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).

Otological complications in inversa type recessive dystrophic epidermolysis bullosa.

BACKGROUND: The rare inversa subtype of recessive dystrophic epidermolysis bullosa (RDEB-I) is characterized by predominant intertriginous skin blistering and marked mucosal involvement. Specific recessive missense mutations in the collagen VII triple helix are implicated in the disease. To date, otological complications have been reported infrequently in this patient group. METHODS: We conducted an observational, retrospective, double institution case record review of patients with RDEB-I who presented with otological complications between January 2000 and June 2020. Diagnosis was established on the basis of clinical features, family history and mutation analysis of the COL7A1 gene. RESULTS: In total, 11 (44%) of 25 patients with RDEB-I in our database (2 paediatric, 9 adult; mean age 40.9 years, range 8-72 years) experienced otological complications. Of these 11 patients, 10 (90.9%) had recurrent otitis externa, 7 (63.6%) had meatal stenosis and 7 (63.6%) had recurrent blistering of the external auditory canals. All 11 patients reported hearing difficulties, with conductive hearing loss confirmed by audiology testing in 6 (54.5%) of these. Of the 11 patients, 3 (27.3%) went on to have implantable hearing aids [2 bone-anchored hearing aids (BAHA) and 1 middle ear implant (MEI)] fitted with favourable outcome, while a fourth paediatric patient presented with a cholesteatoma that was surgically managed. DISCUSSION: We observed a higher prevalence of otological morbidity in RDEB-I than previously reported, and present the first case of cholesteatoma in epidermolysis bullosa (EB). Our data indicate that BAHA and MEI are safe and effective treatment options for hearing loss in EB. Clinicians should be vigilant in screening for ear symptoms in RDEB-I and consider early referral to an Ear, Nose and Throat specialist.

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.

Crescendo response to rituximab in oral pemphigus vulgaris: a case with 7-year follow-up.

Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and mucous membranes. Rituximab, a CD20 chimeric monoclonal antibody, has efficacy in PV management. We report a case of severe oral PV that showed a progressive response to repeated courses of rituximab, culminating in a rapid response within 4 weeks following severe relapse 4 years after initial therapy. It demonstrates the progressively shorter time to achieve partial or complete remission following rituximab infusions, combined with minimal adjuvant therapy over a 7-year follow-up period.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Under-recognition of acral peeling skin syndrome: 59 new cases with 15 novel mutations.

BACKGROUND: Acral peeling skin syndrome (APSS) is a rare skin fragility disorder usually caused by mutations in the transglutaminase 5 gene (TGM5). METHODS: We investigated the mutation spectrum of APSS in the U.K., Germany and Poland. RESULTS: We identified 59 children with APSS from 52 families. The phenotype was readily recognizable, with some variation in severity both within and between families. Most cases had been misdiagnosed as the localized form of epidermolysis bullosa simplex (EBS-loc). Eighteen different TGM5 mutations were identified, 15 of which were novel. Eight mutations were unique to a single family, nine each occurred in two families, while the common p.Gly113Cys mutation linked to a second missense variant p.Thr109Met occurred in 47 of the 52 families and was homozygous in 28. Most patients were of nonconsanguineous white European origin. CONCLUSIONS: We propose that APSS is under-reported and widely misdiagnosed as EBS-loc, with significant counselling implications as APSS is autosomal recessive while EBS-loc is dominant. We recommend screening for TGM5 mutations when EBS-loc is suspected but not confirmed by mutations in KRT5 or KRT14. Our report trebles the number of known TGM5 mutations. It provides further evidence that p.Gly113Cys is a founder mutation in the European population. This is consistent with the striking ethnic distribution of APSS in U.K., where the majority of patients are of nonconsanguineous white European origin, in contrast to the pattern of other recessive skin disorders.

In vitro prediction of clinical drug interactions with CYP3A substrates: we are not there yet.

In 1973, Malcolm Rowland and associates described an approach to predicting clinical pharmacokinetic drug-drug interactions (DDIs) using an inhibition constant determined in vitro (Ki) together with anticipated inhibitor exposure in vivo ([I]). Despite numerous modifications and refinements of the core model over the following 40 years, we still have not achieved a predictive paradigm having accuracy sufficient to justify bypassing all, or even most, clinical DDI studies in the course of drug development.

Pomegranate juice and pomegranate extract do not impair oral clearance of flurbiprofen in human volunteers: divergence from in vitro results.

Nutrient interactions with prescription drugs are a topic of ongoing basic and clinical research. Pomegranate juice and a 1-g capsule containing pomegranate extract were evaluated in vitro and in vivo as inhibitors of cytochrome P450 2C9 (CYP2C9), with flurbiprofen serving as the index substrate. Fluconazole was the positive control inhibitor. The in vitro 50% inhibitory concentration (IC(50)) values for pomegranate juice and extract were below 1% (vol/vol), with no evidence of mechanism-based (irreversible) inhibition. In clinical studies, flurbiprofen pharmacokinetics were unchanged by pomegranate juice or extract as compared to a low-polyphenol placebo control beverage. However, fluconazole significantly reduced the oral clearance of flurbiprofen. Despite inhibition of CYP2C9 in vitro, pomegranate juice and extract had no effect on CYP2C9 activity in human subjects, and can be consumed by patients taking CYP2C9 substrate drugs with negligible risk of a pharmacokinetic interaction.

Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD.

Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid-refractory chronic GVHD (cGVHD), but the optimal frequency and duration of treatment are yet to be established. We report on 82 consecutive patients with mucocutaneous cGVHD who received a bimonthly regimen of ECP treatment for two consecutive days, which could be subsequently tapered to a monthly regimen depending on response. Patients were steroid-refractory, steroid-dependent or steroid-intolerant, and 29 (35%) had multiorgan involvement. The median duration of treatment was 330 days (42-987). The median number of ECP cycles was 15 (1.5-32). Response was assessed by clinical assessment and reduction in immunosuppression after 6 months. 69/82 (84%) had completed 6 months of ECP and 65/69 (94%) had ≥ 50% improvement in symptoms and signs of cGVHD. A total of 77% of patients who completed 6 months of ECP had a reduction in immunosuppression dose and 80% had decreased their steroid dose (27.5% stopped, 30% had ≥ 75% reduction, 17.5% had ≥ 50% reduction and 25% had <50% reduction). OS at 3 years from the start of ECP was 69%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGVHD, and confirms that ECP allows successful reduction of immunosuppression.

Identification of polymorphisms in the 3'-untranslated region of the human pregnane X receptor (PXR) gene associated with variability in cytochrome P450 3A (CYP3A) metabolism.

Single nucleotide polymorphisms in the 3'-untranslated region (3'UTR) of the human pregnane X receptor (PXR) gene might contribute to interindividual variability in cytochrome P450 3A (CYP3A) activity. Genotype-phenotype associations involving PXR-3'UTR single nucleotide polymorphisms were investigated through in vitro (53 human livers from primarily White donors) and in vivo (26 mainly White or African-American volunteers) studies using midazolam 1'-hydroxylation and midazolam apparent oral clearance (CL/F), respectively, as CYP3A-specific probes. PXR-3'UTR resequencing identified twelve single nucleotide polymorphisms, including two that were novel. Although none of the single nucleotide polymorphisms evaluated were associated with altered midazolam 1'-hydroxylation in the liver bank, both rs3732359 homozygotes and rs3732360 carriers showed 80% higher (p < 0.05) CL/F compared with homozygous reference individuals. These differences in CL/F were even larger (100% and 120% higher, respectively; p < 0.01) when only African-American subjects (n = 14) were considered. Five major haplotypes were identified containing the PXR-3'UTR single nucleotide polymorphisms and previously identified intron single nucleotide polymorphisms. Although CL/F differences were not statistically significant within the entire study cohort, African-American carriers of Haplotype-1 (which includes both rs3732359 and rs3732360 variants) exhibited 70% higher median CL/F compared with African-American non-carriers (p = 0.036). The results identify rs3732359 and rs3732360 as PXR-3'UTR single nucleotide polymorphisms associated with higher CYP3A activity in vivo in African-Americans.

Short-term clarithromycin administration impairs clearance and enhances pharmacodynamic effects of trazodone but not of zolpidem.

The kinetic and dynamic interactions of 5 mg zolpidem and 50 mg trazodone with 500 mg clarithromycin (4 doses given over 32 h) were investigated in a 5-way double crossover study with 10 healthy volunteers. The five treatment conditions were: placebo + placebo; zolpidem + placebo; zolpidem + clarithromycin; trazodone + placebo; and trazodone + clarithromycin. Coadministration of clarithromycin increased trazodone area under the curve, prolonged elimination half-life, increased peak plasma concentration (C(max)), and reduced oral clearance. In contrast, clarithromycin had no significant effect on any kinetic parameter for zolpidem. Clarithromycin did not potentiate sedation caused by zolpidem. However, clarithromycin coadministered with trazodone significantly increased self- and observer-rated sedation and ratings of feeling "spacey." Thus, short-term clarithromycin coadministration significantly impairs trazodone clearance, elevates plasma concentrations, and enhances sedative effects. However, clarithromycin has no significant kinetic or dynamic interaction with zolpidem.