FRI0191 CRANIAL-LIMITED AND LARGE-VESSEL GIANT CELL ARTERITIS: PRESENTING FEATURES AND OUTCOME

Background:Giant cell arteritis (GCA) comprises two main phenotypes: cranial (C) and large-vessel (LV) disease1. A full baseline steroid-free vascular imaging evaluation is required to properly diagnose LV involvement2Objectives:To compare presenting and prognostic features of LV-GCA and C-GCA patients after an adequate vascular imaging evaluation at baselineMethods:Data from GCA patients followed-up at our Institution were retrospectively collected. Only patients who underwent large-vessel imaging (PET, CTA, MRA) at disease onset or within 1 week after steroid introduction were included. Patients with evidence of LV involvement were classified as LV-GCA. Differences between LV-GCA and C-GCA patients regarding presenting features, treatment, prognosis were evaluated. Non-parametric tests were usedResults:In our cohort, we identified 161/280 patients who underwent LV-imaging study at baseline. Of these, 100 (62.1%) had signs of LV inflammation. Table 1 compares demographic features, diagnostic delay, pre-existing comorbidities and complementary treatment between the 2 groups. Table 2 compares disease features at diagnosis. Mean follow-up was similar between LV- and C-GCA patients (31.8±31.8 vs 27.8±29.1 months; 70% vs 73.8% followed-up ≥12 months). Corrected cumulative prednisone dose (CCPD, grams/months) was equivalent (LV, 0.67±0.57; C, 0.87±1.37; p=0.871). A DMARD was added in 73% of LV- and in 55.7% of C-GCA patients (p=0.027), but, notably, it was introduced at baseline in 52% of LV- vs 23.5% of C-GCA patients (p=0.006). CCPD was equivalent even considering only patients who did not receive DMARDs (LV, 0.92±0.81; C, 0.94±1.18; p=0.522). Frequency of relapses was not significantly different (LV, 51%; C, 57.3%, p=0.515), even when considering only DMARD-receiving patients (LV, 36.1%; C, 38.2%, p=0.833). Aortic aneurysms incidence at 5 years was similar (LV, 17.3%; C, 15.7%; p=0.826). Rate of metabolic and infective complications was similar, in terms of arterial hypertension (LV, 3%; C, 0%, p=0.286), diabetes (2% vs 0%, p=0.524), osteoporotic fractures (7% vs 5%, p=0.742), severe infections (3% vs 3.3%, p=1)Table 1.Demographic features, diagnostic delay, pre-existing comorbidities, and complementary treatment at baseline in LV and C-GCA patientsLV imaging +n=100 (%)LV imaging-n=61 (%)p-valueAge (years)73.2 ± 8.976 ± 8.80.018Sex (female)65 (65)40 (65)1Diagnostic delay (months)3.5 ± 4.62.3 ± 4.90.001Pre-existing comorbidities- CAD3 (3)7 (11.5)0.043- Diabetes4 (4)6 (9.8)0.181- Dyslipidemia17 (17)17 (27.9)0.114- Hypertension42 (42)34 (55.7)0.105- Stroke3 (3)3 (5)0.674- Cancer20 (20)6 (9.8)0.122Ongoing complementary treatment- Antiplatelet18 (18)15 (25)0.322- Anticoagulant1 (1)6 (9.8)0.012- Statin14 (14)14 (23)0.198Table 2.Diseases features at onset in LV and C-GCA patientsLV imaging +n=100 (%)LV imaging-n=61 (%)p-valueTemporal biopsy positive17/31 (55)9(43)0.573Symptoms- Headache65 (65)52 (85)0.006- Jaw claudication22 (22)20 (32.8)0.142- Scalp tenderness31 (31)26 (42.6)0.174- Ocular symptoms14 (14)20 (32.8)0.006- Ischemic optic neuropathy7 (7)17 (27.9)<0.001- Stroke3 (3)0 (0)0.290- Polymyalgia rheumatica42 (42)31 (50.8)0.328- Fever44 (44)12 (19.7)0.002- Fatigue72 (72)21 (34.4)<0.001- Weight loss37 (37)7 (11.5)<0.001- Cough10 (10)1 (1.6)0.053Laboratory findings, mean- C-reactive protein, mg/L80.8 ± 60.865.7 ± 58.20.057- Erythrocyte sedimentation rate76.8 ± 3071.5 ± 270.360- Hemoglobin, g/dL11.4 ± 1.512 ± 1.60.007- Platelet count389.4 ± 116.6366.8 ± 125.20.758Conclusion:LV-GCA patients are younger and suffer of a greater diagnostic delay. Although a greater systemic inflammation seems to be a feature of LV-GCA patients, the vascular prognosis is similar to C-GCA patients, who, conversely, have a greater incidence of ocular complicationsReferences:[1]Dejaco C, et al. Nat Rev Rheumatol (2017)[2]Kermani T, et al. Rheumatology (2019)Disclosure of Interests:Alessandro Tomelleri: None declared, Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Silvia Sartorelli: None declared, Nicola Farina: None declared, Elena Baldissera Speakers bureau: Novartis, Pfizer, Roche, Alpha Sigma, Sanofi, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOB

FRI0506 EFFICACY AND SAFETY OF CANAKINUMAB IN ADULT-ONSET STILL'S DISEASE: A SINGLE-CENTER REAL-LIFE EXPERIENCE

Background:The pro-inflammatory cytokine interleukin (IL)-1 has a central role in the pathogenesis of adult-onset Still's disease (AOSD), a rare auto-inflammatory condition. Anakinra, has been for years the cornerstone of IL-1-blocking therapy in AOSD. More recently, the monoclonal antibody canakinumab, a new agent blocking IL-1, has become availableObjectives:To describe our real-life experience with CNK in a cohort of AOSD patients from a single Italian CenterMethods:AOSD patients diagnosed according to Yamaguchi's criteria followed-up at our Autoinflammatory Unit and treated with CNK for at least 3 months were included. Demographic features, disease characteristics, reasons for CNK introduction, concomitant therapies, variation in systemic steroids dose, adverse events, and response to treatment were retrospectively evaluated. Non-parametric tests were used for statistical comparisonResults:13 patients (5 women; median age 49 years, range 21-74), treated with subcutaneous CNK 4 mg/kg 4-weekly, were identified. Median disease duration before CNK introduction was 12 (6-240) months. After CNK introduction, 2 patients were followed-up for 18 months, 3 for 12 months, 6 for 6 months, 2 for 3 months. CNK was introduced as first-line biologic DMARD in 6 patients. The other 7 patients had been already treated with at least one other bDMARD, for a total of 15 treatment courses (7, anakinra, ANK; 4, tocilizumab; 4, TNF-inhibitors), with a median bDMARD therapy duration of 8 (4-178) months. Previous bDMARDs had been interrupted because of inefficacy (8 cases) or adverse events (AE, 7 cases); of the 7 ANK-treated patients, therapy interruption was due to inefficacy in 3 cases. At CNK introduction, 11 patients were on systemic steroid therapy, prednisone (PDN) equivalent dose 15 (5-80) mg, and 10 were concomitantly receiving a conventional DMARD (7, methotrexate; 2, colchicine; 1, cyclosporine-A).Graphic 1summarizes main clinical features at CNK introduction. After CNK start, a striking and rapid clinical response was observed, as demonstrated by a substantial decrease of modified Pouchot score and a normalization of acute phase reactants after only 3 months (see Table 1 for details). CNK showed also a significant steroid-sparing effect: median PDN dose was reduced to 7.5 (2.5-12.5) mg at month 3 and 5 (0-7.5) mg at month 6; PDN was stopped in 3 patients (1 at month 3, 1 at month 6, 1 at month 12) due to optimal disease control. CNK was temporarily held-off in 3 patients (zoster reactivation, 1; prostatitis, 1; mild leukopenia, 1). We observed no case of primary inefficacyTable 1.Disease activity and blood tests at canakinumab introduction and during follow-upDaily prednisone dosemgBaseline(n=13)3 months(n=13)6 months(n=11)12 months(n=5)18 months(n=2)Pouchot score15 (5-80)7.5 (2.5-12.5)5 (0-7.5)5 (0-7.5)2.5VAS pain3 (2-5)1 (0-2)0 (0-1)00Erythrocyte sedimentation ratemm/h7 (2-10)3 (1-8)2 (1-4)1 (1-2)1C-reactive proteinmg/L42 (8-120)21 (2-69)13 (2-55)14 (2-41)11Ferritinng/mL20.8 (3-180)3.1 (0.5-22.5)1.6 (0.5-8.4)1 (0.3-6.3)0.5Hemoglobing/dL379.5 (161-914)282 (82-552)215 (34-464)177 (77-401)19913.1 (9.4-15.7)13.2 (10.7-15.3)13.8 (11.5-15.5)13.9 (11.3-14.3)13.5Figure 1.Graphic 1 Main clinical features at canakinumab introductionConclusion:Our real-life data confirm that CNK is highly effective and safe in AOSD treatment and has significant steroid-sparing effects. CNK showed its efficacy both as first-line therapy and after other bDMARDs failure, also in patients who have previously failed IL-1 inhibition through ANKReferences:[1] Cavalli G, et al. Treating rheumatological diseases and co-morbidities with interleukin-1 blocking therapies. Rheumatology (2015)[2] Cavalli G, et al. Efficacy of Canakinumab as First-Line Biologic Agent in Adult-Onset Still's Disease. Arthritis Res Ther (2019)Disclosure of Interests:Alessandro Tomelleri: None declared, Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Giacomo De Luca Speakers bureau: SOBI, Novartis, Celgene, Pfizer, MSD, Nicola Farina: None declared, Elena Baldissera Speakers bureau: Novartis, Pfizer, Roche, Alpha Sigma, Sanofi, Giulio Cavalli Speakers bureau: SOBI, Novartis, Pfizer, Lorenzo Dagna Grant/research support from: Abbvie, BMS, Celgene, Janssen, MSD, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, SG, SOBI, Consultant of: Abbvie, Amgen, Biogen, BMS, Celltrion, Novartis, Pfizer, Roche, SG, and SOB

A collagen IV-derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling

The angiopoietin (Ang)/Tie2 signaling pathway is essential for maintaining vascular homeostasis, and its dysregulation is associated with several diseases. Interactions between Tie2 and α5 β1 integrin have emerged as part of this control; however, the mechanism is incompletely understood. AXT107, a collagen IV–derived peptide, has strong antipermeability activity and has enabled the elucidation of this previously undetermined mechanism. Previously, AXT107 was shown to inhibit VEGFR2 and other growth factor signaling via receptor tyrosine kinase association with specific integrins. AXT107 disrupts α5 β1 and stimulates the relocation of Tie2 and α5 to cell junctions. In the presence of Ang2 and AXT107, junctional Tie2 is activated, downstream survival signals are upregulated, F-actin is rearranged to strengthen junctions, and, as a result, endothelial junctional permeability is reduced. These data suggest that α5 β1 sequesters Tie2 in nonjunctional locations in endothelial cell membranes and that AXT107-induced disruption of α5 β1 promotes clustering of Tie2 at junctions and converts Ang2 into a strong agonist, similar to responses observed when Ang1 levels greatly exceed those of Ang2. The potentiation of Tie2 activation by Ang2 even extended to mouse models in which AXT107 induced Tie2 phosphorylation in a model of hypoxia and inhibited vascular leakage in an Ang2-overexpression transgenic model and an LPS-induced inflammation model. Because Ang2 levels are very high in ischemic diseases, such as diabetic macular edema, neovascular age-related macular degeneration, uveitis, and cancer, targeting α5 β1 with AXT107 provides a potentially more effective approach to treat these diseases.Fil: Mirando, Adam C.. University Johns Hopkins; Estados UnidosFil: Shen, Jikui. University Johns Hopkins; Estados UnidosFil: Silva, Raquel Lima E.. University Johns Hopkins; Estados UnidosFil: Chu, Zenny. University Johns Hopkins; Estados UnidosFil: Sass, Nicholas C.. University Johns Hopkins; Estados UnidosFil: Lorenc, Valeria Erika. University Johns Hopkins; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Green, Jordan J.. University Johns Hopkins; Estados Unidos. AsclepiX Therapeutics; Estados UnidosFil: Campochiaro, Peter A.. University Johns Hopkins; Estados UnidosFil: Popel, Aleksander S.. University Johns Hopkins; Estados UnidosFil: Pandey, Niranjan B.. University Johns Hopkins; Estados Unidos. AsclepiX Therapeutics; Estados Unido

Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study

Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma. Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months. Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype. Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability. Funding: GlaxoSmithKline and UK Medical Research Council

Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.

OBJECTIVES: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities. RESULTS: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis. CONCLUSIONS: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms

Branch retinal vein occlusion associated with quetiapine fumarate

<p>Abstract</p> <p>Background</p> <p>To report a case of branch retinal vein occlusion in a young adult with bipolar mood disorder treated with quetiapine fumarate.</p> <p>Case Presentation</p> <p>A 29 years old gentleman who was taking quetiapine fumarate for 3 years for bipolar mood disorder, presented with sudden vision loss. He was found to have a superior temporal branch retinal vein occlusion associated with hypercholesterolemia.</p> <p>Conclusion</p> <p>Atypical antipsychotic drugs have metabolic side effects which require regular monitoring and prompt treatment.</p

Systemic pharmacological treatment of digital ulcers in systemic sclerosis: a systematic literature review

Objective: To evaluate the evidence concerning systemic pharmacological treatments for SSc digital ulcers (DUs) to inform the development of evidence-based treatment guidelines. Methods: A systematic literature review of seven databases was performed to identify all original research studies of adult patients with SSc DUs. Randomized controlled trials (RCTs) and prospective longitudinal observational studies (OBSs) were eligible for inclusion. Data were extracted, applying the patient, intervention, comparison, outcome framework, and risk of bias (RoB) was assessed. Due to study heterogeneity, narrative summaries were used to present data. Results: Forty-seven studies that evaluated the treatment efficacy or safety of pharmacological therapies were identified among 4250 references. Data from 18 RCTs of 1927 patients and 29 OBSs of 661 patients, at various RoB (total 2588 patients) showed that i.v. iloprost, phosphodiesterase-5 inhibitors and atorvastatin are effective for the treatment of active DUs. Bosentan reduced the rate of future DUs in two RCTs (moderate RoB) and eight OBSs at low to high RoB. Two small studies (moderate RoB) indicate that Janus kinase inhibitors may be effective for the treatment of active DUs, otherwise there are no data to support the use of immunosuppression or anti-platelet agents in the management of DUs. Conclusion: There are several systemic treatments, across four medication classes, that are effective therapies for the management of SSc DUs. However, a lack of robust data means it is not possible to define the optimal treatment regimen for SSc DUs. The relatively low quality of evidence available has highlighted further areas of research need

Non-surgical local treatments of digital ulcers in systemic sclerosis: a systematic literature review

Introduction: Digital ulcers (DUs) are difficult to treat in patients with systemic sclerosis (SSc) and systemic (i.e., pharmacological) therapy is currently considered the 'standard of care'. Our aim was to examine the safety and efficacy of local, non-surgical treatment for SSc-DUs. Methods: A systematic literature review (SLR) of original research articles up to August, 29 2022 was performed according to the PICO framework. References were independently screened by two reviewers and risk of bias was assed using validated tools. Due to study heterogeneity narrative summaries are used to present data. Results: Among 899 retrieved references, 14 articles were included (2 randomised trials (RTs), and 12 observational (OBS) studies). The most frequently studied procedure (5 studies) was botulin A toxin (hand or single finger) injection with a reported healing rate (HR) of 71%-100%. Amniotic and hydrocolloid membranes were examined in one study each and associated with a good HR. Tadalafil 2% cream was studied in a single study with a reduction in the number of DUs. Vitamin E gel was associated with a reduction in ulcer healing time. Low-level light therapy, hydrodissection and corticosteroid injection, extracorporeal shock wave (ESW) and photobiomodulation were evaluated in a single study each and showed a positive trend. Dimethyl sulfoxide was associated with significant local toxicity. Conclusions: A range of non-surgical, local treatments for SSc-DUs have been explored and showed efficacy to some extent. We have identified methodological flaws that should be avoided in the design of future studies to explore locally-acting treatments for SSc-DUs

Surgical management of digital ulcers in systemic sclerosis: A systematic literature review

Background: There is a strong rationale to develop locally-acting surgical treatments for digital ulcers (DUs) in patients with systemic sclerosis (SSc). Our aim was to examine the safety and efficacy of local surgical management for SSc-DU. Methods: A systematic literature review was carried out until to August 2022 using 7 different databases. Original research studies concerning adult patients with SSc-DUs, and local surgical treatments were analysed using the PICO framework. We included randomized controlled trials, prospective/retrospective studies, and case series (minimum of 3 patients) References were independently screened by two reviewers including assessment of the risk of bias using validated tools. Results: Out of 899, 13eligible articles were included. Autologous fat (adipose tissue AT) grafting was the surgical modality most identified (7 studies, 1 randomized controlled double blinded trial and 6 prospective open-label single arm studies). The healing rate (HR) with autologous fat grafting (4 studies) was 66-100&nbsp;%. Three studies reported autologous adipose-derived stromal vascular fraction grafting: HR of 32-60&nbsp;%. Bone marrow derived cell transplantation in a single study showed 100&nbsp;% healing rate over 4-24 weeks. Surgical sympathectomy was examined in 3 studies, prospective without comparator with a median healing rate of 81&nbsp;%. Two surgical studies (of direct microsurgical revascularisation and microsurgical arteriolysis) showed 100&nbsp;% healing of ulcers, with no complications. Conclusion: Several surgical approaches for SSc-DUs have demonstrated some degree of safety and effectiveness for DU healing. However, there are significant methodological issues. Future studies are warranted to rigorously investigate surgical interventions for SSc-DUs