What is the evidence base for atopic eczema treatments? A summary of published randomized controlled trials.

Atopic eczema (AE) is a common chronic inflammatory skin condition. While many AE treatment options are available, the evidence to support their efficacy varies in depth and quality. In 2000, a National Institute for Health Research (NIHR) Health Technology Assessment systematic review identified and evaluated existing randomized controlled trials (RCTs) of AE treatments. To ensure continuing utility, the NIHR commissioned an update to the review. Here, we present an overview of the updated report and its key findings. Systematic reviews and RCTs of AE treatments that included participants with AE (criteria based or diagnosed) were identified using Medline, Embase, CENTRAL, Latin American and Caribbean Health Sciences, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature and Cochrane Skin Group Specialised Register [searched to 31 August 2013 (RCTs) and 31 December 2015 (systematic reviews)]. Outcome measures included symptoms, AE severity, quality of life and adverse effects. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Of the 287 new RCTs identified, only 22 (8%) were judged to have a low risk of bias. When combined with RCTs from the previous review (n = 254), we found 'reasonable evidence of benefit' for corticosteroids, calcineurin inhibitors, Atopiclair® , ciclosporin, azathioprine, ultraviolet radiation and education programmes. Interventions with reasonable evidence of 'no benefit' included some dietary interventions, ion exchange water softeners, multiple daily applications of topical corticosteroids and antibiotic-containing corticosteroids for noninfected AE. Many common treatments lack evidence of efficacy and warrant further evaluation. The evidence base for AE is still hampered by poor trial design and reporting. The trials included in this review were used to establish the Global Resource of EczemA Trials (GREAT) database.

Report from the kick-off meeting of the Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN).

A major obstacle of evidence-based clinical decision making is the use of nonstandardized, partly untested outcome measurement instruments. Core Outcome Sets (COSs) are currently developed in different medical fields to standardize and improve the selection of outcomes and outcome measurement instruments in clinical trials, in order to pool results of trials or to allow indirect comparison between interventions. A COS is an agreed minimum set of outcomes that should be measured and reported in all clinical trials of a specific disease or trial population. The international, multidisciplinary Cochrane Skin Group Core Outcome Set Initiative (CSG-COUSIN) aims to develop and implement COSs in dermatology, thus making trial evidence comparable and, herewith, more useful for clinical decision making. The inaugural meeting of CSG-COUSIN was held on 17-18 March 2015 in Dresden, Germany, as the exclusive theme of the Annual Cochrane Skin Group Meeting. In total, 29 individuals representing a broad mix of different stakeholder groups, professions, skills and perspectives attended. This report provides a description of existing COS initiatives in dermatology, highlights current methodological challenges in COS development, and presents the concept, aims and structure of CSG-COUSIN.

Dietary exclusions for improving established atopic eczema in adults and children: systematic review.

Atopic eczema is the most common inflammatory skin disease of childhood in developed countries. We performed a systematic review of randomized controlled trials to assess the effects of dietary exclusions for the treatment of established atopic eczema. Nine trials (421 participants) were included, most of which were poorly reported. Six were studies of egg and milk exclusion (n = 288), one was a study of few foods (n = 85) and two were studies of an elemental diet (n = 48). There appears to be no benefit of an egg- and milk-free diet in unselected participants with atopic eczema. There is also no evidence of benefit in the use of an elemental or few-foods diet in unselected cases of atopic eczema. There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs - one study found 51% of the children had a significant improvement in body surface area with the exclusion diet as compared with normal diet (95% CI 1.07-2.11) and change in surface area and severity score was significantly improved in the exclusion diet as compared with the normal diet at the end of 6 weeks (MD 5.50, 95% CI 0.19-10.81) and end of treatment (MD 6.10, 95% CI 0.06-12.14). Despite their frequent use, we find little good quality evidence to support the use of exclusion diets in atopic eczema.

Interventions for alopecia areata.

BACKGROUND: Alopecia areata is a disorder in which there is loss of hair causing patches of baldness but with no scarring of the affected area. It can affect the entire scalp (alopecia totalis) or cause loss of all body hair (alopecia universalis). It is a relatively common condition affecting 0.15% of the population. Although in many cases it can be a self-limiting condition, nevertheless hair loss can often have a severe social and emotional impact. OBJECTIVES: To assess the effects of interventions used in the management of alopecia areata, alopecia totalis and alopecia universalis. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register in February 2006, the Cochrane Central Register of Controlled Clinical Trials (The Cochrane Library Issue 1, 2006), MEDLINE (from 2003 to February 2006), EMBASE (from 2005 to February 2006), PsycINFO (from 1806 to February 2006), AMED (Allied and Complementary Medicine, from 1985 to February 2006), LILACS (Latin American and Caribbean Health Science Information database, from 1982 to February 2006), and reference lists of articles. We also searched online trials registries for ongoing trials. SELECTION CRITERIA: Randomised controlled trials that evaluated the effectiveness of both topical and systemic interventions for alopecia areata, alopecia totalis, and alopecia universalis. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted the data. We contacted trial authors for more information. We collected adverse effects information from the included trials. MAIN RESULTS: Seventeen trials were included with a total of 540 participants. Each trial included from 6 to 85 participants and they assessed a range of interventions that included topical and oral corticosteroids, topical ciclosporin, photodynamic therapy and topical minoxidil. Overall, none of the interventions showed significant treatment benefit in terms of hair growth when compared with placebo. We did not find any studies where the participants self-assessed their hair growth or quality of life. AUTHORS' CONCLUSIONS: Few treatments for alopecia areata have been well evaluated in randomised trials. We found no RCTs on the use of diphencyprone, dinitrochlorobenzene, intralesional corticosteroids or dithranol although they are commonly used for the treatment of alopecia areata. Similarly although topical steroids and minoxidil are widely prescribed and appear to be safe, there is no convincing evidence that they are beneficial in the long-term. Most trials have been reported poorly and are so small that any important clinical benefits are inconclusive. There is a desperate need for large well conducted studies that evaluate long-term effects of therapies on quality of life. Considering the possibility of spontaneous remission especially for those in the early stages of the disease, the options of not being treated therapeutically or, depending on individual preference wearing a wig may be alternative ways of dealing with this condition.

Dietary exclusions for established atopic eczema.

BACKGROUND: Atopic eczema (AE) is a non-infective chronic inflammatory skin disease characterised by an itchy red rash. OBJECTIVES: To assess the effects of dietary exclusions for the treatment of established atopic eczema. SEARCH STRATEGY: We searched The Cochrane Skin Group Specialised Register (to March 2006), The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1, 2006), MEDLINE (2003 to March 2006), EMBASE (2003 to March 2006), LILACS (to March 2006), PsycINFO (1806 to March 2006), AMED (1985 to March 2006), ISI Web of Science (March 2006), www.controlled-trials.com, www.clinicaltrials.gov and www.nottingham.ac.uk/ongoingskintrials (March 2006). Pharmaceutical companies were contacted where appropriate for reviews or unpublished trials. SELECTION CRITERIA: People who have atopic eczema as diagnosed by a doctor. DATA COLLECTION AND ANALYSIS: Two independent authors carried out study selection and assessment of methodological quality. MAIN RESULTS: We found 9 RCTs involving a total of 421 participants of which 6 were studies of egg and milk exclusion (N=288), 1 was a study of few foods (N=85) and 2 were studies of an elemental diet (N=48). There appears to be no benefit of an egg and milk free diet in unselected participants with atopic eczema. There is also no evidence of benefit in the use of an elemental or few-foods diet in unselected cases of atopic eczema. There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs - one study found 51% of the children had a significant improvement in body surface area with the exclusion diet compared to normal diet (RR 1.51, 95% CI 1.07 to 2.11) and change in surface area and severity score was significantly improved in the exclusion diet compared to the normal diet at the end of 6 weeks (MD 5.50,95% CI 0.19 to 10.81) and end of treatment (MD 6.10, 95% CI 0.06 to12.14). Methodological difficulties have made it difficult to interpret these studies. Poor concealment of randomisation allocation, lack of blinding and high dropout rates without an intention-to-treat analysis indicates that these studies should be interpreted with great caution. AUTHORS' CONCLUSIONS: There may be some benefit in using an egg-free diet in infants with suspected egg allergy who have positive specific IgE to eggs. Little evidence supports the use of various exclusion diets in unselected people with atopic eczema, but that may be because they were not allergic to those substances in the first place. Lack of any benefit may also be because the studies were too small and poorly reported. Future studies should be appropriately powered focusing on participants with a proven food allergy. In addition a distinction should be made between young children whose food allergies improve with time and older children/adults.

Production of PGE2 by bovine cultured airway smooth muscle cells: regulation by cAMP.

Prostaglandin E2 (PGE2) is thought to be an important inhibitory modulator of inflammatory processes in the airway. Previous studies have shown that it is produced by bovine cultured airway smooth muscle (ASM) cells in large quantities, but its regulation by second messengers has not been studied in this tissue. To determine whether PGE2 production by ASM might be an important action of beta-adrenoceptor agonists in asthma, the regulation of PGE2 production by adenosine 3',5'-cyclic monophosphate (cAMP) was assessed using dibutyryl cAMP (DBcAMP), forskolin, and albuterol. DBcAMP increased PGE2 production over a 24-h time course. Forskolin and albuterol both increased PGE2 production over control cells to similar levels after 24 h. Incubation of albuterol-treated cells with propranolol significantly (70%) reduced the stimulatory effect of albuterol on PGE2 production. Incubation of forskolin-treated cells with Rp-cAMP, a cAMP antagonist, inhibited the PGE2 response evoked by forskolin by 80%. Ro-20-1724, a selective inhibitor of type IV phosphodiesterase, stimulated PGE2 production (P = 0.02). Cycloheximide, a protein-synthesis inhibitor, did not inhibit the response to DBcAMP. The effects of DBcAMP were additive with the effects of bradykinin, a proinflammatory mediator known to increase PGE2 production (P < 0.05). These studies suggest that cAMP may play an important regulatory role in stimulating PGE2 production by ASM. This may be a novel beneficial action of beta-adrenoceptor agonists in asthma.

Production of PGE2 by bovine cultured airway smooth muscle cells and its inhibition by cyclo-oxygenase inhibitors.

1. Prostaglandin E2 (PGE2) is thought to be an important inhibitory modulator of inflammatory processes in the airway. It inhibits inflammatory cell function and cholinergic neurotransmission in vitro and roles have been postulated in vivo in refractoriness and in the mechanism of action of the diuretic agent, frusemide. 2. The production of PGE2 by bovine cultured airway smooth muscle cells has been studied under a range of conditions. The effects of cyclo-oxygenase inhibitors (flurbiprofen, indomethacin, acetyl salicylic acid) on serum-induced production of PGE2 were assessed over a range of concentrations (10(-7)-10(-4) M). 3. Serum-stimulated production of PGE2 in control wells ranged from 350 to 800 ng PGE2 ml-1 in cells from different animals. All three cyclo-oxygenase inhibitors inhibited PGE2 production with an order of potency, flurbiprofen > indomethacin > acetyl salicylic acid. Log IC50 values were -6.24 for flurbiprofen, -5.23 for indomethacin and -3.50 for acetyl salicylic acid. 4. PGE2 production was stimulated by arachidonic acid (10(-5) M) or addition of the proinflammatory mediator, bradykinin (10(-8)-10(-5) M). 5. Incubation of cells for 24 h with 5 bromo deoxyuridine (BRDU) (10(-4) M) to prevent DNA synthesis did not alter PGE2 production in response to serum, suggesting that it was not a function of proliferation per se. 6. Our study suggests that airway smooth muscle may be an important source of PGE2. Production of PGE2 may be a novel feedback mechanism whereby airway smooth muscle cells can negatively modulate airways inflammation. The differing potencies of the cyclo-oxygenase inhibitors may explain the contrasting effect of these drugs in recent studies in asthma.

The host inflammatory response prior to death in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection.

The intensity of the host inflammatory response to pulmonary infection with Pseudomonas aeruginosa immediately prior to death was determined in six patients with cystic fibrosis (CF). Plasma concentrations of neutrophil elastase alpha 1-antiproteinase, tumour necrosis factor-alpha (TNF alpha) and serum C-reactive protein (CRP) were increased in the 7 days prior to death (P < 0.05) when compared with a period of clinical stability during the preceding 6 months. An increased inflammatory response was sustained for many weeks prior to death and was associated with poor symptom and lung function responses to apparently appropriate antibiotic treatment.

Tumour necrosis factor alpha in severe congestive cardiac failure.

OBJECTIVE: To examine the concentration of circulating tumour necrosis factor alpha (TNF alpha) in patients with severe congestive heart failure (New York Heart Association class IV) during one year and to correlate changes in this cytokine with changes in plasma noradrenaline, plasma renin activity, and weight. DESIGN: A prospective study of the role of TNF alpha in severe chronic heart failure. Blood samples were collected at intervals of three months. SETTING: Medical research centre of a teaching hospital. PATIENTS: 16 patients with chronic stable severe heart failure. INTERVENTIONS: Vasodilator treatment with captopril or flosequinan. MAIN OUTCOME MEASURES: Changes in TNF alpha and the correlation with changes in plasma noradrenaline, plasma renin activity, and weight during optimal medical treatment for one year. RESULTS: The mean concentration of TNF alpha was greater than the upper 95% confidence interval for healthy controls throughout the year of the study but there was considerable between and within patient variation. No correlation was seen between TNF alpha and plasma noradrenaline, plasma renin activity, or weight. CONCLUSIONS: The stimulus resulting in enhanced plasma concentrations of TNF alpha in congestive heart failure remains unclear and concentrations at any particular time were not prognostic.

In vitro tumor necrosis factor-alpha secretion by monocytes from patients with cystic fibrosis.

Immunoreactive tumor necrosis factor-alpha (TNF-alpha) concentration is increased in plasma from patients with cystic fibrosis and chronic Pseudomonas aeruginosa pulmonary infection. To determine if circulating monocytes could be the source of plasma TNF-alpha, we determined in vitro basal and endotoxin-stimulated TNF-alpha secretion by monocytes. In 10 adult patients studied at the time of a symptomatic respiratory exacerbation, basal secretion of TNF-alpha was significantly less than that for 10 matched healthy controls (median 265 pg/micrograms DNA, nonparametric 95% confidence interval 193 to 463 pg/micrograms DNA versus 575, 298 to 923 pg/micrograms DNA; P less than 0.006), although both groups responded equally effectively to added Escherichia coli endotoxin at greater than or equal to 25 ng/ml. In six patients and six matched controls, monocyte culture was repeated after completion of 2 wk anti-pseudomonal antibiotic treatment in the patients. The reduced basal TNF-alpha secretion in the patients had reversed and was not significantly different to that of controls. This effect mirrored a significant reduction in plasma immunoreactive TNF-alpha in these patients (mean +/- SD, 258 +/- 59.3 pg/ml pretreatment versus 133 +/- 47.8 pg/ml post-treatment; P less than 0.05). These findings suggest that a reversible downregulation of TNF-alpha secretion occurred at the time of a symptomatic respiratory deterioration in the presence of chronic P. aeruginosa infection. This may represent a physiologic regulatory mechanism to maintain a local inflammatory response to chronic pulmonary infection in cystic fibrosis.