FRI0499 ACROMEGALY ARTROPATHY: IS THERE SOMETHING MORE BEHIND THE PAIN? A CROSS-SECTIONAL STUDY TO EVALUATE RHEUMATIC DISEASE IN GROWTH HORMONE SECRETING TUMOR PATIENTS

Background:Acromegaly is a rare disease with a remarkable impact on patients, both in terms of life expectancy and quality of life. Osteo-articular complications are one of the most frequently reported bothers. The "acromegaly artropathy" characterizes more than 70% of patients at diagnosis. Artropathy affects both spine and peripheral joints. A recent prospective study documented progression of acromegalic arthropathy identified as a worsening of osteophytes and joint space narrowing in 72–74% of patients despite long-term biochemical control. In addiction the Literature has occasionally reported cases of simultaneous presence of rheumatic diseases (rheumatoid arthritis, polymyalgia rheumatica, undifferentiated connective tissue diseases) and acromegaly and in all these cases the treatment has been delayed, because of wrong symptoms attribution to acromegaly artropathy.Objectives:The primary goal of the study is to better characterize joint pain in acromegaly patients and to evaluate the prevalence of rheumatic disease in growth hormone (GH) secreting pituitary tumor patients.Methods:We enrolled 20 acromegaly subjects (AS) and 20 control subjects (CS). In each subject immunological pattern (rheumatoid factor – RF; antinuclear antibodies - ANA, ENA; anti-citrullinated protein antibodies - ACPA; erythrocyte sedimentation rate – ESR) has been evaluated; they, also, underwent bilateral joint ultrasound of hands and wrists and nail capillaroscopy. The Chi square test and the Fisher's exact test were used to evaluate the association between binary variables, while the Spearman's test to evaluate the correlation of continuous ones. A multiple or logistic regression model was calculated in order to define the association between the capillaroscopic alterations and other detected variables.Results:Articular pain emerged as significantly more frequent in AS (p = 0.0269). No statistically significant differences are detected regarding immunological pattern. ANA and ENA screening resulted positive in 10% in AS and in 5% in CS. No IgA ACPA were detected in AS or CS, while IgG ACPA were positive only in one AS subject. No significant differences were detected between IgM and IgG RFin the two groups (AS 5% and CS 0%). Three fold higher IgG FR in AS compared to CS were detected. ESR levels were significantly higher than CS (p = 0.0405), as well as increased power doppler (PWD) articular uptake (AS 30% vs CS 5% p 0.081). The capillaroscopic evaluation showed a significant difference in almost each parameter that has been evaluated (logistic regression: number of enlargement p 0.004, hemorragies p 0.01 and capillaries p 0.001), showing a moderate-severe microangiopathy in AS. Interestingly, analyzing only the acromegaly cohort, we noticed higher GH levels at the enrollment in patients which developed capillary enlargements (GH: 0.95 ng/ml IQ 0,6-1,6) compared to other ones (GH: 0.55 ng/ml IQ 0.4-0.7; p = 0.08) and a significant lower number of hemorrhages (p = 0.02) in patients treated with GH antagonist pegvisomant.Conclusion:Our results demonstrated that joint damage in acromegaly does not seem to have an autoimmune etiology. Therefore, articular damage is mechanical and increased ESR and PWD alterations seems to confirm the presence of an inflammatory component. In addition, acromegaly is characterized by a microvascular pattern of moderate-severe microangiopathy, without correlation to IGF-I, but GH levels. Although requiring further confirmatory studies, our preliminary results seem to indicate how the capillaroscopic examination could be useful to detect earlier microangiopathy and to identify patients with a greater risk of macroangiopathy development..References:[1]Claessen KMJA et al. Bone and joint disorders in acromegaly. Neuroendocrinology. 2016;103(1):86-95.[2]Örük G et al. Is every joint symptom related to acromegaly? Endocrine. 2013 Apr;43(2):404-11.Disclosure of Interests:None declare

POS0090 RISK OF QT INTERVAL PROLONGATION ASSOCIATED WITH CHRONIC USE OF HYDROXYCHLOROQUINE IN RHEUMATIC PATIENTS AND THE EFFECT OF COTREATMENTS

Background:Hydroxychloroquine (HCQ) has been used safely for over 60 years in rheumatic patients. However, following its recent use in covid-19 disease, its safety has been questioned, following controversial reports of cardiac toxicity1, possibly related to a prolongation of the QT interval2.Objectives:To explore the influence of chronic treatment with hydroxychloroquine on QT interval in rheumatic patients, and the possible effects of drug-to-drug interference3.Methods:12-lead electrocardiogram tracings were recorded with standard equipment in 229 ambulatory patients (SLE = 53, RA = 52, SSc = 56, UCTD = 38, Others = 30). The present analysis was performed on corrected QT intervals (QTc) calculated according to Framingham formula (QTc = QT+0.154 (1−RR)), with ULN = 449 ms in males, and 467 ms in females. Estimated glomerular filtrate rate (eGFR) was calculated from serum creatinine with the CKD-EPI equation. The influence on QTc values of demographic variables, chronic (≥3 months) HCQ treatment, and of the use of selected comedications -Statins, Angiotensin Converting Enzyme inhibitors (ACEi), Angiotensin Receptor Blockers (ARBs), Selective Serotonin Reuptake Inhibitors (SSRIs), Proton-Pump Inhibitors (PPI), Calcium Channel Blockers (CCBs) – were evaluated by parametric or non parametric statistical methods, as appropriate. All statistic al analyses were performed with the IBM SPSS statistical package version 25.Results:Table 1.Demographic and clinical variables in patients treated with HCQ (HCQ+) and in controls (HCQ-).NAgeYrs±SDFemaleN%eGFRmL/min/1.73m2StatinsN%ACEiN%ARBN%SSRIN%PPIN%CCBN%All22958.02±14.3620690.087.1418.962912.74821.8198.3146.113860.33013.1HCQ+13258.71±14.4912292.487.0020.041813.63224.2118.396.88060.61712.9HCQ-9757.51±14.308486.687.3217.471111.31616.588.255.25859.81313.4p0.5320.1830.8970.6900.1891.0000.7821.0001.000Demographic variables, and the use of evaluated comedications were not different in HCQ+ and HCQ- patients (Table 1). In the whole population, the QTc mean duration was 416.72 ± 20.70 ms, and was correlated with age (r = 0.215, p= 0.001), but not with gender (p = 0.548), eGFR (r = -0.93, p = 0.163), or disease (p = 0.092). In only 4 patients (HCQ+: 3 (2.3%) – HCQ-: 1 (1%), p = 0.639) QTc duration was above ULN.QTc duration was not associated with the use of Statins, ACEi, ARBs, or SSRIs (p = 0.454, 0.276, 0.475, and 0.131 respectively), but was significantly prolonged in patients treated with HCQ (421.26 ± 19.19 vs 410.55 ± 21.18 msec, p < 0.001), PPIs (420.57 ± 21.45 vs 410.89 ± 18.12 ms, p < 0.001), and CCBs (424.22 ± 25.97 vs 415.59 ± 19.62 ms, p < 0.033). Furthermore, as reported in Fig. 1, our data show a trend - albeit not statistically significant - towards an additive effect on QT prolongation of the association of PPIs and CCBs with HCQ, even more evident in the case of association of the 3 drug classes.Conclusion:In this study, the QTc interval was significantly prolonged in patients treated with hydroxychloroquine as compared to controls, although significant prolongation was extremely infrequent. Furthermore, our data revealed signs of drug-drug interference, suggesting that regular monitoring of the electrocardiogram is advisable in these patients, often undergoing cotreatment with multiple drugs.References:[1]Imad M. Tleyjeh, et al. The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis. Mayo Clin Proc Innov Qual Outcomes. 2020 Nov 2 doi: 10.1016/j.mayocpiqo.2020.10.005 [Epub ahead of print].[2]Teodoro J. Oscanoa, et al. Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: A Meta-analysis. Int J Antimicrob Agents.[3]Byung Jin Choi, et al. Risk of QT prolongation through Drug-drug Interactions between Hydroxychloroquine and Concomitant Drugs Prescribed in Real-world Practice. Preprint from Research Square, 22 Sep 2020 DOI: 10.21203/rs.3.rs-79572/v1 PPR: PPR217328.Disclosure of Interests:None declare

On the Mechanism of Time--Delayed Feedback Control

The Pyragas method for controlling chaos is investigated in detail from the experimental as well as theoretical point of view. We show by an analytical stability analysis that the revolution around an unstable periodic orbit governs the success of the control scheme. Our predictions concerning the transient behaviour of the control signal are confirmed by numerical simulations and an electronic circuit experiment.Comment: 4 pages, REVTeX, 4 eps-figures included Phys. Rev. Lett., in press also available at http://athene.fkp.physik.th-darmstadt.de/public/wolfram.htm

Phase II study of the safety and efficacy of oral capecitabine in patients with platinum-pretreated advanced or recurrent cervical carcinoma

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Treatment of Acute Myeloid Leukemia with 20-30% Bone Marrow Blasts

The transition of patients with ≥20% <30% bone marrow (BM) blast from the FAB category of myelodysplasia to the family of acute myeloid leukemia (AML) according to the recent WHO classification has not resolved the argument as to whether the natural history and responsiveness to therapy of these diseases is comparable to that of AML with > 30% BM blast. These controversies are even more manifest when it comes to elderly patients in whom concern for intensive chemotherapy (IC) related toxicity is the critical determinant for the therapeutic choice. In fact, due to concerns of treatment-related morbidity and mortality associated with delivery of IC, approximately only 30% of all patients ≥65 years are considered eligible for this approach. Therefore, a great deal of attention has been dedicated to alternative agents such as hypomethylators (azacitidine and decitabine). Actually, these agents have shown efficacy with reduced toxicity when administered to elderly patients with 20–30% BM blasts and not eligible for IC. In the present review, we will discuss the clinical results achieved in the treatment of elderly patients with 20%–30% BM blasts AML using intensive chemotherapy (IC) or hypomethylating agents. Overall, our survey of the literature suggests that only controlled, randomized, clinical trials will answer the question as to whether hypomethylating agents has the potential to substitute for IC even in elderly patients with an optimal functional status

Quasiperiodic time dependent current in driven superlattices: distorted Poincare maps and strange attractors

Intriguing routes to chaos have been experimentally observed in semiconductor superlattices driven by an ac field. In this work, a theoretical model of time dependent transport in ac driven superlattices is numerically solved. In agreement with experiments, distorted Poincare maps in the quasiperiodic regime are found. They indicate the appearance of very complex attractors and routes to chaos as the amplitude of the AC signal increases. Distorted maps are caused by the discrete well-to-well jump motion of a domain wall during spiky high-frequency self-sustained oscillations of the current.Comment: 10 pages, 4 figure

Intermittency transitions to strange nonchaotic attractors in a quasiperiodically driven Duffing oscillator

Different mechanisms for the creation of strange nonchaotic attractors (SNAs) are studied in a two-frequency parametrically driven Duffing oscillator. We focus on intermittency transitions in particular, and show that SNAs in this system are created through quasiperiodic saddle-node bifurcations (Type-I intermittency) as well as through a quasiperiodic subharmonic bifurcation (Type-III intermittency). The intermittent attractors are characterized via a number of Lyapunov measures including the behavior of the largest nontrivial Lyapunov exponent and its variance as well as through distributions of finite-time Lyapunov exponents. These attractors are ubiquitous in quasiperiodically driven systems; the regions of occurrence of various SNAs are identified in a phase diagram of the Duffing system.Comment: 24 pages, RevTeX 4, 12 EPS figure

POS0230 INTESTINAL MICROBIOTA CHANGES TNF-INHIBITORS INDUCED IN IBD-RELATED SPONDYLOARTHRITIS

Background:the close relationship between joints and gut inflammation has long been known and several data suggest that the dysbiosis could represents the link between Spondyloarthritis (SpA) and Inflammatory Bowel Diseases (IBD). To date, the manipulation of the intestinal microbiota is considered the key to the cure or control of the natural history of several pathologies sustained or favored by dysbiosis. The introduction of biologic drugs, in particular Tumor Necrosis Factor inhibitors (TNFi), revolutionized the management of both these diseases, thanks to the strong inhibition of inflammation and partially indirectly with mechanisms not yet fully clarified. While the impact of conventional drugs on gut microbiota is well known poor data are available about TNFi.Objectives:to investigate the impact of TNFi on gut microbiota.Methods:we included CD or UC patients fulfilling criteria for axial or peripheral SpA (ASAS 2009) on a typical Mediterranean diet, naïve to biologics needing TNFi. Clinical history, physical examination, instrumental examinations, biochemical examination including C-reactive protein (CRP), erhytrocyte sedimentation rate (ESR), HLA-B27 and fecal calprotectin at the baseline and after 6 months were performed. TNFi included infliximab and adalimumab. Fecal samples were collected by patients themselves by 24 hours before the start of the therapy. The processing was performed through metagenomic NGS (next generation sequencing) including the amplification of the V3 and V4 regions of the 16S (V3 and V4) and sequencing on the Illumina MiSeq platform. All patients received the treatment at least until week 24. Clinical disease indices included Visual Analogue Scale (VAS)-pain and Visual Analgue Scale(VAS)-disease activity for all patients, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for axial involvement, clinical disease activity index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI) for peripheral involvement, Harvey-Bradshaw Index for CD (HBI), or partial Mayo (pMAYO) score for UC, were assessed at baseline and at the end of the study. The study was approved by the ethics committee (approval code 0056924).Results:we evaluated 20 patients affected by enteropatic arthritis, naïve for biologic drugs, treated with TNFi. After six months of therapy we observed a significant increase in Lachnospiracae family (Δ +10.3, p 0.04) and in Coprococcus genus (Δ +2.8, p 0.003). We also observed a decrease trend in Proteobacteria (Δ -8.0 p 0.095) and Gammaproteobacteria (Δ -9, p 0.093) and an increase trend in Clostridia (Δ +8.2 p 0.083). We didn't find differences between TNFi responders (SpA improvement or IBD remission achieved) and not responders in terms of alpha and beta-diversity.Conclusion:the decrease of Proteobacteria and the increase of Lachnospiraceae and Coprococcus is consistent with the hypothesis that TNFi therapy, by decreasing inflammation, tends to restore the intestinal eubiosis. However further studies on larger cohort incuding the evaluation of gut virota and micobiota will be necessary to definitively clarify the effects of TNFi on the composition and function of the gut microbiota.References:[1]Bazin T et al. Sci Rep. 2018;8(1):5446.[2]Aden K et al. Gastroenterology. 2019;157(5):1279-1292.e11.Table 1.Comparison between clinical variables between baseline and T6 (six months)Clinical variablesT0T6P_valueFecal Calprotectin(μg/g)- median (IQR)207.5(125.5-446.2)81(50-197.2)0.004CRP(mg/L)- median(IQR)8.2(4.8-20.8)2.9(1-4)0.001ESR(mm/h)- median(IQR)21.5(10.8-34)11(7.8-21)0.003VAS_pain- median(IQR)50(38.8-60)35(10-42.5)0.001VAS_disease- median(IQR)50(38.8-50)37.5(25-42.5)0.006HAQ- mediana(IQR)0.6(0.1-0.8)0.2(0.1-0.6)0.004BASDAI_score- median(IQR)5.2(4.1-5.6)2.8(2.5-4.3)0.013CDAI_activity- median(IQR)13(10.5-16)7(5.2-11)0.004IBD activity n(%) - 011 (55%)20 (100%)0.174IBD activity n(%) - 16 (30%)0 (0%)IBD activity n(%) - 22 (10%)0 (0%)IBD activity n(%) - 31 (5%)0 (0%)Disclosure of Interests:None declared