AB0563 DISCONTINUATION OF ANTI-TNFα IN PATIENTS WITH PSORIATIC ARTHRITIS: A SINGLE-CENTER EXPERIENCE

Background:TNF inhibitors have been largely demonstrated to be effective and reasonably safe for the treatment of psoriatic arthritis (PsA). Current EULAR guidelines recommend the use of an anti-TNF as first choice treatment in patients with PsA for whom a synthetic DMARD (usually methotrexate or leflunomide) is not efficacious or not well tolerated [1]. In a scenario where biologic treatments are easily available, and the treat to target strategy is widely accepted, a complete disease remission or at least a minimal disease activity are considered realistic goals to be achieved in a growing proportion of patients [2]. However, there remains very little research regarding anti-TNF discontinuation in patients who achieved a complete remission [3-5].Objectives:The primary aim of this study was to measure the disease-free interval after anti-TNF discontinuation, secondary it was investigated whether the use of Power Doppler Ultrasound (PDUS) and Contrast Enhanced Ultrasound (CEUS) could improve the diagnostic accuracy in the recognition of the relapse. Finally, we wanted to characterize the clinical features of the disease recurrence.Methods:From June 2018, 35 patients with PsA (27 males and 8 female) treated with anti-TNF, in stable remission were prospectively monitored for 1 year after treatment discontinuation. Remission was defined as documented absence of clinical and ultrasonographic signs of arthritis or enthesitis. Complete rheumatological and dermatological examinations were performed in all participants, at baseline and every 8-12 weeks: American College of Rheumatology (ACR) 66-68 joint count; Psoriasis Area Severity Index (PASI); patient pain visual analog score (VAS); patient global disease activity VAS; Health Assessment Questionnaire (HAQ); Leeds Enthesitis Index (LEI); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); Bath Ankylosing Spondylitis Functional Index (BASFI); Power Doppler Ultrasound (PDUS) of the involved joints and entheses, Contrast Enhanced Ultrasound (CEUS) of a selected joint or enthesis and laboratory inflammation tests.Results:31 out of the 35 enrolled patients, experienced a disease recurrence with an average disease-free interval of 27.9±21.1 weeks (Figure 1). In 3 patients the treatment was restored for a relapse of the skin psoriasis, 8 patients reported only axial symptoms of disease relapse and 20 patients had both axial and peripheral joints involvement (average DAPSA score of 23.6±11.1; average BASDAI score of 4.7±2.6; average BASFI score 4.5±2.9). In all cases the disease flare was moderate and all patients promptly regained remission after restarting the treatment. Both PDUS and CEUS were safe and reliable showing a good percentage of accordance (95,4%) in detecting synovitis and enthesitis.Conclusion:The rate of disease relapse of PsA after anti-TNF discontinuation is relevant. However the disease-free interval was not short. Retreatment with the same anti-TNF was effective and safe.References:[1]Gossec L, Baraliakos X, Kerschbaumer A, et al. EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update. Ann Rheum Dis. 2020 Jun;79(6):700-712.[2]Dures E, Shepperd S, Mukherjee S, et al. Treat-to-target in PsA: methods and necessity. RMD Open. 2020 Feb;6(1):e001083.[3]Stober C, Ye W, Guruparan T, et al. Prevalence and predictors of tumour necrosis factor inhibitor persistence in psoriatic arthritis. Rheumatology (Oxford). 2018 Jan 1;57(1):158-163.[4]Huynh DH, Boyd TA, Etzel CJ, et al. Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis. RMD Open. 2017 Jan 16;3(1):e000395.[5]Ye W, Tucker LJ, Coates LC. Tapering and Discontinuation of Biologics in Patients with Psoriatic Arthritis with Low Disease Activity. Drugs. 2018 Nov;78(16):1705-1715.Disclosure of Interests:None declared

Post-activation brain warming: A 1-H MRS thermometry study

Purpose Temperature plays a fundamental role for the proper functioning of the brain. However, there are only fragmentary data on brain temperature (Tbr) and its regulation under different physiological conditions. Methods We studied Tbr in the visual cortex of 20 normal subjects serially with a wide temporal window under different states including rest, activation and recovery by a visual stimulation- Magnetic Resonance Spectroscopy Thermometry combined approach.We also studied Tbr in a control region, the centrum semiovale, under the same conditions. Results Visual cortex mean baseline Tbr was higher than mean body temperature (37.38 vs 36.60, P<0.001). During activation Tbr remained unchanged at first and then showed a small decrease (-0.20 CA\ub0) around the baseline value. After the end of activation Tbr increased consistently (+0.60 CA\ub0) and then returned to baseline values after some minutes. Centrum semiovale Tbr remained unchanged through rest, visual stimulation and recovery. Conclusion These findings have several implications, among them that neuronal firing itself is not a major source of heat release in the brain and that there is an aftermath of brain activation that lasts minutes before returning to baseline conditions

Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15)

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15

The brain is hypothermic in patients with mitochondrial diseases

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation. \ua9 2014 ISCBFM

The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in the Chinese population

The c.G4883C variant in the leucine-rich repeat kinase 2 (LRRK2) gene (protein effect: Arg1628Pro) has been recently proposed as a second risk factor for sporadic Parkinson's disease in the Han Chinese population (after the Gly2385Arg variant). In this paper, we analyze the Arg1628Pro variant and the associated haplotype in a large sample of 1,337 Han subjects (834 patients and 543 controls) ascertained from a single referral center in Taiwan. In our sample, the Arg1628Pro allele was more frequent among patients (3.8%) than among controls (1.8%; p = 0.004, OR 2.13, 95% CI 1.29-3.52). Sixty heterozygous and two homozygous carriers of the Arg1628Pro variant were identified among the patients, of which only one was also a carrier of the LRRK2 Gly2385Arg variant. We also show that carriers of the Arg1628Pro variant share a common, extended haplotype, suggesting a founder effect. Parkinson's disease onset age was similar in patients who carried the Arg1628Pro variant and in those who did not carry it. Our data support the contention that the Arg1628Pro variant is a second risk factor for Parkinson's disease in the Han Chinese population. Adding the estimated effects of Arg1628Pro (population attributable risk [PAR] ∼4%) and Gly2385Arg variants (PAR ∼6%) yields a total PAR of ∼10%

Effect of resveratrol on mitochondrial function: Implications in parkin-associated familiar Parkinson's disease

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but the molecular mechanisms controlling these events are not completely understood. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator known as master regulator of mitochondrial functions and oxidative metabolism. Recent studies, including one from our group, have highlighted altered PGC-1α activity and transcriptional deregulation of its target genes in PD pathogenesis suggesting it as a new potential therapeutic target. Resveratrol, a natural polyphenolic compound proved to improve mitochondrial activity through the activation of several metabolic sensors resulting in PGC-1α activation. Here we have tested in vitro the effect of resveratrol treatment on primary fibroblast cultures from two patients with early-onset PD linked to different Park2 mutations. We show that resveratrol regulates energy homeostasis through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) and raise of mRNA expression of a number of PGC-1α's target genes resulting in enhanced mitochondrial oxidative function, likely related to a decrease of oxidative stress and to an increase of mitochondrial biogenesis. The functional impact of resveratrol treatment encompassed an increase of complex I and citrate synthase activities, basal oxygen consumption, and mitochondrial ATP production and a decrease in lactate content, thus supporting a switch from glycolytic to oxidative metabolism. Moreover, resveratrol treatment caused an enhanced macro-autophagic flux through activation of an LC3-independent pathway. Our results, obtained in early-onset PD fibroblasts, suggest that resveratrol may have potential clinical application in selected cases of PD-affected patients

Use of Secukinumab in a Cohort of Erythrodermic Psoriatic Patients: A Pilot Study

Erythrodermic psoriasis (EP) is a dermatological emergency and its treatment with secukinumab is still controversial. Furthermore, no data exist regarding the prognostic value of drug abuse in such a condition. We performed a multi-center, international, retrospective study, enrolling a sample of EP patients (body surface area &gt; 90%) who were treated with secukinumab (300 mg) during the study period from December 2015 to December 2018. Demographics and clinical data were collected. Drug abuses were screened and, specifically, smoking status (packages/year), cannabis use (application/week) and alcoholism-tested with the Alcohol Use Disorders Identification Test (AUDIT)-were assessed. All patients were followed for up to 52 weeks. We enrolled 13 EP patients, nine males, and four females, with a median age of 40 (28-52) years. Patients na\uefve to biologic therapy were 3/13. Regarding drug use, seven patients had a medium-high risk of alcohol addiction, three used cannabis weekly, and seven were smokers with a pack/year index of 295 (190-365). The response rate to secukinumab was 10/13 patients with a median time to clearance of three weeks (1.5-3). No recurrences were registered in the 52-week follow-up and a Psoriasis Area Severity Index (PASI) score of 90 was achieved. The entire cohort of non-responders (n = 3) consumed at least two drugs of abuse (alcohol, smoking or cannabis). Non-responders were switched to ustekinumab and obtained a PASI 100 in 24 weeks. However, given our observed number of patients using various drugs in combination with secukinumab in EP, further studies are needed to ascertain drug abuse prevalence in a larger EP cohort. Secukinumab remains a valid, effective and safe therapeutic option for EP

Deflazacort for the treatment of Duchenne Dystrophy: A systematic review

BACKGROUND: To complete a systematic review and meta-analysis based on the clinical question: Is Deflazacort (DFZ), a prednisolone derivative, an effective therapy for improving strength, with acceptable side effects, in children with Duchenne Dystrophy (DD)? METHODS: MEDLINE, EMBASE, Current Contents, Dissertation Abstracts, Health Star, PsychINFO and Cochrane, were searched using the following inclusion criteria: 1) A randomized controlled trial comparing DFZ with placebo or another therapy; 2) Male participants age 2–18 years with DD; 3) Outcomes of (a) any form of strength or functional testing, or (b) any form of side effect. RESULTS: Fifteen studies of potential relevance were identified, with five meeting the inclusion criteria. These five studies included 291 children and were published in English language journals between 1994 and 2000. Two studies compared DFZ versus placebo, two studies compared DFZ with prednisone and one study had both placebo and prednisone comparisions. Two large trials were identified that have not been published in article format. Due to the heterogeneity in outcome measures and the inconsistent reporting of summary statistics a meta-analytic approach could not be taken. CONCLUSIONS: Examining individual studies it appears that DFZ improves strength and functional outcomes compared to placebo, but it remains unclear if it has a benefit over prednisone on similar outcomes. Two trials found that DFZ causes less weight gain than prednisone

Gene expression differences in peripheral blood of Parkinson's disease patients with distinct progression profiles

The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention