Infections from 7 Clinical Trials of Ixekizumab, an Anti-Interleukin-17A Monoclonal Antibody, in Patients with Moderate-to-Severe Psoriasis

Abstract

Background

Infections are associated with biologic therapies in psoriasis.

Objectives

To summarise the incidence of infections in moderate-to-severe psoriasis patients treated with ixekizumab, an anti-interleukin (IL)-17A monoclonal antibody.

Methods

Infections are summarised from an integrated database of 7 controlled and uncontrolled ixekizumab psoriasis trials. Data are presented from placebo-controlled induction (Weeks 0-12; UNCOVER-1, -2, and -3) and maintenance periods (Weeks 12-60; UNCOVER-1 and -2) as well as all ixekizumab-exposed patients pooled from all 7 trials. Comparisons to etanercept were made during the induction period of two trials (UNCOVER-2 and -3). Incidence and exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) are reported.

Results

Overall, 4209 patients were treated with ixekizumab (6480PY). During induction (Weeks 0-12), overall infection rates were higher in ixekizumab-treated patients (27%) versus placebo (23%, p<0.05); however, specific infection rates were overall comparable across treatment groups. IRs of infections did not increase with longer-term exposure. For all ixekizumab-treated patients (all 7 trials), the incidence of serious infections was low (2%; IR 1.3). Candida infections, including 8 oesophageal candidiasis cases, were adequately managed with anti-fungal therapy, were non-invasive, and did not lead to discontinuation.

Conclusions

Infections overall occurred in a higher percentage of ixekizumab-treated patients versus placebo during the first 12 weeks of treatment; however, specific infection rates were overall comparable across treatment groups. Incidences of serious infections were low and similar across treatment groups.

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Response to MF Holick “Can you have your cake and eat it too? The sunlight D-lema”

Abstract

We read with interest the recent paper by Felton and colleagues (1) describing the effects of solar-simulated ultraviolet radiation (UVR) on cutaneous DNA damage and vitamin D production. However, we were disappointed by the accompanying editorial by Dr Holick (2) proclaiming that healthcare regulators (and by inference, doctors and the public) "could have their cake and eat it too". In particular, his assertion that "sensible sun exposure that does not cause burning" should raise "little concern" about skin cancer risk is at odds with the photodamage observed by Felton and colleagues in the epidermal cells of fair-skinned participants following repeated, low-level sun exposure.

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Inhibition of p38MAPK signaling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis

Abstract

Background

Pemphigus vulgaris (PV) is a skin blistering disease caused by autoantibodies targeting the desmosomal adhesion proteins desmoglein (Dsg) 3 and 1. The mechanisms underlying pemphigus skin blistering are not fully elucidated but p38MAPK activation is one of the signaling events necessary for full loss of cell cohesion. However, it is unclear whether ultrastructural hallmarks of desmosome morphology as observed in patients' lesions are mediated by p38MAPK signaling.

Objective

In this study, we tested the relevance of p38MAPK for blister formation and the ultrastructural changes induced by PV autoantibodies in human skin.

Methods Human skin samples were injected with IgG fractions of one patient suffering from mucocutaneous PV (mcPV-IgG), one from mucosal-dominant PV (mdPV-IgG) or AK23, a pathogenic monoclonal Dsg3 antibody derived from a pemphigus mouse model. Samples were processed for histological and electron microscopy analyses.

Results

McPV-IgG and AK23 but not mdPV-IgG reduced desmosome size, caused interdesmosomal widening and formation of split desmosomes, and altered keratin filament insertion. In contrast, full epidermal blister formation and lower desmosome number were evident in tissue samples exposed to mcPV-IgG only. Pharmacologic inhibition of p38MAPK blunted the reduction of desmosome number and size, ameliorated interdesmosomal widening and loss of keratin insertion and prevented mcPV-IgG-induced blister formation.

Conclusion

Our data demonstrate that blistering can be prevented by inhibition of p38MAPK in human epidermis. Moreover, typical morphologic alterations induced by mcPV-IgG such as interdesmosomal widening and the reduction of desmosome size at least in part require p38MAPK signaling.

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Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a Phase 3b, randomized, double-blinded, active-controlled, multicenter study (PSTELLAR)

Abstract

Background

Phase 3 studies showed some patients maintained response for ≥6 months post-ustekinumab discontinuation.

Objectives

To assess clinical responses with extended ustekinumab maintenance dosing intervals.

Methods

Adults with moderate-to-severe plaque psoriasis received ustekinumab (45mg/90mg for weight ≤100 kg/>100 kg) at Week0, Week4, Week16 during open-label treatment. Patients achieving a Week 28 Physician's Global Assessment score of cleared/minimal (PGA=0/1) were randomized 1:4 to Group1 (approved every-12-weeks [q12wk] maintenance) or Group2 (q12-24wk response-based dosing determined by time–to-loss-of-PGA=0/1). Key endpoints included number of visits with PGA=0/1 (primary endpoint) and ≥75% improvement in Psoriasis Area and Severity Index (PASI75) between Weeks88-112, and PGA/PASI responses between Weeks28-112.

Results

378 patients achieved PGA=0/1 at Week28 and were randomized to Group1 (n=76) or Group2 (n=302). Group1 patients had numerically greater mean numbers of visits with PGA=0/1 than Group2 (4.5 and 4.1, respectively; mean-difference [95%CI]: -0.46 [-1.20; 0.29]) and PASI75 (5.8 and 5.4, respectively; -0.32 [-0.96;0.33]) from Week88-112. A higher proportion of patients in Group1 (55.3%) than Group2 (38.7%) had PGA=0/1 at all seven Week88-112 visits. Maintenance of response was observed with dose-interval extension beyond q12wk (q16wk, q20wk, q24wk) in a subset of patients (28% of patients randomized to Group 2 extended maintenance dosing to q24wks and maintained high levels of response). Extending dosing interval did not affect antibody development or safety.

Conclusions

Efficacy was better maintained among Week28 PGA-responders randomized to continue q12wk ustekinumab versus extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24wk dosing.

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Diagnostic performance of 18fluorodesoxyglucose positron emission/computed tomography and magnetic resonance imaging in detecting T1-T2 head and neck squamous cell carcinoma

Objectives/Hypothesis

The aim of this study was to assess and compare the diagnostic accuracy of ¹⁸fluorodesoxyglucose positron emission/computed tomography (FDG-PET/CT) and magnetic resonance imaging (MRI) to detect T1-T2 head and neck squamous cell carcinoma (HNSCC).

Study Design

Prospective case series.

Methods

Thirty-five consecutive patients with histologically proven T1-T2 HNSCC were prospectively included. All patients underwent pretherapeutic FDG-PET/CT and MRI. Two nuclear medicine physicians and 2 radiologists blindly reviewed all FDG-PET/CT and MRI, respectively. A five-point qualitative scale was used to estimate tumor detection ability. Sensitivity of each modality was compared together using a McNemar test. Interobserver variability was assessed by kappa index (κ) of Cohen statistics. Maximal standardized uptake value (SUV_MAX), metabolic tumor volume (MTV) in FDG-PET/CT, and gadolinium enhancement (%GE) in MRI of each tumor were recorded and compared with T stage using a Mann-Whitney test. Tumor-to-normal tissue ratios in FDG-PET/CT and MRI (TNR_PET and TNR_MRI) were calculated and compared together using a Student t test.

Results

Among the 35 primary tumors, 29 were detected by FDG-PET/CT and 22 by MRI. MRI detected none of the six lesions incorrectly identified by FDG-PET/CT. FDG-PET/CT correctly identified seven of the 13 MRI false-negative results. Sensitivity of FDG-PET/CT to detect T1-T2 HNSCC was significantly higher than MRI (83% vs. 63%, P = .015). T stage was significantly correlated with MTV (P = .002) unlike with SUV_MAX (P = .06) and %GE (P = .70). TNR_PET was significantly higher than TNR_MRI (3.5 ± 3.2 vs. 1.2 ± 0.3, P < .0001).

Conclusions

Our study showed a higher diagnostic accuracy of FDG-PET/CT than MRI to detect T1-T2 HNSCC with a good interobserver agreement.

Level of Evidence

4 Laryngoscope, 2017

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Can the Ni classification of vessels predict neoplasia? A systematic review and meta-analysis

Objectives

The Ni classification of vascular change from 2011 is well documented for evaluating pharyngeal and laryngeal lesions, primarily focusing on cancer. In the planning of surgery it may be more relevant to differentiate neoplasia from non-neoplasia. We aimed to evaluate the ability of the Ni classification to predict laryngeal or hypopharyngeal neoplasia and to investigate if a changed cutoff value would support the recent European Laryngological Society (ELS) proposal of perpendicular vascular changes as indicative of neoplasia.

Data Sources

PubMed, Embase, Cochrane, and Scopus databases.

Review Methods

A systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. We systematically searched for publications from 2011 until 2016. All retrieved studies were reviewed and qualitatively assessed. The pooled sensitivity and specificity of the Ni classification with two different cutoffs were calculated, and bubble and summary receiver operating characteristics plots were created.

Results

The combined sensitivity of five studies (n = 687) with Ni type IV-V defined as test-positive was 0.89 (95% confidence interval [CI]: 0.76-0.95), and specificity was 0.82 (95% CI: 0.72-0.89). The equivalent combined sensitivity of four studies (n = 624) with Ni type V defined as test-positive was 0.82 (95% CI: 0.75-0.87), and specificity was 0.93 (95% CI: 0.82-0.97).

Conclusions

The diagnostic accuracy of the Ni classification in predicting neoplasia was high, without significant difference between the two analyzed cutoff values. Implementation of the proposed ELS classification of vascular changes seems reasonable from a clinical perspective, with comparable accuracy. Attention must be drawn to the accompanying risk of exposing patients to unnecessary surgery. Laryngoscope, 2017

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Social media presence of otolaryngology journals: The past, present, and future

Objectives/Hypothesis

Evaluate the use of Twitter by otolaryngology journals and determine the relationship between social media altmetrics and measures of academic impact.

Study Design

Cross-sectional analysis.

Methods

Twitter profiles from the top 50 otolaryngology journals per 2016 SCImago Journal & Country Rank (SJR) were included. Twitter activity for each profile was calculated using Twitonomy analytics and Riffle software. Social media influence was measured using Klout scores. Annual SJR rank and H-Index scores between 2008 and 2016 were recorded for each journal. Associations between social media influence and academic indices were assessed using Wilcoxon rank sum test, Spearman's rank order test, and Pearson correlation coefficients (α = .05).

Results

Average SJR was 0.86 ± 0.3 and H-Index was 50.9 ± 24. Eighteen journals had Twitter profiles. Journals with social media accounts had significantly higher SJR (P = .03) and H-Index (P = .01) scores compared to those without. The average Klout score of Twitter profiles was 32.5 ± 13. There was a significant association between a journal's Klout score and SJR rank (P = .004). Older Twitter profiles had higher Klout scores (P = .04). There was a direct relationship between a journal's total Twitter followers and H-Index score (P = .009), and a direct relationship between tweets and academic influence (P = .03 and .01 for SJR and H-Index, respectively).

Conclusions

Social media is often underutilized and remains an untapped resource by many journals to increase readership and disseminate research. Journals with social media profiles had significantly higher academic metrics, and among journals with profiles, increased online activity was a predictor for academic influence. Future studies are warranted to elucidate causal relationships.

Level of Evidence

NA Laryngoscope, 2017

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