In the long-term extension study of the ERASURE and FIXTURE trials, the efficacy of secukinumab (a fully human anti-interleukin-17A monoclonal antibody) was demonstrated to have been maintained ...through to year 3 of treatment in moderate-to-severe plaque psoriasis.
To assess the efficacy and safety of secukinumab through to year 5 of treatment in moderate-to-severe plaque psoriasis.
Responders with ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) from two core trials - ERASURE and FIXTURE - were randomized 2 : 1 at year 1 (end of core trials) to either the same dose (300 or 150 mg, continuous treatment) or placebo (treatment withdrawal) every 4 weeks, until year 3 or relapse (> 50% reduction in maximal PASI from core study baseline). Partial responders (achieving PASI 50 but not PASI 75) at year 1 continued at the same dose as in the core trials. At year 3, all patients received open-label secukinumab treatment, with those on secukinumab 300 mg continuing on their dose, while those on secukinumab 150 mg or placebo received secukinumab 150 or 300 mg based on the physician's discretion. The study is registered on ClinicalTrials.gov with the identifier NCT01544595.
Most patients randomized to placebo at year 1 relapsed, but the response was rapidly recaptured upon reinitiation of treatment. PASI responses were sustained with secukinumab through to year 5. The PASI responses for the 300 mg responders + partial responders group at year 1 (PASI 75/90/100: 86.8%/72.8%/45.9%) trended downwards until year 3 (PASI 75/90/100: 82.3%/58.4%/32.7%) and then remained stable through year 4 (PASI 75/90/100: 83.3%/60.1%/32.2%) until year 5 (PASI 75/90/100: 81.1%/62.8%/35.1%). Dermatology Life Quality Index showed sustained benefit up to year 5. Absolute PASI responses were maintained throughout the study. The most common adverse events (AEs) were infections and infestations, nasopharyngitis, and upper respiratory tract infections (URTIs). The overall exposure-adjusted incidence rate (EAIR; with 95% confidence interval) for all AEs was 139.9 (130.3-149.9). EAIRs for Crohn's disease and neutropenia were 0.1 (0.0-0.3) and 0.5 (0.3-0.8), respectively.
The 4-year extension of two pivotal phase III trials demonstrated that secukinumab treatment was effective through to year 5 and improved quality of life in patients with moderate-to-severe plaque psoriasis. The most common AEs were infections and infestations, nasopharyngitis, and URTIs. The safety profile was consistent with that in the secukinumab phase II/III clinical development programme.
Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been ...detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin.
Abstract Objective: To compare the efficacy and safety of continuous terbinafine with intermittent itraconazole in the treatment of toenail onychomycosis. Design: Prospective, randomised, double ...blind, double dummy, multicentre, parallel group study lasting 72 weeks. Setting:35 centres in six European countries. Subjects: 496 patients aged 18 to 75 years with a clinical and mycological diagnosis of dermatophyte onychomycosis of the toenail. Interventions: Study patients were randomly divided into four parallel groups to receive either terbinafine 250 mg a day for 12 or 16 weeks (groups T12 and T16or itraconazole 400 mg a day for 1 week in every 4 weeks for 12 or 16 weeks (groups I and I). Main outcome measures: Assessment of primary efficacy at week 72 was mycological cure, defined as negative results on microscopy and culture of samples from the target toenail. Results: At week 72 the mycological cure rates were 75.7% (81/107) in the T12 group and 80.8% (80/99) in theT16 group compared with 38.3% (41/107) in theI group and 49.1 % (53/108) in the I4 group.All comparisons (T v I,T12 vI4, T16v I3, T16 vI4) showed significantly higher cure rates in the terbinafine groups (all P<0.0001). Also, all secondary clinical outcome measures were significantly in favour of terbinafine at week72. There were no differences in the number or type of adverse events recorded in the terbinafine or itraconazole groups. Conclusion: Continuous terbinafine is significantly more effective than intermittent itraconazole in the treatment of patients with toenail onychomycosis.
Summary
Background
The combination of seawater baths and narrowband ultraviolet B (NB‐UVB) is a known treatment for psoriasis. This study evaluates two treatment regimens that combine bathing in ...geothermal seawater and NB‐UVB therapy in comparison with NB‐UVB monotherapy.
Methods
Sixty‐eight psoriasis patients were randomly assigned to outpatient bathing in geothermal seawater combined with NB‐UVB therapy three times a week, intensive daily treatment involving bathing in geothermal seawater combined with NB‐UVB therapy, or NB‐UVB therapy alone three times a week; treatment period was 6 weeks. Disease severity Psoriasis Area Severity Index (PASI) and Lattice System Physician's Global Assessment scores, quality of life (Dermatology Life Quality Index) and histological changes were evaluated before, during and after treatment. The primary end point was the proportion of patients who achieved PASI 75 at 6 weeks.
Results
At 6 weeks, the percentage of patients who achieved PASI 75 and PASI 90 was significantly greater for both regimens, bathing in geothermal seawater three times a week (68.1% and 18.2%, respectively) and intensive treatment with geothermal seawater (73.1% and 42.3%, respectively) than for NB‐UVB monotherapy (16.7% and 0%, respectively) (P < 0.05 in all comparisons). Clinical improvement was paralleled by improvement in quality of life and histological score and a reduction in NB‐UVB doses.
Conclusion
Bathing in geothermal seawater combined with NB‐UVB therapy in psoriasis induces faster clinical and histological improvement, produces longer remission time and permits lower NB‐UVB doses than UVB therapy alone.
Psoriasis is an autoimmune disease driven by a Th17 response linked to the antimicrobial peptide (AMP) LL‐37 that has been connected to the induction and chronicity of psoriasis. We show that ...keratinocytes secrete various immune biomarkers with a direct link to psoriasis immunopathogenesis. Under pro‐inflammatory microenvironmental conditions, LL‐37 was found to regulate keratinocyte secretion of various immune biomarkers (eg C‐X‐C motif chemokine ligand (CXCL)8 and interleukin (IL)‐1β) and alter extracellular signal‐regulated kinase (ERK)1/2 signalling. However, during neutral conditions LL‐37 induced a different pattern of keratinocyte immune biomarker secretion (eg vascular endothelial growth factor, CXCL8 and IL‐6). Thus, an interesting pattern emerged regarding the immunomodulatory effects of LL‐37 on keratinocytes; in general, expression of immune biomarkers that were upregulated in a Th1‐like microenvironment was downregulated in the presence of LL‐37. In contrast, LL‐37 reinforced the Th17 response. In active psoriatic skin lesions, LL‐37 expression was found to be significantly upregulated, which was also evident from the unique diffuse epidermic expression pattern not found in healthy skin. Finally, successful phototherapy of psoriasis patients converted this LL‐37 inflammatory psoriatic skin pattern into a more localized basal layer expression as found in healthy controls. Thus, these findings demonstrate that LL‐37 has a significant role in skin immune homeostasis and that its interplay with keratinocytes may have a more direct role in the immunopathogenesis of psoriasis than previously thought.
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in ...Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 × 10−9) and BCC (OR = 1.35, P = 1.2 × 10−6). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 × 10−7) and BCC (OR = 1.14, P = 6.1 × 10−4). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.3 × 10−4). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background: Terbinafine is an established drug for the treatment of toenail onychomycosis. Minimizing the total dose of terbinafine and giving it intermittently could improve tolerability as well as ...compliance, provided efficacy is not compromised. Objective: Two identical trials were conducted to compare the efficacy, safety and tolerability of the current standard regimen of terbinafine 250 mg daily with a new formulation of terbinafine given intermittently for three cycles of 2 weeks of treatment (350 mg daily) followed by 2 weeks off treatment. Methods: A total of 2005 patients with a clinical diagnosis of subungual onychomycosis of the large toenail confirmed by microscopy and culture for a dermatophyte were recruited into the two trials and treated for 12 weeks. Results: Patients with onychomycosis of prolonged duration (mean 9 years) and a median nail involvement of 63% with or without spikes, lateral involvement and white superficial onychomycosis (WSO) were included in the trial. The studies found a significant difference (p<0.05) in favour of standard daily dosing with terbinafine. Response rates for the primary variable complete cure (mycological and clinical cure) were lower with the new formulation in both Trial I (−5.8%; 95% CI −11.8, 0.07) and Trial II (difference −5.9%; 95% CI −12, 0.1). Both treatments were equally well tolerated, with approximately 11% of patients in both groups reporting at least one treatment-related adverse event. Conclusions: Pulsed dosing with terbinafine did not provide any clear safety advantages and was significantly less effective. Consequently, continuous treatment with terbinafine tablets remains the optimal therapy for onychomycosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Convenient administration is an important factor for treatment adherence in patients with psoriasis. MATURE study reports the efficacy, safety, tolerability, and pharmacokinetics (PKs) of secukinumab ...300 mg 2 ml autoinjector (AI) from MATURE trial (NCT03589885). Eligible patients were randomized to secukinumab 300 mg 2 ml AI or 2× 1 ml prefilled syringe (PFS) or placebo. The co‐primary endpoints were psoriasis area and severity index (PASI) 75 and investigator's global assessment (IGA) 0/1 response rates at Week 12 versus placebo. Other endpoints included PASI90/100 response, dermatology life quality index (DLQI) 0/1, PKs, 2 ml AI usability rated using self‐injection assessment questionnaire (SIAQ), and safety. The study met both co‐primary and secondary endpoints (p < 0.0001). Secukinumab 300 mg 2 ml AI and 2× 1 ml PFS treatments led to superior PASI75/90/100 (2 ml AI: 95.1%/75.6%/43.9%; 2× 1 mL PFS: 83.2%/62.6%/37.5% and placebo: 10%/5.0%/0.0%, respectively), IGA, and DLQI 0/1 responses compared with placebo, and efficacy was sustained through 52 weeks. SIAQ results showed high usability of self‐injection with 2 mL AI device. No new safety signals were observed. Study design may bias the interpretation of safety profile after Week 12, due to different exposure of secukinumab versus placebo. Secukinumab 300 mg administered with the 2 mL AI demonstrated superior efficacy over placebo, good tolerability, and convenient administration.
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