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Background Quinolones comprise a class of antibiotics that are globally preferred for treating a wide range of bacterial infections due to their potency, broad coverage, favorable pharmacologic profile, and mostly mild to moderate adverse reactions. Spontaneous reports on adverse drug events (ADE) and data from some pharmacoepidemiologic studies have raised concerns regarding quinolones and risk of retinal detachment (RD). This study examined ADE reports submitted to FDA adverse event reporting system (FAERS) for evidence on quinolone-associated RD risk. Research design and methods We identified all reports of RD in FAERS between 2010-2019. We compared ADE signals between quinolones and selected medications that were previously associated with RD, and with reference drugs not known to cause RD. For signal detection, we used two disproportionality techniques: the proportional reporting ratio (PRR) and multi-item gamma Poisson shrinker (MGPS), which are known for their higher sensitivity and specificity for ADE signal detection, respectively. Results Moxifloxacin showed a positive and significant PRR signal for RD [PRR: 2.54 (1.60, 4.04)], and a marginally significant EBGM signal [EBGM: 2.21 (1.41, 3.02)]. Conclusion Moxifloxacin is the only quinolone showing a positive disproportionality signal for RD. Further epidemiologic research is needed to clarify the association between moxifloxacin and the risk of RD.

Objectives We investigated the effect of disease activity-guided dose optimization (DAGDO) of TNF inhibitor (TNFi) on disease activity and TNFi dose in PsA and axial spondyloarthritis (axSpA) patients with low disease activity (LDA). Methods A retrospective cohort study was conducted in PsA and axSpA patients doing well on TNFi and eligible for TNFi DAGDO. Three different treatment periods were defined: (i) full dose continuation period, (ii) TNFi DAGDO period, and (iii) period with stable TNFi dose after DAGDO. A mixed-model analysis was used to estimate mean Disease Activity Score 28-joint count CRP (DAS28-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) during these periods, and a mean percentage of the daily defined dose (%DDD) was calculated as secondary outcome. Results Three hundred and twenty-four patients (153 PsA and 171 axSpA) were included, with a mean of 6.5 DAS28-CRP and 6.4 BASDAI measurements and a median follow-up duration of 46 and 44 months, respectively. A corrected difference of 0.06 (95% CI: −0.09, 0.21) in mean DAS28-CRP was found for the TNFi DAGDO period and 0.03 (95% CI: −0.14, 0.20) for the period with stable TNFi dose, compared with full dose continuation period. Differences for BASDAI were 0.03 (95% CI: −0.21, 0.27) and 0.05 (95% CI: −0.24, 0.34), respectively. The mean %DDD for the three treatment periods was for PsA 108%, 62% and 78%, and for axSpA 108%, 62% and 72%, respectively. Conclusion DAGDO of TNFi reduces drug exposure and has no negative effects on disease activity in PsA and axSpA patients compared with full dose continuation.

Altered miRNA expressions are assigned pathogenic properties in several cancers including mycosis fungoides and could play a role in the early onset of the disease. The aim of this study was to examine disease-specific miRNA expression in early-stage mycosis fungoides patch and plaque lesions. A quantitative real-time PCR platform of 384 human miRNAs was used to study miRNA expression in 154 diagnostic mycosis fungoides biopsies. A total of 110 miRNAs were significantly differentially expressed (>2-fold, p 2-fold, p

Background and Aim Quinolones are globally popular antibiotics with proven potency, broad coverage, and reasonable safety. However, some concerns were raised as to their possible association with acute liver failure (ALF). The aim of this study is to assess ALF risk within 30 days of receiving a systemically administered quinolone antibiotic, in individuals with no history of liver/diseases. Methods We conducted a nested case–control study using electronic health records from the Cerner Health Facts. The initial cohort (n = 35 349 943) included all patients who were admitted between 2000 and 2016, with no history of liver diseases, and had a minimum medical history of one year. Eligible cases were inpatients who were first diagnosed with ALF between 2010 and 2015. Using incidence density sampling, each case was matched with up to five unique controls by sex, race, age at index encounter, and period‐at‐risk. We used conditional logistic regression to calculate the odds ratio and 95% confidence interval for ALF risk, upon adjusting for exposure to other medications, and major confounders (diabetes mellitus and alcohol abuse). We used the STROBE Statement for reporting on our study. Results We identified 3151 cases and 15 657 controls. Our primary analysis did not reveal an association between quinolones and ALF risk. However, some risk was identified among those with no or few comorbidities, those ≤ 60 years of age, women, men, African Americans, and Caucasians. Conclusion Although our study does not suggest an overall association between quinolones and ALF, elevated risks seen in some subgroups warrant further investigation.

Introduction Biologics serve as a cornerstone in psoriasis treatment, with low disease activity or sometimes even clinical remission as a realistic treatment outcome. So far, it is unclear whether biologics should be tapered when this target is achieved. Dose tapering could offer potential benefits by decreasing side effects, the burden of repetitive injections and costs of biological therapy. However, clinical guidelines on dose tapering of biologicals in psoriasis patients are lacking. This scoping review was conducted to provide an overview of the current literature on dose tapering and offer guidance for clinicians in daily clinical practice. Methods Dose tapering is defined as the administration of a lower dose per administration, or the prolongation of the regular dose interval, after initial treatment according to the standard dosing. Four electronic databases (PubMed, EMBASE, Cochrane, and Web of Science) were systematically searched for literature on tapering of biologics in adult patients with psoriasis from 1 January 2000. Results We included 19 original articles on biologic tapering in psoriasis patients: four randomized controlled trials and 15 observational studies. Tapering eligibility criteria, tapering strategies, tapering outcomes, and recapture of response after relapse were assessed. Furthermore, the available evidence on possible predictors for successful tapering, and the effect of tapering on safety, quality of life and costs is summarized. The definition of low disease activity as a measure for tapering eligibility varied widely. Beside tapering criteria, tapering strategies were also heterogeneous. Of note, quality-of-life measurements were barely integrated in the evaluation of tapering outcomes. Literature on regaining response after relapse due to tapering was limited, but restored remission has been described. The included studies did not proclaim a significant effect of tapering on the occurrence of (severe) adverse events. Even though cost savings have been reported, no proper cost-effectiveness analysis has been conducted yet. Conclusion Biologic tapering seems to be effective and safe in psoriasis patients with stable low disease activity or clinical remission. Available data on biologic dose tapering in patients with psoriasis are promising, but more research is warranted to fill the current gaps in knowledge. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-020-01448-z., Plain Language Summary Biologics are effective in treating psoriasis amongst other diseases, such as rheumatoid arthritis and Crohn’s disease. However, biologics are costly, and can cause side effects, such as an increased risk of infection. In patients with rheumatoid arthritis, it is not uncommon to lower the dose of these biologics (also called “dose tapering”), once stable low disease activity, or even remission, is reached. However, in psoriasis patients, dose tapering of biologics is not common practice. In this “scoping review,” we provide an overview of the available literature on dose tapering of biologics in adult patients with plaque psoriasis in order to address the current gaps in literature. We found 19 studies that addressed dose tapering. These studies used different criteria to determine which patients were eligible for tapering, which led to various interpretations of tapering success. This made it difficult for us to draw general conclusions on which tapering criteria and strategies should be further investigated. Dose tapering seems to be effective and safe in patients with a stable low disease activity, although more (high-quality) research is needed. Future studies should focus on generating more data on long-term safety, finding predictors for successful tapering, calculating the cost-effectiveness of dose tapering, and evaluating dose tapering in the newest generation of biologics. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-020-01448-z.

Simple Summary Rapid and reliable identification of patients with homologous recombination deficient (HRD) tumors is important for treatment choice as these tumors tend to respond well to platinum-based chemotherapy and PARP inhibitors (PARPi). In this study, a RAD51-based functional HRD test that can be performed on routine diagnostic formalin-fixed paraffin-embedded (FFPE) tissues (RAD51-FFPE test), was further improved and optimal test parameters were determined. The RAD51-FFPE test was able to determine tumor HR status with high sensitivity and specificity, making it an attractive test to be applied as routine diagnostic tool in the near future. Abstract PARP inhibitor (PARPi) sensitivity is related to tumor-specific defects in homologous recombination (HR). Therefore, there is great clinical interest in tests that can rapidly and reliably identify HR deficiency (HRD). Functional HRD tests determine the actual HR status by using the (dis)ability to accumulate RAD51 protein at sites of DNA damage as read-out. In this study, we further improved and calibrated a previously described RAD51-based functional HRD test on 74 diagnostic formalin-fixed paraffin-embedded (FFPE) specimens (RAD51-FFPE test) from endometrial cancer (EC n = 25) and epithelial ovarian cancer (OC n = 49) patients. We established optimal parameters with regard to RAD51 foci cut-off (≥2) and HRD threshold (15%) using matched endometrial and ovarian carcinoma specimens for which HR status had been established using a RAD51-based test that required ex vivo irradiation of fresh tissue (RECAP test). The RAD51-FFPE test detected BRCA deficient tumors with 90% sensitivity and RECAP-HRD tumors with 87% sensitivity, indicating that it is an attractive alternative to DNA-based tests with the potential to be applied in routine diagnostic pathology.

Sézary syndrome (SS) is a heterogeneous leukemic subtype of cutaneous T-cell lymphoma (CTCL) with generalized erythroderma, lymphadenopathy, and a poor prognosis. Advanced disease is invariably associated with severe immune dysregulation and the majority of patients die from infectious complications caused by microorganisms such as, Staphylococcus aureus, rather than from the lymphoma per se. Here, we examined if staphylococcal enterotoxins (SE) may shape the phenotype of malignant SS cells, including expression of the regulatory T-cell-associated marker FOXP3. Our studies with primary and cultured malignant cells show that SE induce expression of FOXP3 in malignant cells when exposed to nonmalignant cells. Mutations in the MHC class II binding domain of SE-A (SEA) largely block the effect indicating that the response relies at least in part on the MHC class II-mediated antigen presentation. Transwell experiments show that the effect is induced by soluble factors, partly blocked by anti-IL-2 antibody, and depends on STAT5 activation in malignant cells. Collectively, these findings show that SE stimulate nonmalignant cells to induce FOXP3 expression in malignant cells. Thus, differences in exposure to environmental factors, such as bacterial toxins may explain the heterogeneous FOXP3 expression in malignant cells in SS.

BackgroundTumour necrosis factor inhibitors (TNFi) are effective in the treatment of patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). However, these drugs come with some disadvantages such as adverse events, practical burden for patients and high costs. Dose optimisation of TNFi after patients have reached low disease activity (LDA) has been shown feasible and safe in rheumatoid arthritis (RA). However, data on TNFi dose optimisation in PsA and axSpA are scarce, especially pragmatic, randomised strategy studies.MethodsWe developed an investigator-driven, pragmatic, open-label, randomised, controlled, non-inferiority trial (DRESS-PS) to compare the effects of a disease activity-guided treat-to-target strategy with or without a tapering attempt in patients with SpA (PsA and axSpA combined), ≥ 16 years of age, who are being treated with TNFi, and have had at least 6 months of low disease activity. The primary outcome is the percentage of patients in LDA after 12 months of follow up. Patients are assessed at baseline, 3, 6, 9, and 12 months of follow up. Bayesian power analyses with a weakened prior based on a similar study performed in RA resulted in a sample size of 95 patients in total.DiscussionMore knowledge on disease activity-guided treatment algorithms would contribute to better treatment choices and cost savings and potentially decrease the risk of side effects. In this article we elucidate some of our design choices on TNFi dose optimisation and its clinical and methodological consequences.Trial registrationDutch Trial Register,NL6771. Registered on 27 November 2018 (CMO NL66181.091.18, 23 October 2018).

BackgroundRoad traffic noise has been linked to increased risk of ischemic heart disease, yet evidence on stroke shows mixed results. We examine the association between long-term exposure to road traffic noise and incidence of stroke, overall and by subtype (ischemic or hemorrhagic), after adjustment for air pollution.MethodsTwenty-five thousand six hundred and sixty female nurses from the Danish Nurse Cohort recruited in 1993 or 1999 were followed for stroke-related first-ever hospital contact until December 31st, 2014. Full residential address histories since 1970 were obtained and annual means of road traffic noise (Lden[dB]) and air pollutants (particulate matter with diameter 2.5and PM10], nitrogen dioxide [NO2], nitrogen oxides [NOx]) were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals [CI]) for the associations of one-, three-, and 23-year running means of Ldenpreceding stroke (all, ischemic or hemorrhagic), adjusting for stroke risk factors and air pollutants. The World Health Organization and the Danish government’s maximum exposure recommendations of 53 and 58 dB, respectively, were explored as potential Ldenthresholds.ResultsOf 25,660 nurses, 1237 developed their first stroke (1089 ischemic, 148 hemorrhagic) during 16 years mean follow-up. For associations between a 1-year mean of Ldenand overall stroke incidence, the estimated HR (95% CI) in the fully adjusted model was 1.06 (0.98–1.14) per 10 dB, which attenuated to 1.01 (0.93–1.09) and 1.00 (0.91–1.09) in models further adjusted for PM2.5or NO2, respectively. Associations for other exposure periods or separately for ischemic or hemorrhagic stroke were similar. There was no evidence of a threshold association between Ldenand stroke.ConclusionsLong-term exposure to road traffic noise was suggestively positively associated with the risk of overall stroke, although not after adjusting for air pollution.

Staphylococcal enterotoxins are believed to fuel disease activity in cutaneous T-cell lymphoma. Recent data support this by showing that antibiotics inhibit malignant T cells in skin lesions in mycosis fungoides and Sézary syndrome, the most common forms of cutaneous T-cell lymphoma. Yet, it remains incompletely characterized how staphylococcal enterotoxins fuel disease activity. In this study, we show that staphylococcal enterotoxins induce the expression of the oncogenic microRNA miR-155 in primary malignant T cells. Thus, staphylococcal enterotoxins and Staphyloccocus aureus isolates from lesional skin of patients induce miR-155 expression at least partly through the IL-2Rg‒Jak‒signal transducer and activator of transcription 5 pathway, and the effect is augmented by the presence of nonmalignant T cells. Importantly, mycosis fungoides lesions harbor S. aureus, express Y-phosphorylated signal transducer and activator of transcription 5, and display enhanced miR-155 expression, when compared with nonlesional and healthy skin. Preliminary data show that aggressive antibiotic therapy is associated with decreased Y-phosphorylated signal transducer and activator of transcription 5 and miR-155 expression in lesional skin in two patients with Sézary syndrome. In conclusion, we show that S. aureus and its enterotoxins induce enhanced expression of oncogenic miR-155, providing mechanistic insight into the role of S. aureus in cutaneous T-cell lymphoma. Our findings support that environmental stimuli such as bacteria can fuel disease progression in cutaneous T-cell lymphoma.

Supplemental digital content is available in the text., Objective The aims of this study were (1) to compare physical capacity at 1-yr follow-up with physical capacity before and after the training period for the HandbikeBattle event and (2) to identify determinants of the course of physical capacity during follow-up. Design This was a prospective observational study. Former rehabilitation patients (N = 33) with health conditions such as spinal cord injury or amputation were included. A handcycling/arm crank graded exercise test was performed before (January, T1) and after the training period (June, T2) and at 1-yr follow-up (June, T4). Outcomes were peak power output (W) and peak oxygen uptake (L/min). Determinants were sex (male/female); age (years); classification; physical capacity, musculoskeletal pain, exercise stage of change, and exercise self-efficacy at T1; and HandbikeBattle participation at T4. Results Multilevel regression analyses showed that peak power output and peak oxygen uptake increased during the training period and did not significantly change during follow-up (T1: 112 ± 37 W, 1.70 ± 0.48 L/min; T2: 130 ± 40 W, 2.07 ± 0.59 L/min; T4: 126 ± 42 W, 2.00 ± 0.57 L/min). Participants who competed again in the HandbikeBattle showed slight improvement in physical capacity during follow-up, whereas participants who did not compete again showed a decrease. Conclusion Physical capacity showed an increase during the training period and remained stable after 1-yr follow-up. Being (repeatedly) committed to a challenge might facilitate long-term exercise maintenance.

BACKGROUND: Associations between long-term exposure to air pollution and road traffic noise have been established for ischemic heart disease, but findings have been mixed for atrial fibrillation (AF). OBJECTIVES: The goal of the study was to examine associations of long-term exposure to road traffic noise and air pollution with AF. METHODS: Time-varying Cox regression models were used to estimate associations of 1-, 3-, and 23-y mean road traffic noise and air pollution exposures with AF incidence in 23,528 women enrolled in the Danish Nurse Cohort (age >44 y at baseline in 1993 or 1999). AF diagnoses were ascer-tained via the Danish National Patient Register. Annual mean weighted 24-h average road traffic noise levels (L den) at the nurses’ residences, since 1970, were estimated using the Nord2000 model, and annual mean levels of particulate matter with a diameter 2:5) and nitrogen dioxide (NO 2) were estimated using the DEHM/UBM/AirGIS model. RESULTS: Of 23,528 nurses with no prior AF diagnosis at the cohort baseline, 1,522 developed AF during follow-up. In a fully adjusted model (including PM 2:5), the estimated risk of AF was 18% higher [hazard ratio (HR); 95% confidence interval (CI): 1.18; 1.02, 1.36] in nurses with residential 3-y mean L den levels >58 dB vs. 3 increase in 3-y mean PM 2:5 was associated with incident AF before and after adjustment for concurrent exposure to road traffic noise (HR 1.09; 95% CI: 1.00, 1.20 and 1.08; 95% CI: 0.97, 1.19, respectively). Associations with 1-y mean PM 2:5 exposures were positive but closer to the null and not significant. Associations with NO 2 were null for all time periods before and after adjustment for road traffic noise and inverse when adjusted for concurrent PM 2:5. CONCLUSION: Our analysis of prospective data from a cohort of Danish female nurses followed for up to 14 y provided suggestive evidence of independent associations between incident AF and 1-and 3-y exposures to road traffic noise and PM 2:5. https://doi.org/10.1289/EHP8090.

BACKGROUND: Several cancers, including mycosis fungoides (MF), have reported dysregulation of miR-195-5p. miR-195-5p plays a role in cell cycle regulation in several malignant diseases.OBJECTIVES: This study aimed to investigate: (a) the expression level of miR-195-5p in lesional MF skin biopsies and (b) the potential regulatory roles of miR-195-5p in MF.METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) was used to determine miR-195-5p expression in MF skin biopsies and cell lines. The effect of miR-195-5p and ADP-ribosylation factor-like protein 2 (ARL2) on cell cycle and apoptosis was measured by flow cytometry assays. Changes in ARL2 expression were determined by RT-qPCR and Western blotting (WB).RESULTS: We found lower expression levels of miR-195-5p in lesional skin from MF patients compared with non-lesional MF skin and skin from healthy volunteers. Additionally, miR-195-5p showed lower expression levels in the skin from patients with disease progression compared with patients with stable disease. In vitro studies showed that overexpression of miR-195-5p induced a cell cycle arrest in G0G1. Using microarray analysis, we identified several genes that were regulated after miR-195-5p overexpression. The most downregulated gene after miR-195-5p mimic transfection was ARL2. RT-qPCR and WB analyses confirmed downregulation of ARL2 following transfection with miR-195-5p mimic. Lastly, transfection with siRNA against ARL2 also induced a G0G1 arrest.CONCLUSION: Upregulation of miR-195-5p in MF inhibits cycle arrest by downregulation of ARL2. miR-195-5p may thus function as a tumor suppressor in MF and low miR-195-5p expression in lesional MF skin may promote disease progression.

Summary Background Rituximab is an effective treatment for rheumatoid arthritis, given as either two doses of 1000 mg (2 weeks apart) every 6 months (the dose recommended by the US Food and Drug Administration and European Medicines Agency) or two doses of 500 mg (2 weeks apart) or one dose of 1000 mg (a standard low dose) every 6 months. Findings of several small uncontrolled studies suggest that doses lower than the recommended dose or standard low dose might be sufficient for maintenance treatment, potentially improving safety and reducing costs. Therefore, we aimed to compare the efficacy of ultra-low doses of rituximab (one dose of 500 mg or 200 mg) with a standard low dose of rituximab (one dose of 1000 mg) for patients with rheumatoid arthritis who respond to standard doses of rituximab. Methods The REDO study is a randomised, double-blind, non-inferiority trial done at five centres in the Netherlands. Adults (aged ≥18 years) with rheumatoid arthritis responding well to rituximab were randomly allocated (1:2:2) to receive intravenous rituximab as one dose of either 1000 mg, 500 mg, or 200 mg, respectively. Volumes of all doses were equal to achieve masking. Randomisation lists were computer-generated and stratified by rheumatoid factor or anti-citrullinated protein antibody status (positive or negative) and concomitant use of conventional synthetic disease modifying antirheumatic drugs (yes or no). The primary analysis was a per-protocol hierarchical testing procedure comparing ultra-low doses with a standard low dose (500 mg vs 1000 mg at 3 months, followed by 500 mg vs 1000 mg at 6 months, 200 mg vs 1000 mg at 3 months, and 200 mg vs 1000 mg at 6 months), using a non-inferiority margin of 0·60 on change from baseline in the 28-joint disease activity score based on C-reactive protein levels (DAS28-CRP). The study is registered at www.trialregister.nl , NTR6117. Findings Between Dec 15, 2016, and Sept 20, 2018, 142 patients were randomly allocated to either 1000 mg rituximab (n=29), 500 mg rituximab (n=58), or 200 mg rituximab (n=55). The 500 mg dose was non-inferior to 1000 mg at 3 months (mean change from baseline in DAS28-CRP, −0·07, 95% CI −0·41 to 0·27) but not at 6 months (0·29, −0·08 to 0·65). Because of the hierarchical testing procedure, non-inferiority could not be tested for the 200 mg dose. 13 patients had serious adverse events, three (10%) in the 1000 mg group, six (10%) in the 500 mg group, and four (7%) in the 200 mg group. The most frequently reported serious adverse events were cardiovascular. No deaths occurred during the study. A significantly lower incidence of infections was seen in the ultra-low-dose groups compared with the standard dose group (1·24 infections per patient-year with the 1000 mg dose vs 0·52 per patient-year with the 500 mg dose and 0·55 per patient-year with the 200 mg dose; rate ratio 0·42, 95% CI 0·21–0·83; p=0·013 for 500 mg vs 1000 mg; 0·44, 0·22–0·88; p=0·019 for 200 mg vs 1000 mg). Interpretation Our study did not show non-inferiority of ultra-low doses of rituximab for continued treatment of patients with rheumatoid arthritis. Nonetheless, in clinical practice, a strategy with an ultra-low dose of rituximab might be considered after evaluation of risks and benefits, although further studies are needed to establish non-inferiority. Further analyses and a 2-year observational extension are ongoing and should provide further insight into efficacy and safety. Funding Menzis and Centraal Ziekenfonds.

ObjectiveTo determine the hemodynamic conditions associated with optimal neurologic improvement in individuals with acute traumatic spinal cord injury (SCI) who had lumbar intrathecal catheters placed to measure CSF pressure (CSFP).MethodsNinety-two individuals with acute SCI were enrolled in this multicenter prospective observational clinical trial. We monitored mean arterial pressure (MAP) and CSFP during the first week after injury and assessed neurologic function at baseline and 6 months after injury. We used relative risk iterations to determine transition points at which the likelihood of either improving neurologically or remaining unchanged neurologically was equivalent. These transition points guided our analyses in which we examined the linear relationships between time spent within target hemodynamic ranges (i.e., clinical adherence) and neurologic recovery.ResultsRelative risk transition points for CSFP, MAP, and spinal cord perfusion pressure (SCPP) were linearly associated with neurologic improvement and directed the identification of key hemodynamic target ranges. Clinical adherence to the target ranges was positively and linearly related to improved neurologic outcomes. Adherence to SCPP targets, not MAP targets, was the best indicator of improved neurologic recovery, which occurred with SCPP targets of 60 to 65 mm Hg. Failing to maintain the SCPP within the target ranges was an important detrimental factor in neurologic recovery, particularly if the target range is set lower.ConclusionWe provide an empirical, data-driven approach to aid institutions in setting hemodynamic management targets that accept the real-life challenges of adherence to specific targets. Our results provide a framework to guide the development of widespread institutional management guidelines for acute traumatic SCI.

Purpose: Increasing knowledge suggests that nutrition and lifestyle factors affect multiple sclerosis. This study explores how people with multiple sclerosis experience daily multiple sclerosis disease activity and the influence of nutrition and lifestyle factors (e.g., stress, sleep, and environmental temperature).Methods: Four phases mix qualitative and quantitative elements in an exploratory study. The initial two phases consisted of an exploratory study with 14 participants followed by 15 semi-structured interviews. Results from the two first phases were substantiated in a survey completed by 425 respondents (response rate: 42.5%). Finally, findings and inconsistencies were elaborated in three focus group interviews.Results: In the initial exploratory study, several of the participants linked nutrition and lifestyle factors to disease activity. Results from the semi-structured interviews showed that particularly stress, meat, fatty foods, and processed sugar were perceived to have a negative impact on disease activity, and some participants had experienced immediate effects of these factors on their disease activity. The survey supported these findings that were further elaborated in focus groups.Conclusion: People with multiple sclerosis perceive nutrition and lifestyle to affect daily disease activity. Individuals who have experienced links between their multiple sclerosis, and nutrition and lifestyle attribute some of these changes to e.g., stress, and the consumption of sugar, meat, and fatty food.Implications for rehabilitationA majority of the participants in this study perceived nutrition and lifestyle factors to have an effect on their multiple sclerosis, particularly stress, meat, fatty foods, and processed sugar.Some participants with multiple sclerosis experienced that nutrition, stress, environmental temperature, and physical activity had a direct effect on the severity of daily symptom manifestations.Nutrition and lifestyle factors that potentially influence multiple sclerosis disease activity should be considered when organizing rehabilitation and care to better meet the needs of the individual with multiple sclerosis.

Objectives A significant proportion of RA patients, particularly those associated with poor prognostic factors, fail on conventional DMARDs (cDMARDs). Although rituximab (RTX) has been effective in these patients, the cost of therapy makes it unaffordable, particularly in poor and developing countries. Numerous, albeit small, studies using lower doses have shown contradictory results. We aimed to analyse the effectiveness of a low-dose RTX protocol based on clinical outcomes in RA patients. Methods Seropositive RA patients with moderate to high disease activity (DAS28-ESR > 3.2) despite combination cDMARDs, treated with RTX, were included in retrospective analysis. All patients were treated according to a predefined protocol, using 500 mg RTX with ongoing cDMARDs at baseline and repeat dosing at 6 weeks or beyond, on lack of moderate to good EULAR response. The B cell count was assessed at baseline, 2 and 24 weeks. Results At 12 weeks, 93% of 166 patients [mean (s.d.) age, 51.5 (11.96) years, 25 men and 141 women, with a disease duration of 10.4 (6.29) years] achieved moderate to good EULAR response. At 24 weeks, 90.8% of patients achieved moderate to good EULAR response, 19.8% achieved low disease activity and 29.5% achieved remission, with a mean change in DAS28-ESR from baseline of 2.9 (1.3). RTX failure and relapse were seen in 5.4% and 3.6%, respectively. The response was maintained for 12.3 (7.2) months with a mean RTX dose 521.1 (100.8) mg. Adverse events were seen in 9.6%. When compared with the standard dosing regimen with the originator molecule, a cost reduction of 90% was achieved. Conclusion A low-dose RTX regimen achieved reasonably good clinical outcomes at the end of 6 months, with a significantly lower cost.

A major obstacle for translational research in acute spinal cord injury (SCI) is the lack of biomarkers that can objectively stratify injury severity and predict outcome. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a neuron-specific enzyme that shows promise as a diagnostic biomarker in traumatic brain injury (TBI), but has not been studied in SCI. In this study, cerebrospinal fluid (CSF) and serum samples were collected over the first 72-96 h post-injury from 32 acute SCI patients who were followed prospectively to determine neurological outcomes at 6 months post-injury. UCH-L1 concentration was measured using the Quanterix Simoa platform (Quanterix, Billerica, MA) and correlated to injury severity, time, and neurological recovery. We found that CSF UCH-L1 was significantly elevated by 10- to 100-fold over laminectomy controls in an injury severity- and time-dependent manner. Twenty-four-hour post-injury CSF UCH-L1 concentrations distinguished between American Spinal Injury Association Impairment Scale (AIS) A and AIS B, and AIS A and AIS C patients in the acute setting, and predicted who would remain "motor complete" (AIS A/B) at 6 months with a sensitivity of 100% and a specificity of 86%. AIS A patients who did not improve their AIS grade at 6 months post-injury were characterized by sustained elevations in CSF UCH-L1 up to 96 h. Similarly, the failure to gain8 points on the total motor score at 6 months post-injury was associated with higher 24-h CSF UCH-L1. Unfortunately, serum UCH-L1 levels were not informative about injury severity or outcome. In conclusion, CSF UCH-L1 in acute SCI shows promise as a biomarker to reflect injury severity and predict outcome.

Objective Owing to lower mean uric acid excretion in women compared with men, uricosuric agents might be preferred in women over xanthine oxidase (XO) inhibitors. We therefore investigated the differences in response to two urate-lowering therapies (ULTs) with different modes of action within and between sexes. Methods This retrospective cohort study included patients with a clinical diagnosis of gout who started allopurinol and/or benzbromarone. The successful response to ULT, defined as reaching a serum uric acid (sUA) target of Results Allopurinol was started in 255 women and 1045 men, and benzbromarone in 60 women and 205 men. After 6 months, the proportions of women reaching the sUA target were 58.4% and 66.7% for allopurinol and benzbromarone, respectively (difference, −8%; 95% CI: −22%, 5%). The respective proportions in men were 61.0% and 75.6%, respectively (difference, −15%; 95% CI: −21%, −8%). Corrected for confounding, the odds ratio (OR) of reaching the target on benzbromarone vs allopurinol within women was 0.91 (95% CI: 0.47, 1.75), and within men 1.55 (95% CI: 1.04, 2.32). Corrected for confounding, sex was not an effect modifier of the difference in allopurinol and benzbromarone response (OR, 0.59; 95% CI: 0.28, 1.24). Conclusion This study did not demonstrate between-sex differences regarding the response to either a uricosuric agent or an XO inhibitor, negating different treatment choices by sex.

Background: The thioredoxin-interacting protein (TXNIP) is involved in cellular metabolism and cell proliferation, and recently, deficient expression of TXNIP has been associated with progression and poor outcome for cancer patients. Objectives: To assess TXNIP expression and function in malignant T cells from cutaneous T-cell lymphoma (CTCL). Methods: CTCL-derived malignant (MyLa2059, PB2B) and non-malignant (MyLa1850) cell lines were analysed by Western blotting and qPCR for TXNIP expression. Subsequently, the malignant CTCL cell lines were treated with GSK126 – an inhibitor of enhancer of zeste homolog 2 (EZH2) methyltransferase activity or assessed by bisulphite sequencing for TXNIP promoter methylation. Methylation was also assessed with the demethylating agent 5-azacytidine (5AZA). Finally, TXNIP was overexpressed in the malignant PB2B cell line via plasmid transduction, and the effect of TXNIP was further analysed by flow cytometry. Results: We report on low expression of TXNIP protein in all cell lines representing different subtypes and stages of CTCL when compared to non-malignant T cells. Epigenetic silencing and other mechanisms were involved in the repression of TXNIP whereas forced expression of TXNIP strongly inhibited proliferation of malignant T cells. Conclusions: Epigenetic silencing and other as yet unknown mechanisms repress TXNIP expression in malignant T cells. As forced expression of TXNIP inhibits malignant proliferation, we propose that TXNIP is a putative tumour suppressor in CTCL.

Introduction Asthma is a complex, heterogeneous disease and one of the most common chronic diseases among children. Exposure to ambient air pollution in early life and childhood may influence asthma aetiology, but it is uncertain which specific components of air pollution and exposure windows are of importance. The role of socio-economic status (SES) is also unclear. The aims of the present study are, therefore, to investigate how various exposure windows of different pollutants affect risk-induced asthma in early life and to explore the possible effect SES has on that relationship. Methods The study population was constructed using register data on all singleton births in the greater Stockholm area between 2006 and 2013. Exposure to ambient black carbon (BC), fine particulate matter (PM2.5), primary organic carbon (pOC) secondary organic aerosols (SOA), secondary inorganic aerosols, and oxidative potential at the residential address was modelled as mean values for the entire pregnancy period, the first year of life and the first three years of life. Swedish national registers were used to define the outcome: asthma diagnosis assessed at hospital during the first six years of life. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were modelled with Cox proportional hazards model with age as the underlying time-scale, adjusting for relevant potential confounding variables. Results An increased risk for developing childhood asthma was observed in association with exposure to PM2.5, pOC and SOA during the first three years of life. With an interquartile range increase in exposure, the HRs were 1.06 (95% CI: 1.01–1.10), 1.05 (95% CI: 1.02–1.09) and 1.02 (95% CI: 1.00–1.04), for PM2.5, pOC and SOA, respectively, in the fully adjusted models. Exposure during foetal life or the first year of life was not associated with asthma risk, and the other pollutants were not statistically significantly associated with increased risk. Furthermore, the increase in risk associated with PM2.5 and the components BC, pOC and SOA were stronger in areas with lower SES. Conclusion Our results suggest that exposure to air pollution during the first three years of life may increase the risk for asthma in early childhood. The findings further imply a possible increased vulnerability to air pollution-attributed asthma among low SES children.

Background: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is a lymphoproliferative disorder characterized by proliferation of malignant T cells in a chronic inflammatory environment in the skin. The nature of MF is still not fully understood, but aberrant microRNA (miR) expression and function seem to play an important role in the pathogenesis and disease progression and have been proposed as a putative disease marker. Recent studies have reported aberrant expression of miR-93 in situin MF lesions and linked dysregulated miR-93 expression to advanced stages of MF. However, the pathophysiological role of miR-93 in MF is unknown. Objective: Here, we provide the first evidence that miR-93 targets the cell cycle regulator cyclin-dependent kinase inhibitor p21 and promotes growth of malignant T cells in MF. Methods/Results: Thus, inhibition of miR-93 in MF patient-derived malignant T-cell lines increases expression of p21 and inhibition of malignant proliferation. Notably, treatment with the histone deacetylase inhibitor Vorinostat (SAHA) reduces miR-93 expression and enhances p21 expression in the malignant T cells. Importantly, transfection with an miR-93 mimic partly blocks SAHA-induced p21 expression. Conclusions: we provide evidence that enhanced expression of the putative oncogenic miR, miR-93, represses the cell cycle inhibitor p21 and promotes proliferation of malignant T cells. Moreover, we demonstrate that SAHA triggers p21 expression – at least partly – through an inhibition of miR-93.

BackgroundWhile air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the associations of long-term exposure to air pollution and road traffic noise with COPD incidence.MethodsWe defined COPD incidence for 24 538 female nurses from the Danish Nurse Cohort (age >44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with an aerodynamic diameter 2.5) since 1990 and nitrogen dioxide (NO2) since 1970 using the Danish Eulerian Hemispheric Model/Urban Background Model/Air Geographic Information System modelling system, and road traffic noise (Lden) since 1970 using the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and road traffic noise with COPD incidence.Results977 nurses developed COPD during a mean of 18.6 years’ follow-up. We observed associations with COPD for all three exposures with HRs and 95% CIs of 1.19 (1.01–1.41) per 6.26 µg·m−3 for PM2.5, 1.13 (1.05–1.20) per 8.19 µg·m−3 for NO2 and 1.15 (1.06–1.25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after mutual adjustment, but were robust to adjustment for PM2.5. Associations with PM2.5 were attenuated to null after adjustment for either NO2 or Lden. No potential interaction effect was observed between air pollutants and noise.ConclusionLong-term exposure to air pollution, especially traffic-related NO2, and to road traffic noise were independently associated with COPD.

Background: Ambient air pollution is likely a risk factor for asthma, and recent evidence suggests the possible relevance of road traffic noise. Objectives: We examined the associations of long-term exposure to air pollution and road traffic noise with adult-asthma incidence. Methods: We followed 28,731 female nurses (age > 44 years) from the Danish Nurse Cohort, recruited in 1993 and 1999, for first hospital contact for asthma from 1977 until 2015. We estimated residential annual mean concentrations of particulate matter with diameter < 2.5 µm (PM2.5) since 1990 and nitrogen dioxide (NO2) since 1970 with the Danish DEHM/UBM/AirGIS modeling system, and road traffic noise (Lden) since 1970 with the Nord2000 model. Time-varying Cox regression models were used to associate air pollution and road traffic noise exposure with asthma incidence. Results: During 18.6 years’ mean follow-up, 528 out of 23,093 participants had hospital contact for asthma. The hazard ratios (HR) and 95% confidence intervals for asthma incidence associated with 3-year moving average exposures were 1.29 (1.03, 1.61) per 6.3 µg/m3 for PM2.5, 1.16 (1.07, 1.27) per 8.2 µg/m3 for NO2, and 1.12 (1.00, 1.25) per 10 dB for Lden. The HR for NO2 remained unchanged after adjustment for either PM2.5 or Lden, while the HRs for PM2.5 and Lden attenuated to unity after adjustment for NO2. Conclusions: Long-term exposure to air pollution was associated with adult-asthma incidence independently of road traffic noise, with NO2 most relevant. Road traffic noise was not independently associated with adult-asthma incidence.

Ambient air pollution has been linked to stroke, but few studies have examined in detail stroke subtypes and confounding by road traffic noise, which was recently associated with stroke. Here we examined the association between long-term exposure to air pollution and incidence of stroke (overall, ischemic, hemorrhagic), adjusting for road traffic noise. In a nationwide Danish Nurse Cohort consisting of 23,423 nurses, recruited in 1993 or 1999, we identified 1,078 incident cases of stroke (944 ischemic and 134 hemorrhagic) up to December 31, 2014, defined as first-ever hospital contact. The full residential address histories since 1970 were obtained for each participant and the annual means of air pollutants (particulate matter with diameter < 2.5 µm and < 10 µm (PM2.5 and PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx)) and road traffic noise were determined using validated models. Time-varying Cox regression models were used to estimate hazard ratios (HR) (95% confidence intervals (CI)) for the associations of one-, three, and 23-year running mean of air pollutants with stroke adjusting for potential confounders and noise. In fully adjusted models, the HRs (95% CI) per interquartile range increase in one-year running mean of PM2.5 and overall, ischemic, and hemorrhagic stroke were 1.12 (1.01–1.25), 1.13 (1.01–1.26), and 1.07 (0.80–1.44), respectively, and remained unchanged after adjustment for noise. Long-term exposure to ambient PM2.5 was associated with the risk of stroke independent of road traffic noise.

Cutaneous T-cell lymphoma (CTCL) represents a heterogeneous group of potentially devastating primary skin malignancies. Despite decades of intense research efforts, the pathogenesis is still not fully understood. In the early stages, both clinical and histopathological diagnosis is often difficult due to the ability of CTCL to masquerade as benign skin inflammatory dermatoses. Due to a lack of reliable biomarkers, it is also difficult to predict which patients will respond to therapy or progress towards severe recalcitrant disease. In this review, we discuss recent discoveries concerning dysregulated microRNA (miR) expression and putative pathological roles of oncogenic and tumor suppressive miRs in CTCL. We also focus on the interplay between miRs, histone deacetylase inhibitors, and oncogenic signaling pathways in malignant T cells as well as the impact of miRs in shaping the inflammatory tumor microenvironment. We highlight the potential use of miRs as diagnostic and prognostic markers, as well as their potential as therapeutic targets. Finally, we propose that the combined use of miR-modulating compounds with epigenetic drugs may provide a novel avenue for boosting the clinical efficacy of existing anti-cancer therapies in CTCL.

Patients with acute traumatic cervical spinal cord injury (ATCSCI) have an increased risk of catheter-associated urinary tract infection (CAUTI). The effectiveness of silver alloy-coated silicone urinary catheters (SACC) in preventing CAUTI in ATCSCI is unknown and was the objective of this study. We performed a quality improvement initiative in an attempt to reduce CAUTI in patients undergoing spine surgery at a single quaternary center. Prior to July 2015, all patients received a latex indwelling catheter (LIC). All patients with ATCSCI with limited hand function (AIS A,B, or C) received a SACC. Incidence of CAUTI, microbiology, duration of infection, antibiotic susceptibility, and catheter-associated adverse events were recorded prospectively. We studied 3081 consecutive patients over the three years, of whom 302 (9.8%) had ATCSCI; 63% of ATCSCI patients were ASIA Impairment Scale (AIS) A or B. The overall rate of CAUTI was 19% (585/3081), and was 38% (116/302) in patients with ATCSCI. Of 178 ATCSCI patients with LIC, 100 (56%) developed a CAUTI compared with 28 of 124 (23%) patients with SACC (p 0.05). Poly-microbial and gram-positive infection was more common in LIC than in SACC (p 0.05). Median duration of infection was 9 days in SACC group and 12 days in LIC group (p = 0.08). Resistance to trimethoprim (p 0.001) and ciprofloxacin (p 0.05) were more common in LIC group. There was no difference in catheter-associated adverse events or length of stay between the groups. This quality improvement initiative illustrates the effectiveness of antiseptic silver alloy-coated silicone urinary catheters in patients with ATCSCI. In our population, the use of SACC reduces the incidence and the complexity of CAUTI.

Background: While air pollution has been linked to the development of chronic obstructive pulmonary disease (COPD), evidence on the role of environmental noise is just emerging. We examined the association of long-term exposure to air pollution and road traffic noise with COPD incidence. Methods: We defined COPD incidence for 24,538 female nurses from the Danish Nurse Cohort (age > 44 years) as the first hospital contact between baseline (1993 or 1999) and 2015. We estimated residential annual mean concentrations of particulate matter with diameter < 2·5 µm (PM2·5) since 1990 and nitrogen dioxide (NO2) since 1970 by the Danish DEHM/UBM/AirGIS modeling system, and road traffic noise (Lden) since 1970 by the Nord2000 model. Time-varying Cox regression models were applied to assess the associations of air pollution and noise with COPD incidence. Findings: 977 nurses developed COPD during 18·6 years’ mean follow-up. We observed associations with COPD for all three exposures with hazard ratios (HRs) and 95% confidence intervals (CIs) of 1·19 (1·01, 1·41) per 6·26 µg/m3 for PM2·5, 1·13 (1·05, 1·20) per 8·19 µg/m3 for NO2, and 1·15 (1·06, 1·25) per 10 dB for Lden. Associations with NO2 and Lden attenuated slightly after adjustment for each other, but were robust to adjustment for PM2·5. Associations with PM2·5 were attenuated to null after adjustment for either NO2 or Lden. Interpretation: Long-term exposures to traffic-related NO2 and road traffic noise were associated with COPD, independent of each other. Funding Statement: Danish Council for Independent Research, Novo Nordisk Foundation, and China Scholarship Council. Funding Statement: This work was supported by the Danish Council for Independent Research [DFF-4183-00353], the Novo Nordisk Foundation Challenge Programme [NNF17OC0027812], and the China Scholarship Council [No. 201806010406]. Declaration of Interests: We declare that we have no conflicts of interest. Ethics Approval Statement: The establishment of the cohort was approved by the Scientific and Ethical Committee of Copenhagen and Frederiksberg Municipalities, and the Danish Data Protection Agency.

Staphylococcus aureus and its toxins have been linked to disease progression and mortality in advanced stages of cutaneous T-cell lymphoma (CTCL). CD8+ T cells play a crucial role in anti-cancer responses and high CD8+ T cell numbers in tumor lesions are associated with a favorable prognosis in CTCL. Here, we show that CD8+ T cells from both healthy donors and Sézary syndrome patients are highly susceptible to cell death induced by Staphylococcal alpha-toxin, whereas malignant T cells are not. Importantly, alpha-toxin almost completely blocks cytotoxic killing of CTCL tumor cells by peptide-specific CD8+ T cells, leading to their escape from induced cell death and continued proliferation. These findings suggest that alpha-toxin may favor the persistence of malignant CTCL cells in vivo by inhibiting CD8+ T cell cytotoxicity. Thus, we propose a novel mechanism by which colonization with Staphylococcus aureus may contribute to cancer immune evasion and disease progression in CTCL.

A prognostic 3-miRNA classifier for early-stage mycosis fungoides has been developed recently, with miR-106b providing the strongest prognostic power. The aim of this study was to investigate the molecular function of miR-106b in mycosis fungoides disease progression. The cellular localization of miR-106b in mycosis fungoides skin biopsies was determined by in situ hybridization. The regulatory role of miR-106b was assessed by transient miR-106b inhibitor/mimic transfection of 2 mycosis fungoides derived cell lines, followed by quantitative real-time PCR (RT-qPCR), western blotting and a proliferation assay. MiR-106b was found to be expressed by dermal T-lymphocytes in mycosis fungoides skin lesions, and miR-106b expression increased with advancing mycosis fungoides stage. Transfection of miR-106b in 2 mycosis fungoides derived cell lines showed that miR-106b represses the tumour suppressors cyclin-dependent kinase inhibitor 1 (p21) and thioredoxin-interacting protein (TXNIP) and promotes mycosis fungoides tumour cell proliferation. In conclusion, these results substantiate that miR-106b has both a functional and prognostic role in progression of mycosis fungoides.

Objectives The aim of this study was to identify the factors that play a role for patients with RA when considering dose reduction (i.e. gradual tapering until discontinuation) of biological DMARDs (bDMARDs), and to determine their relative importance. Methods A mixed methods design was used in which we identified influencing factors by performing semi-structured interviews and ranked these factors using a Maximum Difference Scaling questionnaire. Also, we looked at the influence of several patient characteristics on this ranking. Results For sub study 1 and 2, 22 and 192 patients with RA were included, respectively, in the analyses. Thirty factors were identified from the interviews-characterized into nine themes-and appraised in the questionnaire. Most respondents had a positive attitude towards bDMARD dose reduction. The study showed that patients are concerned that dose reduction will lead to a disease flare that affects their daily life (pain, function). It is important for them to know that it is possible to increase the dose if (further) reduction fails and that the bDMARD will be effective again. Patients value the opinion of their rheumatologist, and being involved in the decision to start tapering is highly ranked as well. The most important factors were consistent between different groups of patients. Conclusion The results from this study facilitate implementation of bDMARD dose reduction; they inform care providers on what is important for patients and provide a basis for shared decision making.

Sensitivity to PARP inhibitors is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2-related deficiencies. Therefore, there is great interest in a robust method to identify HR-deficient (HRD) carcinomas in routine diagnostics. DNA-based assays that are developed to identify HRD are relatively complex, costly and time-consuming. As an alternative to DNA-based assays we developed the REcombination CAPacity (RECAP) test exploiting the accumulation of RAD51 protein after irradiation of fresh tumor tissue as a biomarker for HR proficiency. The RECAP test reliably identified HRD ovarian (OC) and endometrial (EC) carcinomas including those not related to BRCA1/2 deficiency. However, the implementation of the RECAP test in clinical diagnostics is hampered by dependency on ex vivo irradiation of fresh tumor tissue. We therefore explored the use of diagnostic formalin-fixed paraffin-embedded (FFPE) tumor tissue for the functional analysis of HR and aimed to determine the performance of RAD51 assessment on diagnostic FFPE blocks as compared to RECAP test. FFPE tumor tissue from tumors for which previously published RECAP scores were available (OC n = 49; EC n = 25) were subjected to a three-step quality assessment: 1) Tumor tissue quality analysis of hematoxylin and eosin stained slides by an expert pathologist, 2) Evaluation of yH2AX foci to confirm the presence of DNA damage and 3) Evaluation of the presence of a sufficient number of geminin positive (GMN+) tumor cells. When all quality criteria were met, the capacity of tumor cells to accumulate RAD51 protein at sites of endogenous DNA damage was analyzed using co-immunofluorescent staining. The RAD51-FFPE score was determined as the percentage of GMN+ cells with RAD51 foci. The performance of the RAD51-FFPE test was determined using corresponding RECAP scores. Seventy-four FFPE tumor tissues were subjected to the quality assessment. In total, 58 out of 74 (78%) met our tissue quality criteria. RAD51-FFPE scores correlated significantly with RECAP scores (p= We demonstrated that the RAD51-FFPE test on diagnostic FFPE tumor tissue is an attractive alternative to DNA-based tests to identify HRD in OC and EC. Although the optimal RAD51-FFPE threshold to identify HRD tumors needs to be established using larger cohorts with genomic and clinical trial outcome data, the RAD51-FFPE test is a promising candidate to serve as a low-cost routine diagnostic HRD test in the clinic. Citation Format: Lise M. van Wijk, Claire J. Kramer, Sylvia Vermeulen, Natalja T. ter Haar, Cor D. de Kroon, Marthe M. de Jonge, Katja N. Gaarenstroom, Harry Vrieling, Violeta Serra, Tjalling Bosse, Maaike P. Vreeswijk. The RAD51-FFPE test rapidly and reliably identifies homologous recombination deficient ovarian and endometrial carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 364.

Background Two reviews and an overview were produced for the Canadian Task Force on Preventive Health Care guideline on screening for esophageal adenocarcinoma in patients with chronic gastroesophageal reflux disease (GERD) without alarm symptoms. The goal was to systematically review three key questions (KQs): (1) The effectiveness of screening for these conditions; (2) How adults with chronic GERD weigh the benefits and harms of screening, and what factors contribute to their preferences and decision to undergo screening; and (3) Treatment options for Barrett’s esophagus (BE), dysplasia or stage 1 EAC (overview of reviews). Methods Bibliographic databases (e.g. Ovid MEDLINE®) were searched for each review in October 2018. We also searched for unpublished literature (e.g. relevant websites). The liberal accelerated approach was used for title and abstract screening. Two reviewers independently screened full-text articles. Data extraction and risk of bias assessments were completed by one reviewer and verified by another reviewer (KQ1 and 2). Quality assessments were completed by two reviewers independently in duplicate (KQ3). Disagreements were resolved through discussion. We used various risk of bias tools suitable for study design. The GRADE framework was used for rating the certainty of the evidence. Results Ten studies evaluated the effectiveness of screening. One retrospective study reported no difference in long-term survival (approximately 6 to 12 years) between those who had a prior esophagogastroduodenoscopy and those who had not (adjusted HR 0.93, 95% confidence interval (CI) 0.58–1.50). Though there may be higher odds of a stage 1 diagnosis than a more advanced diagnosis (stage 2–4) if an EGD had been performed in the previous 5 years (OR 2.27, 95% CI 1.00–7.67). Seven studies compared different screening modalities, and showed little difference between modalities. Three studies reported on patients’ unwillingness to be screened (e.g. due to anxiety, fear of gagging). Eleven systematic reviews evaluated treatment modalities, providing some evidence of early treatment effect for some outcomes. Conclusions Little evidence exists on the effectiveness of screening and values and preferences to screening. Many treatment modalities have been evaluated, but studies are small. Overall, there is uncertainty in understanding the effectiveness of screening and early treatments. Systematic review registrations PROSPERO (CRD42017049993 [KQ1], CRD42017050014 [KQ2], CRD42018084825 [KQ3]).

Background Rituximab (RTX) is an effective treatment for patients with Rheumatoid Arthritis (RA). 1000mg (1 × 1000mg or 2 × 500mg) has similar 6-month efficacy as the registered dose of 2 × 1000mg. Based on several case reports and a case series even lower doses might be sufficient for maintenance treatment, potentially improving safety and decreasing costs.(1) Objectives To compare effectiveness of RTX retreatment with ultra-low doses (1 × 500mg or 1 × 200mg) to standard low dose (1 × 1000mg). Methods A 6-month double-blind randomised controlled non-inferiority trial (REDO study (2)) was performed in 5 centres in the Netherlands. Patients with RA responding well to RTX (based on DAS28-CRP Results The projected inclusion was met (n=142, table 1a). In both ultra-low dose groups 2 patients received an extra dose of 1000mg RTX due to a flare. The 500mg dose was non-inferior to 1000mg at 3 months (-0.04 (95% CI -0.39 to 0.30)), but not at 6 months (0.31 (95% CI -0.05 to 0.68). The 200mg dose was non-inferior to 1000mg at both time points. Because of our pre-defined hierarchical testing, non-inferiority could not formally be inferred for the 200mg dose. Mean DAS28-CRP scores remained low in all groups throughout the study, and B-cell counts decreased similarly at 3 months (figure 1). In the 200mg group, more patients received intramuscular corticosteroid injection(s) compared to the 1000mg group (table 1b). Conclusion Non-inferiority of retreatment with 1 × 500mg or 1 × 200mg rituximab versus 1 × 1000mg after 6 months could not formally be established. However, ultra-low doses appear similarly effective in the majority of RA patients, judged by DAS28-CRP course over time and B-cell results, with use of slightly more co-medication. References [1] Shenoy et al. Arthritis Rheumatol 2015;67(suppl 10). [2] Den Broeder et al. Trials 2017;30;18(1):403. Disclosure of Interests L.M. Verhoef: None declared, Nathan den Broeder: None declared, R.M. Thurlings Grant/research support from: Congress invitations: Roche, Abbvie, Cellgene, W.H. van der Laan: None declared, W. van der Weele: None declared, Marc Kok: None declared, H.J. Bernelot Moens: None declared, Thasia Woodworth: None declared, Bart van den Bemt Grant/research support from: UCB, Pfizer, Abbvie, Bristol-Myers Squibb, Consultant for: UCB, Novartis and Pfizer, Speakers bureau: Pfizer, AbbVie, UCB, Biogen, Sandoz, Frank van den Hoogen Grant/research support from: Grants, speakers fee, advisory boards: AbbVie, Actelion, Amgen, Boehringer Ingelheim, Biogen, BMS, Celgene, Celltrion Healthcare, Corbus, Janssen, Eli Lilly, Mundipharma, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme., Alfons den Broeder Grant/research support from: Congress invitations: Roche, Cellgene, Abbvie, Biogen, Consultant for: Expert Witness for Fresenius, BI, BMS, Amgen

Background: Rituximab (RTX), a monoclonal anti CD20 B-cell antibody is safe and effective in the treatment of Rheumatoid Arthritis (RA). The most optimal retreatment strategy in responding patients is still unclear. A recent study by Chatzidionysiou et al suggests that RTX retreatment with Fixed-Interval (FI) strategy is better than retreatment with an On-Demand (OD) strategy. [1] However, whether FI treatment strategy is also superior in a treat to target setting is not known. At our centre (Sint Maartenskliniek, the Netherlands), patients were retreated with RTX using the FI strategy and the OD strategy, by discretion of the rheumatologist, and using treat to target of DAS28CRP In the FI strategy, patients receive retreatment after a predefined fixed period, mostly every 6 months. In the OD strategy, patients receive retreatment in case they experience increase in disease activity. In our hospital, most of the OD strategy patients were switched to the FI strategy in 2014 based on best evidence at that time, enabling us to retrospectively compare effectivity of these strategies. Objectives: To compare the effectivity of retreatment of RA patients with RTX following the FI or OD retreatment strategy. Methods: Adult (≥18) RA patients (clinical diagnosis) who started RTX treatment (1 or 2 x 1000mg or 2 x 500mg intravenous) between 1-1-2008 and 1-6-2016 and received at least 3 infusion cycles were included. Patients were treated with either FI or OD strategy, or crossed over from OD to FI. For on demand treatment, RTX retreatment could be planned at the daycare within 2-4 weeks. Primary outcome was DAS28-CRP, secondary outcome was mean yearly dose of RTX. Baseline characteristics and follow up data (DAS28-CRP scores, information on RTX infusions, and steroid injections) were retrospectively extracted from patients’ health records. A linear mixed model was used to analyse the influence of the strategies on DAS28-CRP score. Time since start of RTX, calendar year, RTX dose, intra-articular (IA) or intramuscular (IM) steroid injection Results: 213 patients were included. 154 following FI strategy, 25 following the OD strategy and 34 switching from OD to FI. Median duration of follow up was 38 months (IQR: 23-64), with a median number of 8 (IQR 5-12) DAS28-CRP measurements per patient. Patient characteristics are shown in Table 1. The OD strategy was not associated with higher DAS28-CRP score compared to FI strategy: adjusted difference was 0.09 DAS28-CRP point (95% CI: -0.08 to 0.26). Regardless of used strategy, DAS28-CRP improved significantly both over year of treatment, and by time from the start of RTX treatment. Furthermore was rheumatoid factor positivity associated with an lower DAS28-CRP in all patients, with adjusted difference of - 0.37 (95%CI: - 0.60 to - 0.14). Average yearly RTX dose was 1899mg/yr (SD: 604) under the FI strategy and 1740mg/yr (SD: 732) under the OD strategy (95% CI difference: -336 to 34mg/yr). Conclusion: Retreatment of RA patients with a fixed interval strategy does not seem to lead to better disease control or more drug use compared to an on demand strategy. A possible explanation might be the use of treat to target in our centre. Our study suggests that either strategy might be chosen in shared decision making and following treat to target. References [1] Chatzidionysiou, et al. J Rheumatol. 2017 Feb;44(2):162-169. Disclosure of Interests: None declared

Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine. A biobank of ovarian cancer organoids recapitulates the histopathological and molecular hallmarks of patient tumors and provides a resource for preclinical research.

Diagnosis of mycosis fungoides and Sézary syndrome can be very challenging. Clinical and histopathologicadata for patients with mycosis fungoides and Sézary syndrome in Denmark are limited. A retrospective study was performed in Region Zealand, Denmark from 1990 to 2016. A total of 43 patients with mycosis fungoides or Sézary syndrome were identified during the period. At the time of diagnosis the patients’ mean age was 64.3 years and 74.5% had early-stage (≤IIA) disease. The mean time from onset of skin disease to diagnosis was 4.4 years. Surprisingly, 43% progressed to a higher disease stage, and risk of disease progression was higher for stage IB than IA (p = 0.01)All cases displayed some degree of epidermotropism and the infiltrates consisted of pleomorphic lymphocytes with a T-helper (CD4 +/CD8 –) phenotype. This study describes, for the first time, all aspects of clinical and histopathological findings in patients with mycosis fungoides and Sézary syndrome in a well-characterized Danish cohort.

Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL.

Objective: To investigate the cost-effectiveness of five different tumour necrosis factor inhibitor tapering strategies in patients with rheumatoid arthritis (RA) and stable low disease activity, using a modelling design. Method: Using Markov models based on data from the DRESS and STRASS randomized controlled trials, and the Nijmegen RA cohort, five tapering strategies for etanercept and adalimumab were tested against continuation: 1, four-step tapering (DRESS strategy); 2, five-step tapering; 3, tapering without withdrawal; 4, use of a stricter flare criterion; and 5, use of a theoretical predictor for successful tapering. We also examined how well a biomarker should be able to predict in order for strategy 5 to become cost-effective compared to the other strategies. Results: All examined tapering strategies were cost saving (range: EUR 5128 to 7873) but yielded more short-lived flares compared to continuation. The change in utilities compared to continuation was minimal and not clinically relevant (range: −0.005 to 0.007 quality-adjusted life-years). Strategy 1 was cost-effective compared to all other strategies [highest incremental net monetary benefit (iNMB)]. However, there was a large overlap in credible intervals, especially between strategies 1 and 2. Scenario analyses showed that 50% reduction of drug prices would result in the highest iNMB for strategy 2. A biomarker only becomes cost-effective when it is inexpensive and has a sensitivity and specificity of at least 84%. Conclusion: Because our study showed a comparable iNMB for tapering in four or five steps (including discontinuation), we recommend a choice between these strategies, based on shared decision making.

It is difficult to distinguish erythrodermic mycosis fungoides from Sézary syndrome due to their similar clinical and histological features. The main purpose of this study was to investigate whether microRNA expression profiles in lesional skin could discriminate patients with erythrodermic mycosis fungoides from those with Sézary syndrome. A further aim was to assess whether the microRNA expression profiles in erythrodermic mycosis fungoides skin was more comparable to microRNA expression profiles of Sézary syndrome or early-stage mycosis fungoides. RNA was extracted from diagnostic skin biopsies, followed by quantitative reverse transcription polymerase chain reaction analysis of 383 microRNAs. Twenty-seven microRNAs were significantly differentially expressed between erythrodermic mycosis fungoides and Sézary syndrome. Moreover, erythrodermic mycosis fungoides showed microRNA features overlapping with Sézary syndrome and early-stage mycosis fungoides, although hierarchical cluster analysis co-clustered erythrodermic mycosis fungoides with early-stage mycosis fungoides rather than with Sézary syndrome. These findings underscore that erythrodermic mycosis fungoides and Sézary syndrome are different diseases.

Background:Urate lowering therapies (ULT) are used to reduce hyperuricemia in gout patients (1). When gout remission is reached, patients often ask if ULT should be continued lifelong (treat to target strategy, T2T), or if tapering or stopping (a treat to symptom approach, T2S) can be attempted. In fact, although current rheumatology guidelines (1,2) suggest continuation, conclusive evidence for this is absent. Since ULT therapy adherence also remains suboptimal, exploring gout patients’ beliefs on different long term ULT treatment strategies is of great value.Objectives:To identify cognitions and emotions on ULT treatment strategies (T2T continuation and T2S cessation) of gout patients in remission with current or previous ULT use.Methods:Purposive sampling (3) was used to recruit patients from a general practice and a rheumatology department (Nijmegen, the Netherlands), with a clinical diagnosis of gout, current or previous ULT use and remission according to adapted (without serum urate criterion) preliminary gout remission criteria(4). Semi-structured interviews were conducted by two interviewers and audio-records were fully transcribed. Inductive thematic analysis (5) was used to analyse and interpret our data using the ATLAS.ti. software.Results:From a total of 18 patients (16 male/2 female), 14 patients were treated by a rheumatologist (10 currently using ULT, 1 intermittent and 3 previously) and 4 were treated by a general practitioner (all currently using ULT). Patients were satisfied with a T2T strategy, due to the absence of flares, a feeling of certainty and the reassurance of serum urate monitoring. Reluctance towards medication was reported, the importance of indefinite ULT use was questioned and its chronic use was addressed as a drawback. Reducing medication use by a T2S strategy was assessed positively and this strategy was considered less burdensome. A wish for and the willingness to follow a T2S approach was expressed. Fear and concerns of flaring after ULT cessation were expressed and were deemed both acceptable and unacceptable. See Table 1 for a schematic overview of the results.Table 1.Overview of patients’ perspectives on ULT treatment strategiesMotivation for a T2T strategyDrawbacks of a T2T strategy1. Being free of flares2. Acceptance of and contentment with chronic ULT use3. Feels secure due to regular SU monitoring4. No desire for change1. Resistance to (any) medication use2. Side effects of ULT3. Possibly detrimental to healthcare costsMotivation for a T2S strategyDrawbacks of a T2S strategy1. Doubt if chronic ULT use is necessary a. Possible restorative capacity of the body b. Curious to effects of ULT cessation2. Being free of ULT side effects3. Long term damage ULT unknown4. Less burdensome for patient and body5. Wish for minimization of (any) medication use1. Fear and insecurities on a. Flaring and not being able to function b. Joint damage2. Feels uncontrolled3. Hassle with visits, blood tests and medication adjustments when a flare occurs.Conclusion:This study provides an overview of perspectives on ULT treatment strategies of gout patients in remission. These results must be considered in developing educational material for patients and in future research on gout management, particularly in designing randomised clinical trials on this subject.References:[1]Richette P et al. Ann Rheum Dis. 2017;76(1):29-42.[2]FitzGerald JD et al. Arthritis Care Res (Hoboken). 2020;72(6):744-60.[3]Pope C et al. Qual Saf Health Care. 2002;11(2):148-52.[4]de Lautour H et al. Arthritis Care Res (Hoboken). 2016;68(5):667-72.[5]Pope C et al. Bmj. 2000;320(7227):114-6.Acknowledgements:We would like to thank dr. Erik Bischoff for his cooperation and help in including primary care patients from his general practice UGC Heyendael, Nijmegen the Netherlands.Disclosure of Interests:None declared

Background:Tumor Necrosis Factor inhibitors (TNFi) have proven to be safe and effective in the treatment of psoriatic arthritis (PsA) [1]. However, they carry disadvantages, such as adverse effects, patient burden, and costs, which could be reduced by treat-to-target (T2T) tapering. Although there is lack of high level evidence, guidelines suggest that T2T tapering and discontinuation might be considered, but no studies comparing this strategy to continuation in PsA were published [2].Objectives:To assess the effect of T2T TNFi tapering on disease activity and TNFi dosage in PsA patients with low disease activity (LDA).Methods:PsA patients using TNFi who visited the clinic between April 2012 and October 2018 were included if eligible for tapering, according to local protocol: ≥ 6 months of TNFi treatment and ≥ 6 months of at least LDA (DAS28-CRP < 2.4 (or 2.9 in patients with disease duration > 3 years) or by judgement of physician and patient). Patients with concomitant inflammatory disease preventing tapering were excluded. Three different time periods were defined: i) full-dose TNFi continuation; ii) TNFi tapering; iii) stable TNFi dosage after tapering. A mixed-model analysis was used to estimate mean DAS28-CRP during these three time periods. This model included: age, gender, disease duration, and the following time-varying components: current dose reduction status (three time periods mentioned above), time since eligibility for tapering and use of concomitant conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs), and a random intercept to account for inter-patient variability. Furthermore, a mean percentage of the Daily Defined Dose (%DDD) was calculated as secondary outcome.Results:152 patients were included, with a mean of 6.5 DAS28-CRP measurements, of whom 125 attempted dose reduction during follow-up. Median follow-up duration was 41 months (Inter Quartile Range (IQR) 24-59) for patients who never attempted dose reduction and 43 months (IQR 28-58) for those who did (table 1). The mixed model showed no significant difference in DAS28-CRP between the three time periods. Adjusted for gender, age, disease duration at baseline, time since follow-up and csDMARD use, the mean DAS28-CRP was 1.91 in the continuation period (95% Confidence Interval (CI) [1.76-2.05]) and 2.0 in both the TNFi tapering (95%CI [1.90-2.12], difference with continuation: 0.11, p=0.19) and stable TNFi dosage after tapering (95%CI 1.88-2.11], difference with continuation: 0.09, p=0.31) period. The mean percentage of the DDD for the three time periods was 107% for the continuation period; 62% in the TNFi tapering period and 79% in the stable TNFi dosage period.Conclusion:T2T tapering of TNFi appears to have no negative effects on disease activity in PsA patients compared with full dose continuation, and reduces drug exposure. DAS28-CRP might however not capture the full disease spectrum in PsA. Trials using PsA specific endpoints are needed to investigate tapering in a prospective and randomized manner.References:[1]Gossec L. et al. Ann Rheum Dis. 2016;75(3):499-510.[2]Verhoef LM. et al. Cochrane Database Syst Rev. 2019;5:CD010455.Table 1.Baseline characteristics of PsA patientsCharacteristicPsA (N=152)Female, n (%)60(39%)Age in years at inclusion, mean (SD)52(11)Disease duration at inclusion, years, median(IQR)9(3-14)Rheumatoid factor negative, n (%)*132 (87%)Anti-CCP negative, n (%)**136 (89%)Erosions on radiographic imaging, n (%)34(22%)Number of previous bDMARD, n (%) -0102(67%) -139(26%) -2 or 311(7%)Number of previous csDMARD, n (%) -021(14%) -150(33%) -≥ 281(53%)Current bDMARD use, n (%) -Adalimumab49(32%) -Etanercept81(53%) -Golimumab3(2%) -Infliximab19(13%)Current csDMARD use, n (%) -None71(46%) -Methotrexate65(43%) -Leflunomide12(8%) -Hydroxychloroquine1(1%) -Sulfasalazine3 (2%)Duration of current bDMARD use at inclusion, years, median (IQR)3(1-5)Duration of follow-up, months, median (IQR)43(28-58)*Available for 144 of 152 patients** Available for 145 of 152 patientsDisclosure of Interests:Celia Michielsens: None declared, Nathan den Broeder: None declared, Michelle Mulder: None declared, Mark Wenink: None declared, Frank van den Hoogen Consultant of: Advisor board Abbvie and Galapagos, L.M. Verhoef: None declared, Alfons den Broeder Consultant of: received consultancy honoraria from Abbvie, Amgen, Cellgene, Roche, Biogen, Lilly, Novartis, Celltrion Sanofi, Gilead., Grant/research support from: received research grants (to the institution) from Abbvie, Amgen, Cellgene, Roche, Biogen, Lilly, Novartis, Celltrion Sanofi, Gilead.

Background:Several risk factors for severe COVID-19 have been identified1. An important question is whether in addition to these generic risk factors, patients with a potentially altered immune response, either by disease (inflammatory rheumatic diseases (IRDs)) or use of immunomodulatory agents (IA), carry a higher or lower risk of severe COVID-19. In addition, several other potential risk factors for severe COVID-19 have been suggested, such as vitamin D status and specific medication (NSAIDs, ACE-inhibitors)2.Objectives:To identify risk factors for severe COVID-19, requiring hospitalization, in patients with IRDs.Methods:Multicenter, unmatched nested case control study in four rheumatology centers in the Netherlands. Cases are IRD patients requiring hospitalization for COVID-19 between March 1st 2020 and May 31st 2020. Control patients are IRD patients not hospitalized for COVID-19 within this period and were included in a 1:4 ratio. Patient-, disease- and treatment characteristics were extracted (still ongoing) from electronic patient files, and a questionnaire was used to collect additional data (e.g. on behavioral aspects). Potential risk factors for severe COVID-19 were analyzed using unconditional logistic regression, corrected for confounders.Results:77 cases and 198 controls were included. 26 case patients died as a result of COVID-19, 14 were admitted to the ICU. Crude ORs for female sex, age, BMI and presence of one or more comorbidities were 0.46 (95% CI 0.27-0.29), 1.1 (95%CI 1.0-1.1), 1.0 (95%CI 0.98-1.1) and 3.0 (95%CI 1.7-5.2) respectively. Table 1 displays corrected OR, highlighted when OR 2.0. Corrected ORs were not significantly increased for any IRD, but a trend for gout was present. Use of hydroxychloroquine (HCQ) shows a protective effect, while use of other csDMARDs than methotrexate or HCQ leads to a higher risk of severe COVID-19. Trends were present for increased risk for rituximab (RTX), glucocorticoids and ACE inhibitors, and protective effect for IL-6R blockers.Conclusion:The outcomes of this study are in agreement with other research regarding risk of severe COVID-19 related to IRDs and use of IA1. The suggested increased risk of severe COVID-19 in RTX use is of concern and should be monitored closely. Strengths of this study include low bias due to behavioral effects as only cases early in the pandemic were included, completeness of the determinants of interest and ultimately, it provides answers to a relevant and urgent question.References:[1]Williamson, Elizabeth J et al. “Factors associated with COVID-19-related death using OpenSAFELY.” Nature vol. 584,7821 (2020): 430-436.[2]Rizk, John G et al. “Pharmaco-Immunomodulatory Therapy in COVID-19.” Drugs vol. 80,13 (2020): 1267-1292.[3]Rentsch, Christopher T et al. “Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.” The Lancet Rheumatology vol. 3,1 (2021): e19-e27.Table 1.Corrected ORs for several potential risk factorsPotential risk factorCorrected OR (95% CI)IRDRA*1.38 (0.68 – 2.8)Spondylarthritis0.60 (0.25-1.5)Gout2.8 (0.80-9.8)Polymyalgia0.54 (0.18-1.6)Systemic diseases1.6 (0.49-5.0)DMARDscsDMARDs (any)0.39 (0.17-0.88) Methotrexate0.90 (0.46-1.7)HCQ0.40 (0.16-0.98)Other2.0 (0.99-4.1)bDMARDs (any)0.96 (0.43-2.2) TNF-inhibitors1.0 (0.43-2.6) IL6R-blockers0.43 (0.044 – 4.2)RTX4.5 (0.25-79)tsDMARDs0.89 (0.08-9.8)OtherGlucocorticoids > 10 mg/day2.5 (0.70-9.0)NSAIDs0.82 (0.37-1.8)ACE-inhibitors3.4 (1.6-7.1)Vitamin D sufficient0.77 (0.40-1.5)*incl. unspecified arthritisDisclosure of Interests:Merel Opdam Grant/research support from: has received research grants (to the institution) from Gilead, S Benoy: None declared, L.M. Verhoef: None declared, Sandra van Bijnen: None declared, Femke Lamers-Karnebeek: None declared, R.A.M. Traksel: None declared, Petra Vos: None declared, Alfons den Broeder Grant/research support from: has received consultancy honoraria, congress invitations and research grants (to the institution) from Abbvie, Amgen, Cellgene, Roche, Biogen, Lilly, Novartis, Celltrion Sanofi, Gilead. Is coinventor on a rituximab related patent (pending)., Jasper Broen Consultant of: has received consultancy fees from Gilead and Galapagos.

Background:Immune mediated inflammatory diseases (IMIDs) like rheumatoid arthritis (RA) are often treated with immunomodulatory agents (IA). Infection risks appear to be slightly increased in IMID patients using IA1. However, it remains uncertain whether it is best to continue or temporary interrupt IA in case of an infection For this decision, it is essential to know patient’s perceptions about both strategies. Unfortunately, little is known about the patients’ perceptions on this topic.Objectives:To explore the patients’ perspectives on continuation and temporary interruption of IA in case of an infection and assess possible barriers and facilitators.Methods:Semi-structured interviews were conducted in IMID patients using IA. Patients were recruited from the rheumatology, dermatology and gastroenterology departments of two hospitals in the Netherlands. Purposive sampling was used to select a diverse patient population. Semi-structured interviews were performed until data saturation was reached and analyzed using inductive thematic analysis.Results:19 patients with 6 different IMIDs and 17 different IA were interviewed. The majority was female, mean age 51 years and mean disease duration 17 years. Four had experienced a severe infection (requiring hospitalization). 15 patients indicated that they would prefer to continue their IA in case of an infection, however, for most patients this would depend on the infection severity. Several facilitators and barriers were identified (Table 1). Patients mentioned disease flare as a barrier for temporary interruption. Beliefs about susceptibility to infections form barriers and facilitators for both temporary interruption and continuation. Patients also mentioned that they would follow their physician’s advice on continuation/temporary interruption.Table 1.Identified barriers and facilitatorsTemporary interruptionBarriersDisease flare and its impactLoss of IA effects or increased side effects after restartingLong duration of interruptionBelief: IA has no/a positive effect on infection (risk)Belief: not more susceptible for infectionsPractical barriersNot aware of possibility of interruptionNot following physician’s adviceFacilitatorsMore severe and/or longer lasting infectionInteractions with medication needed for infectionPositive effect of interruption on immune systemShort duration of interruptionBelief: more susceptible for infectionsBelief: IA has a negative effect on infection (risk)Concerned about infectionsCurrent stable diseasePhysician’s adviceLong duration of IA effectsWish to taper/stop IA in generalNegative impact of infection on daily activitiesContinuationBarriersBelief: more susceptible for infectionsBelief: IA has a negative effect on infection (risk)Negative previous experiences during infectionLoss of IA effects after long useInteractions with medication needed for infectionFacilitatorsBelief: not more susceptible for infectionsBelief: IA has no/a positive effect on infection (risk)Not concerned about infectionsIA needed to control IMIDMild infectionPositive previous experiences with continuationPhysician’s adviceConclusion:Interviewed patients seemed to prefer continuation of IA during an infection if possible. The concern of disease flare might form a barrier for temporary interruption, this is in line with a previous study, showing that RA patients fear disease flare after dose reduction 2.References:[1]Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. 2015;386(9990):258-65.[2]Verhoef LM, Selten EMH, Vriezekolk JE, de Jong AJL, van den Hoogen FHJ, den Broeder AA, et al. The patient perspective on biologic DMARD dose reduction in rheumatoid arthritis: a mixed methods study. Rheumatology. 2018;57(11):1947-55.Disclosure of Interests:Merel Opdam Grant/research support from: has received research grants (to the institution) from Gilead, L.M. Verhoef: None declared, Johanna Vriezekolk: None declared, Bart van den Bemt: None declared, Alfons den Broeder Grant/research support from: has received consultancy honoraria, congress invitations and research grants (to the institution) from Abbvie, Amgen, Cellgene, Roche, Biogen, Lilly, Novartis, Celltrion Sanofi, Gilead. Is coinventor on a rituximab related patent (pending)

Objective Previous studies have suggested that transportation noise may increase risk for breast cancer, but existing literature is scarce and inconclusive. We aimed to investigate associations between road traffic and railway noise and risk for breast cancer across the entire Danish female population. Methods For all 2.8 million residential addresses across Denmark, we modelled road and railway noise at the most and least exposed facades for the period 1990–2017. We calculated 10-year time-weighted mean noise exposure for 1.8 million women aged >35 years, of whom 66,006 developed breast cancer during follow-up from 2000 to 2017. We analysed data using Cox proportional hazards models with noise exposure included as 10-year running means and adjusted for a number of individual and area-level socioeconomic co-variates and air pollution with fine particles estimated for all addresses. Results For exposures at the least exposed facade, we found that a 10 dB increase in 10-year time-weighted noise was associated with incidence rate ratios (IRRs) and 95% confidence intervals (CI) for breast cancer of 1.032 (1.019–1.046) for road noise and 1.023 (0.993–1.053) for railway noise. For exposures at the most exposed facade, the IRRs (95% CIs) were 1.012 (1.002–1.022) for road noise and 1.020 (1.001–1.039) for railway noise. Associations were strongest among women with human epidermal growth factor receptor 2 negative breast cancer. Conclusions Road traffic and railway noise were associated with higher risk for breast cancer, especially noise at the least exposed facade, which is a proxy for noise exposure during sleep.

Background: Few studies have investigated whether road traffic noise is associated with gestational diabetes mellitus (GDM), and have yielded inconsistent findings. We aimed to investigate whether maternal exposure to residential transportation noise, before and during pregnancy, was associated with GDM in a nationwide cohort. Methods: From the Danish population (2004–2017) we identified 629,254 pregnancies using the Danish Medical Birth Register. By linkage with the National Patient Registry, we identified 15,973 pregnancies complicated by GDM. Road traffic and railway noise (Lden) at the most and least exposed façades for all residential addresses from five years before pregnancy until birth were estimated for all. Analyses were conducted using generalized estimating equation models with adjustment for various individual and area-level sociodemographic covariates gathered from Danish registries, as well as green space and air pollution (PM2.5) estimated for all addresses. Results: We found no positive associations between road traffic noise at either façade and GDM. For railway noise, a 10 dB increase in railway noise at the most and least exposed façades during the first trimester was associated with GDM, with an odds ratio (OR) of 1.06 (95% confidence interval (CI): 1.03–1.10) and 1.07 (95% CI: 1.02–1.13), respectively. We found indications of higher odds of GDM among women exposed to both high road traffic and railway noise at the least exposed facade during the first trimester (OR: 1.24; 95% CI: 1.07–1.44). Conclusion: In conclusion, this nationwide study suggests that railway noise but not road traffic noise might be associated with GDM.

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. The inflammatory microenvironment in mycosis fungoides is complex. There is accumulating evidence that the neoplastic T-cells take control of the microenvironment and thereby promote their own expansion by suppressing cellular immunity. B-cells have proved to be upregulated in large-cell transformed mycosis fungoides, and could potentially play a role in disease progression. To investigate the presence of B-cells in mycosis fungoides compared with controls, this study analysed 85 formalin-fixed and paraffin-embedded mycosis fungoides biopsies. MS4A1 gene expression was significantly upregulated in mycosis fungoides compared with controls (p < 0.0001) and further upregulated in disease progression, (p = 0.001). Digital quantification of PAX5+/ CD20+ cells confirmed the increased presence of Bcells in mycosis fungoides compared with controls. No co-labelling of CD3/CD20 was observed in the neoplastic T-cells. This study found a significantly increased presence of B-cells in the tumour-associated microenvironment in mycosis fungoides. These findings could potentially lead to new treatment strategies for mycosis fungoides.