Real-world reported adverse events related to systemic immunomodulating therapy in patients with atopic dermatitis: Results from the TREAT NL (TREatment of ATopic eczema, the Netherlands) registry.

BACKGROUND: Evidence on the (long-term) safety of systemic immunomodulating therapies in atopic dermatitis (AD) generated by real-world data is sparse. OBJECTIVES: To describe real-world reported adverse drug reactions (AEs) related to systemic immunomodulating therapy in patients with AD and to compare the incidence rates of AEs with the Summaries of Product Characteristics (SmPCs). METHODS: We conducted an observational prospective multi-centre cohort study, using the TREAT NL registry. All severe AEs, AEs of special interest and serious AEs in adult and paediatric patients on systemic immunomodulating treatment (ciclosporin, methotrexate, azathioprine, mycophenolic acid, dupilumab, tralokinumab, baricitinib and upadacitinib) were assessed. Incidences rates of all (potentially) drug-related AEs were standardized in patient years and compared to the cumulative incidences in the associated SmPCs. RESULTS: We collected 422 patient years of safety data from 266 patients, of whom 129 (48.5%) reported a total of 224 (potentially) drug-related AEs. Compared to dupilumab's SmPC, higher incidence rates were found for four AEs (reported ≥5 times): eosinophilia, blepharitis, dry eyes and head and neck erythema (i.e. dupilumab facial redness). A higher incidence rate of fatigue was found in patients on oral methotrexate in our cohort compared to the SmPC. Two new drug-related AEs (reported ≥5 times) were found in patients on dupilumab, including non-infectious conjunctivitis and meibomian gland dysfunction. CONCLUSIONS: Real-world reported AEs captured in AD patient registries can add information on the estimated incidence of AEs and benefit clinical decision aids. Future studies using data derived from the TREAT NL registry combined with data from other registries within the TREAT Registry Taskforce will provide more information on (rare) AEs associated with immunomodulating therapy in AD patients.

Virtual Reality Experience during Labour (VIREL); a qualitative study.

BACKGROUND: There is increasing evidence that virtual reality (VR) is effective in the reduction of labour pain. The implementation of alternative methods like VR to reduce labour pain can contribute to reduce patient request for pharmacological pain management methods and associated side effects. The aim of this study is to examine women's experiences, preferences and satisfaction in regard to the use of VR during labour. METHODS: A qualitative interview study was conducted in a non-university teaching hospital in The Netherlands. Two VR applications, respectively a guided meditation and an interactive game were tested in eligible women with a singleton pregnancy, scheduled for induction of labour. For the primary outcome, patients' VR experience and application preference (meditation vs. game) were examined using a post-intervention questionnaire and a semi-structured interview. Three categories (with sub-categories) were used to guide interviews: "The VR experience", "Pain reduction", and "Usability of the VR application". Labour pain before and directly after VR was evaluated using the NRS score. RESULTS: Twenty-four women, of whom 14 were nulliparous and ten multiparous, were included and 12 of these women participated in semi-structured interviews. Using within-subject paired t-test comparisons, compared to pain pre-VR, patients reported a highly significant 26% decrease in mean NRS scores during VR meditation (pain pre-VR = 6.71 + - 1.65 vs. pain after VR = 4.96 + - 2.01) [p < 0.001]. Compared to pain before VR game, patients also reported a highly significant 19% decrease in mean NRS scores during VR game (pain before VR game = 6.89 + - 1.88 vs. pain after VR game = 5.61 + - 2.23) [p = 0.001]. CONCLUSION: All women were highly satisfied with VR use during labour. Patients reported a highly significant reduction in pain during the interactive VR game and during meditation, patients preferred guided meditation. These results can contribute to the development of a potential promising new non-pharmacological tool to reduce labour pain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04858984, date of registration: 26/04/2021 (retrospectively registered).

Rheumatoid arthritis synovial tissue harbours dominant B-cell and plasma-cell clones associated with autoreactivity.

OBJECTIVE: To identify potential autoreactive B-cell and plasma-cell clones by quantitatively analysing the complete human B-cell receptor (BCR) repertoire in synovium and peripheral blood in early and established rheumatoid arthritis (RA). METHODS: The BCR repertoire was screened in synovium and blood of six patients with early RA (ERA) (<6 months) and six with established RA (ESRA) (>20 months). In two patients, the repertoires in different joints were compared. Repertoires were analysed by next-generation sequencing from mRNA, generating >10 000 BCR heavy-chain sequence reads per sample. For each clone, the degree of expansion was calculated as the percentage of the total number of reads encoding the specific clonal sequence. Clones with a frequency ≥ 0.5% were considered dominant. RESULTS: Multiple dominant clones were found in inflamed synovium but hardly any in blood. Within an individual patient, the same dominant clones were detected in different joints. The majority of the synovial clones were class-switched; however, the fraction of clones that expressed IgM was higher in ESRA than ERA patients. Dominant synovial clones showed autoreactive features: in ERA in particular the clones were enriched for immunoglobulin heavy chain gene segment V4-34 (IGHV4-34) and showed longer CDR3 lengths. Dominant synovial clones that did not encode IGHV4-34 also had longer CDR3s than peripheral blood. CONCLUSIONS: In RA, the synovium forms a niche where expanded--potentially autoreactive--B cells and plasma cells reside. The inflamed target tissue, especially in the earliest phase of disease, seems to be the most promising compartment for studying autoreactive cells.

Supportive care for women with recurrent miscarriage: a survey to quantify women's preferences.

BACKGROUND: Supportive care is regularly offered to women with recurrent miscarriages (RMs). Their preferences for supportive care in their next pregnancy have been identified by qualitative research. The aim of this study was to quantify these supportive care preferences and identify women's characteristics that are associated with a higher or lower need for supportive care in women with RM. METHODS: A questionnaire study was conducted in women with RMs (≥ 2 miscarriages) in three hospitals in the Netherlands. All women who received diagnostic work-up for RMs from January 2010 to December 2010 were sent a questionnaire. The questionnaire quantified supportive care options identified by a previous qualitative study. We next analysed associations between women's characteristics (age, ethnicity, education level, parity, pregnancy during questionnaire and time passed since last miscarriage) and their feelings about supportive care options to elucidate any differences between groups. RESULTS: Two hundred and sixty-six women were asked to participate in the study. In total, 174 women responded (response rate 65%) and 171 questionnaires were analysed. Women with RM preferred the following supportive care options for their next pregnancy: a plan with one doctor who shows understanding, takes them seriously, has knowledge of their obstetric history, listens to them, gives information about RM, shows empathy, informs on progress and enquires about emotional needs. Also, an ultrasound examination during symptoms, directly after a positive pregnancy test and every 2 weeks. Finally, if a miscarriage occurred, most women would prefer to talk to a medical or psychological professional afterwards. The majority of women expressed a low preference for admission to a hospital ward at the same gestational age as previous miscarriages and for bereavement therapy. The median preference, on a scale from 1 to 10, for supportive care was 8.0. Ethnicity, parity and pregnancy at the time of the survey were associated with different preferences, but female age, education level and time passed since the last miscarriage were not. CONCLUSIONS: Women with RM preferred a plan for the first trimester that involved one doctor, ultrasounds and the exercise of soft skills, like showing understanding, listening skills, awareness of obstetrical history and respect towards the patient and their miscarriage, by the health care professionals. In the event of a miscarriage, women prefer aftercare. Women from ethnic minorities and women who were not pregnant during the questionnaire investigation were the two patient groups who preferred the most supportive care options. Tailor-made supportive care can now be offered to women with RM.

Tailored expectant management: a nationwide survey to quantify patients' and professionals' barriers and facilitators.

BACKGROUND: Prognostic models for natural conception help to identify subfertile couples with high chances of natural conception, who do not need fertility treatment yet. The use of such models and subsequent tailored expectant management (TEM) is not always practiced. Previous qualitative research has identified barriers and facilitators of TEM among patients and professionals. The aim of this study was to assess the prevalence of those barriers and facilitators and to evaluate which factors predict patients' appreciation of TEM and professionals' adherence to TEM. METHODS: We performed a nationwide survey. Based on the previously identified barriers and facilitators two questionnaires were developed and sent to 195 couples and 167 professionals. Multivariate analysis was performed to evaluate which factors predicted patients' appreciation of TEM and professional adherence to TEM. RESULTS: In total, 118 (61%) couples and 117 (70%) professionals responded and 96 couples and 117 professionals were included in the analysis. Patients' mean appreciation of TEM was 5.7, on a 10-point Likert scale. Patients with a lower appreciation of TEM had a higher need for patient information (P = 0.047). The professionals reported a mean adherence to TEM of 63%. Adherence to TEM was higher when professionals were fertility doctors (P = 0.041). Facilitators in the clinical domain were associated with a higher adherence to TEM (P = 0.091). Barriers in the professional domain had a negative impact on adherence to TEM (P = 0.008). CONCLUSIONS: The limited implementation of TEM is caused by both patient and professional-related factors. This study provides practical tools to improve the implementation of TEM.

The effect of recombinant LH on embryo quality: a randomized controlled trial in women with poor ovarian reserve.

BACKGROUND: Poor ovarian response is a common clinical problem, affecting up to 26% of IVF cycles. For these women, addition of recombinant luteinizing hormone (rLH) to ovarian hyperstimulation with recombinant FSH has a beneficial effect on ongoing pregnancy rates, but its effect on the yield of top-quality embryos is unknown. METHODS: We conducted a randomized controlled trial in women expected to respond poorly under ovarian hyperstimulation during their first IVF cycle [all women aged 35-41 and women with FSH > 12 IU/ml and antral follicle count (AFC) ≤ 5]. Women were randomly allocated to rFSH and rLH (2:1 ratio) or rFSH alone (control group) after down-regulation with a GnRH agonist. The primary outcome was the proportion of top-quality embryos per woman on the day of transfer. Secondary outcomes were the number of stimulation days, the number of follicles ≥17 mm, the number of oocytes, the fertilization rate, the number of embryos, the number of women with ≥1 top-quality embryo, the biochemical, clinical and ongoing pregnancy rates and the miscarriage rate. RESULTS: There were 116 women allocated to the rLH group and 128 allocated to the control group. The proportion of top-quality embryos per woman was 17% in the rLH group and 11% in the control group [mean difference 0.06; 95% confidence interval (CI) -0.01-0.14]. In the rLH and control groups respectively, 47 (41%) and 41 (32%) women had at least one top-quality embryo on the day of transfer (relative risk: 1.3, 95% CI 0.91-1.77). The ongoing pregnancy rate was 13 versus 12% (relative risk: 1.1; 95% CI 0.57-2.16) for the rLH group compared with the control group. CONCLUSIONS: This study found no significant difference in embryo quality after the addition of rLH to rFSH for ovarian stimulation in women with poor ovarian reserve. CLINICAL TRIALS IDENTIFIER: NTR1457.

Women's perspectives regarding subcutaneous injections, costs and live birth rates in IVF.

BACKGROUND: The addition of recombinant LH (rLH) to controlled ovarian hyperstimulation (COH) shows a beneficial effect on ongoing pregnancy rates in poor responder women, with an increase of ongoing pregnancy rate. Next to this possible beneficial effect, there are two potential drawbacks of adding rLH to COH; women have to administer extra injections, and daily rLH injections generate additional costs. We therefore investigated women's perspectives on an additional injection of rLH with respect to live birth rates (LBR) and out-of-pocket costs in a discrete choice experiment. METHODS: Women eligible for IVF were asked to choose between treatments that differed in LBR after one IVF cycle, the amount of self-administered injections and out-of-pocket costs or reimbursement. The relative weights that women place on these attributes were estimated with a logistic regression model. To test for heterogeneity of preferences among women, patient characteristics were included in the model. RESULTS: Two-hundred and thirty-four women were asked to participate in the study. In total, 223 women responded (response rate 95%) and 206 questionnaires were analysed. An increase of one daily injection did not alter women's treatment preference. LBR and costs did have a significant (P < 0.001) impact on women's choice of IVF treatment. Patient characteristics significantly influenced the effect of costs on women's preferences. CONCLUSIONS: One extra daily injection will not cause a woman to refrain from a certain IVF treatment. However, to compensate for the out-of-pocket costs of this extra daily injection, the expected LBR should at least be 6%.

Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review.

BACKGROUND: Preimplantation genetic diagnosis (PGD) has been stated to improve live birth rates compared with natural conception in couples with recurrent miscarriage (RM) carrying a structural chromosome abnormality. It is unclear to what extent this claim can be substantiated by evidence. A systematic review of the literature was performed on the reproductive outcome of these couples after natural conception or after PGD. METHODS: MEDLINE, EMBASE and the Cochrane database were searched until April 2009. Trials, patient series and case reports describing reproductive outcome in couples with RM carrying a structural chromosome abnormality after natural conception and/or after PGD were included. Since no randomized controlled trials or non-randomized comparative studies were found, separate searches for both groups were conducted. Primary outcome measure was live birth rate per couple. Secondary outcome measure was miscarriage rate per couple. RESULTS: Four observational studies reporting on the reproductive outcome of 469 couples after natural conception and 21 studies reporting on the reproductive outcome of 126 couples after PGD were found. After natural conception, live birth rate per couple varied between 33 and 60% (median 55.5%) after parental chromosome analysis; miscarriage rate ranged from 21 to 40% (median 34%). After PGD, live birth rate per couple varied between 0 and 100% (median 31%) after parental chromosome analysis; miscarriage rate ranged from 0 to 50% (median 0%). CONCLUSIONS: Currently, there are insufficient data indicating that PGD improves the live birth rate in couples with RM carrying a structural chromosome abnormality.

Supportive care for women with unexplained recurrent miscarriage: patients' perspectives.

BACKGROUND Supportive care is currently the only 'therapy' that can be offered to women with unexplained recurrent miscarriage (RM). What these women themselves prefer as supportive care in their next pregnancy has never been substantiated. Therefore the aim of this study was to explore what women with unexplained RM prefer as supportive care during their next pregnancy. METHODS We performed explorative, semi-structured, in-depth interviews. The interviews were performed with 15 women with unexplained RM who were actively seeking conception. All interviews were conducted by telephone. The interviews were fully transcribed and two researchers independently identified text segments from the transcribed interviews and categorized them in the appropriate domain. RESULTS Women identified 20 different supportive care options; 16 of these options were preferred for their next pregnancy. Examples of the preferred supportive care were early and frequently repeated ultrasounds, ßHCG monitoring, practical advice concerning life style and diet, emotional support in the form of counselling, a clear policy for the upcoming 12 weeks and medication. The four supportive care options that were not preferred by the women were admittance to a hospital ward at the same gestational age as previous miscarriages, Complementary Alternative Medicine, ultrasound every other day and receiving supportive care from their general practitioner. CONCLUSIONS Our study identified several relevant preferences for supportive care in women with unexplained RM. Many of these can be offered by the gynaecologist and will help in guaranteeing high-quality patient-centred care.

Beta-cell dysfunction and insulin resistance after subarachnoid haemorrhage.

BACKGROUND: Hyperglycaemia is a common finding and an independent risk factor for increased morbidity and mortality in aneurysmal subarachnoid haemorrhage (SAH). Although in these patients hyperglycaemia is commonly ascribed to insulin resistance, there is little understanding of underlying mechanisms. AIMS: To prospectively study temporal disturbances of glucose metabolism after aneurysmal SAH in patients without known abnormalities of glucose metabolism and to explore possible correlations with markers of stress. METHODS: In consecutive aneurysmal SAH patients not subjected to insulin therapy, in-hospital and follow-up oral glucose tolerance tests (OGTTs) and assessments of insulin resistance, pancreatic ß-cell function, free fatty acids (FFA) and cortisol were performed and compared with reference values. RESULTS: We included 13 patients. In the first 2 weeks of admission, median fasting glucose and FFA levels were elevated while insulin levels were not. OGTTs were indicative of glucose intolerance in all patients at days 3 and 7, while on follow-up 1 patient had glucose intolerance and all patients had normal fasting glucose levels. Pancreatic ß-cell function was impaired throughout the first week and insulin resistance from day 4 to 10. Levels of cortisol correlated with higher fasting glucose and increased FFA. FFA in turn correlated with pancreatic ß-cell dysfunction. CONCLUSIONS: Aneurysmal SAH patients have transient abnormalities of glucose metabolism. During the first week, it appears to result predominantly from transient pancreatic ß-cell dysfunction, in combination with insulin resistance.