINE, Embase and the Cochrane Library between 1965 and December 2015. The proportions of responders to AMs according to CLE subtypes were extracted from individual studies and pooled using random‐effects or fixed models. The odds ratio (OR) was used as the measure of association to compare the response rates between CLE subtypes and AMs.
Results
Among 1990 courses of treatment with AMs from 31 included studies, the overall response rate to AMs was 63% 95% confidence interval (CI) 55–70, with important statistical heterogeneity across the included studies. HCQ had a higher overall efficacy than CQ, but this was not significant (OR 1·48, 95% CI 0·98–2·23). The response rate to AMs was different between CLE subtypes, ranging from 31% (95% CI 20–44) for chilblain lupus to 91% (95% CI 87–93) for acute CLE. The response was significantly higher for acute CLE than for subacute CLE and intermittent CLE. In case of failure of monotherapy with AM, the combination of quinacrine with HCQ or CQ seemed effective, whereas too little data were available to assess the efficacy of the switch to another AM agent.
Conclusions
Wide discrepancies in cutaneous response to AMs are observed between CLE subtypes. A specific therapeutic approach considering CLE subtypes may improve CLE management.
What's already known about this topic?
The antimalarials (AMs) hydroxychloroquine (HCQ) and chloroquine (CQ) are usually recommended as the first‐line systemic treatment of cutaneous lupus erythematosus (CLE).
AMs have demonstrated variable cutaneous response rates in CLE.
Cutaneous response rates to HCQ and CQ, particularly between CLE subtypes, remain largely unknown.
What does this study add?
In this meta‐analysis, the pooled cutaneous response rate to AMs was 63%, 95% confidence interval (CI) 55–70.
The response rate to AMs differed between CLE subtypes, ranging from 31% (95% CI 20–44) for chilblain lupus to 91% (95% CI 87–93) for acute CLE.
The response to AMs was significantly higher for acute CLE than for subacute CLE and intermittent CLE.
Linked Comment: McCourt. Br J Dermatol 2017; 177:14–15
Plain language summary available online
Summary
Background
A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome (‘Vacuoles, E1 Enzyme, X‐linked, Autoinflammatory, Somatic ...syndrome’).
Objectives
To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome.
Methods
One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow‐up, were recorded.
Results
The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow‐up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild‐to‐moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C‐reactive protein levels and less frequent chondritis). The 5‐year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis.
Conclusions
VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.
What is already known about this topic?
VEXAS syndrome is a recently described autoinflammatory disease related to UBA1 mutation. The clinical phenotype includes patients with thrombosis, fever, chondritis, neutrophilic dermatosis and MDS.
What does this study add?
The main clinical features of VEXAS patients remain recurrent fever (64.7% vs. 72%, in original description by Beck et al.), skin lesions (83.6% vs. 88%), lung infiltrates (49.1% vs. 72%), unprovoked thrombosis (35.5% vs. 44%), with new features such as arthralgia (28.4%), ocular involvement (40.5%) or lymph node enlargement (34.5%), expanding the previous clinical phenotype of VEXAS syndrome.
We identified 3 clusters of VEXAS syndrome, including an MDS‐related phenotype; mild‐to‐moderate disease with less fever, chondritis and thromboembolism, and one with more ‘inflammatory' profile characterized by cutaneous vasculitis lesions and relapsing profile.
A phenotype–genotype association was observed for UBA1 p.Met41Leu which was associated with less ‘inflammatory' and mild‐to‐moderate phenotype and better overall prognosis.
Linked Comment: L.T. Nicholson and L.M. Madigan. Br J Dermatol 2022; 186:392–393.
Plain language summary available online
Summary
Background
The outbreak of chilblain‐like lesions (CLL) during the COVID‐19 pandemic has been reported extensively, potentially related to SARS‐CoV‐2 infection, yet its underlying ...pathophysiology is unclear.
Objectives
To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold‐induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus.
Methods
This observational study was conducted during 9–16 April 2020 at Saint‐Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID‐19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included.
Results
Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic–natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL.
Conclusions
Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN‐polarized cells leading to clinical manifestations.
What is already known about this topic?
Chilblain‐like lesions have been reported during the COVID‐19 pandemic.
They are associated with systemic type I interferon polarization, but the precise pathophysiology is still unclear.
What does this study add?
We demonstrate cutaneous and systemic immune activation and vascular alteration.
Histological patterns were similar and transcriptomic signatures overlapped in chilblain‐like lesions and a comparator group with seasonal chilblains.
A systemic immune response was associated with high prevalence of IgA antineutrophil cytoplasmic antibodies and an elevated type I interferon signature.
We confirmed endothelial dysfunction in chilblain‐like lesions.
What is the translational message?
Chilblain‐like lesions and seasonal chilblains seem to share a common pathophysiology.
The strong type I interferon response can be explained by a viral trigger.
Similar endothelial dysfunctions have been described during mild COVID‐19.
Local or systemic anti‐inflammatory treatment could reverse cutaneous manifestations.
Linked Comment: S.M. Pilkington and R.E.B. Watson. Br J Dermatol 2021; 185:1090–1091.
Plain language summary available online
Summary
Background
Alemtuzumab has been proposed as salvage therapy for refractory cutaneous T‐cell lymphomas (CTCLs). Long‐term follow‐up data are scarce.
Objectives
To assess the efficacy and ...safety of alemtuzumab in the treatment of advanced CTCL.
Methods
A multicentre retrospective analysis was carried out of 39 patients with advanced CTCL treated with alemtuzumab between 2003 and 2013.
Results
Thirty‐nine patients (median age 62 years, range 20–83) with Sézary syndrome (SS, n = 23) or advanced mycosis fungoides (MF, n = 16) received alemtuzumab 30 mg two to three times per week for a median duration of 12 weeks (range 1–35). Fifteen patients received maintenance therapy for a median duration of 24 weeks (range 6–277). Eleven patients (28%) had transformed disease (MF, n = 10; SS, n = 1). After a median follow‐up of 24 months (range 0·3–124), eight patients (21%) were still alive. The overall response rate was 51% in the whole study group (partial response, n = 13; complete response, n = 7); 70% in patients with SS and 25% in patients with MF (P = 0·009). The median time to progression was 3·4 months (range 0·4–42). Six patients (15%; SS, n = 5; MF, n = 1) remained progression free for > 2 years (median 56 months, range 28–117). Five patients experienced cutaneous large T‐cell transformation during alemtuzumab treatment and one patient developed primary cutaneous large B‐cell lymphoma. Twenty‐four patients (62%) had a grade three or higher infectious adverse event and 10 (26%) a haematological toxicity, which led to treatment discontinuation in 17 cases (44%) and death in two (5%).
Conclusions
Alemtuzumab may induce long‐term remission in SS but seems ineffective in MF and transformed CTCL.
What's already known about this topic?
Alemtuzumab has shown short‐term efficacy in small numbers of patients with advanced primary cutaneous T‐cell lymphomas.
What does this study add?
Alemtuzumab may induce long‐term remission (> 2 years) in patients with Sézary syndrome.
Alemtuzumab is poorly effective in nontransformed mycosis fungoides and transformed CTCL.
Background
Nemolizumab is a humanized anti‐IL‐31 receptor blocker in phase 3 for atopic dermatitis (AD).
Objective
Analyse onset of action of nemolizumab 30 mg and compare efficacy and safety vs ...placebo (SC q4wk plus loading dose) in moderate‐to‐severe AD.
Methods
Post hoc analysis of patients with Eczema Area and Severity Index (EASI) scores ≥ 16 from a phase 2b trial of moderate‐to‐severe AD. Endpoints were change in EASI score at week 16, peak pruritus numeric rating scale (PP‐NRS), Investigator’s Global Assessment (IGA), changes in sleep and responders with ≥ 4‐point improvement on PP‐NRS.
Results
There was a significantly greater itch relief apparent by Day 2 (−22.8% vs –12.3% PP‐NRS; P = 0.005) which continued to improve through week 16 (−68.5% vs −30.9% PP‐NRS; P < 0.001). At week 16, PP‐NRS ≥ 4‐point response of itch was observed in 68.0% nemolizumab vs 15.9% placebo patients (P ≤ 0.001). There was also a rapid improvement of sleep disturbance with nemolizumab 30 mg, with a significant separation from placebo by Day 3 (−26.6% vs –9.0%; P < 0.001) which further improved till week 16 (−76.0% vs −36.5%; P < 0.001). Also for the EASI score a separation between groups in favour of nemolizumab was observed by week 1 (P ≤ 0.001), which increased through week 16 (−68.6% vs. −42.6%; P = 0.002). Finally, the degree of response was greater in nemolizumab‐treated patients; clinically relevant reductions of 75% EASI were observed in 50.0% of nemolizumab patients versus 15.9% of placebo patients, while 90% reductions were reported for 36.0% and 6.8% of patients, respectively (P < 0.001 for both). IGA success (score of 0/1) was 32.0% for nemolizumab vs 6.8% for placebo (P = 0.002).
Nemolizumab was safe and well‐tolerated in this population; nasopharyngitis and upper respiratory tract infection were the most common adverse events.
Conclusions
Nemolizumab resulted in very rapid, sustained improvements of inflammation, pruritus and sleep in patients with EASI ≥ 16 at baseline.
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