Randomized controlled pilot trial with ion-exchange water softeners to prevent eczema (SOFTER trial).

BACKGROUND: Observational studies suggest an increased risk of eczema in children living in hard versus soft water areas, and there is, therefore, an interest in knowing whether softening water may prevent eczema. We evaluated the feasibility of a parallel-group assessor-blinded pilot randomized controlled trial to test whether installing a domestic ion-exchange water softener before birth in hard water areas reduces the risk of eczema in infants with a family history of atopy. METHODS: Pregnant women living in hard water areas (>250 mg/L calcium carbonate) in and around London UK, were randomized 1:1 antenatally to either have an ion-exchange water softener installed in their home or not (ie to continue to receive usual domestic hard water). Infants were assessed at birth and followed up for 6 months. The main end-points were around feasibility, the primary end-point being the proportion of eligible families screened who were willing and able to be randomized. Clinical end-points were evaluated including frequency of parent-reported doctor-diagnosed eczema and visible eczema on skin examination. Descriptive analyses were conducted, and no statistical testing was performed as this was a pilot study. RESULTS: One hundred and forty-nine families screened were eligible antenatally and 28% (41/149) could not have a water softener installed due to technical reasons or lack of landlord approval. Eighty of 149 (54%) were randomized, the primary end-point. Two participants withdrew immediately after randomization, leaving 39 participants in each arm (78 total). Attrition was 15% (12/78) by 6 months postpartum. All respondents (n = 69) to the study acceptability questionnaire reported that the study was acceptable. Fifty-six of 708 (7.9%) water samples in the water softener arm were above the hard water threshold of 20 mg/L CaCO3 . At 6 months of age 27/67 infants (40%) developed visible eczema, 12/36 (33%) vs. 15/31 (48%) in the water softener and control groups, respectively, difference -15% (95% CI -38, 8.3%), with most assessments (≥96%) remaining blinded. Similarly, a lower proportion of infants in the water softener arm had parent-reported, doctor-diagnosed eczema by 6 months compared to the control arm, 6/17 (35%) versus 9/19 (47%), difference -12% (95% CI -44, 20%). CONCLUSION: A randomized controlled trial of water softeners for the prevention of atopic eczema in high-risk infants is feasible and acceptable. TRIAL REGISTRATION: NCT03270566 (clinicaltrials.gov).

Longitudinal analysis of the effect of water hardness on atopic eczema: evidence for gene-environment interaction.

BACKGROUND: Several studies have identified an association between water hardness and atopic eczema (AE); however, there is a paucity of longitudinal data in early life. OBJECTIVES: To examine whether water hardness is associated with an increased risk of AE and skin barrier dysfunction in infants and to assess effect modification by filaggrin (FLG) loss-of-function variants. METHODS: We performed a longitudinal analysis of data from infants in the Enquiring About Tolerance (EAT) study, who were enrolled at 3 months and followed up until 36 months of age. RESULTS: Of 1303 infants enrolled in the EAT study, 91·3% (n = 1189) attended the final clinic visit and 94·0% (n = 1225) of participants' families completed the 36-month questionnaire. In total, 761 (58·4%) developed AE by 36 months. There was no overall association between exposure to harder (> 257 mg L-1 CaCO3 ) vs. softer (≤ 257 mg L-1 CaCO3 ) water: adjusted hazard ratio (HR) 1·07, 95% confidence interval (CI) 0·92-1·24. However, there was an increased incidence of AE in infants with FLG mutations exposed to hard water (adjusted HR 2·72, 95% CI 2·03-3·66), and statistically significant interactions between hard water plus FLG and both risk of AE (HR 1·80, 95% CI 1·17-2·78) and transepidermal water loss (0·0081 g m-2 h-1 per mg L-1 CaCO3 , 95% CI 0·00028-0·016). CONCLUSIONS: There is evidence of an interaction between water hardness and FLG mutations in the development of infantile AE.

Risankizumab vs. ustekinumab for plaque psoriasis: a critical appraisal.

AIM: Gordon et al. investigated the efficacy and safety of risankizumab [an anti-interleukin (IL)-23p19 biologic] compared with ustekinumab (anti-IL-12/23p40) and placebo in patients with moderate-to-severe chronic plaque psoriasis. This was a parallel-group controlled study up to 16 weeks with a planned switch of the placebo group to risankizumab at 16 weeks. SETTING AND DESIGN: This study consisted of two replicate phase III, double-blinded randomized controlled trials (UltIMMa-1 and UltIMMa-2) conducted across 139 centres in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain and the U.S.A. STUDY EXPOSURE: Patients with a minimum 6-month history of chronic plaque psoriasis were randomly assigned to receive either 150 mg risankizumab, 45 mg or 90 mg ustekinumab or placebo. Prior to this, each group was also stratified by weight (either more than or less than 100 kg) and previous exposure to tumour necrosis factor inhibitors. Those assigned to receive placebo were transitioned onto risankizumab at week 16. The study drugs were given at weeks 0, 4, 16, 28 and 40. OUTCOMES: The severity of psoriasis was measured using the Psoriasis Area and Severity Index (PASI) and a static Physician's Global Assessment (sPGA). The authors additionally recorded the number of adverse events in each treatment arm, and a measure of quality of life. PRIMARY OUTCOME MEASURES: The coprimary outcomes were the proportions of patients achieving ≥ 90% reduction in their baseline PASI (PASI 90) and an sPGA score of 0 or 1 (clear or almost clear) at week 16. RESULTS: In total 506 patients were included in UltIMMa-1 and 491 patients in UltIMMa-2. In UltIMMa-1, PASI 90 by week 16 was achieved by 75·3% of patients receiving risankizumab, compared with 42·0% receiving ustekinumab and 4·9% receiving placebo (P < 0·001 vs. placebo and ustekinumab). sPGA of 0 or 1 by week 16 was achieved by 87·6% of patients receiving risankizumab, compared with 63·0% receiving ustekinumab and 7·8% receiving placebo (P < 0·001 vs. placebo and ustekinumab). The results for UltIMMa-2 are similar. The frequencies of adverse events in the risankizumab, ustekinumab and placebo groups were similar in both studies. CONCLUSIONS: Gordon et al. conclude that risankizumab has a higher efficacy than placebo and ustekinumab in the treatment of moderate-to-severe chronic plaque psoriasis, and that the adverse-event profiles were similar across all treatment groups.

Persistence and effectiveness of nonbiologic systemic therapies for moderate-to-severe psoriasis in adults: a systematic review.

BACKGROUND: The persistence and effectiveness of systemic therapies for moderate-to-severe psoriasis in current clinical practice are poorly characterized. OBJECTIVES: To systematically review observational studies investigating the persistence and effectiveness of acitretin, ciclosporin, fumaric acid esters (FAE) and methotrexate, involving at least 100 adult patients with moderate-to-severe psoriasis, exposed to therapy for ≥ 3 months. METHODS: MEDLINE, Embase, the Cochrane Library and PubMed were searched from 1 January 2007 to 1 November 2017 for observational studies reporting on persistence (therapy duration or the proportion of patients discontinuing therapy during follow-up) or effectiveness [improvements in Psoriasis Area and Severity Index (PASI) or Physician's Global Assessment (PGA)]. This review was registered with PROSPERO, number CRD42018099771. RESULTS: Of 411 identified studies, eight involving 4624 patients with psoriasis were included. Variations in the definitions and analyses of persistence and effectiveness outcomes prevented a meta-analysis from being conducted. One prospective multicentre study reported drug survival probabilities of 23% (ciclosporin), 42% (acitretin) and 50% (methotrexate) at 1 year. Effectiveness outcomes were not reported for either acitretin or ciclosporin. The persistence and effectiveness of FAE and methotrexate were better characterized, but mean discontinuation times ranged from 28 to 50 months for FAE and 7·7 to 22·3 months for methotrexate. At 12 months of follow-up, three studies reported that 76% (FAE), 53% (methotrexate) and 59% (methotrexate) of patients achieved ≥ 75% reduction in PASI, and one reported that 76% of FAE-exposed patients achieved a markedly improved or clear PGA. CONCLUSIONS: The comparative persistence and effectiveness of acitretin, ciclosporin, FAE and methotrexate in real-world clinical practice in the past decade cannot be well described due to the inconsistency of the methods used.

Subcutaneous methotrexate in patients with moderate-to-severe psoriasis: a critical appraisal.

AIM: Warren et al. set out to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate-to-severe chronic plaque psoriasis. SETTING AND DESIGN: This was a prospective, double-blind, randomized (3 : 1), placebo-controlled study, conducted across 16 centres in Germany, France, the Netherlands and the U.K. STUDY EXPOSURE: Methotrexate-naive adults with a diagnosis of moderate-to-severe chronic plaque psoriasis for at least 6 months before baseline were randomly assigned to receive weekly subcutaneous injections of either methotrexate at a starting dose of 17·5 mg, or placebo for 16 weeks (first phase). Dose escalation to 22·5 mg per week was implemented after 8 weeks if patients did not achieve ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50). Treatment was combined with folic acid 5 mg per week. The first phase of the study was followed by an open-label period from 16 to 52 weeks (second phase), in which both groups received weekly methotrexate injections. At week 24, dose escalation to 22·5 mg per week was possible in patients not achieving PASI 50. OUTCOMES: Psoriasis severity was measured using PASI. The authors also used two other psoriasis severity measures and two quality-of-life measures, looked at safety indices and performed a substudy analysing paired skin biopsies at baseline and week 16 (histopathology, immunohistochemistry and expression of interleukin-17A, interferon-γ and tumour necrosis factor-α). PRIMARY OUTCOME MEASURES: The primary outcome was the proportion of patients reaching PASI 75 at week 16. RESULTS: In total 120 patients were included in this trial, most of whom were middle-aged white men with long-standing psoriasis, and the mean body mass index was 30·1 kg m-2 . PASI 75 was achieved in 41% of patients receiving methotrexate vs. 10% of patients receiving placebo (relative risk 3·93, 95% confidence interval 1·31-11·81; P = 0·0026) at week 16. Subcutaneous methotrexate was generally well tolerated, with no serious adverse events related to this treatment over the 52-week study. CONCLUSION: Warren et al. conclude that the 52-week risk-benefit profile of subcutaneous methotrexate is favourable in patients with psoriasis.

Kidney disease in moderate-to-severe psoriasis: a critical appraisal.

AIM: Using a population-based cohort, Wan et al. examined the risk of moderate-to-advanced (stage 3-5) chronic kidney disease (CKD) in patients with psoriasis. SETTING AND DESIGN: A population-based cohort was constructed using The Health Improvement Network (THIN) database. THIN is an electronic primary healthcare records database containing routinely collected medical diagnosis and drug prescribing data on > 9 million patients in the U.K. Data were collected prospectively on 143 883 adults (aged 18-90 years) with psoriasis. Of these, 7354 had severe psoriasis, as defined by prescription codes for systemic medication or treatment codes for phototherapy. Patients with psoriasis were matched with up to five nonpsoriasis age- and practice-matched controls. Patients with a diagnosis of CKD before study entry were excluded. In addition, baseline data from the Incident Health Outcomes and Psoriasis Events (iHOPE) study, a cohort of 8731 primary care patients aged 25-64 years with psoriasis, was included. Psoriasis severity was categorized according to body surface area (BSA) involvement as estimated by general practitioners. A similar method using a patient-reported BSA assessment tool was previously validated by the same group. Patients were matched by age and practice with 10 nonpsoriasis controls. STUDY EXPOSURE: Psoriasis, identified on the basis of a recorded diagnostic code for psoriasis. OUTCOMES: Incident CKD was defined as the presence of a recorded diagnostic code consistent with moderate-to-advanced (stage 3-5) CKD or laboratory parameters consistent with the diagnosis (estimated glomerular filtration rate < 60 mL min(-1)  1·73 m(-2) ) during follow-up. Prevalent CKD (as defined above) in the cross-sectional data from the iHOPE study. RESULTS: The adjusted hazard ratios for incident CKD were 1·05 [95% confidence interval (CI) 1·02-1·07], 0·99 (95% CI 0·97-1·02) and 1·93 (95% CI 1·79-2·08) in the overall, mild and severe psoriasis groups, respectively. In the nested cross-sectional study (iHOPE) the adjusted prevalence odds ratios for CKD were 0·89 (95% CI 0·72-1·10), 1·36 (95% CI 1·06-1·74) and 1·58 (95% CI 1·07-2·34) in the mild, moderate and severe psoriasis groups, respectively. CONCLUSIONS: Moderate-to-severe psoriasis is associated with an increased risk of moderate-to-advanced CKD, independently of traditional risk factors.

Methotrexate and liver fibrosis in people with psoriasis: a systematic review of observational studies.

Methotrexate (MTX) is an effective treatment for psoriasis but concerns regarding the development of liver fibrosis prevent optimal use. The primary objective of this systematic review was to assess whether MTX use increases the risk of developing fibrosis in people with psoriasis. Searches were performed on Medline, Embase, the Cochrane Database and Clinical Trials Register from inception until September 2013 for studies including at least two liver biopsies in people with psoriasis. Double extraction using predefined data fields was performed. Randomized controlled trials and observational studies were considered. Statistical analysis was performed using Review Manager 5. Quality of observational studies was assessed using a study quality bias checklist. Eight observational studies met the inclusion criteria (n = 429 patients). The pooled risk difference (RD) of developing significant liver fibrosis was 0·09 [95% confidence interval (CI) -0·03 to 0·20]. The RD for developing 'any fibrosis' was 0·22 (95% CI 0·04-0·41). The RD for cirrhosis was 0·04 (95% CI 0·02-0·07). There was no clear association between cumulative dose of MTX and fibrosis. Obesity, diabetes and alcohol use were under-reported. The quality of the included studies was weak and the degree of selection bias means the results are not generalizable to all patients with psoriasis taking MTX. High-quality, population-based studies that consider potential confounders common in psoriasis population are justified for better prediction of the subset of patients at risk of liver fibrosis. In this highly selected review population, MTX use appears to contribute to the development of 'any' fibrosis without clear evidence of risk stratifiers.