In two trials in patients with moderate-to-severe plaque psoriasis, the anti–interleukin-17A monoclonal antibody secukinumab was more effective than placebo and etanercept. Infectious complications ...occurred more often with secukinumab than with placebo.
Psoriasis is a chronic, immune-mediated inflammatory skin disease that is associated with substantial impairment of physical and psychological quality of life.
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Our understanding of the pathogenesis of psoriasis was advanced by the discovery of the class of type 17 helper T (Th17) cells, which regulates innate and adaptive immunity. The proinflammatory cytokine interleukin-17A is the primary effector of Th17 cells, but it is also produced by other cell types in psoriatic lesions, including γδ T cells, neutrophils, and possibly mast cells.
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Interleukin-17A stimulates keratinocytes to secrete chemokines and other proinflammatory mediators that recruit additional inflammatory cells, including neutrophils, . . .
Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms ...(SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.
Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to ...sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions--four not previously implicated in the normal variation of human pigmentation--and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aims
The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL.
Methods
A phase 1 ...study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1‐mL prefilled syringe or 1 × 2‐mL prefilled syringe.
Results
Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1‐year phase 3 study in patients confirmed PK results observed in the phase 1 study.
Conclusion
Collective evidence from both studies demonstrated that 2‐mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions.
We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 ...Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Evidence shows good tolerability in patients for subcutaneous injection volumes up to 3 mL.
We investigated efficacy, pharmacokinetics, and tolerability of secukinumab 300 mg/2 mL pre-filled syringe ...(PFS) in patients with moderate to severe plaque psoriasis.
ALLURE was a 52-week, multicenter, randomized (1:1:1), double-blind, placebo-controlled, parallel-group study. Co-primary endpoints were secukinumab Psoriasis Area Severity Index (PASI) 75 and Investigator's Global Assessment modified 2011 0/1 (IGA mod 2011 0 or 1) responses at week 12 versus placebo. Other endpoints included the Self-Injection Assessment Questionnaire (SIAQ), and the ability to follow the instructions for use (IFU).
Overall, 214 patients were randomized. The secukinumab 300 mg/2 mL PFS showed superiority over placebo for both PASI 75 (88.9% versus 1.7%; p<.0001) and IGA mod 2011 0 or 1 (76.4% versus 1.4%; p<.0001) responses at week 12. All secondary efficacy endpoints were met. The SIAQ scores were similar across groups and improved similarly over 12 weeks. All patients completed critical steps in the IFU at week 1.
The secukinumab 300 mg/2 mL PFS groups showed superiority versus placebo, and it was a safe, effective, and convenient option for patients with psoriasis. NCT02748863.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background Carriage of the HLA-Cw*0602 allele is associated with a particular set of clinical features and treatment responses in psoriasis. Tonsillectomy can improve psoriasis. Objectives We sought ...to evaluate whether HLA-Cw*0602 predicts a favorable outcome after tonsillectomy of patients with psoriasis. Methods This prospective case series followed up 28 tonsillectomized patients with plaque psoriasis for 24 months. The Psoriasis Area and Severity Index, Psoriasis Disability Index, and Psoriasis Life Stress Inventory were used for assessment. Tonsils were swabbed for bacteria and patients genotyped for HLA-Cw*0602. Results After tonsillectomy, HLA-Cw*0602 homozygotes showed significantly more improvement, compared with heterozygous and HLA-Cw*0602–negative patients. Thus, Psoriasis Area and Severity Index score was reduced by 82% in the homozygous patients compared with 42% and 31%, respectively ( P < .001), Psoriasis Disability Index score improved by 87% compared with 38% and 41%, respectively ( P < .001), and Psoriasis Life Stress Inventory score was 82% reduced compared with 60% and 54%, respectively ( P < .001). The homozygotes more often had psoriasis onset associated with a throat infection ( P = .007) and an increased frequency of streptococcal throat infections per lifetime ( P = .038). Limitations Few patients were included and some data were retrospective. Conclusions Homozygous HLA-Cw*0602 carriage in plaque psoriasis may predict a favorable outcome after tonsillectomy.
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and ...small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782G, P = 5.5 × 10−17, OR = 1.29) and RGS22 (rs7006527C, P = 8.7 × 10−13, OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
To assess the role of foot dermatomycosis (tinea pedis and onychomycosis) and other candidate risk factors in the development of acute bacterial cellulitis of the leg.
A case-control study, including ...243 patients (cases) with acute bacterial cellulitis of the leg and 467 controls, 2 per case, individually matched for gender, age (+/-5 years), hospital and admission date (+/-2 months).
Overall, mycology-proven foot dermatomycosis was a significant risk factor for acute bacterial cellulitis (odds ratio, OR: 2.4; p < 0.001), as were tinea pedis interdigitalis (OR: 3.2; p < 0.001), tinea pedis plantaris (OR: 1.7; p = 0.005) and onychomycosis (OR: 2.2; p < 0.001) individually. Other risk factors included: disruption of the cutaneous barrier, history of bacterial cellulitis, chronic venous insufficiency and leg oedema.
Tinea pedis and onychomycosis were found to be significant risk factors for acute bacterial cellulitis of the leg that are readily amenable to treatment with effective pharmacological therapy.
Introduction:
Current topical treatments for onychomycosis are unsatisfactory. New topical agents that offer efficacy without the potential adverse effects of oral antifungal therapy would benefit ...patients with this condition and encourage a greater treatment rate.
Areas covered:
Currently available topical therapies are reviewed, and new approaches for enhancing delivery of the established antifungal terbinafine through the nail are summarized. We focus on the use of ultra-deformable lipid vesicles to facilitate delivery of terbinafine to the nail and surrounding tissue. TDT 067 (terbinafine in Transfersome®) is the only such therapy in development for onychomycosis, and we review published preclinical and clinical studies on this formulation.
Expert opinion:
TDT 067 offers the use of new technology to deliver an established antifungal, terbinafine. Preclinical data suggest that the Transfersome® accelerates entry of terbinafine released from TDT 067 into fungi and potentiates its antifungal effects, resulting in enhanced activity, compared with conventional terbinafine. This translated into high rates of mycological cure and evidence of clinical effect in a study of TDT 067 administered twice daily for 12 weeks in patients with onychomycosis. An ongoing Phase-III trial involving more than 700 patients treated for 48 weeks is investigating the efficacy and safety of TDT 067.
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