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.

Baricitinib improves symptoms in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: patient-reported outcomes from two randomized monotherapy phase III trials.

BACKGROUND: Itch, skin pain, and sleep disturbance are burdensome symptoms in atopic dermatitis (AD) that negatively influence a patient's quality of life (QoL). OBJECTIVE: To evaluate the impact of baricitinib on patient-reported outcomes (PROs) in adult patients with moderate-to-severe AD, and explore the association between improvement in key signs and symptoms of AD with improvements in QoL and patient's assessment of disease severity. METHODS: Data were analyzed from two phase III monotherapy trials (BREEZE-AD1/BREEZE-AD2) in which patients were randomized 2:1:1:1 to once-daily placebo, baricitinib 1-mg, 2-mg, or 4-mg for 16 weeks and assessed using PRO measures. RESULTS: At week 16, baricitinib 4-mg and 2-mg significantly reduced itch severity (Itch Numeric Rating Scale (NRS) (BREEZE-AD1: percent change from baseline -36.6% and -29.4% vs. placebo (-12.0%), p≤.001 and p≤.05; BREEZE-AD2: -47.2% and -46.9% vs. placebo (-16.6%), p≤.001). Baricitinib significantly reduced SCORing AD (SCORAD) pruritus (4-mg in BREEZE-AD1 and 2-mg in BREEZE-AD2) and Patient Oriented Eczema Measure (POEM) itch (both doses). Improvements in skin pain severity and sleep disturbance were also observed. Improvements in AD symptoms showed higher correlations with patients' assessment of AD severity and QoL than improvements in skin inflammation. CONCLUSIONS: Baricitinib significantly improved symptoms in patients with moderate-to-severe AD. CLINICALTRIALS.GOV IDENTIFIERS: NCT03334396 (BREEZE-AD1) and NCT03334422 (BREEZE-AD2).

Development of the Scalp Hair Assessment PRO™ measure for alopecia areata.

BACKGROUND: Valid patient-reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments. OBJECTIVES: To develop a content-valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five-response-level Alopecia Areata Investigator Global Assessment (AA-IGA™). METHODS: A draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed. RESULTS: Adults (round 1: n = 25; round 2: n = 15) and adolescents aged 15-17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self-report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five-level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1-20%; moderate, 21-49%; large, 50-94%; nearly all or all, 95-100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success. CONCLUSIONS: The Scalp Hair Assessment PRO™ is a content-valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline.

The Alopecia Areata Investigator Global Assessment scale: a measure for evaluating clinically meaningful success in clinical trials.

BACKGROUND: Content-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA). OBJECTIVES: To develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies. METHODS: Qualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA. RESULTS: Expert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss. CONCLUSIONS: We recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials.

BACKGROUND: Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids. OBJECTIVES: To evaluate the efficacy and safety of baricitinib in patients with moderate-to-severe AD who had an inadequate response to topical therapies. METHODS: In two independent, multicentre, double-blind, phase III monotherapy trials, BREEZE-AD1 and BREEZE-AD2, adults with moderate-to-severe AD were randomized 2 : 1 : 1 : 1 to once-daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks. RESULTS: At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE-AD1 [N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%], and BREEZE-AD2 [N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%]. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night-time awakenings, skin pain and quality-of-life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage. CONCLUSIONS: Baricitinib improved clinical signs and symptoms in patients with moderate-to-severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.

Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative).

This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to predefined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.

Adequacy assessment of mathematical models in the dynamics of litter decomposition in a tropical forest Mosaic Atlantic, in southeastern Brazil.

The study of litter decomposition and nutrient cycling is essential to know native forests structure and functioning. Mathematical models can help to understand the local and temporal litter fall variations and their environmental variables relationships. The objective of this study was test the adequacy of mathematical models for leaf litter decomposition in the Atlantic Forest in southeastern Brazil. We study four native forest sites in Parque Estadual do Rio Doce, a Biosphere Reserve of the Atlantic, which were installed 200 bags of litter decomposing with 20 × 20 cm nylon screen of 2 mm, with 10 grams of litter. Monthly from 09/2007 to 04/2009, 10 litterbags were removed for determination of the mass loss. We compared 3 nonlinear models: 1 - Olson Exponential Model (1963), which considers the constant K, 2 - Model proposed by Fountain and Schowalter (2004), 3 - Model proposed by Coelho and Borges (2005), which considers the variable K through QMR, SQR, SQTC, DMA and Test F. The Fountain and Schowalter (2004) model was inappropriate for this study by overestimating decomposition rate. The decay curve analysis showed that the model with the variable K was more appropriate, although the values of QMR and DMA revealed no significant difference (p > 0.05) between the models. The analysis showed a better adjustment of DMA using K variable, reinforced by the values of the adjustment coefficient (R2). However, convergence problems were observed in this model for estimate study areas outliers, which did not occur with K constant model. This problem can be related to the non-linear fit of mass/time values to K variable generated. The model with K constant shown to be adequate to describe curve decomposition for separately areas and best adjustability without convergence problems. The results demonstrated the adequacy of Olson model to estimate tropical forest litter decomposition. Although use of reduced number of parameters equaling the steps of the decomposition process, no difficulties of convergence were observed in Olson model. So, this model can be used to describe decomposition curves in different types of environments, estimating K appropriately.

Synanthropy of mosquitoes and sand flies near the Aimorés hydroelectric power plant, Brazil.

The environmental changes resulting from the construction of hydroelectric dams may affect the fauna of insect vectors and consequently the epidemiology of the diseases they transmit. This work examined the mosquito and sand fly fauna in the area of the Aimorés hydroelectric power plant, analyzing the seasonal distribution and the degree of species synanthropy in different ecotopes. Between November, 2008 and September, 2009, entomological captures were performed with the help of HP light traps in the rural, urban, and forest areas of Aimorés, Ituêta, Resplendor, and Baixo Guandu counties. The fauna proved to be quite diversified. Twenty-two species of mosquitoes and 11 species of sand flies were found. Culex quinquefasciatus was predominant among mosquitoes (76.7%), while Lutzomyia intermedia prevailed among sand flies (34.5%). Some of the captured species have medical interest. Supported by the high degree of synanthropy, those species reinforce the need for epidemiological surveillance.

Crotoxin is responsible for the long-lasting anti-inflammatory effect of Crotalus durissus terrificus snake venom: involvement of formyl peptide receptors

In the present study, it was investigated which components are responsible for the antiinflammatory properties of Crotalus durissus terrificus venom (CdtV). The effect of crotoxin,as well as of other CdtV components was evaluated on edema, cell migration and alterations in leukocyte–endothelium interactions induced by carrageenan. Crotoxin (40 mg kg 1) was injected at different time periods before or after the injection of carrageenan (15 mg kg 1)into the mouse hind paw, peritoneum or scrotum. Results showed that crotoxin, but not other CdtV components, significantly inhibited inflammatory edema and cell migration when administered before or after carrageenan injection in mice. This toxin also prevented the occurrence of alterations in leukocyte–endothelium interactions induced by carrageenaninjection, such as the increase in adhered cells. In animals pretreated with Boc2 (a selective antagonist of formyl peptide receptors), crotoxin showed neither inhibitoryeffects on edema and cell migration, nor prevented alterations in leukocyte–endothelium interactions induced by carrageenan. These findings demonstrate that crotoxin is thecomponent responsible for the long-lasting anti-inflammatory activity of crude C. durissus terrificus venom, and activation of formyl peptide receptors seems to play a major role inthis effect.

Crotoxin is responsible for the long-lasting anti-inflammatory effect of Crotalus durissus terrificus snake venom: involvement of formyl peptide receptors.

In the present study, it was investigated which components are responsible for the anti-inflammatory properties of Crotalus durissus terrificus venom (CdtV). The effect of crotoxin, as well as of other CdtV components was evaluated on edema, cell migration and alterations in leukocyte-endothelium interactions induced by carrageenan. Crotoxin (40 microg kg(-1)) was injected at different time periods before or after the injection of carrageenan (15 mg kg(-1)) into the mouse hind paw, peritoneum or scrotum. Results showed that crotoxin, but not other CdtV components, significantly inhibited inflammatory edema and cell migration when administered before or after carrageenan injection in mice. This toxin also prevented the occurrence of alterations in leukocyte-endothelium interactions induced by carrageenan injection, such as the increase in adhered cells. In animals pretreated with Boc2 (a selective antagonist of formyl peptide receptors), crotoxin showed neither inhibitory effects on edema and cell migration, nor prevented alterations in leukocyte-endothelium interactions induced by carrageenan. These findings demonstrate that crotoxin is the component responsible for the long-lasting anti-inflammatory activity of crude C. durissus terrificus venom, and activation of formyl peptide receptors seems to play a major role in this effect.

Effect of dexamethasone associated with serum therapy on treatment of Bothrops jararaca venom-induced paw edema in mice.

OBJECTIVE AND DESIGN: The present study investigates the supposed advantage of using an association of anti-inflammatory drugs and serum therapy to treat mouse paw edema induced by injection of Bothrops jararaca snake venom (BjV). MATERIAL AND METHODS: Edema was induced by injecting BjV (2 microg) into the footpad of male Swiss mice (20-25 g) and measured by plethysmography. Groups of mice were treated 15, 30 or 45 min after BjV injection with Bothrops antivenom or anti-inflammatory drugs (dexamethasone, indomethacin or zileuton), or with the association of antivenom and each one of these drugs. RESULTS: Antivenom, dexamethasone and indomethacin were effective in reducing the paw edema when used up to 30 min after BjV injection. Zileuton had the same effect, but only if used up to 15 min after BjV injection. The association of antivenom and dexamethasone showed the greatest inhibitory effect when used up to 45 min after BjV injection. At this time, antivenom or anti-inflammatory drugs administered alone were ineffective. CONCLUSION: Results suggest that dexamethasone combination with serum therapy can be beneficial for treatment of inflammatory edema caused by B. jararaca envenomation.

Serum IgE levels in neurofibromatosis 1.

A descriptive case study was performed on 75 patients with NF1 (neurofibromatosis type 1) from the CNNF (Brazil) database. Serum IgE levels were determined using the IgE radioimmunosorbent test, with the reference values of 75-502 IU mL(-1). The patients were divided into groups, with 25 patients presenting plexiform neurofibromas, 25 presenting neurofibromas and 25 presenting no neurofibromas. The purposes of this study were to determine the serum IgE levels of patients with NF1 presenting plexiform neurofibromas, neurofibromas and no neurofibromas, as well as to determine possible correlations between serum IgE levels and the size of the plexiform neurofibromas and neurofibromas presented by these patients. Elevated serum IgE levels were observed in all the patient groups. We did not observe a correlation between IgE levels and age in these patients; however, we did observe correlations between IgE levels and neurofibroma and plexiform neurofibroma size. We suggest further studies to confirm these results and to investigate in greater depth the possible role of IgE in the development and growth of neurofibromas and plexiform neurofibromas in NF1.

Cilindromatose: apresentação de um caso / cylindromatosis

Os aoutores descrevem um caso de cilindromatose em um paciente de 45 anos. O paciente natural e residente em Teresópolis- RJ, possui uma história familiar composta de cinco gerações, das quais três apresentam comprometimento dermatológico em graus variados. Os exames laboratórias não apresentam alterações patológics, os raios X e a tomografia computadorizada mostram sinais caracteristicos de cilindromatose. Discute-se o diagnóstico diferencial desta rara enfermidade, da qual em nosso levantamento bibliográfico, não há refereência na literatura

[Sycosis of the beard (tinea barbae). Analysis of 42 cases]. / Sicose por fungos dermatófitos (tinha da barba). Análise de 42 casos.

42 patients suffering from dermatophytic fungus infection involving the bearded area, face and neck (tinea barbae) were seen in the Clinic between 1970 and 1977. The clinical diagnosis was confirmed by microscopic examination (KOH) of skin and hair scrapings in all the patients. The material obtained from 39 patients and inoculated gave a positive culture; in were isolated and following fungi: T rubrum-18, T. mentagrophytes-16, T. megninii-1, T. violaceum-2, M. canis-2. From the clinical point of veiw it was possible to classify the patients in 3 main types: --Superficial type-11 patients. --Kerion-10 patients (T. mentagrophytes-9, M. canis-1). --Nodular type-deep seated nodules, without discharging, very slow evolution - 21 patients (T. mentagrophytes-4, T. rubrum-13, T. megninii-1, T. violaceum-1). It was obtained material for histology in 13 patients: 3 suffering from kerion and 10 with the nodular clinical type. The histology of the Kerion type showed a marked inflammatory reaction consisting largely of neutrophils surrounding the hair follicles. Only in one examination, out of the 3 patients studied with Kerion, showed fungi, on PAS. The 10 patients suffering from the nodular type of infection who were studied histologically showed a more or less uniform picture, which consisted in a more deep seated infiltration specially consisting of lymphocytes and plasmocytes, on the derme but not so perifollicular as in Kerion and, in 2 cases, there was a tendency to form a tuberculoid structure. The PAS was positive in 6 patients. The fungi were always intrafollicular. All the patients were treated with griseofulvin 1 gr. per day. All of them healed after a period of 4-8 weeks of treatment.