A Systematic Review for the Management of the Genetically Defined Il-1-Mediated Autoinflammatory Diseases, Caps, Traps, Mkd and Dira

Background:Ultra-rare genetically defined IL-1 mediated autoinflammatory diseases (AIDs) include mevalonate kinase deficiency (MKD), tumor necrosis factor receptor associated periodic syndrome (TRAPS), cryopyrinopathies (CAPS) and deficiency of the IL-1 receptor antagonist (DIRA). These disorders start perinatally, the clinical disease manifestations include systemic inflammation; and late diagnosis and inappropriate treatment cause irreversible organ damage. The varying skills of treating rheumatologists and paediatricians illustrate the need for management guidance, however criteria for validated methodology is geared towards common diseases with more heterogeneous pathogenesis.Objectives:The focus of this systematic review includes the evaluation of the existing literature and the evaluation of existing EULAR methodology for use in the ultra-rare diseases with defined pathomechanisms, CAPS, TRAPS, MKD and DIRAMethods:EULAR standardized operating procedures were followed during the review, including a meeting of experts to discuss key words, inclusion/exclusion criteria and PICO questions. Three fellows established the protocol of the review under the supervision of the EULAR methodologist and PubMed, Embase, and Cochrane databases were searched up to September 30, 2019.Results:We found 1582 articles for CAPS, 1109 articles for TRAPS,1741 articles for MKD and 557 articles for DIRA. Duplications, animal models and basic science studies, conference papers, systematic reviews/meta-analysis and articles not in English language is excluded. If we excluded case reports (n<4), then 72 articles for CAPS, 40 articles for TRAPS,44 articles for MKD and 1 article for DIRA should be included for full text evaluation and data extraction (Figure 1). However among the case reports, patients excluded achieved complete remission, assessed by clinical criteria and biomarkers. Of the studies included only few randomized studies for CAPS, TRAPS, MKD, and DIRA and would achieve higher level of evidence (Figure 1).Figure 1.Flow-charts of systematic review for CAPS, TRAPS and MKD.Conclusion:CAPS, TRAPS, MKD and DIRA are monogenic diseases with defined pathways and outcomes that include inflammatory remission based on clinical and biomarker data. Current methodological evaluations for genetically complex diseases undervalue the published evidence in case reports that report on remission and IL-1 biomarkers. We suggest that case studies that include hard outcomes includinginflammatory remission, and open label withdrawal studies that are both backed by biomarkers could be allowed to be included and be considered for a stronger evidence level.References:[1]van der Heijde D, Aletaha D, Carmona L, et al 2014 Update of the EULAR standardised operating procedures for EULAR-endorsed recommendations Annals of the Rheumatic Diseases 2015;74:8-13.[2]Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I, Anton J, Arostegui JI, Barron K, Ben-Cherit E, Brogan PA, Cantarini L, Ceccherini I, De Benedetti F, Dedeoglu F, Demirkaya E, Frenkel J, Goldbach-Mansky R, Gul A, Hentgen V, Hoffman H, Kallinich T, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Laxer RM, Livneh A, Obici L, Ozen S, Rowczenio D, Russo R, Shinar Y, Simon A, Toplak N, Touitou I, Uziel Y, van Gijn M, Foell D, Garassino C, Kastner D, Martini A, Sormani MP, Ruperto N; Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO). Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025-1032.Disclosure of Interests:Roberta Berard: None declared, micol romano: None declared, Zehra Serap Arici: None declared, David Piskin: None declared, Olcay Jones: None declared, Karen Durrant: None declared, Raphaela Goldbach-Mansky: None declared, Marco Gattorno Consultant of: Sobi, Novartis, Speakers bureau: Sobi, Novartis, Erkan Demirkaya: None declare

Targeting of human interleukin-12B by small hairpin RNAs in xenografted psoriatic skin

<p>Abstract</p> <p>Background</p> <p>Psoriasis is a chronic inflammatory skin disorder that shows as erythematous and scaly lesions. The pathogenesis of psoriasis is driven by a dysregulation of the immune system which leads to an altered cytokine production. Proinflammatory cytokines that are up-regulated in psoriasis include tumor necrosis factor alpha (TNFα), interleukin-12 (IL-12), and IL-23 for which monoclonal antibodies have already been approved for clinical use. We have previously documented the therapeutic applicability of targeting TNFα mRNA for RNA interference-mediated down-regulation by anti-TNFα small hairpin RNAs (shRNAs) delivered by lentiviral vectors to xenografted psoriatic skin. The present report aims at targeting mRNA encoding the shared p40 subunit (IL-12B) of IL-12 and IL-23 by cellular transduction with lentiviral vectors encoding anti-IL12B shRNAs.</p> <p>Methods</p> <p>Effective anti-IL12B shRNAs are identified among a panel of shRNAs by potency measurements in cultured cells. The efficiency and persistency of lentiviral gene delivery to xenografted human skin are investigated by bioluminescence analysis of skin treated with lentiviral vectors encoding the luciferase gene. shRNA-expressing lentiviral vectors are intradermally injected in xenografted psoriatic skin and the effects of the treatment evaluated by clinical psoriasis scoring, by measurements of epidermal thickness, and IL-12B mRNA levels.</p> <p>Results</p> <p>Potent and persistent transgene expression following a single intradermal injection of lentiviral vectors in xenografted human skin is reported. Stable IL-12B mRNA knockdown and reduced epidermal thickness are achieved three weeks after treatment of xenografted psoriatic skin with lentivirus-encoded anti-IL12B shRNAs. These findings mimick the results obtained with anti-TNFα shRNAs but, in contrast to anti-TNFα treatment, anti-IL12B shRNAs do not ameliorate the psoriatic phenotype as evaluated by semi-quantitative clinical scoring and by immunohistological examination.</p> <p>Conclusions</p> <p>Our studies consolidate the properties of lentiviral vectors as a tool for potent gene delivery and for evaluation of mRNA targets for anti-inflammatory therapy. However, in contrast to local anti-TNFα treatment, the therapeutic potential of targeting IL-12B at the RNA level in psoriasis is questioned.</p

Expression of the chemokine receptor CCR5 in psoriasis and results of a randomized placebo controlled trial with a CCR5 inhibitor

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis

30-Day morbidity and mortality of bariatric metabolic surgery in adolescence during the COVID-19 pandemic – The GENEVA study

Background: Metabolic and bariatric surgery (MBS) is an effective treatment for adolescents with severe obesity. Objectives: This study examined the safety of MBS in adolescents during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This was a global, multicentre and observational cohort study of MBS performed between May 01, 2020, and October 10,2020, in 68 centres from 24 countries. Data collection included in-hospital and 30-day COVID-19 and surgery-specific morbidity/mortality. Results: One hundred and seventy adolescent patients (mean age: 17.75 ± 1.30 years), mostly females (n = 122, 71.8%), underwent MBS during the study period. The mean pre-operative weight and body mass index were 122.16 ± 15.92 kg and 43.7 ± 7.11 kg/m2, respectively. Although majority of patients had pre-operative testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 146; 85.9%), only 42.4% (n = 72) of the patients were asked to self-isolate pre-operatively. Two patients developed symptomatic SARS-CoV-2 infection post-operatively (1.2%). The overall complication rate was 5.3% (n = 9). There was no mortality in this cohort. Conclusions: MBS in adolescents with obesity is safe during the COVID-19 pandemic when performed within the context of local precautionary procedures (such as pre-operative testing). The 30-day morbidity rates were similar to those reported pre-pandemic. These data will help facilitate the safe re-introduction of MBS services for this group of patients

30-day morbidity and mortality of sleeve gastrectomy, Roux-en-Y gastric bypass and one anastomosis gastric bypass: a propensity score-matched analysis of the GENEVA data

Background: There is a paucity of data comparing 30-day morbidity and mortality of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and one anastomosis gastric bypass (OAGB). This study aimed to compare the 30-day safety of SG, RYGB, and OAGB in propensity score-matched cohorts. Materials and methods: This analysis utilised data collected from the GENEVA study which was a multicentre observational cohort study of bariatric and metabolic surgery (BMS) in 185 centres across 42 countries between 01/05/2022 and 31/10/2020 during the Coronavirus Disease-2019 (COVID-19) pandemic. 30-day complications were categorised according to the Clavien–Dindo classification. Patients receiving SG, RYGB, or OAGB were propensity-matched according to baseline characteristics and 30-day complications were compared between groups. Results: In total, 6770 patients (SG 3983; OAGB 702; RYGB 2085) were included in this analysis. Prior to matching, RYGB was associated with highest 30-day complication rate (SG 5.8%; OAGB 7.5%; RYGB 8.0% (p = 0.006)). On multivariate regression modelling, Insulin-dependent type 2 diabetes mellitus and hypercholesterolaemia were associated with increased 30-day complications. Being a non-smoker was associated with reduced complication rates. When compared to SG as a reference category, RYGB, but not OAGB, was associated with an increased rate of 30-day complications. A total of 702 pairs of SG and OAGB were propensity score-matched. The complication rate in the SG group was 7.3% (n = 51) as compared to 7.5% (n = 53) in the OAGB group (p = 0.68). Similarly, 2085 pairs of SG and RYGB were propensity score-matched. The complication rate in the SG group was 6.1% (n = 127) as compared to 7.9% (n = 166) in the RYGB group (p = 0.09). And, 702 pairs of OAGB and RYGB were matched. The complication rate in both groups was the same at 7.5 % (n = 53; p = 0.07). Conclusions: This global study found no significant difference in the 30-day morbidity and mortality of SG, RYGB, and OAGB in propensity score-matched cohorts

Herpes simplex virus encephalitis in pregnancy - a case report and review of reported patients in the literature

BACKGROUND: Herpes simplex virus (HSV) encephalitis is the most common sporadic cause of encephalitis with significant morbidity and mortality that is drastically reduced by early antiviral treatment. CASE PRESENTATION: We report a 37 year old woman, 33 weeks pregnant, who presented with seizures due to proven HSV-1 encephalitis, and who had had a previous episode of probable viral encephalitis aged 14 years. She was successfully treated with aciclovir on both occasions and, in the latter, went on to deliver a healthy infant. This case is compared with 17 cases of HSV encephalitis in pregnancy in the literature identifying a predominance in the late 2nd and 3rd trimesters, perhaps in part due to immunological changes in pregnancy. The clinical presentation is also compared with non-pregnant patients with HSV encephalitis in the largest prospective UK and European studies. We also present practical advice on management from recent national guidelines. CONCLUSION: When pregnant women present with new seizures, headache, impaired consciousness or altered behaviour urgent investigation is required to identify common diagnoses, such as eclampsia, venous sinus thrombosis and metabolic disturbances. Nevertheless, viral encephalitis is a very treatable cause of this presentation with potentially serious complications if missed, and may be more common in latter stages of pregnancy. Encephalitis should not be discounted if the patient is afebrile, has a normal Glasgow coma score, or the cerebrospinal fluid white cell count is only slightly elevated, as these features are well recognised in viral encephalitis

USE OF HIGH SURFACE NANOFIBROUS MATERIALS IN MEDICINE

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