Prediction of treatment response in psoriasis with measurement of serum levels of adalimumab,etanercept, and antidrug antibodies: a pilot study

BackgroundA substantial proportion of patients with psoriasis do not respond or lose initial response to tumour necrosis factor antagonists. This may partly be attributable to development of an immunogenic antibody response which causes subtherapeutic drug levels because of the clearance of drug-antidrug complexes. The aim of this study was to investigate the association between serum drug (adalimumab and etanercept) levels, antidrug antibodies, and clinical response in a cohort of psoriasis patients.MethodsIn a single-centre cohort of 56 adults with psoriasis initiated on adalimumab or etanercept between 2009 and 2011, drug and antidrug antibody levels were measured with a commercially available ELISA at the patients’ routine clinic reviews (4, 12, and 24 weeks of treatment and the last available observation). Responders were defined as having a 75% reduction in psoriasis area and severity index from baseline (PASI 75) within 6 months of treatment, or physician's global score of clear or nearly clear. Non-responders were defined as not achieving a 50% reduction in PASI from baseline (PASI 50) within 6 months or having a loss of PASI 50 treatment response.FindingsAfter 4 weeks of therapy, adalimumab levels were significantly higher in responders than in non-responders (median 5·00 μg/mL [IQR 4·30–5·00] vs 0·12 μg/mL [0·10–1·79], p=0·003) and these higher levels were sustained at 12 and 24 weeks. Anti-adalimumab antibodies were detected in 25% of non-responders (2/8 patients, mean follow-up 22·5 weeks) and not in any responders (n=23, mean follow-up 26·1 weeks). There was no significant association between etanercept levels and clinical response at 4 weeks (median 2·94 μg/mL [IQR 0·78–3·68] vs 1·40 [0·82–2·12], p=0·317), and no anti-etanercept antibodies were detected.InterpretationAdalimumab drug level monitoring at 4 weeks may be useful in predicting treatment response, in contrast to etanercept drug levels. The majority of adalimumab non-responders did not have antidrug antibodies; however, lack of serum trough levels and assay limitations may have underestimated their prevalence. Larger studies are required to investigate other factors contributing to low drug levels and to assess the usefulness of these drug and antidrug assays in personalising therapy in psoriasis.FundingNational Institute for Health Research.     

Use of a Web-Based Delphi Study in the Development of a Training Resource for Workers Supporting Families where Parents Experience Mental Illness

Given the needs of families where a parent has a mental illness, it is essential that workers are provided with effective training in order better to support such families, particularly children. Previous research has suggested that workforce training might focus on worker attitude, skill and knowledge, as well as inter-agency collaboration. A review of current training packages revealed common themes, with family-centred practice considered important. Barriers and issues for workers implementing family-sensitive practice were also identified. This study sought to develop a sound theory and evidence base for workforce training components. A web-based Delphi study was used to obtain consensus on the content of a training resource for mental health practitioners supporting families experiencing parental mental illness. Fourteen experts, including consumers and carers, responded to questions about curriculum content. Suggested topics were translated into seven themes which were then refined to create the final broad content for the training resource modules. A clear structure for the development of future workforce training packages is suggested. The results are discussed in light of previous literature and existing training packages.     

Hematopoietic cell phosphatase associates with erythropoietin (Epo) receptor after Epo-induced receptor tyrosine phosphorylation: identification of potential binding sites

Erythropoietin (Epo) binding to its receptor (EpoR) induces tyrosine phosphorylation in responsive cells and this ability is required for a mitogenic response. One of the substrates of tyrosine phosphorylation is the Epo receptor (EpoR). The carboxyl region of EpoR cytoplasmic domain is required for EpoR phosphorylation and has been shown to negatively affect the response to Epo both in vivo and in cell lines. Hematopoietic cell phosphatase (HCP) has also been hypothesized to negatively regulate erythropoiesis, based on the hypersensitivity to Epo of erythroid lineage cells in moth-eaten mice that genetically lack HCP. In the studies presented here, we show that HCP binds the tyrosine phosphorylated Epo receptor through the amino-terminal src-homology 2 (SH2) domain of HCP. Using a series of phosphotyrosine-containing peptides, potential HCP binding sites in the cytoplasmic domain of the EpoR are identified. The results support the concept that, after Epo stimulation, phosphorylation of EpoR provides a docking site for HCP in the receptor complex. Recruitment of HCP to the complex and its subsequent dephosphorylation of substrates and/or associated kinases may be important to mitigate the ligand-induced mitogenic response.     

The relationship between health-related quality of life, pain and coping strategies in juvenile idiopathic arthritis

OBJECTIVES: To investigate the relationship between health-related quality of life (HRQL), experience of pain and pain coping strategies in children with juvenile idiopathic arthritis (JIA). To compare reports describing these variables obtained from children and their parents. METHODS: Participants were 59 children aged 8 to 18 yr with JIA and their parents. Parents and children completed the PedsQL generic core scales and arthritis module, the visual analogue scale of the Varni-Thompson Pediatric Pain Questionnaire, and the Waldron/Varni Pediatric Pain Coping Inventory. Parents rated children's functional disability using the Childhood Health Assessment Questionnaire. RESULTS: Parents reported significantly lower scores (indicating worse HRQL) than children on five of the eight PedsQL scales rating children's HRQL. Parents and children reported a significant negative relationship between pain levels and the PedsQL scores assessing children's physical, emotional and social functioning. They also reported a significant negative relationship between scores on several pain coping scales and scores on the PedsQL scales. However, the pattern of these relationships varied for reports from parents and children. CONCLUSIONS: Pain intensity and pain coping strategies have a significant and independent relationship with several domains that comprise the HRQL of children with JIA. However, parents and children have differing perceptions of the nature of these relationships. The differences emphasize the importance of clinicians obtaining information about children's HRQL, pain levels and pain coping strategies from both parents and children.     

Assessing the utility of methods for menopausal transition classification in a population-based cohort: The CARDIA Study

Objectives

Perimenopause significantly impacts women's health, but is under-researched due to challenges in assessing perimenopause status. Using CARDIA data, we compared the validity of six approaches for classifying perimenopause status in order to better understand the performance of classification techniques which can be applied to general cohort data. Specifically, we examined the validity of a self-reported question concerning changes in menstrual cycle length and two full prediction models using all available data concerning menstrual cycles as potential indicators of perimenopause. The validity of these three novel methods of perimenopause classification were compared to three previously established classification methods.

Methods

For each method, women were classified as pre- or peri-menopausal at Year 15 of follow-up (ages 32–46). Year 15 perimenopause status was then used to predict Year 20 post-menopausal status (yes/no) to estimate measures of validity and area under the curve.

Results

The validity of the methods varied greatly, with four having an area under the curve greater than 0.8.

Conclusions

When designing studies, researchers should collect the data required to construct a prediction model for classifying perimenopause status that includes age, smoking status, vasomotor symptoms, and cycle irregularities as predictors. The inclusion of additional data regarding menstrual cycles can be used to construct a full prediction model which may offer improved validity. Valid classification methods that use readily available data are needed to improve the scientific accuracy of research regarding perimenopause, promote research on this topic, and inform clinical practices.     

Impact of prehypertension on left ventricular mass and QT dispersion in adult black Nigerians

The heterogeneity of individuals with blood pressure (BP) < 140/90 mmHg in terms of cardiovascular (CV) risk was reported as early as 1939 by Robinson and Brucer.1 BP in the range of 120–139/80–89 mmHg (labelled then as prehypertension) was observed to be associated with high risk of progression to hypertension (HT) and cardiovascular disease (CVD) later in life when compared with BP < 120/80 mm Hg.1The term prehypertension was adopted in May 2003 by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High blood Pressure (JNC-7) to describe BP range of 120–139/80–89 mmHg.2 The resuscitation of this terminology/concept in JNC-7 was a sequel to the documentation of a higher morbidity in individuals with prehypertension in landmark publications.3-5 Prehypertension (PHT) was defined in JNC-7 not only to emphasise the excess risk associated with BP in this range, but also to focus increased clinical and public health attention on prevention.2,6,7Prevalence rates of PHT among adults in the United States, Ghana and northern Nigeria have been reported to be 31, 40 and 58.7%, respectively.7-9 In most studies, including the ones above, PHT was more prevalent than hypertension.7-9 Though PHT is associated with increased risk of major CV events independently of other CV risk factors,10 most individuals (90%) with PHT have at least one cardiovascular risk factor such as dyslipidaemia, abdominal obesity, hyperinsulinaemia, impaired fasting glucose levels, insulin resistance, a prothrombotic state, tobacco use, endothelial dysfunction, and impaired vascular distensibility.6,7,9,10QT interval dispersion (QTd) (the difference between the longest and the shortest QT intervals on a surface ECG), when excessive, is associated with increased risk of cardiovascular morbidity and mortality in population studies, and many clinical conditions, including hypertension.11,12 This has been related to ventricular electrical instability, providing the necessary substrate for lethal ventricular arrhythmias.12,13 Greater QTd and left ventricular mass have been demonstrated in hypertensive individuals compared with normal individuals.11,13,14Considering the well-established, linear relationship between BP and the risk of cardiovascular events, the CV risk associated with PHT is intermediate between normotension and hypertension.2,03 Hence, electrocardiographic and echocardiographic indices of target-organ damage in PHT may also be intermediate between normotension and hypertension. The aims of this study were: (1) to compare the QTd and indices of left ventricular hypertrophy in adult black normal and prehypertensive subjects, and (2) to evaluate the relationship of QTd with electrocardiographic and echocardiographic indices in these subjects.     

The effect of interleukin 3 and GM-CSA-2 on megakaryocyte and myeloid clonal colony formation

Two separate helper T cell-derived lymphokines, interleukin 3 and granulocyte-macrophage colony-stimulating activity-2, were found to stimulate a broad and similar range of hemopoietic colonies in in vitro soft agar cultures including granulocyte, macrophage, granulocyte- macrophage, megakaryocyte, and mixed megakaryocyte colonies. Both lymphokines were potent stimulators of in vitro megakaryocyte colony formation. At plateau levels of IL-3, megakaryocyte colony formation was increased by biologic activity in pokeweed mitogen spleen- conditioned media.