Background Improvement on health-related quality of life (HRQoL) in patients with Systemic Lupus Erythematosus (SLE) remains a challenge. There is limited data on the level of agreement on remission according to physician and patient and remission impact on HRQoL and long-term outcomes. Objectives To investigate the prevalence and level of agreement between remission according to physician and patient criteria and to evaluate the impact of remission on HRQoL in patients with SLE. Methods Prospective study of patients included in RELESSER-PROS, a multicenter register of SLE patients. Protocol of the register has been previously described [1]. Remission according to physician was defined in agreement with DORIS 2021 criteria: clinical SLEDAI 0, physician global assessment ≤2 on a 0-10 Likert scale (equivalent to ≤0.5 on a 0-3 scale), stable low-dose prednisone (≤5mg) and stable immunosuppressive/ biologic agents if remission on therapy. Remission according to patient was defined as SLAQ (Systemic Lupus Activity Questionnaire) question 1 with no flare in the last 3 months (score 0).Patients were classified in three groups according to remission status by DORIS, SLAQ or both. Level of agreement was assessed using kappa statistics. Acceptable level of agreement was considered if kappa >0.60. Results 1102 patients, with a follow-up of at least 2 years (data from 3 visits available) were included in this analysis. Patient characteristics according remission status at baseline are presented in the Table 1. At baseline, remission by DORIS was present in 16.1%, by SLAQ 16.7% and 2.45% by both. Remission by DORIS was more frequent among patients with higher education, on immunosuppressant and biological therapy and patients with history of hospitalization; remission by SLAQ was more frequent among women, obese patients, and those on antimalarials (p<0.05). Symptoms reported in patients who considered themselves in remission were mainly cutaneous and articular (53.3%). Mean SLEDAI in patients on remission by SLAQ was 3.28 (3.78). Patients in remission by DORIS had significantly better results in patient reported outcomes (PRO) measured by EQ-5D and LIT (p<0.05). Level of agreement in remission according to physician and patient was 78.04% (k=0.061) at baseline, 63.39% (k=0.039), and 62.73% (k=0.099) in year 2 and 5 respectively. Kappa level of agreement was low. Conclusion Our results reflect low level of agreement between physician and patients in terms of remission status with increasing disagreement in the follow-up. Patients in remission by DORIS shows better results in EQ-5D and LIT. Reference [1] Rúa-Figueroa I, et al. Reumatol Clin. 2014;10(1):17-24. Acknowledgements: NIL. Disclosure of Interests None Declared.Table 1Patient characteristics according remission status at baselineRemission by DORIS (n=177)Remission by SLAQ (n=184)Remission by both criteria (n=27)p-valueAge at diagnosis (years), mean (SD)34.6 (14.87)36.64 (13.74)33.77 (13.12)0.181Female sex, n (%)160/176 (90.9%)166/182 (91.2%)27/27 (100%)0.004Disease duration (yrs), mean (SD)15.26 (8.18)13.71 (7.7)19.8 (7.66)0.069Highest education57/172 (33.1%)40/180 (22.2%)13/26 (50%)<0.001Medication, n (%)Off-therapyAntimalarialsImmunosuppressants (AZA, MTX, MMF)Biological therapy (rituximab, belimumab)0/177 (0%)79/176 (44.9%)63/175 (36%)14/176 (8%)36/182 (19.8%)100/182 (54.9%)36/180 (20%)8/178 (4.5%)0/27 (0%)14/27 (51.9%)12/27 (44.4%)4/27 (14.8%)1<0.001<0.001<0.001Obesity (BMI>30), n (%)18/162 (11.1%)44/176 (25%)3/24 (12.5%)0.003Hospital admission, n (%)57/176 (32.4%)40/182 (22%)7/26 (26.9%)<0.001SLEDAI, mean (SD)1.66 (1.66)3.28 (3.78)1.78 (1.5)<0.001SLAQ, mean (SD)26.15 (2.55)27.98 (1.81)27.63 (1.96)<0.001EQ-5D67.53 (19.31)63.22 (20.12)64.54 (17.7)0.041LIT26.68 (21.76)34.37 (20.34)31.3 (18.34)0.0007SLICC/ACR Damage Index1.57 (1.74)1.42 (1.84)1.37 (1.9)0.437Mortality0/177 (0%)0/184 (0%)0/27 (0%)1AZA azathioprine, MTX methotrexate, MMF mycophenolate, BMI body mass index, EQ-5D EuroQol-5D, LIT lupus impact tracker

Background Since lipid metabolism impact immune cell plasticity regulating cell activation, differentiation and function, the extensive analysis of the lipidomic profile using novel high-throughput metabolomic techniques in chronic inflammatory diseases such as Rheumatoid Arthritis (RA) might contribute to better characterise the pathogenesis of the disease. Objectives To analyse the whole lipidomic profile in the serum of RA patients, its association with the disease activity and its modulation by biological and targeted synthetic therapies. Methods Two hundred and fifty consecutive RA patients were included in this study. Serum samples and clinical data (disease activity, acute phase reactants, autoimmune profile, etc) were obtained from all subjects. The lipidomic profile was analysed by using nuclear magnetic resonance (NMR) spectroscopy from Nightingale LTD technology which included more than 200 lipid markers. In parallel, active RA patients from this cohort were prospectively followed up after 6 months of therapy with biologics [anti-TNF (n=50), anti-IL6R (n=15)], and JAK inhibitors (JAKi, n=20) and serum samples were obtained before and after those therapies where changes in the lipid and clinical profile were also evaluated. Results RA patients were stratified according to high (68), moderate (117) and low (65) disease activity and approximately 100 lipid markers were significantly altered in the serum of patients from these groups. Interestingly, most of the lipid markers were found reduced in the group of patients with high disease activity including apolipoproteins, cholesterol (free and in lipoproteins), fatty acids [saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), Omega 3 and 6, Linoleic acid (LA), Docosahexaenoic acid (DHA)], triglycerides (alone and in lipoproteins), cholines, phospholipids, lipoproteins [high-density lipoproteins (HDL), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL)], and the total lipid content present in those lipoproteins. These alterations of the lipidomic profile might be associated with an abnormal liver function linked to an exacerbated inflammatory status. Furthermore, multiple correlations were also found among those lipids markers and inflammatory [C-reactive protein (CRP) and erythrocyte sedimentation rate CRP (ESR)] and autoimmune parameters [anti-citrullinated protein antibodies (ACPAS) and rheumatoid factor (RF)]. Interestingly, after six months of therapy, in parallel to the improvement in clinical and analytical profiles of RA patients, a significant upregulation of lipid markers was observed, including common and distinctive molecules reversed by each drug. Conclusion The circulating lipidomic profile of active RA patients is deeply reduced and directly linked to the activity of the disease, its inflammatory and autoimmune profile. In parallel to the clinical improvement of the disease, biological therapies and JAKi re-establish the altered lipid metabolism. Acknowledgements Supported by ISCIII (PI21/0591, CD21/00187, and RICOR-RD21/0002/0033), and Junta de Andalucía (P20_01367) co-financed by FEDER; Fundacion Andaluza de Reumatología (FAR). Disclosure of Interests None Declared.

Background: Objectives 1- To analyze the levels of NAD+ and genes involved in its metabolism in Rheumatoid Arthritis (RA) patients. 2- To evaluate the effect of anti-TNF therapy in the NAD+ metabolism. 3- To explore mechanistically the anti-inflammatory effects of NAD+ boosters in leukocytes from RA patients. Methods Plasma and PBMCs were purified from 100 RA patients and 50 healthy donors (HDs). NAD+ levels were determined by using the NAD/NADH-Glo Assay. Gene expression analysis of markers related to the synthesis (NAMPT, NMNATs, etc), transport (Cx43), and consumption of NAD+ (PARPs, SIRTs, CD38, etc) were performed in PBMCs by RT-PCR. Public datasets from GEO repository were used to validate the analyses. A panel of 92 inflammatory mediators was also analyzed in the RA serum using Olink platform. In a second cohort of 50 RA patients treated with anti-TNF therapy, NAD+ levels were analyzed before and after 6 months of treatment. PBMCs from a third cohort of 10 active RA patients were treated ex vivo with 1 mM of NAD+ boosters including nicotinamide (NAM) and nicotinamide riboside (NR) in the presence of inhibitors of NAMPT (FK866) and Cx43 (GAP19). After 24 hours, the Olink inflammatory panel was used to evaluated anti-inflammatory effects. Results NAD+ levels were significantly reduced in the plasma of RA patients and the expression of genes involved in the consumption (PARPs, SIRTs, CD38, CD157) and biosynthesis (NMNATs) of NAD+ were increased and reduced respectively in RA PBMCs. NAMPT and Cx43 were also upregulated in those patients. The results were validated in an independent dataset. Unsupervised clustering analysis of the inflammatory proteome identified 3 cluster of patients, where cluster 1 was characterised by higher levels of inflammatory mediators and disease activity (DAS28) and lower levels of NAD+, and cluster 3 by lower levels of inflammatory mediators and DAS28 and higher levels of NAD+. Cluster 2 showed intermediate profiles. Anti-TNF therapy restored the altered NAD+ levels in RA patients towards those exhibited by HD. Moreover, changes in DAS28 and NAD+ levels were correlated. In vitro, NAD+ boosters promoted a significant increase in NAD+ levels of RA PBMCs. The FK866 treatment highlighted the key role of NAMPT in the generation of NAD+ promoted by NAM. The inhibition of the extracellular transport of NAD+ with GAP19 further increased the intracellular NAD+ content in the presence of NAM and NR. Both boosters reduced the levels of numerous secreted inflammatory mediators in the supernatant, which was enhanced by effect of GAP19. In parallel, the gene expression of key inflammatory mediators was deeply reduced along with markers of oxidative stress and apoptosis. Conclusion 1- The NAD+ levels and its metabolism is altered in RA patients and directly linked to their inflammatory profile and disease activity. 2- Anti-TNF therapy restore NAD+ altered levels in line with the clinical response. 3- NR and NAM increase the NAD+ levels in PBMCs from active RA patients, through a mechanism mediated in part by NAMPT, promoting an extensive anti-inflammatory effect which is enhanced by Cx43 inhibition. NAD+ boosters might be considered as novel therapeutic approach to reduce inflammation in RA. Supported by: RYC2021-033828-I, MCIN/AEI/10.13039/501100011033 and “NextGenerationEU”/PRTR. CLP lab: ISCIII (PI21/0591, CD21/00187 and RICORS, RD21/0002/0033), JdA (P20_01367) co-financed by FEDER and FAR. JMV lab: MCIU/AEI grants RTI2018-100695-B-I00, PID2021-126280OB-I00 and PRE2019-087438 (FPI); JdA (P18-RT-4264, 1263735-R and BIO-276), (FEDER); and UCO (PPIT-2022E-026295). REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared.

Background Patients with Systemic lupus erythematosus (SLE) have a well-known increased risk of major comorbidities, but they are also very heterogeneous in term of prevalence of comorbid conditions. The relationship of the comorbidities with the outcomes and the severity of index disease is less known. Objectives Evaluate the interactions between comorbid conditions, on a large multicenter SLE cohort from RELESSER register, and its impact in severity and outcomes. Methods Data about 14 cumulative comorbidities, as previously defined [1], where derived from patients with SLE (ACR-97 criteria) included in the retrospective phase of RELESSER. Severity Katz Index (SKI) and SLICC/ACR Damage Index (SDI) were calculated.An unsupervised cluster analysis using K-means method was implemented to define clusters. ANOVA and Tukey tests were used to compare continuous numerical variables; Kruskal-Wallis test to discrete variables and the Chi-square test (or Fisher's exact test) to categorical ones. Results A total of 3658 SLE patients (ACR-97 criteria) were included. Median SKI: 2 (interquartile range (IQR):1-3); median SDI:1(IQR:0-2). Demographic data are shown in Table 1.The comorbidities considered and their prevalence were: Thyroiditis (8.3%), peptic ulcer (3.8%), severe hepatopathy (1.0%), obstructive pulmonary disease (2.7%), Diabetes (5.0%), cardiovascular event (CVE) (11.0%), cardiac arrhythmia (4.2%), pulmonary embolism (3.4%), dementia (0.7%), malignancy (5.9%); serious infection (19.3%), end stage renal disease (2.8%), osteoporosis (7.3%) and depression (17.1%).Four cluster, with markedly different comorbidity profiles and outcomes were identified (table 3): one subgroup was clustered around depression (100% of the cases) (cluster 2), another cluster (cluster 3) with > 1 serious infection (100%) and cluster 4, with 100% of CVE. In cluster 1, no patient had any of the 3 defining comorbidities in the rest of the clusters. There were no statistically significant differences between clusters in death by SLE. The clusters are characterized in more detail in table 1, where a just summary of the main comorbidities included in the analysis is displayed. Conclusion Cluster analysis identifies well-differentiated subgroups of SLE patients as regard comorbidities and associated mortality and severity of the disease. Reference [1]Rúa-Figueroa I et al. National registry of patients with systemic lupus erythematosus of the Spanish Society of Rheumatology: objectives and methodology. Reumatol Clin 2014;10(1):17-24. Acknowledgements Research Unit of the Spanish Society of Rheumatology. Spanish Foundation of.Rheumatology financial supporting, through the research intensification grants program. GSK financial.supporting, Disclosure of Interests None Declared.Table 1Cluster of comorbidities and outcomes, N (%) unless specifiedCluster 1 dCluster 2 aCluster 3 bCluster 4 cp-valueAge, mean (SD)44.8 (14.1)49.8 (14.1)46.7 (14.3)46.7 (14.3)<0.001Male sex214 (9.2) a,c25 (4.8)51 (12.2) a63 (16.3) a,d<0.001Time with SLE (years), mean (SD)129.2 (95.9)159.3 (101.4) d170.3 (100.3) d169 (113) d<0.001Cardiovascular event0 (0) c0 (0) c0 (0) c388 (100)<0.001Cardiac arrhythmia53 (2.3) b,c17 (3.3) c19 (4.5) c,d61 (15.7)<0.001Malignancy110 (4.7) a,c46 (8.9) d25 (6.0)31 (8.0) d0.001Serious infection0 (0)122 (23.6)418 (100)165 (42.5)<0.001End stage renal disease27 (1.2) b,c11 (2.1) b,c26 (6.2) a,d34 (8.8) a,d<0.001Osteoporosis79 (3.4)71 (13.8) d41 (9.8) c,d69 (17.8) b,d<0.001Depression0 (0) a,c516 (100)0 (0) a,c94 (24.4)<0.001Glucocorticoids1890 (86)451 (91.3) b,d400 (98)354 (93.2) b,d<0.001Cyclophosphamide or mycophenolate501 (23.5)145 (29.7)216 (54.3)139 (37.4)<0.001Antimalarials1869 (85.4) b,c433 (86.9) b,c317 (78.3)263 (71.1)<0.001SKI*, mean (SD)2.3 (1.4)2.8 (1.8)3.5 (1.8) a,d3.5 (2) a,d<0.001SDI**, mean (SD)0.7 (1)1.3 (1.8)1.6 (1.8)3.3 (2.5)<0.001Death46 (2.2)27 (5.6)45 (11.6)90 (25.2)<0.001Death by lupus14 (36.8) #8 (40) #8 (19.5) #24 (30.4) #0.27*Severity Katz Index; ** SLICC/ACR Damage Index. Regarding age, the p-value for the comparation between group 1 and 3 is 0.0498. #: no significant. a,b,c or d means the only significant comparison.

Background FIL is a Janus kinase (JAK) 1 preferential inhibitor for the treatment of RA. Data from the ORAL Surveillance post-marketing study (NCT02092467) suggest that in patients with active RA aged ≥50 years with ≥1 CV risk factor, the risks of cancer and major adverse cardiovascular events (MACE) are higher with the pan-JAK inhibitor tofacitinib vs tumor necrosis factor inhibitors, with higher rates in those aged ≥65 vs <65 years.[1] Objectives To assess the incidence of malignancies excluding non-melanoma skin cancer (NMSC), NMSC, MACE and venous thromboembolism (VTE) in patients treated with FIL 200 mg (FIL200) and FIL 100 mg (FIL100) in RA clinical trials. Methods Data were pooled from patients treated with FIL200 or FIL100 from DARWIN 1–3 (NCT01888874, NCT01894516, NCT02065700) and FINCH 1–4 (NCT02889796, NCT02873936, NCT02886728, NCT03025308). Data cuts used for the ongoing DARWIN 3 and FINCH 4 studies were May 2, 2022, and May 6, 2022, respectively. Exposure-adjusted incidence rates (EAIRs) per 100 patient-years of exposure (PYE) were calculated for MACE, VTEs, malignancies excluding NMSC, NMSC and treatment-emergent adverse events (TEAEs) leading to death, according to FIL dose (200 vs 100 mg) and age (<65 vs ≥65 years); no statistical testing was performed, so all differences are numerical. MACE and VTE were adjudicated by an independent committee; the cutoff for adjudication was April 3, 2022. Results Overall, 3691 patients were treated with FIL for a total of 12,541 PYEs. Median (max) PYE was 3.8 (8.3) years for FIL200 and 3.3 (7.8) years for FIL100. Baseline characteristics are shown in the Table 1. A greater proportion of those aged ≥65 years vs <65 years had a CV medical history in both the FIL200 (75.7% vs 36.1%) and FIL100 (71.8% vs 40.9%) groups. Overall EAIRs (95% confidence interval [CI]) were 0.40 (0.3, 0.5) for MACE, 0.19 (0.1, 0.3) for VTEs, 0.69 (0.6, 0.9) for malignancy excluding NMSC, 0.29 (0.2, 0.4) for NMSC and 0.65 (0.5, 0.8) for TEAEs leading to death. EAIRs of MACE and VTE were higher in patients aged ≥65 vs <65 years but were generally similar for FIL200 and FIL100 within each age group (Figure 1). EAIRs of malignancies, NMSC and TEAEs leading to death were also higher in the ≥65- vs <65-year group. Within the ≥65-year group, EAIRs (95% CI) of these events were numerically higher in the FIL200 vs FIL100 group: 2.0 (1.3, 2.9) vs 0.99 (0.5, 1.9) for malignancies, 1.38 (0.8, 2.2) vs 0.44 (0.1, 1.1) for NMSC, and 1.59 (1.0, 2.5) vs 1.20 (0.6, 2.2) for TEAEs leading to death, respectively. Conclusion Rates of MACE and VTE in FIL-treated patients were low and similar for FIL200 and FIL100. There was a higher proportion of patients aged ≥65 years vs <65 years with a CV medical history. In patients aged ≥65 years, EAIRs of malignancies, NMSC and TEAEs leading to death were higher with FIL200 vs FIL100, although CIs overlapped. Reference [1]Ytterberg SR, et al. N Engl J Med 2022;386:316-26 Acknowledgements We thank the physicians and patients who participated in the studies. The studies were funded by Gilead Sciences (Foster City, CA, United States) and Galapagos NV (Mechelen, Belgium). Publication coordination was provided by Fabien Debailleul, PhD, of Galapagos NV. Writing support was provided by Debbie Sherwood, BSc, CMPP (Aspire Scientific, Bollington, UK), and was funded by Galapagos NV. Disclosure of Interests Xavier Mariette Consultant of: AstraZeneca, BMS, Galapagos, GSK, Novartis, Pfizer, Sven Borchmann Shareholder of: Liqomics, Consultant of: Galapagos, Sandrine Aspeslagh Speakers bureau: AstraZeneca, BMS, Pfizer, Roche, Sanofi, Grant/research support from: AstraZeneca, BMS, Merck, MSD, Pfizer, Roche, Sanofi, Jaime Calvo Speakers bureau: GSK, Galapagos, Novartis, Biogen, Lilly, Paid instructor for: GSK, Consultant of: GSK, AstraZeneca, AbbVie, Sanofi, Novartis, Lilly, Grant/research support from: Roche, BMS, Richard Moriggl Consultant of: Galapagos, Zoltan Szekanecz Speakers bureau: Pfizer, AbbVie, Roche, Lilly, Novartis, Galapagos, Sobi, Gedeon Richter, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Galapagos, Sobi, Gedeon Richter, Grant/research support from: Pfizer, Francesco De Leonardis Employee of: Galapagos, Nadia Verbruggen Shareholder of: Galapagos, Employee of: Galapagos, Paul Van Hoek Consultant of: Galapagos, Aspen, AOP Health, Sanofi-Genzyme, Astellas, Employee of: Schering Plough, MSD, Janssen, Marc Schmalzing Speakers bureau: Novartis, AbbVie, AstraZeneca, Chugai/Roche, Janssen-Cilag, Gilead, Boehringer Ingelheim, Mylan, Galapagos, EUSA-Pharma, Consultant of: Chugai/Roche, Hexal/Sandoz, Gilead, AbbVie, Janssen-Cilag, Boehringer Ingelheim, onkowissen.de, EUSA-Pharma, Novartis, AstraZeneca, Amgen, medac, Lilly, Galapagos, UCB, Grant/research support from: Chugai/Roche, Boehringer Ingelheim, Celgene, Medac, UCB, Mylan, Galapagos, Andreas Stallmach Speakers bureau: AbbVie, BMS, Celltrion, CLS Behring, De Prom, Falk Foundation, Ferring, Janssen, Kompetenznetz Darmerkrankungen, MedUpdate, MSD, Recordati Pharma, Sobi, Takeda, Consultant of: AbbVie, Amgen, BMS, Consal, Galapagos, Gilead, Janssen, Lilly, MSD, Repha GmbH, Roche, Pfizer, Pharmacosmos GmbH, Takeda, Tillotts Pharma, Christina Charles-Schoeman Consultant of: Priovant, AbbVie, BMS, Pfizer, Grant/research support from: AbbVie, BMS, Pfizer, CSL Behring, Vijay Rajendran Shareholder of: Galapagos, Employee of: Galapagos, Christine Rudolph Shareholder of: Galapagos, Employee of: Galapagos, Chris Watson Shareholder of: Galapagos, Employee of: Galapagos, Yoshiya Tanaka Speakers bureau: Boehringer Ingelheim, Eli Lilly, AbbVie, Gilead, AstraZeneca, BMS, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, Grant/research support from: Asahi-Kasei, AbbVie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Boehringer Ingelheim, Ernest Choy Speakers bureau: AbbVie, Amgen, BMS, Chugai Pharma, Eli Lilly, Fresenius Kai, Galapagos, Gilead, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, Consultant of: AbbVie, Amgen, Biogen, Therapeutics, Chugai Pharma, Eli Lilly, Fresenius Kai, Galapagos, Gilead, GSK, Janssen, Novartis, Roche, R-Pharm, SynAct Pharma, Sanofi-Genzyme, UCB, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi.Table 1Baseline characteristicsFIL200FIL100<65 y (n=1860)≥65 y (n=407)<65 y (n=1321)≥65 y (n=326)Age, y, mean (SD)48.8 (10.7)70.0 (4.4)49.0 (10.5)70.2 (4.5)Female, n (%)1506 (81.0)322 (79.1)1075 (81.4)244 (74.8)BMI, kg/m2, mean (SD)27.5 (6.3)28.1 (5.9)27.7 (6.4)27.2 (5.1)Creatinine clearance, mL/min, mean (SD)122 (37.4)84 (23.4)122 (38.1)83 (22.5)CRP, mg/L, mean (SD)19.0 (24.3)18.4 (25.2)18.9 (25.9)17.2 (24.7)Current smoker, n (%)*207 (14.4)37 (10.9)165 (15.3)28 (9.7)CV family history, n (%)†43 (3.0)10 (2.9)47 (4.3)12 (4.2)Any CV medical history, n (%)672 (36.1)308 (75.7)540 (40.9)234 (71.8)Current alcohol use, n (%)*296 (20.6)78 (22.9)213 (19.7)54 (18.7)*FIL200 <65 y: n=1436, ≥65 y: n=340; FIL100 <65 y: n=1081, ≥65 y: n=289.†FIL200 <65 y: n=1434, ≥65 y: n=339; FIL100 <65 y: n=1081, ≥65 y: n=289.BMI, body mass index; CRP, C-reactive protein; CV, cardiovascular; FIL100/200, filgotinib 100 mg/200 mg; SD, standard deviation.

Aims: Extracellular vesicles (EVs) are nanoparticles secreted by all cells, enriched in proteins, lipids, and nucleic acids related to cell-to-cell communication and vital components of cell-based therapies. Mesenchymal stromal cell (MSC)-derived EVs have been studied as an alternative for osteoarthritis (OA) treatment. However, their clinical translation is hindered by industrial and regulatory challenges. In contrast, platelet-derived EVs might reach clinics faster since platelet concentrates, such as platelet lysates (PL), are already used in therapeutics. Hence, we aimed to test the therapeutic potential of PL-derived extracellular vesicles (pEVs) as a new treatment for OA, which is a degenerative joint disease of articular cartilage and does not have any curative or regenerative treatment, by comparing its effects to those of human umbilical cord MSC-derived EVs (cEVs) on an ex vivo OA-induced model using human cartilage explants. Methods: pEVs and cEVs were isolated by size exclusion chromatography (SEC) and physically characterized by nanoparticle tracking analysis (NTA), protein content, and purity. OA conditions were induced in human cartilage explants (10 ng/ml oncostatin M and 2 ng/ml tumour necrosis factor alpha (TNFα)) and treated with 1 × 109 particles of pEVs or cEVs for 14 days. Then, DNA, glycosaminoglycans (GAG), and collagen content were quantified, and a histological study was performed. EV uptake was monitored using PKH26 labelled EVs. Results: Significantly higher content of DNA and collagen was observed for the pEV-treated group compared to control and cEV groups. No differences were found in GAG quantification nor in EVs uptake within any treated group. Conclusion: In conclusion, pEVs showed better performance than cEVs in our in vitro OA model. Although further studies are needed, pEVs are shown as a potential alternative to cEVs for cell-free regenerative medicine. Cite this article: Bone Joint Res 2023;12(10):667–676.

Background The prevalence of depression and associated factors in systemic lupus erythematosus (SLE) are not well known and there are no longitudinal studies addressing this relevant subject in SLE. Objectives We aimed to evaluate the prevalence of self-perceived depression in patients with SLE and associated factors in a large, multicenter cohort (RELESSER-PROS). Methods Prospective longitudinal study of patients with SLE (1997 ACR criteria) answering positively to the depression question of the Lupus Impact Tracker (LIT) questionary (namely: “I was depressed” question number 7) (LITQ7), over 4 years of follow-up (5 annual visits, V1 to V5). Self-perceived depression was addressed as “depression any time” or “depression most of time”, according to the kind of answer to the LITQ7 (answers 1,2,3 or 4 and answers 3 or 4 respectively). Only patients with no missing values in the covariates, making possible run longitudinal models, were included in the multivariable analysis. The following covariates, with potential impact in depression, were considered: SLEDAI, age, duration of the disease, SLICC/AR DI (SDI), fibromyalgia, Charlson index, smoking, BMI, menopause, sedentary lifestyle, marital status, unemployment and glucocorticoid use. Friedman test was used to test if the change in repeated measures was significative. Generalized estimating equation (GEE) models with binomial response, were built exploring the associations of individual longitudinal determinants with longitudinal assessment of depression. The best model was selected using quasi-likelihood under the independence model information criterion (QIC) Results A total of 1463 were included. Mean age: 55 (DS±13.59) years, 90% were female. Mean duration of the disease: 14 (±8.59) years. Fibromyalgia was present in 5.7% (76/1343). Corticosteroids use ranged from 49.4% to 57%, depending on the visit. Median SLEDAI ranged from 0 to 2 and SDI ranged from 1 to 2. Prevalence of “depression any time” was 89.9% (1104/1228) and 34.6% (200/578) were in depression “most of time”. Up to 26.5% (153/578) answered to LITQ7 “depression most of time” in the five visits; 89.7% of the patients which perceived themselves as depressed at least in 2 out of 5 visits. Only 6.9% of the patients with previous diagnosis of depression answered “0” to the Q7 of LIT (“none of the time”). Only following covariates showed changes, statistically significative, during the follow up: SLEDAI, SDI, Charlson and glucocorticoids use (Friedman test). Patients with “depression any time” develop more damage at V5 than patients without depression (answer to LITQ7=0) (p = 0.00931, T-test). In the GEE binomial analysis considering all the predefined covariates, that included only patients with no missing values for any of them (namely, 155 patients), fibromyalgia (OR 2.79; 95%CI: 1.28-6.05), unemployment (OR 1.95; 95%CI 1.02 -3.73), and glucocorticoids use (OR 1.88; 95%CI 1.18-2.99) were significant associated with “depression any time”. The best model (according QIC) displayed a statistically significant association only with fibromyalgia (OR 2.90; 95%CI: 1.58-5.33) and glucocorticoids use (OR 1.85; 95%CI 1.17-2.93). Neither SDI nor unemployment reached significance here (Table 1). Without entering glucocorticoids, SLEDAI turns significant in the model, suggesting collinearity. Conclusion The prevalence of self-perceived depression is high in SLE. Longitudinal data analysis suggests a causal relationship between glucocorticoids use, fibromyalgia and self-perceived depression. Acknowledgements Research Unit of the Spanish Society of Rheumatology. Spanish Foundation of Rheumatology financial supporting, through the research intensification grants program. GSK financial supporting, Disclosure of Interests None Declared.

Background Glucocorticoids (GC) are the mainstay therapy in Giant Cell Arteritis (GCA), initially at high doses (40-60 mg/day) followed by gradual glucocorticoid tapering. This treatment, especially in older patients, is associated with numerous adverse effects (AE). In addition, there are frequent relapses. Therefore, conventional synthetic immunosuppressants such as methotrexate (MTX), leflunomide, azathioprine, cyclophosphamide or mycophenolate, have been used with controversial results. Studies with biological immunosuppressants, such as TNFi have been ineffective; in contrast, tocilizumab (TCZ) has obtained positive results and was approved for the treatment of GCA. Objectives In the ARTESER study we describe a ) treatment with GC, synthetic or biological immunosuppressants; b ) AE of CG; and c ) evolution. Methods ARTESER is a retrospective observational study sponsored by the Spanish Society of Rheumatology. 26 Spanish centers participated and all new patients diagnosed with GCA from June 1, 2013 to March 29, 2019 were included. Data on GC and immunosuppressants were collected at the beginning and during the follow-up of GCA patients. For the calculation of the cumulative dose of GC, an application was developed that, by including the periods of time, dose and type of GC received during follow-up, performs the automatic calculation in mg of prednisone. Results Of the 1675 patients included, GC treatment was adequately recorded in 1650 patients (Table 1). All received oral treatment, being prednisone the most frequently drug used (N=1602, 97.09%). In addition, 426 (25.82%) patients received at least one iv pulse of methylprednisolone, being the 1000 mg regimen the most frequent (n=217; 50.9%). The total mean duration of GC treatment was 22.65 months. The mean cumulative dose per patient at the end of follow-up was 8514.98 mg of prednisone. Table 1. Corticosteroid treatment and immunosuppressive treatment Patients taking oral corticosteroid 1650 Prednisone, n (%) 1602 (97.09) Methylprednisolone, n (%) 164 (9.94) Deflazacort, n (%) 64 (3.88) Patients receiving intravenous corticosteroid, n (%) 426 (25.82) Mean duration of steroid treatment, mean (SD) 22.65 (17.36) Mean cumulative dose at the end of follow-up per patient, mg of prednisone, mean (SD) 8514.98 (6570.21) Methotrexate at diagnosis*, n (%) 165 (9.9) Leflunomide at diagnosis*, n (%) 2 (0.1) Azathioprine at diagnosis*, n (%) 3 (0.2) Cyclophosphamide at diagnosis*, n (%) 7 (0.4) Mycophenolate at diagnosis*, n (%) 1 (0.1) Tocilizumab at diagnosis*, n (%) 22 (1.3) Methotrexate during follow-up, n (%) 532 (31.8) Leflunomide during follow-up, n (%) 19 (1.2) Azathioprine during follow-up, n (%) 26 (1.5) Cyclophosphamide during follow-up, n (%) 10 (0.6) Mycophenolate during follow-up, n (%) 10 (0.6) Tocilizumab during follow-up, n (%) 153 (9.1) The most widely used immunosuppressant was MTX both at diagnosis (n=165; 9.9%) and during follow-up (n=532; 31.8%), followed by TCZ, at diagnosis (22; 1.3%) and at follow-up (153; 9.1%). AE with GC were described in 393 patients (23.8%), highlighting serious infections (n=67; 10.03%) followed by diabetes mellitus (n=63; 9.43%), steroid myopathy (n=53; 7.9%), vertebral fractures (n=47; 7.04%), non-vertebral fractures (n=36; 5.39%), heart failure (n=36; 5.39%), arterial hypertension (n=34; 5.09%) and neuropsychiatric alterations (n=27; 4.04%). During the follow-up, 334 (19.9%) patients had relapses, 532 (31.8%) were hospitalized on some occasion, and 142 patients (8.48%) died. The main cause of death were infections (n=44; 30.99%), neoplasms (n=23; 16.2%), cardiovascular (n=15; 10.56%), and cerebrovascular (n=10; 7.04%). Conclusion The main treatment for GCA was oral GC, which were required for almost two years on average, in a quarter of patients associated with IV pulses. The cumulative steroid dose was high as well as the side effects. MTX was the most widely used immunosuppressant and TCZ was prescribed in 10%. Relapses and admissions at the hospital were relatively frequent. Acknowledgements This study has been funded by ROCHE Farma. The funder has not participated in the design, analysis, or interpretation of the results Disclosure of Interests None declared

Background: Objectives: Analyse the effect of secukinumab in terms of the patient´s own variables, specifically: fatigue, sleep, pain and quality of life in patients with psoriatic arthritis or spondyloarthritis. Methods: A multicentric longtitudinal observational prospective study was carried out at 6 months in patients who begin treatment with secukinumab. At the start and after 6 months the following data was collected on the outcome: pain through an visual analogue scale (VAS), fatigue using the FACIT-fatigue scale, sleeping problems using the insomnia severity index (ISI) and quality of life with the EuroQol-3L-5D and the PsAQoL. The sample can be described in terms of the distribution of the variables through measures of central tendency.It was analysed if the change after 6 months was statistically relevant using Student´s t-test for paired data in the case of FACIT, VAS, PsAQoL and ISI and chi-squared for the dimensions of the EQ-5D. The size of the effect of each of the measurements taken was calculated using Cohen’s D. the results are given grouped by disease and globally. The analysis was carried out using Stata v12 (College Station Tx, USA) Results: In table 1, the changes in the scales of normal distribution can be seen. Apart from general VAS, all the scales experience significant relevant changes. The PROs preferred by the patient with the best therapeutic response is the quality of sleep. The adjustment of the regression models does not produce changes in the results, apart from small adjustments to the condidence intervals (final column table 1). The subdomain in which the most significant change in the EQ-5D is produced is in that of pain and discomfort. Conclusion: After 6 months patients who begin treatment with secukinumab, present with improvements in all sizes of the effects of the treatment in the various studied scales. The improvement achieves global and generalised statistical significance after 6 months of study. The greatest effect is on sleep, quality of life and fatigue. The measurements of the outcomes reported by the patients are a clinical value added to our objective evaluations of the health and activity of the disease, and allow us, in a more integrated and comprehensive manner, to undertake a more exact and close evaluation of their state of health and wellbeing. Disclosure of Interests: JUAN JOSE LERMA: None declared, Antonio Gracia: None declared, Antonio Perez: None declared, Amalia Rueda: None declared, Clara Molina: None declared, M. Dolores Pastor: None declared, Isabel Balaguer Trull: None declared, Inmaculada Valiente: None declared, Cristina Campos Fernández: None declared, Javier Calvo: None declared, Loreto Carmona Grant/research support from: Novartis Farmaceutica, SA, Pfizer, S.L.U., Merck Sharp & Dohme España, S.A., Roche Farma, S.A, Sanofi Aventis, AbbVie Spain, S.L.U., and Laboratorios Gebro Pharma, SA (All trhough institution)

Background: Apremilast (APR) has demonstrated efficacy in the treatment of oral and/or genital aphthous ulcers in Behçet´s disease (BD). Combination of APR to other disease-modifying anti-rheumatic drugs (DMARDs) has not been assessed. Objectives: To compare the efficacy and safety of APR in monotherapy or combined with DMARDs in refractory BD. Methods: National multicenter open-label study on 51 BD patients with oral and/or genital ulcers refractory to conventional treatment. Results: We included 51 patients (35 women/16 men), mean age 44.7±13.2 years. Before APR, all patients had received several systemic conventional drugs. The main clinical symptoms for starting APR were oral (n=19) and genital (2) aphthous ulcers or both (30). Excluding corticosteroids, colchicine or NSAIDs, APR was given at standard dose of 30 mg twice daily in monotherapy (n=31), or combined with conventional DMARDs in 16 cases (6 azathioprine, 5 methotrexate, 4 hydroxychloroquine, 4 sulfasalazine, 1 dapsone) or with biologic DMARDs in 4 (2 tocilizumab, 1 adalimumab, 1 infliximab). There were not found statistically significant differences in demographic features, previous therapy, clinical manifestations or reported adverse effects. After a median follow-up of 6 [3-12] months, most of the patients experienced improvement of the orogenital ulcers in both groups (89.8% in the first 2 weeks), without statistically significant differences. (TABLE ) Conclusion: APR leads to a rapid and maintained improvement in most patients with refractory BD orogenital ulcers. APR seems as effective and safe in monotherapy as combined. TABLE: Week 1-2 Week 4 Month 6 Month 12 Month 24 Outcome of oral and/or genital ulcers n, (% ) C n=19 M n=30 C n=19 M n=26 C n=12 M n=17 C n=7 M n=6 C n=1 M n=1 Complete resolution 8 (42.1) 11 (36.7) 12 (63.2) 20 (77) 7 (58.4) 14 (82.4) 3 (42.8) 3 (50) 1 (100) 1 (100) Partial resolution 9 (47.4) 16 (53.4) 7 (36.8) 3 (11.5) 5 (41.6) 2 (11.7) 4 (57.2) 3 (50) 0 0 No response 2 (10.5) 3 (9.9) 0 3 (11.5) 0 1 (5.9) 0 0 0 0 p value 0.9 0.1 0.1 0.8 0.7 Abbreviations : C= combined; M= monotherapy; n= available data. Disclosure of Interests: Alba Herrero Morant: None declared, Belen Atienza Mateo: None declared, J. Loricera: None declared, Vanesa Calvo del Rio Grant/research support from: MSD and Roche, Speakers bureau: Abbott, Lilly, Celgene, Grünenthal, UCB Pharma, José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Jenaro Graña: None declared, Gerard Espinosa: None declared, Clara Moriano: None declared, Trinidad Pérez Sandoval: None declared, Manuel Martín Martínez: None declared, Elvira Diez: None declared, María Dolores García-Armario: None declared, Esperanza Martínez: None declared, Ivan Castellví Consultant of: Boehringer Ingelheim, Actelion, Kern Pharma, Speakers bureau: Boehringer Ingelheim, Actelion, Bristol-Myers Squibb, Roche, Patricia Moya Alvarado: None declared, Francisca Sivera: None declared, Jaime Calvo Grant/research support from: Lilly, UCB, Consultant of: Abbvie, Jansen, Celgene, Isabel de la Morena: None declared, Francisco Ortiz Sanjuán: None declared, José Andrés Román Ivorra: None declared, Ana Pérez Gómez: None declared, Sergi Heredia: None declared, Alejandro Olive: None declared, Águeda Prior: None declared, Carolina Díez: None declared, Juanjo J Alegre-Sancho Consultant of: UCB, Roche, Sanofi, Boehringer, Celltrion, Paid instructor for: GSK, Speakers bureau: MSD, GSK, Lilly, Sanofi, Roche, UCB, Actelion, Pfizer, Abbvie, Novartis, D Ybáñez-García Speakers bureau: Lilly, Roche, Sanofi, Ángels Martínez-Ferrer: None declared, J. Narváez: None declared, Ignasi Figueras: None declared, Ana Isabel Turrión: None declared, Susana Romero-Yuste: None declared, Pilar Trénor: None declared, Soledad Ojeda Speakers bureau: AMGEN, LILLY, GEBRO, Miguel Á. González-Gay Grant/research support from: AbbVie, MSD and Roche, Speakers bureau: AbbVie, MSD and Roche, Ricardo Blanco Grant/research support from: Abbvie, MSD and Roche, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD

Background: Apremilast (APR) has demonstrated efficacy in orogenital ulcers of Behçet´s disease (BD). Response of other clinical manifestations remains unknown. Objectives: To assess the efficacy and safety of APR in monotherapy or combined with disease-modifying anti-rheumatic drugs (DMARDs) in non-aphthous ulcers of BD. Methods: National multicenter open-label study on 34 BD patients treated with APR at maintained standard dose of 30 mg twice daily. Results: From a cohort of 51 patients with APR by refractory orogenital ulcers of BD, we selected 34 (24 women/10 men, mean age 43.8±14.3 years), cases with another clinical manifestation/s. Excluding CTs, colchicine or NSAIDs, APR was given in monotherapy (n=21) or combined with conventional and/or biologic DMARDs in 13 cases (5 methotrexate, 3 azathioprine, 3 hydroxychloroquine, 1 sulfasalazine, 1 dapsone, 2 tocilizumab, 1 IFX). Other active manifestations present at APR onset were: arthralgia/arthritis (16, true arthritis in 5), folliculitis/pseudofolliculitis (14), erythema nodosum (3), furunculosis (2), paradoxical psoriasis by TNFi (2), intestinal ileitis (2), deep venous thrombosis (2), leg ulcers (1), erythematosus and scaly skin lesions (1), fever (1), unilateral anterior uveitis (1) and neurobehçet (1). After a median follow-up of 6 [3-12] months, folliculitis and ileitis improved, neurobehçet remained stable and musculoskeletal manifestations evolved in a variable way. (TABLE) TABLE. Conclusion: In addition of orogenital ulcers, APR in monotherapy or combined, seems to be useful in skin manifestations of BD Disclosure of Interests: Alba Herrero Morant: None declared, Belen Atienza Mateo: None declared, J. Loricera: None declared, Vanesa Calvo del Rio Grant/research support from: MSD and Roche, Speakers bureau: Abbott, Lilly, Celgene, Grünenthal, UCB Pharma, José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Gerard Espinosa: None declared, Jenaro Graña: None declared, Clara Moriano: None declared, Trinidad Pérez Sandoval: None declared, Manuel Martín Martínez: None declared, Elvira Diez: None declared, María Dolores García-Armario: None declared, Esperanza Martínez: None declared, Ivan Castellví Consultant of: Boehringer Ingelheim, Actelion, Kern Pharma, Speakers bureau: Boehringer Ingelheim, Actelion, Bristol-Myers Squibb, Roche, Patricia Moya Alvarado: None declared, Francisca Sivera: None declared, Jaime Calvo Grant/research support from: Lilly, UCB, Consultant of: Abbvie, Jansen, Celgene, Isabel de la Morena: None declared, Francisco Ortiz Sanjuán: None declared, José Andrés Román Ivorra: None declared, Ana Pérez Gómez: None declared, Alejandro Olive: None declared, Carolina Díez: None declared, Juan José Alegre: None declared, D Ybáñez-García Speakers bureau: Lilly, Roche, Sanofi, Ángels Martínez-Ferrer: None declared, Javier Narvaez: None declared, Ignasi Figueras: None declared, Ana Isabel Turrión: None declared, Susana Romero-Yuste: None declared, Pilar Trénor: None declared, Soledad Ojeda Speakers bureau: AMGEN, LILLY, GEBRO, Miguel Á. González-Gay Grant/research support from: AbbVie, MSD and Roche, Speakers bureau: AbbVie, MSD and Roche, Ricardo Blanco Grant/research support from: Abbvie, MSD and Roche, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD

Aims Platelet concentrates, like platelet-rich plasma (PRP) and platelet lysate (PL), are widely used in regenerative medicine, especially in bone regeneration. However, the lack of standard procedures and controls leads to high variability in the obtained results, limiting their regular clinical use. Here, we propose the use of platelet-derived extracellular vesicles (EVs) as an off-the-shelf alternative for PRP and PL for bone regeneration. In this article, we evaluate the effect of PL-derived EVs on the biocompatibility and differentiation of mesenchymal stromal cells (MSCs). Methods EVs were obtained first by ultracentrifugation (UC) and then by size exclusion chromatography (SEC) from non-activated PL. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and the expression of CD9 and CD63 markers by western blot. The effect of the obtained EVs on osteoinduction was evaluated in vitro on human umbilical cord MSCs by messenger RNA (mRNA) expression analysis of bone markers, alkaline phosphatase activity (ALP), and calcium (Ca2+) content. Results Osteogenic differentiation of MSCs was confirmed when treated with UC-isolated EVs. In order to disprove that the effect was due to co-isolated proteins, EVs were isolated by SEC. Purer EVs were obtained and proved to maintain the differentiation effect on MSCs and showed a dose-dependent response. Conclusion PL-derived EVs present an osteogenic capability comparable to PL treatments, emerging as an alternative able to overcome PL and PRP limitations.

Background: The eRA (evolving the management of RA) programme was initiated in Europe to provide practical educational tools that address unmet needs in the management of rheumatoid arthritis (RA). Several eRA tools – covering early access to care, management of comorbidities, treat-to-target strategies, and patient empowerment – are available to the rheumatology community. Through ongoing activities, the eRA Steering Committee (SC) identified a need for tools on non-pharmacological management of RA. Objectives: To improve accessibility to eRA tools for rheumatology professionals; to review the evidence base of non-pharmacological interventions to create new eRA resources that may support management decisions. Methods: A web platform providing information on eRA programme and tools was developed in 2019. The platform collects survey-based metrics to quantify perception of eRA and use of eRA tools in clinical practice. Platform and tools are translated to further support access and use across Europe. To address unmet needs in non-pharmacological patient management, the eRA SC reviewed the core literature on agreed priority interventions, including physical activity, diet, patient education and self-management, psychosocial interventions, occupational therapy and orthotics, hand exercises, and hydrotherapy/balneotherapy. Available evidence for each intervention was assessed and graded according to the Oxford Centre for Evidence-based Medicine Levels of Evidence. Results: The eRA web platform is now live in 3 countries ( www.evolvingthemanagementofRA.com ), hosting translated copies of the eRA tools, with additional countries launching throughout 2020. From a review of core literature on non-pharmacological interventions, the eRA SC determined that strong evidence exists to support use of physical activity, patient education and self-management, psychosocial interventions, and occupational therapy and orthotics. Evidence was lacking or conflicting for diet and nutrition, hand exercises, and balneotherapy/hydrotherapy. A set of educational slides was produced by the eRA SC to summarise the evidence (Fig. 1) and provide top-line guidance on use of interventions in practice that should engage relevant members of the multi-disciplinary team. These slides are available through eRA dissemination activities. Conclusion: The eRA programme content is now freely available to health care professionals in several countries on a web platform, supported by translations of the eRA tools. An additional slide set on non-pharmacological management serves to further increase the practical guidance of this programme’s educational offering. Acknowledgments: The eRA programme is funded by Sanofi Genzyme. Programme direction and content creation are driven by an independent Steering Committee Disclosure of Interests: Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Jose-Maria Alvaro-Gracia Grant/research support from: Abbvie, Elli-Lilly, MSD, Novartis, Pfizer, Consultant of: Abbvie, BMS, Janssen-Cilag, Elli-Lilly, MSD, Novartis, Pfizer, Sanofi, Tigenix, Roche, UCB, Paid instructor for: Elli-Lilly, Pfizer, Roche, Speakers bureau: Abbvie, BMS, Janssen-Cilag, Elli-Lilly, Gedeon Richter, MSD, Novartis, Pfizer, Sanofi, Tigenix, Roche, UCB, Neil Betteridge Consultant of: Amgen, Eli Lilly and Company, Grunenthal, GSK, Sanofi Genzyme, Jaime Calvo Grant/research support from: Lilly, UCB, Consultant of: Abbvie, Jansen, Celgene, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Patrick Durez Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Pfizer, Sanofi, Ricardo J. O. Ferreira Grant/research support from: Abbvie, Consultant of: Sanofi Genzyme, Amgen, MSD, Paid instructor for: UCB, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Annamaria Iagnocco Grant/research support from: Abbvie, MSD and Alfasigma, Consultant of: AbbVie, Abiogen, Alfasigma, Biogen, BMS, Celgene, Eli-Lilly, Janssen, MSD, Novartis, Sanofi and Sanofi Genzyme, Speakers bureau: AbbVie, Alfasigma, BMS, Eli-Lilly, Janssen, MSD, Novartis, Sanofi, Carlomaurizio Montecucco: None declared, Mikkel Ǿstergaard Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Merck, and Novartis, Consultant of: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo Nordisk, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi, and UCB, Sofia Ramiro Grant/research support from: MSD, Consultant of: Abbvie, Lilly, Novartis, Sanofi Genzyme, Speakers bureau: Lilly, MSD, Novartis, Andrea Rubbert-Roth Consultant of: Abbvie, BMS, Chugai, Pfizer, Roche, Janssen, Lilly, Sanofi, Amgen, Novartis, Tanja Stamm Grant/research support from: AbbVie, Roche, Consultant of: AbbVie, Sanofi Genzyme, Speakers bureau: AbbVie, Roche, Sanofi, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen, Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Mart van de Laar Consultant of: Sanofi Genzyme, Speakers bureau: Sanofi Genzyme

Background: The Hemophagocytic Syndrome (HPS) is has been classified into 2 groups: primary and secondary. The secondary form is mainly associated with hemato-oncological diseases (HOD) and autoimmune diseases (AID). The present work aims to obtain clinical and analytical data that can guide us to an etiological diagnosis. Objectives: To describe and identify the differences between HPS secondary to AID and HOD during their admission to a tertiary hospital between 2005 and 2019. Methods: This is a retrospective observational study. We include patient meeting the diagnostic criteria for HLH proposed by Henter JI. (1), or who presented haemophagocytic cells (HC) in the bone marrow biopsy (BMB), or who had HPS in the hospital discharge report. Demographic, clinical, analytical, etiological, underlying disorders and prognosis variables were collected. Continuous variables are described with the mean or median according to the degree of normality. Kruskal Wallis, Fisher test and Mann-Whitney U test were used for the bivariate analysis, and also a multivariate logistic regression analysis was performed. Results: We found 30 patients with secondary HPS, 22 of which corresponded to the AID [Systemic Lupus Erythematosus (n=5), Adult Still’s Disease (n=3), Rheumatoid arthritis (n=1) and IgG4 Sclerosing Disease (n=1)] and HOD [Non-Hodgkin’s Lymphoma (n=3), Myelodysplastic syndrome (n=3), Acute leukemia (n=3), Extranodal NK cell lymphoma (n=1), Multiple Myeloma (n=1) and probable lymphoproliferative process (n=1)]. The coincidence of an infectious disease with HPS was observed in 8 of the 22 cases [AID: 5 cases (2 Cytomegalovirus , 2 viral respiratory infections and 1 bacterial infection) and HOD: 3 cases (2 Epstein Barr virus and 1 bacterial infection)]. In two patients with HPS secondary to HOD (acute leukemia), allogeneic transplantation was associated as a possible trigger. In a patient with myelodysplastic syndrome, HPS was associated with the development of graft versus host disease. The age at diagnosis was lower in the AID [40 (26.5 - 56.3); p 0.001]. The HOD had more severe cytopenias [platelets 4500 (650 - 15,750; p 0.009), leukocytes 2050 (20 - 728; p 0.0001) and neutrophils 0 (0 - 280; p 0.002)]. Overall mortality (n=30 patients) was 43.3% (HOD: 66.7%; p 0.029) (table 1). In the final multivariate model according to AID and HOD, the following independent associations were observed: age (p 0.002), platelets (p 0.031), GOT (p 0.012), GPT (p 0.015), total proteins (p 0.007) and mortality (p 0.007). Table 1. Characteristics and comparative analysis of HPS secondary to AID and HOD Total AID HOD n 30 10 12 *p<0,05 Age (x ± s) 55,5 ±18,3 40 26,5-56,3 68 57,5-73,8 0,001 Gender, male 14 46,7% 3 30% 9 75% 0,084 Spenomegaly 16 53,3% 5 50% 8 66,7% 0,666 Hepatomegaly 10 33,3% 4 40% 4 33,3% 1,000 Hb (g/dL) 7,1 6,4-7,9 7,2 6,6-8,4 6,5 5,9-7,3 0,05 Pt (x10 9 /L) 13 500 5 000-52 500 31 650 11 000-100 250 4 500 650-15 750 0,004 Leu (x10 9 /L) 1 250 238-3 153 1 985 1 350-3 382 185 20 – 728 0,000 Neu (x10 9 /L) 615 0-1 550 948 633-1 808 0 0-280 0,001 Fb (mg/dL) (n=24) 171 111-358 212 90-450 167 114-354 1,00 Fer (ng/mL) (n=28) 15 330 5 434-38 284 14 263 4 254-14 263 16 796 8 287 - 56 969 0,314 Tg (mmol/L) 341 226-438 411,5 234-572 321 233,8-403,8 0,314 GOT (U/L) 139 78-406 457 289-1 140 106 71-193 0,003 GPT (U/L) 162 46-388 432 174-599 109 54-263 0,017 T.P. (n=29) 4,8 ±,1,04 5,0 4,5-5,8 4,3 3,9-4,5 0,003 Hospital stay 35,5 20,0-60,8 30,5 9,5-53,3 61,5 29,3-93,3 0,036 Hospital stay pre-dx 16,5 8,5-29,8 10 5,0-16,5 26 10-39 0,038 Mortality 13 43,3% 1 10% 8 66,7% 0,011 Hb: hemoglobin, Pt: platelets, Leu; leukocytes, Neu, neutrophils, Fb: fibrinogen, Fer: ferritin, Tg: triglycerides, GOT: aspartate aminotransferase, GPT: alanine aminotransferase, T.P.: total proteins, pre-dx: prior to the diagnosis of HPS according to BMO. *Analysis between AID and HOD. Conclusion: The HOD presented higher mortality and severe cytopenias. The AID presented a higher elevation of transaminases and better prognosis. References: [1]Henter JI, et al. HLH-2004: Diagnostic and therapeutic guidelines for HLH.Pediatr Blood Cancer. 2007;48:124. Disclosure of Interests: César Antonio Egües Dubuc: None declared, Andrea De Diego: None declared, Patricia Cabrera Miranda: None declared, Nerea Alcorta Lorenzo: None declared, Jesús Alejandro Valero Jaimes: None declared, Jose Ramon Furundarena Salsamendi: None declared, Luis Maria Lopez Dominguez: None declared, Jorge Jesús Cancio Fanlo: None declared, Olga Maiz-Alonso: None declared, Esther Uriarte Isacelaya: None declared, Jaime Calvo Grant/research support from: Lilly, UCB, Consultant of: Abbvie, Jansen, Celgene, Joaquin Maria Belzunegui Otano: None declared

Background: The Hemophagocytic Syndrome (HPS) had a mortality rate between 20% and 90%. The mortality of HPS secondary to autoimmune diseases (AID) is lower than hemato-oncological diseases (HOD). In general, the HOD, thrombocytopenia, age, and a prolongation of prothrombin are considered to be an adverse prognostic factor.(1) Objectives: To describe and identify differences between patients who survived and did not survive to HPS during hospital admission to a tertiary hospital between 2005 and 2019. Methods: This is a retrospective observational study. All patients who met the diagnostic criteria for LHH were included, or who presented haemophagocytic cells in the bone marrow biopsy, or who had diagnosis of HPS in the hospital discharge report.(2) Demographic, clinical, analytical, etiological, underlying disorder and prognosis variables were collected. Continuous variables are described with the mean or median according to the degree of normality. Kruskal Wallis, Fisher test and Mann-Whitney U test were used for the bivariate analysis, and also a multivariate logistic regression analysis was performed. Results: Thirty patients with HPS were included. They were distributed in 5 subgroups (Table 1). Overall mortality was 43.3%, statistically significant higher in the HOD [8 patients (66.7%); p 0.029]. Also, they were divided into 2 groups (survivor vs. non-survivor; Table 2). In the multivariate model the age and INR prolongation were confirmed to be independently associated with the outcome of mortality. Table 1. Etiology of HPS Etiology n = 30 Mortality AID 10 n = 1 Systemic lupus erythematosus 5 1 Adult Still’s Disease 3 No Rheumatoid arthritis 1 No Sclerosing Disease IgG4 1 No HOD 12 n = 8* Non-Hodgkin’s lymphoma 3 1 Myelodysplastic syndrome 3 2 Acute leukemia 3 3 Extranodal NK cell lymphoma 1 1 Multiple Myeloma 1 No Probable lymphoproliferative process 1 1 Infectious diseases 2 n = 1 Pneumocystis carinii in patient with H.I.V. 1 1 Campylobacter yeyuni 1 No Glyoblastoma multiforme with temozolomida 1 n = 0 HPS without defined aetiology 5 3 HIV: Human Immunodeficiency Virus, NK: Natural Killer. *p = 0,029 Table 2. Characteristics and differences between survivor and non-survivor groups Total Non-survivor survivor n 30 13 17 p<0,05 Age 55,5 ±18,3 68 58,2-74,5 40 34-57 0,043 Women 16 53,3% 7 61,5% 9 47,1% 1,00 Comorbidities (≥ 2 ) 5 16,7% 2 15,4% 3 17,6% 1,000 Hospital stay 35,5 20-60,8 29 15,5-39 13 8-17 0,563 Splenomegaly 16 53,3% 7 53,8% 9 52,9% 1,000 Hepatomegaly 10 33,3% 5 38,5% 5 29,4% 0,705 Hb (g/dL ) 7,1 6,4-7,9 710% 6,2-7,8 7,1 6,6-7,8 0,094 Pt (x10 9 /L ) 13 500 5 000-52 500 16 000 11 000-44 000 12 000 5 000-99 000 0,281 Pt ≤ 100 000 25 83,3% 13 100% 12 70,6% 0,052 Leu (x10 9 /L ) 1 250 238-3 153 1 300 150-3 940 1 400 200-3 340 0,457 Neu (x10 9 /L ) 615 0-1 550 1 290 20-3 300 650 0-1 400 0,805 Fb (mg/dL) (n=24 ) 171 111-358 167,00 106-253 169,00 103-451 0,796 Fer (ng/mL) (n=28 ) 15 330 5 434-38 284 29 063 5 728-74 604 13 225 8 287-28 729 0,108 Tg (mmol/L ) 341 226-438 254,00 184-382 471,00 341-604 0,053 GOT (U/L ) 139 77,5-406,3 133,00 101-513 179,00 101-512,5 0,483 GPT (U/L ) 162 46-389 109,00 41-333 199,00 99-298 0,198 INR (n=29 ) 1,5 1,1-1,9 2,1 1,2-3,7 1,5 1,1-1,6 0,028 Hb: Hemoglobin, Pt: platelets, Leu: leukocytes, Neu: neutrophils, Fb: fibrinogen, Fer: ferritin, Tg: triglycerides, GOT: aspartate aminotransferase, GPT: alanine aminotransferase Conclusion: The HOD presented higher mortality. The non-survivor group presented a longer INR prolongation and a higher age at the time of diagnosis. References: [1]Parikh SA. Prog. factors and outcomes of adults with HLH. Mayo Clin Proc. 2014;89:484–492. [2]Henter JI. HLH-2004: Diag. and therapeutic guidelines for HLH.Pediatr Blood Cancer. 2007;48:124. Disclosure of Interests: César Antonio Egües Dubuc: None declared, Andrea De Diego: None declared, Patricia Cabrera Miranda: None declared, Nerea Alcorta Lorenzo: None declared, Jesús Alejandro Valero Jaimes: None declared, Jose Ramon Furundarena Salsamendi: None declared, Olga Maiz-Alonso: None declared, Luis Maria Lopez Dominguez: None declared, Esther Uriarte Isacelaya: None declared, Jorge Jesús Cancio Fanlo: None declared, Jaime Calvo Grant/research support from: Lilly, UCB, Consultant of: Abbvie, Jansen, Celgene, Joaquin Maria Belzunegui Otano: None declared