Summary
Background
Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II ...studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms.
Objectives
To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments.
Methods
In two 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator’s Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885.
Results
At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 difference 8·6%, 95% confidence interval (CI) 4·1–13·1; P = 0·002 and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8–16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5–17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8–27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16‐week initial period.
Conclusions
Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
There is a need for safe and effective long‐term treatment options for AD.
Tralokinumab is a fully human monoclonal antibody that binds specifically to IL‐13 with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with topical corticosteroids showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
These are the first pivotal phase III trials demonstrating that by specifically targeting IL‐13 alone, patients can achieve significant improvements in AD signs and symptoms and quality of life, and maintain these improvements over time without the requirement for topical corticosteroids.
These trials provide evidence that tralokinumab offers a long‐term, well‐tolerated treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online
Summary
Background
Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar.
Objectives
To assess the impact of multiple ...switches between GP2017 and reference adalimumab (ref‐ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate‐to‐severe plaque psoriasis.
Methods
This 51‐week double‐blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref‐ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups.
Results
Equivalent efficacy between GP2017 and ref‐ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI −7·46 to 11·15) and key secondary end points (−60·7% and −61·5%, respectively; 95% CI –3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref‐ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching.
Conclusions
Following the demonstration of GP2017 biosimilarity to ref‐ADMB, switching up to four times between GP2017 and ref‐ADMB had no detectable impact on efficacy, safety or immunogenicity.
What's already known about this topic?
Adalimumab is indicated for use in rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, Crohn disease, ulcerative colitis and uveitis.
GP2017 is a proposed biosimilar to adalimumab.
Previous analytical studies have shown that GP2017 and reference adalimumab have identical amino acid sequences, indistinguishable secondary and tertiary structures, the same level of post‐translational modifications and similar in vitro functionality.
What does this study add?
This phase III confirmatory efficacy and safety study demonstrated equivalent efficacy and similar safety of GP2017 and reference adalimumab in patients with moderate‐to‐severe plaque psoriasis.
Additionally, switching up to four times between GP2017 and reference adalimumab had no impact on the incidence of adverse events or injection‐site reactions.
The frequency of antidrug antibody development was similar between the switched and continued treatment groups, and there was no impact on efficacy.
Linked Comment: Cline and Feldman. Br J Dermatol 2018; 179:557–558.
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Summary
The use of antibodies against programmed death (PD)1, such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma. Nivolumab is also ...approved in advanced squamous cell nonsmall‐cell lung cancer. These immunotherapies are associated with a unique set of toxicities termed immune‐related adverse events, which are different from toxicities observed with conventional cytotoxic chemotherapy. We report the case of a 56‐year‐old man who was diagnosed with metastatic melanoma and who received nivolumab. One week after the second infusion, he developed pulmonary symptoms, dry eye syndrome and a bilateral swelling of the parotid glands. Investigations were negative for infection. The bronchoalveolar lavage differential cell count showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies revealed noncaseating epithelioid granulomas, without malignant cells. The clinical and radiological courses were rapidly favourable with oral corticosteroid. This case illustrates that sarcoidosis can be induced by nivolumab treatment. With the increasing use of anti‐PD1 inhibitors in patients with advanced melanoma and squamous cell nonsmall‐cell lung cancer, clinicians should be aware of this potential associated immune‐related adverse event.
What's already known about this topic?
Antiprogrammed death (anti‐PD)1 antibodies such as nivolumab have dramatically changed the landscape of melanoma treatment.
Nivolumab is also indicated in advanced squamous cell nonsmall‐cell lung cancer.
Sarcoid‐like reaction may occur during melanoma treatment, but it has never been reported with anti‐PD1 therapy.
What does this study add?
Pulmonary sarcoid‐like reaction can occur during nivolumab therapy.
With the increasing use of PD1 inhibitors for the treatment of cancers, clinicians should be familiar with this associated adverse event.
Summary
Background
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids.
...Objectives
To evaluate the efficacy and safety of baricitinib in patients with moderate‐to‐severe AD who had an inadequate response to topical therapies.
Methods
In two independent, multicentre, double‐blind, phase III monotherapy trials, BREEZE‐AD1 and BREEZE‐AD2, adults with moderate‐to‐severe AD were randomized 2 : 1 : 1 : 1 to once‐daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.
Results
At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE‐AD1 N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%, and BREEZE‐AD2 N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night‐time awakenings, skin pain and quality‐of‐life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage.
Conclusions
Baricitinib improved clinical signs and symptoms in patients with moderate‐to‐severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic heterogeneous inflammatory skin disease with few approved therapies for patients with moderate‐to‐severe disease.
What does this study add?
These two phase III trials show that baricitinib, an oral inhibitor of Janus kinase 1 and 2, significantly improved clinical signs and symptoms of AD compared with placebo within the first 16 weeks of treatment.
Baricitinib may represent a first‐in‐class oral treatment option for adult patients with moderate‐to‐severe AD.
Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.
Plain language summary available online
Background
Secukinumab is a fully human anti–interleukin‐17A monoclonal antibody.
Objective
Determine the efficacy, safety and usability of secukinumab administered via autoinjector/pen.
Methods
This ...phase III trial randomized subjects with moderate to severe plaque psoriasis to secukinumab 300 mg, 150 mg or placebo self‐injection once weekly to Week 4, then every 4 weeks. Co‐primary end points at Week 12 were ≥75% improvement in Psoriasis Area and Severity Index (PASI 75) and clear/almost clear skin by investigator's global assessment 2011 modified version (IGA mod 2011 0/1). Secondary end points included autoinjector usability, assessed by successful, hazard‐free self‐injection and subject‐reported acceptability on Self‐Injection Assessment Questionnaire.
Results
Week 12 PASI 75 and IGA mod 2011 0/1 responses were superior with secukinumab 300 mg (86.7% and 73.3%, respectively) and 150 mg (71.7% and 53.3%, respectively) vs. placebo (3.3% and 0%, respectively) (P < 0.0001 for all). All subjects successfully self‐administered treatment at Week 1, without critical use‐related hazards. Subject acceptability of autoinjector was high throughout 12 weeks. Adverse events were higher with secukinumab (300 mg, 70.0%; 150 mg, 63.9%) vs. placebo (54.1%), with differences largely driven by mild/moderate nasopharyngitis.
Conclusion
Secukinumab delivered by autoinjector/pen is efficacious, well‐tolerated and associated with high usability in moderate to severe plaque psoriasis.
Cutaneous melanoma is one of the most aggressive cancers characterized by a high plasticity, a propensity for metastasis, and drug resistance. Melanomas are composed of phenotypically diverse ...subpopulations of tumor cells with heterogeneous molecular profiles that reflect intrinsic invasive abilities. In an attempt to identify novel factors of the melanoma invasive cell state, we previously investigated the nature of the invasive secretome by using a comparative proteomic approach. Here, we have extended this analysis to show that PTX3, an acute phase inflammatory glycoprotein, is one such factor secreted by invasive melanoma to promote tumor cell invasiveness. Elevated PTX3 production was observed in the population of MITF
invasive cells but not in the population of MITF
differentiated melanoma cells. Consistently, MITF knockdown increased PTX3 expression in MITF
proliferative and poorly invasive cells. High levels of PTX3 were found in tissues and blood of metastatic melanoma patients, and in BRAF inhibitor-resistant melanoma cells displaying a mesenchymal invasive MITF
phenotype. Genetic silencing of PTX3 in invasive melanoma cells dramatically impaired migration and invasion in vitro and in experimental lung extravasation assay in xenografted mice. In contrast, addition of melanoma-derived or recombinant PTX3, or expression of PTX3 enhanced motility of low migratory cells. Mechanistically, autocrine production of PTX3 by melanoma cells triggered an IKK/NFκB signaling pathway that promotes migration, invasion, and expression of the EMT factor TWIST1. Finally, we found that TLR4 and MYD88 knockdown inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4-dependent pathway. Our work reveals that tumor-derived PTX3 contributes to melanoma cell invasion via targetable inflammation-related pathways. In addition to providing new insights into the biology of melanoma invasive behavior, this study underscores the notion that secreted PTX3 represents a potential biomarker and therapeutic target in a subpopulation of MITF
invasive and/or refractory melanoma.
Summary
Background The treatment of vitiligo remains unsatisfactory.
Objectives To assess in patients with vitiligo the effect of a laser dermabrasion in addition to the association of topical ...steroids and ultraviolet (UV) B in difficult‐to‐treat areas.
Methods This was a single‐centre prospective randomized trial including patients with nonsegmental vitiligo who had at least two symmetrical lesions located on bony prominences and/or extremities. An erbium laser‐assisted dermabrasion was first performed on one side (randomly assigned). After 48 h, hydrocortisone 17‐butyrate cream applied daily for three periods of 3 weeks followed by a 1‐week steroid‐free interval and narrowband UVB treatment was performed on both sides twice weekly for 12 weeks. The evaluation was performed on standardized pictures by two physicians blinded to the type of treatment received. The criterion of success was a repigmentation of at least 50%, 1 month after the end of the treatment.
Results Eighteen patients were included (24 paired lesions treated). Two patients dropped out for personal reasons. Almost 50% of lesions achieved at least 50% repigmentation in the dermabrasion side while only 4·2% did so with topical steroids and UVB alone (P < 10−4). Side‐effects were delayed healing, pain and two hypertrophic scars. The tolerance and patient satisfaction were 4·2 and 4/10 for the laser‐treated side and 8·4 and 3/10 in the UVB+ steroids alone group, respectively.
Conclusions Laser dermabrasion significantly improves the repigmentation rate in vitiligo lesions. Despite a high rate of repigmentation in such difficult‐to‐treat areas the high rate of side‐effects and the poor tolerance strongly limit its use in current practice.
Summary
Background
It has been shown that the interleukin (IL)‐23/IL‐17 axis is critical in the pathogenesis of psoriasis.
Objectives
To present the primary end point (week 12) and safety and ...efficacy data up to week 24 from a head‐to‐head trial (IXORA‐S) of the IL‐17A inhibitor ixekizumab (IXE) vs. the IL‐12/23 inhibitor ustekinumab (UST).
Methods
Randomized patients received IXE (160‐mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight‐based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel‐adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4‐point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale.
Results
At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8−44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE‐treated patients had significantly higher response rates than UST‐treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299).
Conclusions
The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.
What's already known about this topic?
With the advancements in new biologics targeting the interleukin (IL)‐17A pathway, the majority of patients with moderate‐to‐severe psoriasis are now able to achieve complete or near complete clearance of psoriasis.
What does this study add?
The IL‐17A inhibitor ixekizumab provides superior efficacy over the IL‐12/23 inhibitor ustekinumab, with a similar safety profile after 24 weeks of treatment.
Linked Comment: Chu et al. Br J Dermatol 2017; 177:896–897.
Background
ASSURE‐CSU revealed differences in physician and patient reporting of angioedema. This post hoc analysis was conducted to evaluate the actual rate of angioedema in the study population and ...explore differences between patients with and without angioedema.
Methods
This international observational study assessed 673 patients with inadequately controlled chronic spontaneous urticaria (CSU). Physicians ed angioedema data from medical records, which were compared with patient‐reported data. Patients in the Yes‐angioedema category had angioedema reported in the medical record and a patient‐reported source. For those in the No‐angioedema category, angioedema was reported in neither the medical record nor a patient‐reported source. Those in the Misaligned category had angioedema reported in only one source. Statistical comparisons between Yes‐angioedema and No‐angioedema categories were conducted for measures of CSU activity, health‐related quality of life (HRQoL), productivity and healthcare resource utilization (HCRU). Regression analyses explored the relationship between Dermatology Life Quality Index (DLQI) score and angioedema, adjusting for important covariates.
Results
Among evaluable patients, 259 (40.3%), 173 (26.9%) and 211 (32.8%) were in the Yes‐angioedema, No‐angioedema and Misaligned category, respectively. CSU activity and impact on HRQoL, productivity, and HCRU was greater for Yes‐angioedema patients than No‐angioedema patients. After covariate adjustment, mean DLQI score was significantly higher (indicating worse HRQoL) for patients with angioedema versus no angioedema (9.88 vs 7.27, P < .001). The Misaligned category had similar results with Yes‐angioedema on all outcomes.
Conclusions
Angioedema in CSU seems to be under‐reported but has significant negative impacts on HRQoL, daily activities, HCRU and work compared with no angioedema.
(A) Initial frequency: Angioedema in the past 12 months was more frequently reported by CSU patients who completed the survey (65.8%) than recorded in the medical record (41.0%). (B) Revised frequency: Among all CSU patients, only 26.9% had no angioedema episodes at all. Of the 32.8% of patients with misaligned reporting of angioedema in the past 12 months, 97.2% reported having had angioedema, but it was not noted in the medical record. (C) Regression analysis: CSU patients with angioedema have significantly lower HRQoL than patients without angioedema*: least‐squares mean DLQI total scores by angioedema category. *LS means are from an analysis of covariance model with covariates: angioedema classification, UAS7TD score (continuous), age at enrolment (continuous), sex (male and female), country (Canada, France, Germany, Italy, Spain, the Netherlands and the United Kingdom), disease duration from diagnosis to enrolment (continuous) and comorbidities at enrolment (hypersensitivity to NSAIDs yes/no, Hashimoto's yes/no and asthma yes/no). DLQI, Dermatology Life Quality Index; HRQoL, health‐related quality of life; NSAID, nonsteroidal anti‐inflammatory drug; SE, standard error; UAS7TD = Urticaria Activity Score over 7 Days, twice‐daily assessment.
Background
Q‐switched nanosecond lasers demonstrated their efficacy in treating most types of tattoos, but complete disappearance is not always achieved even after performing numerous laser sessions. ...Picosecond lasers are supposed to be more efficient in clearing tattoos than nanosecond lasers, but prospective comparative data remain limited.
Objective
To compare on different types of tattoos the efficacy of a nanosecond laser with two types of picosecond lasers.
Methods
We conducted a prospective randomized study performed from December 2014 to June 2016 on adult patients with all types of tattoos. The tattoos were divided into two halves of equal size. After randomization, half of the tattoo was treated with a picosecond laser and the other half with a nanosecond laser. The evaluation was performed on standardized pictures performed before treatment and 2 months after the last session, by two physicians, not involved in the treatment, blinded on the type of treatments received. The main end point was a clearance above 75% of the tattoos.
Results
A total of 49 patients were included. Professional tattoos represented 85.7%, permanent make‐up 8.2% and non‐professional tattoo 6.1%. The majority were black or blue and 10.2% were polychromatic. No patient was lost during follow‐up. A reduction of 75% or more of the colour intensity was obtained for 33% of the tattoos treated with the picosecond lasers compared to 14% with the nanosecond laser (P = 0.008). An improvement superior to 75% was obtained in 34% monochromic black or blue tattoos with the picosecond lasers compared to 9% for the nanosecond laser. Only one of the five polychromic tattoos achieved more than 75% of improvement with the two types of laser.
Conclusion
Our results show a statistically significant superiority of the picosecond lasers compared to the nanosecond laser for tattoo clearance. However, they do not show better efficacy for polychromic tattoos and the difference in terms of side‐effects was also minimal with a tendency of picosecond lasers to be less painful.
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