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Background:Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterized by heterogeneous articular and periarticular manifestations. The achievement of remission or low disease activity is the goal of therapy. However, some patients experience primary failure and lack or loss of response to cs-, b- and ts-DMARDs. The treatment response could be affected by multiple factors, including epigenetic factors. Recently, some studies have suggested the possible involvement of lncRNAs in modulating treatment response [1]. In this context, the identification of genetic and epigenetic factors associated to treatment response could help to define new biomarkers for a more effective and personalized therapy.Objectives:The main aim of this study was to prospectively investigate lncRNAs potentially related to treatment response in a cohort of PsA patients treated with TNFi and IL17i, to identify potential predictors of drug treatment effectiveness. In addition, we analysed retrospectively a cohort of PsA patients treated with TNFi to look for possible association between lncRNAs genetic variants and the response after 6 and 12 months of TNFi.Methods:For the expression study, a cohort of 48 PsA patients starting a TNFi (n=28) or IL17i (n=20) drugs was recruited, monitoring their treatment response for 12 months in order to identify subgroup of patients Reponder e Non-Responder. For the genotyping study, we retrospectively analysed 163 PsA patients treated with TNFi. For each patient was estimated the Disease Activity in Psoriatic Arthritis (DAPsA) score at 6 and 12 months after the beginning of therapy. The expression level of lncRNA was analysed in a panel of 84 lncRNAs, after the extraction of total RNA from PBMCs. Then we validated the differentially expressed lncRNAs, resulted from the array experiments, by qRT-PCR using specific primer assay. Web-based data analysis tool (NPInter v4.0 and DIANALncBase v3) were used to confirm miRNA target genes of the validated lncRNAs. For the genotyping study, we extracted genomic DNA from PBMCs and we performed allelic discrimination assay by TaqMan assays. We evaluated a possible association between the selected SNPs and the response to therapy at 6 and 12 months from the beginning of the TNFi treatment, using the clinical parameter of DAPsA value.Results:We observed a significant difference in the expression level between Responder and non-Responder patients, of 4 lncRNAs in the group of PsA patients treated with TNFi and of 3 lncRNAs in the group of patients treated with IL17i. Then, we confirmed a significant decrease of MEG3 expression in non-Responder patients compared to Responder patients, both considering the whole cohort (P= 0.01) and stratifying patients by drugs (P= 0.05 and P= 0.03, respectively for TNFi and IL17i) (Figure 1). In addition, we observed an association between the variant allele of rs7158663 and a lower expression of MEG3 compared to the wild-type allele, although without statistical significance. We also observed that the variant allele of rs941576 (MEG3) was associated with a better response at T6 and T12, with a linear decrease of mean DAPsA value among wildtype, heterozygous and homozygous variant patients. Interestingly, we noticed that the variant allele of rs941576 SNV resulted associated with a better response regarding joints involvement. Indeed, the number of TJ and SJ decreases more in patients carrying the variant allele, both at T6 and T12 (P= 0.0006 and P= 0.032, respectively) (Table 1).Conclusion:Our study suggests a possible role, both in terms of genetic variability and expression, of the lncRNA MEG3 in the treatment response to TNFi and IL17i in PsA patients.REFERENCES:[1] De Benedittis G, Latini A, Ciccacci C, et al. Impact of TRAF3IP2, IL10 and HCP5 Genetic Polymorphisms in the Response to TNF-i Treatment in Patients with Psoriatic Arthritis. J Pers Med. 2022;12(7):1094.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Telomeres are specific regions of repetitive nucleotide sequences that protect chromosome ends and preserve genetic information. In each cell division, telomeres shorten, leading finally to apoptosis and cell cycle arrest when reaching a critical point. The telomere-associated protein (telomeric repeat-binding factor 1 [TERF1]) is essential for the maintenance of telomeres, acting as an inhibitor of telomerase, and its levels correlate with telomere length (TL).Shortened telomeres have been demonstrated in Rheumatoid Arthritis (RA). Furthermore, they are a recognized risk factor for idiopathic pulmonary fibrosis. Few data are present in the literature regarding TL in RA-associated interstitial lung disease (RA-ILD), while no data are present regarding TERF1 in RA and RA-ILD.Objectives:We aimed to evaluate the TL and TERF1 expression levels in RA-ILD.Methods:TL and TERF1 expression levels were evaluated in patients with RA-ILD compared to age-matched RA patients without lung involvement (RA-non-ILD) and healthy controls. Genomic DNA and total RNA were isolated from peripheral blood mononuclear cells. Relative TL was measured using real-time quantitative polymerase chain reaction (qPCR) assay, which quantifies a ratio of telomeric repeat copy signal and a reference single-copy gene (human beta globin) signal. Expression analysis of TERF1 was performed by qPCR assay. T-test was used to compare mean TL and TERF1 expression data among the different phenotypic groups. RA patients were divided according to whether their TL fell within or above the first quartile of the cohort. A multivariate logistic regression analysis was used to correct the p-value for sex, age and disease duration.Results:Eighty-nine RA patients were included (mean age 63.6 ± 13.8 years, median disease duration 9 [IQR 8.4-11.6] years): 42 RA-ILD and 47 RA-non-ILD. 21 age- and sex-matched controls were collected. RA-ILD patients were older and with minor disease duration than RA-non-ILD patients. They exhibited higher disease activity, CRP levels, positivity for RF and ACPA, and were more treated with bDMARDs than RA-non-ILD patients (Table 1). TL in all patients was significantly shorter compared to controls (p = 0.0016). RA-ILD patients presented significantly shorter TL compared to controls (p = 0.00001) and compared to RA-non-ILD (p = 0.0006) (Figure 1A). In the multivariate regression analysis, TL was reduced in RA-ILD compared with RA-non-ILD when adjusted for sex, age and disease duration (p<0.001). After patients stratification according to their TL, it is observed that the prevalence of ILD was significantly higher in patients with short vs normal-length telomeres (82.6% vs 34.8% p=0.00008). In RA-ILD, TL correlated negatively with disease duration (p= 0.007 r= -0.408). TERF1 expression levels were reduced in RA compared with controls (p= 2.17E-17). Both RA-ILD patients and RA-non-ILD patients exhibited reduced TERF1 expression levels than controls (p= 3.37E-10 and p= 2.78E-10, respectively. Figure 1B). TERF1 levels correlated positively with TL (p= 0.004 r= 0.328).Conclusion:Telomere shortening is a feature of immunosenescence and it has been linked to more severe articular disease. Shorter TL and reduced TERF1 expression levels characterize RA. In particular, RA-ILD patients displayed higher disease activity, negative prognostic factors, received more biologic treatments, and exhibited shorten TL than RA-non-ILD patients suggesting that TL might represent a hallmark of a more aggressive disease with lung involvement.Table 1.Figure 1.Acknowledgements:NIL.Disclosure of Interests:None declared.

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease typically associated with psoriasis and classified in the group of spondyloarthritis (1). The pathogenesis is based on an interplay of different genes interacting with several environmental factors including stress, trauma, infections, triggering an inflammatory response related to the activation of innate and acquired immunity in different tissues and organs (2). However, the risk for the development of PsA is not clearly understood. The aim of this study was to evaluate, in a cohort of Italian PsA out-patients of the Rheumatology Unit of the University of Rome Tor Vergata, the association of genetic variants in candidate genes for PSA susceptibility and their possible contribute in the modulation of clinical and laboratory features. The genes were selected according to previous studies describing these genes as involved in susceptibility to rheumatoid arthritis (RA) (3), since a common genetic background can be shared between these diseases. Nine SNPs (single nucleotide polymorphism) in eight candidate genes were analysed: STAT4 (rs7574865), TRAF3IP2 (rs33980500), TNFAIP3 (rs6920220 and rs2230926), MIR146A (rs2910164), PSORS1C1 (rs2233945), IL-10 (rs1800872), HCP5 (rs3099844) and ERAP1 (rs27524). Polymorphisms were analysed in 163 consecutive PsA out-patients and 198 healthy controls (HC). Genotyping was performed by allelic discrimination by TaqMan assay. Alleles frequencies differences between cases and controls or between phenotypic groups were compared using Pearson's χ 2 test. We have observed an association between PSA susceptibility and the variant alleles of STAT4 [OR= 1.60 (1.15-2.21), P= 0.005], TRAF3IP2 [OR= 1.65 (1.01-2.65), P= 0.04], ERAP1 [OR= 1.40 (1.05-1.85), P= 0.02] and TNFAIP3 (rs6920220) [OR= 1.75 (1.19-2.57), P= 0.004]. On the contrary, the variant allele of IL-10 polymorphism seems to play a protective role [OR= 0.74 (1.05-1.85), P= 0.05]. Moreover, in order to define a genetic risk profile, we have counted the total number of risk alleles in each subject, considering as risk alleles the allelic variant of rs7574865 (STAT4), rs33980500 (TRAF3IP2), rs6920220 (TNFAIP3) and rs27524 (ERAP1) SNPs. Then, we have compared the risk allele number distribution between patients and HC (Fig.1). Classes with 3 or more risk alleles are significantly more represented in patients than in HC (OR= 2.03, P=0.004). The risk to develop the disease increases significantly in subjects with at least four risk alleles (OR= 2.96, P=0.002). We confirm the associations between five SNPs, already studied in RA, and PSA susceptibility, suggesting a common inflammatory pathway in chronic inflammatory rheumatological diseases. Moreover, we show how the genotyping of only few associated SNPs could help to define a genetic risk profile for PSA development. [1]Calabresi E, et al. One year in review 2019: psoriatic arthritis. Clin Exp Rheumatol. 2020;38:1046-55. [2]Chimenti MS, Triggianese P, De Martino E, Conigliaro P, Fonti GL, Sunzini F, Caso F, Perricone C, Costa L, Perricone R. An update on pathogenesis of psoriatic arthritis and potential therapeutic targets. Expert Rev Clin Immunol. 2019 Aug;15(8):823-836. [3]Ciccacci C, et al. Polymorphisms in STAT-4, IL-10, PSORS1C1, PTPN2 and MIR146A genes are associated differently with prognostic factors in Italian patients affected by rheumatoid arthritis. Clin Exp Immunol. 2016;186:157-63. None declared [Display omitted]

The aim of this investigation was to elucidate whether the analgesic effect was due to the local aspirin or to the systemic drug. This was done by comparing skin and plasma levels of acetylsalicylic acid (ASA) and salicylic acid (SA) after topically administered ASA/diethyl ether (ADE) mixture in acute herpetic neuralgia (AHN) and postherpetic neuralgia (PHN). The analgesia and the plasma and skin levels of ASA were also determined after oral administration of aspirin. Nineteen patients, 11 (57.9%) with AHN and 8 (42.1 %) with PHN were given, on different days, a single 500-mg oral dose of ASA or a topical dose (750 mg) of (ADE) daubed onto the painful skin. The analgesic effect was assessed by means of a visual analogue scale (VAS). Overall pain relief was graded as: excellent, good, fair, or poor. AHN as well as PHN patients had severe pain at baseline (6.83 and 5.93). Levels of ASA and SA in plasma and in the stratum corneum after adhesive tape stripping of the treated area were determined by HPLC. After ADE application, the analgesic effect was very rapid and VAS scores were lower than at baseline. Pain significantly decreased by 82.6% after topical and 15.4% after oral ASA. After ADE, 95% of the patients had excellent or good pain relief, but after oral administration 79% of the patients had a poor response. Pain relief was similar in the two subgroups after ADE. Skin concentrations of ASA, but not of SA, after ADE were about 80- to 100-fold those after oral administration. Levels of ASA and SA in plasma after oral administration were similar to those previously found, but after ADE were undetectable or very low. Patients with excellent pain relief showed a trend towards higher ASA skin concentrations. The analgesic effect can be obtained only after topical administration, because by this route the skin levels of ASA are much higher than after oral administration. The mechanism is exclusively local; there are no active drugs in plasma after topical administration.

The aim of the present study was to compare cranial arteries blood flow velocity as measured by means of transcranial Doppler sonography (TCD) with mean regional cerebral blood flow (rCBF) as measured by means of single photon emission computed tomography (SPECT) in migraine with and without aura during headache-free periods and spontaneous and/or induced attacks. Regional cerebral blood flow (rCBF) and systematic ultrasonic Doppler flow were studied by Technetium-99m hexamethylpropilaminoxime (99mTc-HM-PAO) single photon emission computed tomography (SPECT) and transcranial Doppler sonography (TCD) respectively in controls (n=14) and in migraine with (n=13) and without aura (n=35) during headache free-intervals and spontaneous/histamine-induced attacks. In the migraine without aura group, Doppler flow examinations of the common carotid artery, external and internal carotid artery, ophthalmic artery and middle cerebral artery bilaterally did not reveal significant changes as compared with controls. During attacks, TCD examinations showed a moderate, although not statistically significant, reduction of blood flow velocity in the middle cerebral artery and in the internal carotid artery bilaterally as related to the interictal phase, concomitant with an increase of the flow velocity in the ophthalmic and external carotid artery. SPECT of these patients did not show, on the average, rCBF asymmetries during pain-free periods, although positive findings (i.e., focal hypoperfusion) were found in approximately half of the cases. During attacks, 74% of patients displayed a unilateral hypoperfusion, mainly in the occipital region. Low-flow areas were generally but not always consistent with the site of pain. In the migraine with aura group, significant reduction of blood flow velocity in middle cerebral artery was recorded by TCD on the affected side during attacks, as compared with the pain-free side. Hypoperfusion was registered between attacks by SPECT in approximately 2/3 of the patients. During attacks, a marked reduction of rCBF occurred in most patients (85%), mainly in the parieto-occipital region. The posterior rCBF asymmetries revealed at the SPECT and consistent with the general reduction of blood flow velocity documented by TCD may be related to cerebrovascular tone instability. Our findings do not support the paradigm that migraine with and without aura are two different entities.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression--and consequently, H3K36 trimethylation--was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.