Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2).

BACKGROUND: The phase III reSURFACE 1 and reSURFACE 2 (NCT01722331/NCT01729754) trials of the anti-interleukin-23p19 monoclonal antibody tildrakizumab (TIL) for psoriasis treatment are complete. OBJECTIVES: We present 5-year pooled data from reSURFACE 1 and reSURFACE 2. METHODS: reSURFACE 1 and reSURFACE 2 were double-blind, randomized, controlled studies with optional long-term extensions. Adults with moderate-to-severe chronic plaque psoriasis were randomized 2 : 2 : 1 to TIL 100 mg (TIL 100) or 200 mg (TIL 200) or placebo at weeks 0 and 4, and every 12 weeks thereafter [reSURFACE 2 included an etanercept (ETN) arm]. Efficacy outcomes included proportions of patients achieving absolute and relative improvement from baseline Psoriasis Area and Severity Index (PASI) score through week 244 in TIL responders (≥ 75% improvement from baseline PASI; PASI 75 response) continuously receiving the same dose and ETN partial responders and nonresponders (PASI < 75 response) switched to TIL 200 at week 28. Safety was assessed from adverse events (AEs) in all patients as treated. RESULTS: Efficacy analyses included 329 and 227 week 28 responders to TIL 100 and TIL 200, respectively, and 121 ETN partial responders/nonresponders switched to TIL 200 at week 28. Of TIL 100 or TIL 200 responders and ETN partial responders/nonresponders entering the extensions, 235/302, 176/213 and 85/107, respectively, were evaluated at week 244, and 88·7%, 92·5% and 81·3%, respectively, achieved PASI 75 response. Exposure-adjusted rates of serious AEs were 6·3 and 6·0 patients with events per 100 patient-years of TIL 100 and TIL 200, respectively. CONCLUSIONS: TIL treatment provided sustained disease control over 5 years in week 28 TIL responders and ETN partial responders/nonresponders, with a reassuring safety profile.

The clinical course of actinic keratosis correlates with underlying molecular mechanisms.

BACKGROUND: Actinic keratoses (AKs) are common premalignant skin lesions triggered by excessive ultraviolet exposure. The majority of AKs regress or persist, but some progress to squamous cell carcinomas. Biomarkers associated with their persistence, progression and regression have not been characterized. OBJECTIVES: We performed skin biopsies in patients with extensive actinic damage to identify biomarkers that correlate with clinical progression and regression of AKs. METHODS: This was an observational study of a cohort of patients with extensive actinic damage. AKs were mapped on a clear plastic template in 26 patients at months 3, 6, 9 and 11. Biopsies were taken from randomly selected, predetermined AKs and were evaluated for p53, E-cadherin, Snail, Slug and Twist. The study is registered at Clinicaltrials.gov: NCT00027976. RESULTS: p53 exhibited greater expression in clinically apparent AKs (histological score 2·89 ± 1·45) than in regressed AKs (0·75 ± 0·96); P < 0·01. There was also significantly less membrane E-cadherin, the lack of which is a marker of epithelial-mesenchymal transition, in clinically apparent AKs (1·89 ± 1·81) than in sun-exposed skin (3·07 ± 1·75); P < 0·005. The E-cadherin transcription repressors Snail, Slug and Twist were increased in AKs compared with sun-exposed skin. A limitation of the study is that measurement of histological biomarkers was not a primary end point. In addition, patients were allowed to apply sunscreens. CONCLUSIONS: At the molecular level, loss of E-cadherin and an increase in p53 are linked to the dynamic interplay between the persistence, progression and regression of AKs. What's already known about this topic? Actinic keratoses (AKs) are common dysplastic epidermal lesions that result from chronic and excessive ultraviolet exposure. Biomarkers associated with progression and regression of AK have not been characterized. What does this study add? Decreased E-cadherin and increased p53, Snail, Slug and Twist (E-cadherin transcription factors) were associated with progression from AK to nonmelanoma skin cancer. What is the translational message? Strategies targeting these molecules may be effective in reversing rising skin cancer rates. E-cadherin, p53, Snail, Slug and Twist are potential biomarkers that may be used to assess the efficacy of existing chemopreventive agents.

Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks.

BACKGROUND: Tildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody approved for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks. METHODS: Pooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50-75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4-week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). RESULTS: At week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100-mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient-years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure-adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low. CONCLUSIONS: Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What's already known about this topic? Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short-term use in the treatment of patients with moderate-to-severe plaque psoriasis. What does this study add? High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab. There is a favourable long-term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.

Dispersion Aerosol Indirect Effect in Turbulent Clouds: Laboratory Measurements of Effective Radius.

Cloud optical properties are determined not only by the number density n d and mean radius r ¯ of cloud droplets but also by the shape of the droplet size distribution. The change in cloud optical depth with changing n d , due to the change in distribution shape, is known as the dispersion effect. Droplet relative dispersion is defined as d = σ r / r ¯ . For the first time, a commonly used effective radius parameterization is tested in a controlled laboratory environment by creating a turbulent cloud. Stochastic condensation growth suggests d independent of n d for a nonprecipitating cloud, hence nearly zero albedo susceptibility due to the dispersion effect. However, for size-dependent removal, such as in a laboratory cloud or highly clean atmospheric conditions, stochastic condensation produces a weak dispersion effect. The albedo susceptibility due to turbulence broadening has the same sign as the Twomey effect and augments it by order 10%.

Influence of Turbulent Fluctuations on Cloud Droplet Size Dispersion and Aerosol Indirect Effects.

Cloud droplet relative dispersion, defined as the standard deviation over the mean cloud droplet size, is of central importance in determining and understanding aerosol indirect effects. In recent work, it was found that cloud droplet size distributions become broader as a result of supersaturation variability and that the sensitivity of this effect is inversely related to cloud droplet number density. The subject is investigated in further detail using an extensive dataset from a laboratory cloud chamber capable of producing steady-state turbulence. An extended stochastic theory is found to successfully describe properties of the droplet size distribution, including an analytical expression for the relative dispersion. The latter is found to depend on the cloud droplet removal time, which in turn increases with the cloud droplet number density. The results show that relative dispersion decreases monotonically with increasing droplet number density, consistent with some recent atmospheric observations. Experiments spanning fast to slow microphysics regimes are reported. The observed dispersion is used to estimate time scales for autoconversion, demonstrating the important role of the turbulence-induced broadening effect on precipitation development. An initial effort is made to extend the stochastic theory to an atmospheric context with a steady updraft, for which autoconversion time is the controlling factor for droplet lifetime. As in the cloud chamber, relative dispersion is found to increase with decreasing cloud droplet number density.

Prison Meditation Movements and Mass Incarceration.

By some estimates, more than half of inmates held in jails and prisons in the United States have a substance use disorder. Treatments involving the teaching of meditation and other contemplative practices have been developed for a variety of physical and mental disorders, including drug and alcohol addiction. At the same time, an expanding volunteer movement across the country has been bringing meditation and yoga into jails and prisons. This review first examines the experimental research on one such approach-mindfulness meditation as a treatment for drug and alcohol addiction, as well as the research on mindfulness in incarcerated settings. We argue that to make a substantial impact on recidivism, such programs must mirror volunteer programs which emphasize interdependency and non-duality between the "helper" and the "helped," and the building of meditation communities both inside and outside of prison.

Rosacea: a review of current topical, systemic and light-based therapies.

Rosacea is a common chronic inflammatory disorder of the facial skin characterized by periods of exacerbation, remission and possible progression. The principle subtypes include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea. Although the pathogenesis is unknown, rosacea is largely recognized as an inflammatory disorder. Individual subtypes are likely a result of different pathogenic factors and respond best to different therapeutic regimens. The non-pharmacologic approach to therapy is adequate skin care, trigger avoidance and photoprotection; in addition, there are several topical, herbal, systemic and light based therapies available. Standard Food and Drug Administration (FDA) approved treatments include topical sodium sulfacetamide, metronidazole, and azelaic acid. Anti-inflammatory dose doxycycline, a controlled-release 40 mg formulation offers a non-antibiotic, anti-inflammatory treatment option. Combination of azelaic acid or topical metronidazole with anti-inflammatory doxycycline appears to have a synergistic effect. Oral isotretinoin may be effective for phymatous rosacea and treatment resistant rosacea. Light based therapies with pulsed dye laser and intense pulsed light are effective in treatment of erythema and telangiectasias. As our knowledge of rosacea and its therapeutic options expand, a multifaceted approach to treatment is warranted.

Onychomycosis and diabetes.

OBJECTIVE: This study aims to discuss factors specific to diabetics in the diagnosis and treatment of onychomycosis. DISCUSSION: Onychomycosis has the potential to cause severe complications in diabetics and should be treated promptly. The existence of comorbid conditions and potential for drug-drug interactions complicates the selection of an appropriate treatment regimen. The role of Candida in onychomycosis is controversial but may be of increased significance in the diabetic population due to an underlying vulnerability to this organism. CONCLUSIONS: Terbinafine is an excellent choice in diabetics due to its low risk of drug-drug interaction and proven efficacy against the typical pathogens that cause onychomycosis. Itraconazole, while an effective treatment for onychomycosis, is not a first-choice therapy due to its black-box cardiac warning and numerous drug interactions. Larger studies are needed in diabetics to determine the frequency of candidal nail infections.

Diclofenac sodium 3% gel as a potential treatment for disseminated superficial actinic porokeratosis.

BACKGROUND: Disseminated superficial actinic porokeratosis (DSAP) is a chronic cutaneous disorder of keratinization for which there is no known cure. Current therapies are often ineffective, painful, or unappealing. OBJECTIVE: To investigate the efficacy and safety of diclofenac sodium 3% gel for the treatment of DSAP. METHODS: Seventeen adult patients with a diagnosis of DSAP applied diclofenac sodium 3% gel to a target area (forearm) twice daily for 3 months up to a maximum of 6 months in an open-label, multicentre pilot study. Target area lesion counts were performed monthly, and global lesion counts were performed at baseline and at weeks 12 and 24. A treatment satisfaction questionnaire was completed at weeks 12 and 24. RESULTS: Thirteen patients completed 12 weeks of treatment and 10 completed 24 weeks. Among patients who completed 12 weeks, there was a mean decrease of 4% in target area lesions, while a mean increase of 12% was noted in global lesions. Among patients who completed 24 weeks, there was a mean increase of 19% in global lesions, but only a 10% increase noted in the target area. Seven of 13 patients had a decrease in target area lesions at week 12 and 3 of 10 patients at week 24. Questionnaire responses indicated 6 out of 10 patients would use the medication again. CONCLUSION: Target area DSAP lesions in the majority of patients treated with diclofenac sodium 3% gel (both 12 and 24 weeks) progressed to a lesser extent as compared to the global lesion count.

Infliximab therapy for sarcoidosis (lupus pernio).

Sarcoidosis is a chronic granulomatous disease of unknown aetiology in which the primary cytokine tumour necrosis factor (TNF)-alpha appears to play a major role. Older immune-modulating drugs including corticosteroids, antimalarials and thalidomide, as well as cytotoxic drugs with immune modulatory effects, have been used to control disease. We present a patient with severe mutilating cutaneous sarcoidosis (lupus pernio) who had showed only partial response to courses of a wide spectrum of immune modulators and cytotoxic therapies, and who had developed significant side-effects due to prolonged high-dose corticosteroids. However, the patient's cutaneous disease responded rapidly to the TNF-alpha inhibitor infliximab.

Penetrating tracheal injury in a child.

A case is reported of a 3.5-year-old child with a stab wound in the neck, that penetrated the trachea. A pneumomediastinum was present. The anaesthetic problems are discussed and the child's management outlined.