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Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.

BackgroundAnti-small ubiquitin-like modifier-1 activating enzyme (anti-SAE) antibodies are rare myositis-specific antibodies, which are mainly associated with cutaneous involvement in inflammatory myositis (IIM).ObjectivesTo analyse clinical characteristics of anti-SAE positive Dermatomyositis (DM) patients in a monocentric cohort. We focused on clinical manifestations and type of organ involvement.MethodsIn a monocentric cohort of 169 patients with IIM, anti-SAE antibody positive patients were included in the study. Anti-SAE antibodies were investigated by immunoblotting. We considered the presentation symptoms at disease onset and during follow-up, focusing on musculoskeletal, cutaneous and pulmonary domains. Muscular involvement was evaluated by Manual Muscle Test-8 and creatin kinase (CK) levels. To determine interstitial lung disease (ILD), high-resolution computed tomography (HRCT) was performed at diagnosis and during follow-up and evaluated by an expert radiologist. Skin and joint involvement was evaluated by clinical judgment. Therapeutic approach was also considered.ResultsOf the 169 patients with IIM, 6 were positive for anti-SAE antibodies (3,5%). Among them, five were female and one male. The mean age at onset of symptoms was 46.3 years (range 5-78 years). Cutaneous manifestations were the most prevalent clinical features at disease onset. Indeed, all of the patients had photosensitive rash, heliotrope rash and Gottron papules. Mechanic’s hands were noted only in one patient with ILD. Four (70%) had arthritis. Muscular involvement, which was mostly mild, was evidenced by muscular weakness and high levels of CK (mean value 538 U/l) in 30% of patients (n=2). Three patients (50%) had radiological evidence of ILD at onset or during follow-up. Non-specific Interstitial Pneumonia (NSIP) was the main pattern found. Story of malignancy was noted only in the male patient. Half of the patients (n=3) were treated with methotrexate (MTX). Because of drug intolerance, MTX was substituted by mycophenolate mophetil (MMF) in two of them. One patient received intravenous immunonoglobulin (IGIV) and cyclophosphamide (CYC) for persistent cutaneous disease activity.ConclusionIn our small cohort of patients, anti-SAE antibodies were strongly associated with skin disease, in one case severe. Lung involvement was another common clinical feature described and malignancy was noted in one case.Table 1.Clinical and serological characteristics of anti-SAE positive patientsParametersCase 1Case 2Case 3Case 4Case 5Case 6Age of onset (years)56145327857Age at diagnosis (years)66147327858GenderFMFFFFPresentationFever−+++−−Muscle weakness+−−−+−Dysphagia+−−++−Photosensitive rash+++Voice change−−−+−−Dyspnea−−+++−Myalgia+−−+−−Arthritis+−++−+Heliotrope rash+++Gottron papule+++Mechanic’s hand−−−−+−Skin ulcer−−−−−−Malignancy−+−−−−Interstitial lung disease−−+−++Laboratory valuesCK (U/L)NA564110100512128AST (U/L)NA274920NANALDH (U/L)NA7080386NANATreatmentANAENA+MTXMMF+PM-Scl-100MMF+MTX, IgIV,CYC, MMF+Tif-1-gammaMTX+NA+NACK creatine kinase, AST aspartate transaminase, LDH lactate dehydrogenase, ANA anti-nuclear antibody,MMF mycophenolate mofetil, MTX methotrexate, IgIV intravenous immunoglobulin, CYC cyclophosphamideREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:The 2023 ACR/EULAR antiphospholipid syndrome (APS) classification criteria offer a more precise clinical characterisation and a higher sensitivity profile than the previous revised Sapporo criteria. APS can be associated with other connective tissue diseases, specifically with systemic lupus erythematosus (SLE).Objectives:To evaluate the use of 2023 ACR/EULAR APS classification criteria in patients affected by SLE with a previous diagnosis of secondary APS according to Revised Sapporo Criteria for APS.Methods:A retrospective monocentric cohort study was performed. Patients affected by SLE and diagnosed with APS according to Revised Sapporo Criteria for APS and fulfilling entry criteria for 2023 ACR/EULAR APS classification criteria were included. Data regarding anti-cardiolipin antibodies (aCL) and anti-beta2 glicoprotein I (anti-B2GPI) IgG and IgM refer to serum analysis performed by ELISA assays and confirmed with two measurements 12 weeks apart. Lupus anticoagulant (LA) measurement was considered persistent if confirmed in 3 or more measurements. Clinical and serological data were collected according to items proposed by the new classification criteria.Results:44 patients affected by SLE and previously diagnosed with APS were included, 27 (61.4%) of which females. Mean age at diagnosis was 28.7±11.3 years, mean disease duration was 25.4±8.5 years. Regarding participants’ APS clinical manifestations, we observed venous thromboembolism (VTE) in 40 (90.9%) patients, 24 (54.6%) of which without a high VTE profile; eleven (25%) had arterial thrombosis, 6 of which (13.64%) without a high cardiovascular risk profile; seven (15.9%) had suspected microvascular lesions and 3 (6.8%) had pathology-proved aPL nephropathy; two (4.6%) had cardiac valve thickening and 3 (6.8%) had thrombocytopenia not likely to be related to SLE disease activity. 6 (13.6%) had obstetric manifestations, 3 (6.8%) of which had ≥3 consecutive pre-fetal/fetal death (<16w) and 3 (6.8%) had preeclampsia with severe features. At the moment of APS clinical manifestations, 33 (75%) had an active SLE, 5 (11, 4%) had nephrotic syndrome and 6 (13.6%) were being treated with prednisone ≥25 mg. Regarding the serological profile, we observed positive LA in 39 cases (88.6%), in 36 (81.8%) cases LA was persistently positive. We observed moderate-high titers of aCL IgM in 14 cases (31.8%) and IgG in 28 cases (63.6) and of antiB2GPI IgM in 8 cases (18.2%) and IgG in 23 (52.3%). Mean clinical score was 4.2±2.3. Mean laboratory score was 7.8±3.1.Four (9.1%) patients did not meet the new APS classification criteria, having a clinical score <3, as thethe only clinical manifestation was an episode of VTE in patients with a high risk profile for VTE.Conclusion:Almost 1 out of 10 SLE patients with a previous diagnosis of concomitant APS did not meet 2023 ACR/EULAR APS classification criteria. The latest criteria offer a more specific and sensitive patient profiling, although further studies need to be conducted to assess the applicability in secondary APS syndrome.REFERENCES:[1] Barbhaiya M, Zuily S, Naden R, et al. The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol. 2023;75(10):1687-1702. doi:10.1002/art.42624.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Extracellular vesicles (EVs) deliver small molecules across several cell types including microRNA (miRNA) which are involved in regulation of gene expression and were proven to play a role in several autoimmune rheumatic diseases. Idiopathic inflammatory myopathies (IIM) display heterogeneity in both phenotype and pathogenic mechanisms which may inform on disease course and prognosis.Objectives:To investigate the epigenetic footprint in IIM through characterization of circulating EVs and the expression of EV-derived small non-coding RNAs (sncRNAs).Methods:In this cross-sectional study, EVs were isolated by size-exclusion chromatography from plasma of patients with IIM and matched healthy donors (HD). EV-derived sncRNAs were sequenced and quantified using Next-Generation Sequencing (NGS). Following quality control and normalization, filtered count reads were used for differential miRNAs expression analyses. Putative gene targets enriched for pathways implicated in IIM were analyzed. Patients’ clinical and laboratory characteristics at the time of sampling were recorded.Results:Forty-seven IIM patients and 45 HD were enrolled. We showed a significant upregulation of MiR-486-5p (p<0.01), miR-122-5p, miR-192-5p, and miR-32-5p (p<0.05 for all), while a downregulaion of miR-142-3p (p<0.001), miR-141-3p (p<0.01), let-7a-5p (p<0.05) and miR-3613-5p (p<0.05) in EVs from IIM patients versus HD (Figure 1). MiR-486-5p was associated with increased muscle enzymes levels. Several target genes of up/downregulated miRNAs in IIM participate in inflammation, necroptosis, interferon and immune signaling. Within IIM, miR-335-5p was selectively upregulated and miR-27a-5p downregulated in dermatomyositis (n=21, p<0.01). Plasma EV levels were significantly increased in cancer-associated myositis (CAM, n=12) versus non-CAM IIM (n=35, p=0.02) and HD (p<0.01). EVs cargo in CAM was significantly enriched of let-7f-5p and depleted of miR-143-3p.Conclusion:Through an unbiased screening of EV-derived sncRNAs, we show differential patterns of miRNAs expression in the EVs cargo of different IIM subtypes, submitting their role as potential biomarkers and modifiers of diverse IIM phenotypes.REFERENCES:NIL.Figure 1.Study design and main resultsAcknowledgements:NIL.Disclosure of Interests:Mariele Gatto GSK, AZ, Janssen, Chiara Franco: None declared, Alessandra Giannella: None declared, Michela Gasparotto: None declared, Anna Ghirardello: None declared, Elisabetta Zanatta Janssen, Luca Iaccarino GSK, AZ, GSK, Giulio Ceolotto: None declared, Andrea Doria GSK, AZ, Pfizer, Celgene, Eli Lilly, BMS, Roche, GSK.

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by involvement of multiple organ systems and a wide range of clinical phenotypes. Prior research has endeavoured to stratify SLE patients into distinct endotypes based on their unique serological profiles, but how B cell subtypes could contribute to such patient characterisation remains unclear.A more refined characterisation of SLE patient subgroups might enhance our understanding of underlying pathogenesis and serve as a guide in therapeutic decisions.Objectives:To determine SLE patient endotypes according to B cell immunophenotype and serological profile and assess their response to belimumabMethods:We analysed data from 796 patients with SLE from the phase III trial BLISS-SC clinical trial of belimumab. An unsupervised machine learning algorithm employing principal components analysis and a subsequent unsupervised clustering methodology was used to explore patient subgroups based on B cell immunophenotyping and serology. Cox regression analysis was used to assess the effect of belimumab vs placebo on inducing sustained lupus low disease activity state (LLDAS) or sustained DORIS remission across clusters.Results:Cluster 1 (n=193) was characterised by higher proportions [mean (SD)] of CD19+CD24b+CD27+ regulatory B cells [35.8%, (12.6%)], CD19+CD20+CD27+ bulk memory B cells [32.0% (9.9%)], CD19+CD20+CD69+ activated B cells [0.2%, (0.3%)], CD19+CD20-CD138+ long-lived plasma cells [0.6%, (1.0%)], and CD19+CD38b+CD27b+ SLE-associated plasma cells [6.6%, (7.0%)]. Cluster 2 (n=358) comprised higher proportions of CD19+CD24b+CD38b+CD27- transitional B cells [6.5% (9.2%)], and CD19+CD20+CD27- naïve B cells [85.5% (7.2%)], and lower proportions of CD19+CD20-CD138+ peripheral long-lived plasma cells [0.2% (0.3%)] and CD19+CD38b+CD27b+ SLE-associated plasma cells [1.6% (6.1%)]. Cluster 3 was characterised by a higher proportion of CD19+CD20+CD138+ short-lived plasma cells [0.1%, (0.1%)]. Cluster 2 was dominated by musculoskeletal and mucocutaneous manifestations. Patients within cluster 3 had the greatest baseline Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores and average prednisone dose, and a greater proportion of patients in this cluster had renal involvement. Use of belimumab in cluster 2 yielded an increased probability of attaining sustained LLDAS [HR 2.12; 95% CI: 1.1-4.0; p<0.005] and DORIS remission [HR 3.45; 95% CI: 1.2-9.9; p<0.005] compared with placebo, while no such benefit from belimumab was seen in clusters 1 and 3.Conclusion:Three distinct SLE endotypes were identified based on B cell immunophenotyping and autoantibody profiles. Cluster 2, dominated by an abundance of immature B cells and musculoskeletal/mucocutaneous manifestations, appears to be more benefited by belimumab therapy.REFERENCES:NIL.Figure 1.1A. t-distributed stochastic neighbor embedding plot (t-SNE) describing the three clusters of patients with systemic lupus erythematosus identified by an unsupervised analysis using B cell subsets and serology. 1B. Across-cluster and pairwise comparisons regarding immunological items, namely B-cell populations, autoantibodies, and low complement levels; demographics, disease related activity and damage total scores and medications; SDI items; SLEDAI-2K items. Statistically significant associations based on post-hoc analysis are denoted with asterisks (*p<0.05, **p=0.001, ***p<0.001). Eq: equivalent; CNS: central nervous system; GFR: glomerular filtration rate; SDI: SLICC/ACR Damage Index; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; SD: standard deviationFigure 2.2A. DORIS remission trajectories across clusters until the end of the follow-up period. 2B. LLDAS response trajectories across clusters until the end of the follow-up periodAcknowledgements:NIL.Disclosure of Interests:None declared.

Background : Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by involvement of multiple organ systems and a wide range of clinical phenotypes. Prior research has endeavoured to stratify SLE patients into distinct endotypes based on their unique serological profiles, but how B cell subtypes could contribute to such patient characterisation remains unclear. A more refined characterisation of SLE patient subgroups might enhance our understanding of underlying pathogenesis and serve as a guide in therapeutic decisions. Objectives : To determine SLE patient endotypes according to B cell immunophenotype and serological profile and assess their response to belimumab. Methods : We analysed data from 796 patients with SLE from the phase III trial BLISS-SC clinical trial of belimumab. An unsupervised machine learning algorithm employing principal components analysis and a subsequent unsupervised clustering methodology was used to explore patient subgroups based on B cell immunophenotyping and serology. Cox regression analysis was used to assess the effect of belimumab vs placebo on inducing sustained lupus low disease activity state (LLDAS) or sustained DORIS remission across clusters. Results : Cluster 1 (n=193) was characterised by higher proportions [mean (SD)] of CD19+CD24b+CD27+ regulatory B cells [35.8%, (12.6%)], CD19+CD20+CD27+ bulk memory B cells [32.0% (9.9%)], CD19+CD20+CD69+ activated B cells [0.2%, (0.3%)], CD19+CD20-CD138+ long-lived plasma cells [0.6%, (1.0%)], and CD19+CD38b+CD27b+ SLE-associated plasma cells [6.6%, (7.0%)]. Cluster 2 (n=358) comprised higher proportions of CD19+CD24b+CD38b+CD27- transitional B cells [6.5% (9.2%)], and CD19+CD20+CD27- naïve B cells [85.5% (7.2%)], and lower proportions of CD19+CD20-CD138+ peripheral long-lived plasma cells [0.2% (0.3%)] and CD19+CD38b+CD27b+ SLE-associated plasma cells [1.6% (6.1%)]. Cluster 3 was characterised by a higher proportion of CD19+CD20+CD138+ short-lived plasma cells [0.1%, (0.1%)]. Cluster 2 was dominated by musculoskeletal and mucocutaneous manifestations. Patients within cluster 3 had the greatest baseline Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores and average prednisone dose, and a greater proportion of patients in this cluster had renal involvement. Use of belimumab in cluster 2 yielded an increased probability of attaining sustained LLDAS [HR 2.12; 95% CI: 1.1-4.0; p<0.005] and DORIS remission [HR 3.45; 95% CI: 1.2-9.9; p<0.005] compared with placebo, while no such benefit from belimumab was seen in clusters 1 and 3. Conclusion : Three distinct SLE endotypes were identified based on B cell immunophenotyping and autoantibody profiles. Cluster 2, dominated by an abundance of immature B cells and musculoskeletal/mucocutaneous manifestations, appears to be more benefited by belimumab therapy.

BackgroundIdiopathic inflammatory myopathies are a heterogeneous group of autoimmune disorders characterized by muscle inflammation frequently associated with the involvement of other organ systems. Due to variety of presentations and severity degree, treatment of inflammatory myopathies is challenging. Considering the immunopathogenic role of B cell in myositis, Rituximab (RTX), as B cell depleting agent, could be an effective therapy in patients refractory to others immunomodulatory drugs.ObjectivesThe aim of the present study is to demonstrate the efficacy of RTX for the treatment of idiopathic inflammatory myopathies in multi refractory patients. We also considered the effectiveness of a low-dose RTX as a remission-maintenance therapy.MethodsFrom a monocentric cohort of patients with inflammatory myopathies, we considered all patients who have been treated with RTX (2 infusions of 1 gram, week 0-2). We also considered low-dose RTX as a single dose of 1g every 6 months. The response to RTX was considered based on physician judgement (complete CR, partial PR, no-response NR), focused on muscle and lung manifestations.Improvement in muscle involvement was based on reduction of 30% of creatine kinase levels and/or an increase in Manual Muscle Test score (MMT-8) of 20%.Interstitial Lung disease (ILD) was evaluated by pneumologist judgement based on chest computer tomography and spirometry.A response was considered partial if it was maintained less than 6 months from RTX administration and complete if it persisted more than 6 months.ResultsThirty-six patients were included, 15 with diagnosis of polymyositis, 13 with antisynthetase syndrome, 6 with dermatomyositis, 1 with inclusion body myositis and 1 with necrotizing myopathy.Anti-Jo1 autoantibodies were found in 12 patients, anti-SSA in 9, anti-SRP in 5, anti-PM/Scl 75 in 2, anti-Mi2 in 2, anti-PL7 in 1, anti-PL 12 in 1, anti-SSB in 1, anti-TIF1-γ in 1, anti Ku in 1 and anti Sp100 in 1.Most patients (50 %, n=18) were treated with RTX for muscle involvement, 17 % (n= 6) for ILD, 33 % (n=12) for both muscular and lung disease.All patients received oral glucocorticoid before starting RTX administration. The others previous therapies were: methotrexate in 72% of patients, mycophenolate mofetil in 50%, IVIG in 27%, azathioprine in 22%, hydroxychloroquine in 14%, cyclosporine in 14%, leflunomide in 11%, tacrolimus in 3%, cyclophosphamide in 3%.We observed CR to RTX in 70% of patients, PR in 19%, NR in 11%. In the subgroup treated for muscle involvement (n=18), we found a CR in 10 patients, a PR in 5 and NR in 3. In patients with ILD, 5 patients got a CR and 1 PR. In the group of patients with both lung and muscle manifestations, we observed 10 CR, 1 with PR and 1 with NR.Five patients were treated with a low dose maintenance therapy after having achieved remission with standard dose. Three patients had a diagnosis of polymyositis, one of dermatomyositis and one of antisynthetase syndrome. Patients received a minimum of 3 infusions and a maximum of 5 infusions of low dose RTX.Therapy was administrated for an average of 3 years. All of them maintained a CR to RTX.ConclusionIn our cohort, RTX was effective in 89% multi-drug refractory patients and the low-dose was efficacious as a maintenance therapy in all cases.References[1]Oddis CV et. al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial. Arthritis Rheum. 2013 Feb;65(2):314-24. doi: 10.1002/art.37754. PMID: 23124935; PMCID: PMC3558563.[2]Schmidt J. Current Classification and Management of Inflammatory Myopathies. J Neuromuscul Dis. 2018;5(2):109-129. doi: 10.3233/JND-180308. PMID: 29865091; PMCID: PMC6004913Acknowledgements:NIL.Disclosure of InterestsNone Declared.

BackgroundWhether late-onset (LO) SLE is associated with a different, more benign disease course and better prognosis than early-onset SLE is still contradictory.[1-3]ObjectivesTo describe the prevalence and clinical features of LO-SLE and very late onset (VLO) SLE and to compare their outcomes with those of non-LO SLE.MethodsWe performed a retrospective study using prospectively collected data from our cohort involving 516 patients with SLE (ACR criteria) followed between 2008 and 2022. Patients older than 50 or older than 60 years at SLE onset were defined as LO-SLE and VLO-SLE, respectively. Demographic data, and clinical and treatment history were retrieved from clinical charts. SLEDAI-2K, daily prednisone dose, SLICC Damage Index (SDI), and low disease activity (according to LLDAS definition) [1] at last follow-up in 2022 were assessed. Early mortality, within 10 years after diagnosis, was assessed in patients diagnosed in the last 15 years.ResultsAmong 516 SLE patients regularly followed, 38 (7.4%) were LO-SLE: mean±SD age at diagnosis 56.5 ±5.7 years (range 50-72), females 78%. Of them, 10 (2% of the overall cohort) were VLO-SLE: mean±SD age at diagnosis 65 ±4.0 years (range 60-72), females 60%. Compared to early-SLE patients, LO-SLE patients had more frequently skin involvement and positive antiSSA/SSB antibodies (Table 1). Compared to non-LO-SLE, no difference in life-threatening manifestations was observed, including renal and neuropsychiatric involvement. The same trend was found in VLO-SLE. Accordingly, the use of immunosuppressants (including types of drugs) and biologics was similar (Table 1). At last follow-up, SLEDAI-2K was lower in LO-SLE patients (1±2 vs. 2±3, p=0.01), whereas the proportion of patients on glucocorticoids (21% vs 37%) and in LLDAS (84% vs 74%) was similar to that observed in non-LO-SLE. Despite that, SDI was higher in LO-SLE (2, range 0-8) than in non-LO-SLE patients (1, range 0-10, p=0.004) but after excluding items possibly related to aging (cataract, osteoporosis, low GFR, malignancy) the difference was not significant anymore. Among 165 patients diagnosed in the last 15 years, mortality was similar in LO and early-onset SLE, although deaths within 10 years after diagnosis (2 cases) all occurred in early-SLE patients.ConclusionAccording to our data, LO- and VLO-SLE are uncommon and seem not to be associated with more benign disease outcomes. Since life-threatening manifestations can occur in LO-SLE, these patients deserve regular follow-up.References[1] Arnaud L, et al. Late-onset systemic lupus erythematosus: epidemiology, diagnosis and treatment1 Drug Aging 2012;29(3):181-189.[2] Lin H et al. Survival analysis of late-onset systemic lupus erythematosus: a cohort study in China. Clin Rheumatol 2012;31(12):1683-9.[3] Riveros Frutos A et al. Late-onset versus early-onset systemic lupus: characteristics and outcome in a national multicentre register (RELESSER) Rheumatology 2021 6;60(4):1793-1803.Table 1.Clinical and therapeutic features of late-onset and early-onset SLELate onset SLE(N=38)Early onset SLE(N=478)P valueSkin rash13 (34.2)262 (54.8)0.027Alopecia3 (7.8)60 (12-.5)n.s.Cutaneous vascu-litis1 (2.6)45 (9.4)n.s.Arthritis23 (61)353 (73.8)n.s.Leukopenia17 (44.7)191 (40)n.s.Thrombocitopenia11 (29.9)86 (18)n.s.Serositis8 (21)91 (19)n.s.Lupus nephritis16 (42.1)258 (54)n.s.Neuro-SLE8 (21)81 (16.9)n.s.Anti-dsDNA Abs25 (66)335 (70)n.s.Anti-SSA/SSB Abs23 (61)201 (42)0.044Anti-U1RNP Abs9 (23.6)129 (27)n.s.Antiphospholipid Abs13 (34.2)138 (28.9)n.s.Immunosuppressants everMMFCYCAZAMTXBelimumabRituximab23 (61)13 (34.2)4 (10.5)6 (15.7)8 (15.7)6 (16)3 (7.6)339 (71-)210 (44)103 (21.5)143 (29.9)87 (18.1)75 (15.7)39 (8.2)n.s.HCQ ever35 (92)454 (95)n.s.Acknowledgements:NIL.Disclosure of InterestsIlenia Anna Gennaio: None declared, Margherita Zen Speakers bureau: GSK, AstraZeneca, Enrico Fuzzi: None declared, Mariele Gatto Speakers bureau: GSK, AstraZeneca, Maddalena Larosa: None declared, Luca Iaccarino Speakers bureau: GSK, AstraZeneca, Andrea Doria Consultant of: GSK, AstraZeneca.

BackgroundInterstitial lung disease (ILD) is the most frequent organ involvement in patients with idiopathic inflammatory myopathies (IIMs). Some patients with connective tissue diseases including IIMs may develop a progressive fibrosing (PF-)ILD [1]. The chemokine CCL18 is constitutively expressed by dendritic cells and macrophages in lung tissues and may induce collagen synthesis in lung fibroblasts. Circulating CCL18 correlated with fibrosis severity in idiopathic pulmonary fibrosis and it predicts ILD progression in patients with systemic sclerosis (SSc) [2]. OX40 ligand (OX40L) is a glycoprotein expressed on activated antigen-presenting cells and in vivo OX40L blockade prevents inflammation-driven skin, lung, and vessels fibrosis in mouse models of SSc [3].ObjectivesTo assess the potential role of CCL-18 and OX40L as biomarkers of ILD and PF-ILD in patients with IIMs.MethodsPatients affected with IIMs (EULAR/ACR 2017 criteria) followed in our referral center were consecutively enrolled from September 2020 to March 2021. Clinical and serological variables, and organ involvement were recorded. Pulmonary involvement was investigated by high-resolution CT (HRCT) and pulmonary function tests (PFTs). CCL-18 (pg/ml) and OX40L (pg/ml) serum levels were measured by validated ELISA assays (according to the manufacturer’s instructions) in patients and in 35 controls (matched for age and sex). Follow-up data including worsening of respiratory symptoms, and repeated PFTs and HRCT were recorded. PF-ILD was defined according to the INBUILD criteria [1].ResultsNinety-three IIMs patients (64.5% females) with median age 62 (IQR 54.5-71) years and disease duration 3 (IQR 2-9) years were enrolled; ILD was detected in 52 (54.7%) patients. OX40L serum levels were similar between patients and controls, whereas CCL-18 serum levels were higher in IIMs patients than in controls (232.9 [IQR 134.7-399.07] vs. 48.4 [IQR 29.9-147.5], p<0.0001, Figure 1A). Among IIMs patients, those with ILD exhibited higher levels of CCL-18 than those without (305.6 [181.6-518] vs. 164.3 [79.6-270.7], p=0.001, Figure 1B). No association between CCL-18 values with autoantibodies, PFTs or any other clinical features was detected. During follow-up 16/52 (31%) patients developed a PF-ILD. At baseline, patients who developed PF-ILD had higher CCL-18 serum levels than non-progressors (306.4 [198.9-621.9] vs. 207.8 [102.6-376.8], p=0.03]. Higher CCL-18 values, Anti-Ro52 and anti-MDA5 positivity, lower Creatine Kinase levels and diffusing capacity for carbon monoxide (DLCO) values were predictors of PF-ILD occurrence at univariate but not at multivariate analysis.ConclusionCCL-18 but not OX40L may be a useful biomarker in the assessment of patients with IIMs-ILD.References[1]Flaherty KR et al, N Engl J Med 2019;381(18):1718-1727.[2]Schupp J et al, Eur Respir J 2014;43(5):1530-2.[3]Elhai M et al, Proc Natl Acad Sci USA 2016;113:E3901-10.Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.