A ciliary synapse for "short-circuit" neuromodulation.

Nearly all neurons contain a primary cilium, but little is known about how this compartment contributes to neuromodulatory signaling. In a new study, Sheu et al. use cutting-edge electron microscopy and fluorescence imaging techniques to reveal a new type of synapse that enables chemical transmission between serotonergic axons and the primary cilia of hippocampal neurons.

p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.

Spatiotemporal Control of CNS Myelination by Oligodendrocyte Programmed Cell Death through the TFEB-PUMA Axis.

Nervous system function depends on proper myelination for insulation and critical trophic support for axons. Myelination is tightly regulated spatially and temporally, but how it is controlled molecularly remains largely unknown. Here, we identified key molecular mechanisms governing the regional and temporal specificity of CNS myelination. We show that transcription factor EB (TFEB) is highly expressed by differentiating oligodendrocytes and that its loss causes precocious and ectopic myelination in many parts of the murine brain. TFEB functions cell-autonomously through PUMA induction and Bax-Bak activation to promote programmed cell death of a subset of premyelinating oligodendrocytes, allowing selective elimination of oligodendrocytes in normally unmyelinated brain regions. This pathway is conserved across diverse brain areas and is critical for myelination timing. Our findings define an oligodendrocyte-intrinsic mechanism underlying the spatiotemporal specificity of CNS myelination, shedding light on how myelinating glia sculpt the nervous system during development.

Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling.

During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving axon degeneration upon local deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present in axons, the cell body is an active participant in gating axonal caspase activation and axon degeneration. Loss of trophic support in axons initiates retrograde activation of a somatic pro-apoptotic pathway, which, in turn, is required for distal axon degeneration via an anterograde pro-degenerative factor. At a molecular level, the cell body is the convergence point of two signaling pathways whose integrated action drives upregulation of pro-apoptotic Puma, which, unexpectedly, is confined to the cell body. Puma then overcomes inhibition by pro-survival Bcl-xL and Bcl-w and initiates the anterograde pro-degenerative program, highlighting the role of the cell body as an arbiter of large-scale axon removal.

Pathological axonal death through a MAPK cascade that triggers a local energy deficit.

Axonal death disrupts functional connectivity of neural circuits and is a critical feature of many neurodegenerative disorders. Pathological axon degeneration often occurs independently of known programmed death pathways, but the underlying molecular mechanisms remain largely unknown. Using traumatic injury as a model, we systematically investigate mitogen-activated protein kinase (MAPK) families and delineate a MAPK cascade that represents the early degenerative response to axonal injury. The adaptor protein Sarm1 is required for activation of this MAPK cascade, and this Sarm1-MAPK pathway disrupts axonal energy homeostasis, leading to ATP depletion before physical breakdown of damaged axons. The protective cytoNmnat1/Wld(s) protein inhibits activation of this MAPK cascade. Further, MKK4, a key component in the Sarm1-MAPK pathway, is antagonized by AKT signaling, which modulates the degenerative response by limiting activation of downstream JNK signaling. Our results reveal a regulatory mechanism that integrates distinct signals to instruct pathological axon degeneration.

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.

iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging.

The visualization of molecularly labeled structures within large intact tissues in three dimensions is an area of intense focus. We describe a simple, rapid, and inexpensive method, iDISCO, that permits whole-mount immunolabeling with volume imaging of large cleared samples ranging from perinatal mouse embryos to adult organs, such as brains or kidneys. iDISCO is modeled on classical histology techniques, facilitating translation of section staining assays to intact tissues, as evidenced by compatibility with 28 antibodies to both endogenous antigens and transgenic reporters like GFP. When applied to degenerating neurons, iDISCO revealed unexpected variability in number of apoptotic neurons within individual sensory ganglia despite tight control of total number in all ganglia. It also permitted imaging of single degenerating axons in adult brain and the first visualization of cleaved Caspase-3 in degenerating embryonic sensory axons in vivo, even single axons. iDISCO enables facile volume imaging of immunolabeled structures in complex tissues. PAPERCLIP:

Trial of Cinpanemab in Early Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

Locally renewing resident synovial macrophages provide a protective barrier for the joint.

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.

Dopamine Pathway and Parkinson's Risk Variants Are Associated with Levodopa-Induced Dyskinesia.

BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2. OBJECTIVES: Our goal was to investigate the effects of genetic variants on risk and time to LID. METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147). CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Young-GRAPPA 2023: The Future Is Bright.

Two years after its inception, Young Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (Y-GRAPPA) has established itself as a productive network for junior investigators and clinicians. The group's achievements in the last year include updating the educational GRAPPA slide library, the "Bring a Derm" campaign to expand the GRAPPA community to include more dermatologists, and the publication of multiple "Do Not Miss" newsletters covering the highlights on PsDs from the major international conferences (American Academy of Dermatology [AAD] Annual Meeting, European Alliance of Associations for Rheumatology [EULAR] Congress, European Academy of Dermatology and Venereology [EADV] Congress, and American College of Rheumatology [ACR] Convergence).

The effect of sleep restriction therapy for insomnia on REM sleep fragmentation: A secondary analysis of a randomised controlled trial.

Rapid eye movement sleep fragmentation is hypothesised to be a reliable feature of insomnia, which may contribute to emotion dysregulation. Sleep restriction therapy, an effective intervention for insomnia, has the potential to reduce rapid eye movement sleep fragmentation through its manipulation of basic sleep-wake processes. We performed secondary data analysis of a randomised controlled trial to examine whether sleep restriction therapy reduces rapid eye movement sleep fragmentation in comparison to a matched control arm. Participants (n = 56; 39 female, mean age = 40.78 ± 9.08 years) were randomly allocated to 4 weeks of sleep restriction therapy or 4 weeks of time in bed regularisation. Ambulatory polysomnographic recordings were performed at baseline, week 1 and week 4. Arousals during rapid eye movement and non-rapid eye movement sleep were scored blind to group allocation. The following rapid eye movement sleep fragmentation index was the primary outcome: index 1 = (rapid eye movement arousals + rapid eye movement awakenings + non-rapid eye movement intrusions)/rapid eye movement duration in hours. Secondary outcomes were two further indices of rapid eye movement sleep fragmentation: index 2 = (rapid eye movement arousals + rapid eye movement awakenings)/rapid eye movement duration in hours; and index 3 = rapid eye movement arousals/rapid eye movement duration in hours. A non-rapid eye movement fragmentation index was also calculated (non-rapid eye movement arousals/non-rapid eye movement duration in hours). Linear-mixed models were fitted to assess between-group differences. There was no significant group difference for the primary rapid eye movement fragmentation index at week 1 (p = 0.097, d = -0.31) or week 4 (p = 0.741, d = -0.06). There was some indication that secondary indices of rapid eye movement fragmentation decreased more in the sleep restriction therapy group relative to control at week 1 (index 2: p = 0.023, d = -0.46; index 3: p = 0.051, d = -0.39), but not at week 4 (d ≤ 0.13). No group effects were found for arousals during non-rapid eye movement sleep. We did not find clear evidence that sleep restriction therapy modifies rapid eye movement sleep fragmentation. Small-to-medium effect sizes in the hypothesised direction, across several indices of rapid eye movement fragmentation during early treatment, demand further investigation in future studies.

The effect of single-component sleep restriction therapy on depressive symptoms: A systematic review and meta-analysis.

Sleep restriction therapy is a behavioural component within cognitive behavioural therapy for insomnia and is an effective standalone treatment for insomnia, but its effect on depressive symptoms remains unclear. This review aimed to synthesise and evaluate the impact of single-component sleep restriction therapy on depressive symptoms relative to a control intervention. We searched electronic databases and sleep-related journals for randomised controlled trials and uncontrolled clinical trials, published from 1 January 1986 until 19 August 2023, that delivered sleep restriction therapy to adults with insomnia. Random-effects meta-analysis of standardised mean differences and Cochrane risk of bias assessment were performed on randomised controlled trials, while uncontrolled clinical trials were discussed narratively. The meta-analysis was pre-registered on PROSPERO (ID: CRD42020191803). We identified seven randomised controlled trials (N = 1102) and two uncontrolled clinical trials (N = 22). Findings suggest that sleep restriction therapy is associated with a medium effect for improvement in depressive symptoms at post-treatment (Nc = 6, g = -0.45 [95% confidence interval = -0.70 to -0.21], p < 0.001) and a small effect at follow-up (Nc = 4, g = -0.31 [95% confidence interval = -0.45 to -0.16], p < 0.001). Five of the seven included randomised controlled trials were judged to have a high risk of bias. Standalone sleep restriction therapy appears to be efficacious for improving depressive symptoms at post-treatment and follow-up. However, conclusions are tentative due to the small number of trials and because none of the trials was performed in a population with clinically defined depression. Large-scale trials are needed to test the effect of sleep restriction therapy in patients experiencing depression and insomnia. Findings also highlight the need to improve the standardisation and reporting of sleep restriction therapy procedures, and to design studies with more rigorous control arms to reduce potential bias.

Trends and factors associated with recent HIV testing among women in Haiti: a cross-sectional study using data from nationally representative surveys.

INTRODUCTION: In the Latin America and Caribbean region, Haiti is one of the countries with the highest rates of HIV. Therefore, this study examined the factors associated with HIV testing among women in Haiti and trends in HIV testing in 2006, 2012, and 2016/17. METHODS: Data from the last three Haitian Demographic and Health Surveys (2006, 2012, and 2016/17) were used. The analysis was restricted to women aged of 15-49 years who made their sexual debut. STATA/SE 16.0 was employed to analyze the data by computing descriptive statistics, Chi­square, and multilevel regression model to describe the trends and identify factors associated with HIV testing in Haiti. P-value less than 0.05 was taken as a significant association. RESULTS: HIV testing prevalence increased more than twofold from 2006 (8.8%) to 2017 (21.3%); however, it decreased by 11.6% between 2012 and 2016/17. Additionally, the results indicated that age, place of residence, region, education level, wealth index, mass media exposure, marital status, health insurance, age at first sex and number of sexual partners were significantly associated with HIV testing. CONCLUSIONS: To significantly increase HIV testing prevalence among women, the Haitian government must invest much more in their health education while targeting vulnerable groups (youth, women in union, and women with low economic status).

Plastic Quantification and Polyethylene Overestimation in Agricultural Soil Using Large-Volume Pyrolysis and TD-GC-MS/MS.

Quantification of microplastics in soil is needed to understand their impact and fate in agricultural areas. Often, low sample volume and removal of organic matter (OM) limit representative quantification. We present a method which allows simultaneous quantification of microplastics in homogenized, large environmental samples (>1 g) and tested polyethylene (PE), polyethylene terephthalate (PET), and polystyrene (PS) (200-400 µm) overestimation by fresh and diagenetically altered OM in agricultural soils using a new combination of large-volume pyrolysis adsorption with thermal desorption-gas chromatography-tandem mass spectrometry (TD-GC-MS/MS). Characteristic MS/MS profiles for PE, PET, and PS were derived from plastic pyrolysis and allowed for a new mass separation of PET. Volume-defined standard particles (125 × 125 × 20 µm3) were developed with the respective weight (PE: 0.48 ± 0.12, PET: 0.50 ± 0.10, PS: 0.31 ± 0.08 µg), which can be spiked into solid samples. Diagenetically altered OM contained compounds that could be incorrectly identified as PE and suggest a mathematical correction to account for OM contribution. With a standard addition method, we quantified PS, PET, and PEcorrected in two agricultural soils. This provides a base to simultaneously quantify a variety of microplastics in many environmental matrices and agricultural soil.

Invader removal triggers competitive release in a threatened avian predator.

Changes in the distribution and abundance of invasive species can have far-reaching ecological consequences. Programs to control invaders are common but gauging the effectiveness of such programs using carefully controlled, large-scale field experiments is rare, especially at higher trophic levels. Experimental manipulations coupled with long-term demographic monitoring can reveal the mechanistic underpinnings of interspecific competition among apex predators and suggest mitigation options for invasive species. We used a large-scale before-after control-impact removal experiment to investigate the effects of an invasive competitor, the barred owl (Strix varia), on the population dynamics of an iconic old-forest native species, the northern spotted owl (Strix occidentalis caurina). Removal of barred owls had a strong, positive effect on survival of sympatric spotted owls and a weaker but positive effect on spotted owl dispersal and recruitment. After removals, the estimated mean annual rate of population change for spotted owls stabilized in areas with removals (0.2% decline per year), but continued to decline sharply in areas without removals (12.1% decline per year). The results demonstrated that the most substantial changes in population dynamics of northern spotted owls over the past two decades were associated with the invasion, population expansion, and subsequent removal of barred owls. Our study provides experimental evidence of the demographic consequences of competitive release, where a threatened avian predator was freed from restrictions imposed on its population dynamics with the removal of a competitively dominant invasive species.

[Head-to-head studies on psoriasis and psoriatic arthritis]. / Head-to-Head-Studien bei Psoriasis und Psoriasisarthritis.

Given the ever-increasing number of approved therapies for the treatment of psoriasis (PsO) and psoriatic arthritis (PsA), head-to-head (H2H) comparative studies are essential. These are aimed primarily at a comparative analysis of treatment effectiveness. In both PsO and PsA, biological disease-modifying antirheumatic drugs (bDMARD) have been shown to be superior to conventional therapies in H2H studies. In PsO interleukin 17 (IL-17) and IL-23 inhibitors proved superiority compared to tumor necrosis factor (TNF) inhibitors (etanercept and adalimumab) in several studies. Ustekinumab was more effective than etanercept, but less effective than IL-17 and IL-23 inhibitors. Only a few H2H studies have been published on the treatment of PsA. In the Spirit H2H study ixekizumab was superior to adalimumab using a combined endpoint of arthritis and psoriasis response (ACR-50 and PASI-100). When looking at arthritic symptoms only (ACR-20), secukinumab was not significantly superior to adalimumab in the EXCEED study but was superior in terms of the effect on skin involvement (PASI90). Other H2H studies focused on the treatment of enthesitis (ECLIPSA study), the efficacy of Janus kinase (JAK) inhibition (SELECT-PSA-1) or the additional administration of methotrexate to bDMARD treatment (MUST study). The H2H data have been incorporated into the treatment guidelines and have led to IL-17 and IL-23 inhibition being preferred over TNF inhibition in cases of relevant skin involvement in PsA.

Higher orthorexia tendency among female fashion models: an empirical international study.

PURPOSE: Female fashion models are more at risk for developing eating disorders than non-models due to the intense occupational pressure they face. The present study focuses on assessing whether female models are more prone to report orthorexia nervosa signs and symptoms than non-models. METHODS: Female fashion models (n = 179, mean age: 25.9 SD = 4.40 years) and an age adjusted control group (n = 261, mean age: 25.0 SD = 4.97 years) were selected by snowball sampling. Participants filled out an online survey containing anthropometric questions and the 18-item Eating Habits Questionnaire. RESULTS: According to BMI, fashion models were underweight (mean BMI = 18.1 SD = 1.68) while control participants' BMI was in the normal range (mean = 22.1 SD = 4.23, p < 0.001). On all three of Eating Habits Questionnaire subscales fashion models showed significantly higher average value (Knowledge subscale: M = 2.42 among models versus M = 2.08 in the control group, p < 0.01, Cohen's d = 0.52; Problems subscale: M = 1.93 among models versus M = 2.61 in the control group, p < 0.01, Cohen's d = 0.49; Feelings subscale: M = 3.20 among models versus M = 2.96 in the control group, p < 0.01, Cohen's d = 0.38). Orthorexic tendencies were reported by 35.1% of the models versus 20.2% of controls. CONCLUSION: Fashion models are at risk for the development of eating disorders. Even though not yet included in the DSM-5, the assessment of orthorexia nervosa among fashion models seems to be important. It is suggested to take appropriate measures to prevent the spread of disordered eating habits among models as they can lead to the development of anorexia nervosa or bulimia nervosa. LEVEL OF EVIDENCE: Level III, well-designed cohort study.

Prevalence and clinical associations of ultrasound-confirmed enthesitis in systemic lupus erythematosus.

OBJECTIVES: To assess the prevalence of US-confirmed enthesitis in a cohort of patients with SLE and to analyse the clinical associations to enthesitis during the course of SLE. METHODS: In a retrospective analysis of the SLE cohort of the Lupus Unit of the Careggi University Hospital, US examinations of SLE patients presenting with tender and/or swollen joints were retrieved to assess the presence of enthesitis. Patients with US-proven enthesitis were compared with SLE controls with tender and/or swollen joints who showed no US evidence of enthesitis. Clinical and laboratory features were compared at disease onset and during follow-up. RESULTS: A total of 400 patients fulfilling EULAR/ACR classification criteria for SLE were assessed. Of these, 106 underwent articular US examination. Evidence of enthesitis was found in 31/106 (29.2%) patients. Seventy-one patients without US-enthesitis were included as controls; four were excluded due to lack of follow-up data. Laboratory and clinical features were comparable between cases and controls at disease onset. Throughout a median follow-up of 10.0 (interquartile range [IQR] 8.3-23.3) years for cases and 12.4 (IQR 7.2-13.3) years for controls, patients with enthesitis were less likely to develop renal involvement (22.6% vs 46.5%, P = 0.028) and failed B cell depletion more frequently (75.0% vs 0%). CONCLUSION: In SLE patients with clinically active joints, US-proven enthesitis is a fairly common finding. Enthesitis in SLE could be the hallmark of a distinct disease phenotype with less renal involvement, more arthritis and low response to anti-CD 20 therapy, potentially requiring a tailored treatment.

Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis.

OBJECTIVE: miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. METHODS: Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. RESULTS: A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) ≥0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. CONCLUSION: miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.