Estimands for atopic dermatitis clinical trials: Expert opinion on the importance of intercurrent events.

Despite the emergence of novel targeted treatments for atopic dermatitis (AD), there is a lack of guidelines on standardizing analysis of clinical trial data. To define and estimate meaningful treatment comparisons, several factors, including intercurrent events, must be taken into account. Intercurrent events are defined as events occurring after treatment initiation that affect either the interpretation or existence of the measurements associated with clinical questions of interest. Due to the relapsing, unpredictable nature of AD, intercurrent events frequently occur in AD trials, such as use of rescue therapy for intense itch and sleep deprivation. Despite the impact of intercurrent events in AD, they are often handled in an inconsistent manner across trials, which limits results interpretation. The estimand framework is increasingly used to estimate treatment effects while accounting for intercurrent events. This review explores how guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) on the use of estimands can be applied to support AD clinical trial design and analysis. We propose that estimands are used in AD trials and defined early during trial design. The use of estimands can provide clinicians with interventional trial results that are more reflective of clinical practice, help facilitate comparisons across clinical trials, and are more informative to enable improved treatment selection for patients.

Improvement in aspects of sleep with etanercept and optional adjunctive topical therapy in patients with moderate-to-severe psoriasis: results from the PRISTINE trial.

BACKGROUND: Impaired sleep in patients with moderate-to-severe psoriasis and improvement on therapy has not been widely studied. OBJECTIVE: Quantify baseline aspects of sleep and improvement in patients with psoriasis receiving etanercept (ETN) when allowed concomitant topical medications (PRISTINE study). METHODS: Patients with moderate-to-severe psoriasis were randomized to 50 mg ETN once weekly (QW/QW) or 50 mg ETN twice weekly (BIW/QW) for weeks 1-12, followed by 50 mg QW for weeks 13-24; a broad range of topical therapies were permitted during weeks 13-24. Sleep impairment was measured by the Medical Outcomes Study (MOS) sleep questionnaire Index II (population norm = 25.8; minimum clinically important difference = 5.1); quality of life (QoL) measures included Dermatology Life Quality Index (DLQI), EuroQoL 5 Dimension (EQ-5D) Utility Index and Visual Analogue Scale (VAS) and Functional Activity in Chronic Therapy-Fatigue (FACIT-Fatigue). ancova and Fisher's exact test or chi-squared tests were used for between-group testing. RESULTS: Mean baseline MOS-Sleep scores were 34.0 for both groups indicating impairment (N = 270; QW/QW n = 137; BIW/QW n = 133, approximately 64% had impaired sleep). At week 12 of treatment, MOS-Sleep scores improved to 30.8 and 30.1, and at week 24, to 28.4 and 28.2 respectively. Poor sleep was significantly associated with clinically important problems in EQ-5D utility, VAS and FACIT-Fatigue; sleep improvement was associated with improved EQ-5D utility and FACIT-Fatigue (P < 0.001). CONCLUSION: This study confirms that most patients with moderate-to-severe psoriasis have impaired sleep which is associated with impaired QoL. Treatment with etanercept significantly improved sleep, with most improvement occurring before a broad range of topicals were allowed. Sleep improvement was associated with improved QoL.

Basement membrane zone as a target for human neutrophil elastase in psoriasis.

Human neutrophil elastase was found, by indirect immunofluorescence using rabbit anti-elastase anti-serum, to be bound to basement membrane of psoriatic plaques in vivo. The enzyme was also identified inside the migrating neutrophils in the reticular dermis and dermal papillae, as well as outside the cells in micro-abscesses in psoriatic skin. In vitro incubation of normal skin with human neutrophil elastase resulted in the destruction of hemidesmosomes and separation of the epidermis from the dermis above localizations of bullous pemphigoid antigen. These findings are direct evidence that human neutrophil elastase could play a role in psoriasis in in vivo destruction of the epidermal-dermal junction.

[Cutaneous mastocytosis with bullous changes simulating xanthoma tuberosum]. / Mastocytoza skórna ze zmianami guzowatymi imitujacymi xanthoma tuberosum.

A 20-year-old female patient is reported with urticaria pigmentosa and coexisting nodules (mastocytoma) resembling clinically lesions of the type of xanthoma tuberosum. An analysis of microscopic image and ultrastructural changes was carried out and modern views on treatment of cutaneous mastocytosis are discussed.

[Pagetoid reticulosis (Woringer-Kolopp disease)]. / Pagetoid reticulosis (morbus Woringer-Kolopp).

The first Polish report of a case of the limited variety of the Woringer-Kolopp disease (pagetoid reticulosis) is presented. The diagnosis was based on histological examination. Numerous pagetoid cells were found in the epidermis and only few in the dermis. In ultramicroscopy two types of mononuclear cells were disclosed, one with large nucleus and scattered chromatin, and other with smaller nucleus and nuclear chromatin condensed at the periphery. The immunopathological examination of isolated pagetoid cells with monoclonal antibodies showed on their surface a slight prevalence of suppressor T-cell receptors. Radiotherapy was applied with a very good result.

Apoptosis in Bowen's disease. An ultrastructural study.

We performed ultrastructural studies of apoptosis (previously referred to as "malignant dyskeratosis") in a case of genital Bowen's carcinoma in which human papillomavirus (HPV) type 33 genome was identified and in two cases of cutaneous Bowen's disease with no detectable viral DNA; herein we present the sequential stages in the development of apoptotic bodies. The apoptotic process in the HPV-containing genital Bowen's disease was similar to that in the cutaneous lesions with no detectable HPV. The presence of a large number of apoptotic bodies in Bowen's disease may be responsible for the slow progression and noninvasive growth of this carcinoma in situ.

Ultrastructural changes of the skin induced by human leukocyte elastase and cathepsin G.

Human neutrophil elastase and cathepsin G at a concentration of 10(-6) M were found to attack various substrates when normal skin biopsy specimens were incubated at 37 degrees C for 1 h with either of these enzymes. Elastase damaged primarily hemidesmosomes, leading to the epidermal cleavage from the dermis, whereas cathepsin G damaged the membrane structures. Both these neutral proteinases were highly specific to basal lamina of blood vessels. This indicates that neutrophil elastase and neutrophil cathepsin G may play different roles in various skin diseases related to enhanced activity and infiltration of neutrophils.