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Objective:To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis.Patients and methods:Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up.Results:Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed.Conclusion:The data confirm that a LD IVCY regimen followed by AZA—the “Euro-Lupus regimen”—achieves good clinical results in the very long term.

Among the unmet needs in psoriatic arthritis (PsA), the precise mechanisms underlying the contribution of genetic susceptibility, environmental triggers and systemic inflammation are still under investigation. As a complex and multi-factorial condition, metabolomics in PsA may offer additional insight into pathways driving the pathogenesis, allowing for a better understanding of the disease-related variations downstream of the genome and proteome. In this study, the serum metabolomics profile of PsA was compared with healthy controls, by nuclear magnetic resonance spectroscopy ( 1 H-NMR). Twenty-nine PsA patients according to CASPAR criteria and DAPSA > 14 score plus 33 healthy controls matched for mean age and gender ratio, were enrolled. The sera metabolomics profile was analysed with a Varian Unity Inova 500 MHz NMR spectrometer, combined with multivariate statistical analysis (MVA). The MetaboAnalyst program was used to generate ROC curves and to perform the enrichment analysis. The OPLS-DA models exhibited a clear separation between the two groups, and the metabolomic profile of PsA patients was characterized by a significant increase in glucose and glycyl proline, and a significant decrease in alanine, glutamine, methionine, serine and the branched-chain amino acids leucine, isoleucine and valine. The ROC curve was 0.842 (95% CI 0.735–0.949), and a significant direct correlation of alanine and leucine levels with the DAPSA score was recorded. Finally, the enrichment analysis unveiled that in PsA patients, the most enriched pathways were glucose-alanine cycle, glycine and serine, glutathione, selenoamino acid, alanine and tryptophan metabolism, with a close relationship between pathways. The metabolomic profiling in PsA may offer additional insight to elucidate the metabolite unbalance on inflammatory burden, oxidative stress, energy and collagen metabolism, but also on peculiar features of the disease, such as metabolic disorders and diabetes.

Among the unmet needs in psoriatic arthritis (PsA), the discovery of molecular players and biomarkers of disease activity or clinical remission achievement, remains unsolved. Metabolomics is a valuable technology in identifying biomarkers, by the study of a set of small molecules produced by the catabolism or anabolism of an organism in response to physiological or pathological states, allowing to better understand the disease-related variations downstream of the genome and proteome. In this pilot study, we have compared the serum metabolomics profile of patients with psoriatic arthritis with active or clinically inactive disease state compared with healty controls, using Nuclear Magnetic Resonance Spectroscopy (1H-NMR). From a cohort of 300 PsA patients according to CASPAR criteria, we selected 30 PsA with active disease state by DAPSA > 14 score (no bDMARDs ongoing) (A), 38 patients (peripheral arthritis subset) with >1-year remission by antiTNFα assessed by DAPSA ≤ 4 (B) and 32 healthy controls (C) matching for mean age and gender ratio. The sera metabolomics profile of 100 subjects was analyzed with a Varian UNITY INOVA 500 MHz NMR spectrometer, combined with Multivariate statistical Analysis (MVA). Principal Component Analysis (PCA) and Orthogonal Partial Least-Squares Discriminant Analysis (OPLS-DA) were applied. The model's goodness was evaluated using a permutation test (Q2 intercept value <0.005). The represented OPLS-DA models (Figure 1) exhibited a clear separation between subjects with active disease (red dots) and healthy controls (green dots), and patients with active disease or clinical remission state (blue dots), indicating significant differences in the serum metabolomics profile between all compared conditions. Interestingly, the OPLS-DA model shows how the PsA patients in the remission state have a profile which does not completely overlap with healthy subjects. The validity of the OPLS-DA models was evaluated through a permutation test using 500 times (Table 1) and indicate the great statistical validity of the OPLS-DA reported models. The metabolomic profile of PsA patients with different disease state and healthy subjects reveal a high grade of dissimilarity between all compared conditions: remarkably, the metabolomic profile of patients with the drug-induced clinical remission appears still different from a healthy condition, perhaps reflecting molecular modifications induced by the great response to TNFalpha inhibition sustaining the clinical remission of PsA disease. Supplementary analysis of single-spectra is ongoing to obtain a list of metabolites differentially expressed in all conditions, and on this field further explorations are needed to validate metabolomics biomarkers that can accurately and reliably measure PsA disease activity or remission achievement, as well as to identify the metabolic fingerprint of antiTNFα-treatment success. All staff of the Rheumatology Unit of the AOU of Cagliari, patients and volunteer donors. None Declared. [Display omitted] Table 1Parameters for OPLS-DA modelsOPLS-DA modelsPermutation (500 times)*active PsA patients vs healthy controlsComponentsaR2XcumbR2YcumcQ2cumdR2 interceptQ2 intercept1P+1O0.4060.6650.5170.330-0.336active PsA patients vs remission PsA patients1P+2O0.4810.8240.5040.461-0.424remission PsA patients vs healthy controls1P+1O0.3890.6110.4290.318-0.331aThe number of Predictive and Orthogonal components used to create the statistical models.b,c R2X and R2Y indicated the cumulative explained fraction of the variation of the X block and Y block for the extracted components.d Q2 cum values indicated cumulative predicted fraction of the variation of the Y block for the extracted components.*An Q2 intercept value less than 0.005 are indicative of a valid model.

Background:The efficacy of belimumab in reducing disease activity in Systemic Lupus Eythematosus (SLE) has been extensively explored across clinical trials and real-life studies (1, 2). However, few studies have evaluated its efficacy upon stratification for different skin and joint phenotypes.Objectives:To assess potential disparity in efficacy of belimumab on different skin and joint manifestations from a multicentre nation-wide cohort (BeRLiSS).Methods:Adult SLE patients treated with belimumab (intravenous 10 mg/kg monthly or subcutaneous 200 mg weekly) included in the pre-existing BeRLiSS cohort (1, 2) were retrospectively analysed. Participating centres were asked to enrich the old BeRLiSS database with these new variables: skin (acute, subacute, chronic, skin vasculitis, alopecia/lupus hair, livedo reticularis, ulcer/chilblain) and joint involvement (non-deforming non-erosive arthritis – NDNE -, Jaccoud’s arthropathy, and rhupus). These different subtypes were assessed for variation in DAS28, CLASI-A (Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity), SRI-4 (SLE responder Index-4) and SLEDAI-2K scores at baseline, 12 and 24 months. Parametric and non-parametric tests were used as appropriate.Results:A total of 312 patients was recruited, 284 females and 28 males, F:M ratio 9.9:1, mean age at diagnosis 29.1±12.7 years, mean treatment duration 52.2±38.0 months. At belimumab initiation 213 patients with joint manifestations (68.3%) were identified: 174 NDNE (55.8%), 22 Jaccoud’s arthropathy (7.1%) and 17 rhupus (5.5%). Skin manifestations were found in 167 patients (53.5%): 88 acute (28.2%), 46 subacute (14.7%), and 11 chronic (3.5%) phenotype, 38 skin vasculitis (12.2%), 17 livedo reticularis (5.4%), 62 alopecia/lupus hair (19.7%) and 46 ulcer/chilblain (14.7%). Achievement of response as measured by SRI-4 was significant in patients with either articular or cutaneous manifestations, albeit independent of joint (p = 0.75; p = 0.63) and skin subtype (p = 0.24; p= 0.37) at 12 and 24 months, respectively. Similarly, SLEDAI-2K reduction was significant in both groups (p < 0.001), regardless of joint (p=0.80) and skin phenotype (p=0.14). Organ-specific measures such as DAS28 and CLASI-A decreased from baseline at 12 and 24 months across all phenotypes (Table 1 and 2). A statistically significant decrease in DAS28 from baseline at 12 and 24 months was observed for NDNE (baseline-12 months: p < 0.001; baseline-24 months: p < 0.001), Jaccoud’s arthropathy (baseline-12 months: p = 0.015; baseline-24 months: p = 0.006) and rhupus (baseline-12 months: p = 0.034; baseline-24 months: p = 0.045). However, by ANOVA rhupus did not show improvement, possibly due to insufficient sample size. Comparison of CLASI-A variation from baseline at 12 and 24 months for the acute (baseline-12 months: p = 0.001; baseline-24 months: p < 0.001) and subacute subtype (baseline-12 months: p < 0.001; baseline-24 months p < 0.001) resulted to be significant. On the other hand, for the chronic subtype it only appeared to become significant at 24 months (p = 0.033). Variation of CLASI-A was not significant among different timepoints in patients with SLE-nonspecific skin manifestations.Conclusion:In our cohort of SLE patients, belimumab was effective in patients with joint and skin manifestations with no significant difference in DAS28, SRI-4 or SLEDAI-2K variation across the various joint involvement subtypes. On the other hand, the acute and subacute skin phenotypes were associated with an earlier response to belimumab on CLASI-A than the chronic phenotype. Finally, a clear response to belimumab was not found in patients with SLE-nonspecific skin manifestations alone.REFERENCES:[1] Zen M, et al. J Pers Med. 2023;13(4):691.[2] Gatto M, et al. Arthritis Rheumatol. 2020;72(8):1314-1324.Acknowledgements:NIL.Disclosure of Interests:Luca Iaccarino LI received honoraria (speaker fee) from GSK., Marisol Bracalenti: None declared, Margherita Zen MZ received honoraria (speaker fee) from GSK., Martina Tizian: None declared, Elena Ruffato: None declared, Alberto Cauli: None declared, Rossella De Angelis: None declared, Roberto Gerli: None declared, Marcello Govoni: None declared, Renato Lo Gullo: None declared, Simone Negrini: None declared, Luca Quartuccio: None declared, Carlo Salvarani: None declared, Angelo Vacca: None declared, Andrea Doria AD received honoraria (speaker fee) from GSK.

Background:Cognitive deficits (CDs) are frequent and worsen the quality of life of Systemic Lupus Erythematosus (SLE) patients. The Montreal Cognitive Assessment (MoCA) is a feasible test used to screen the presence of cognitive deficits.Objectives:The aim of the study is to evaluate whether the MoCA is a valid test for identifying SLE patients who require a targeted neuropsychological evaluation for CDs and to discriminate which factors influence MoCA’s alterations (including subjective cognitive symptomatology).Methods:A cross-sectional study was conducted between April 2019 and November 2022 in which adult patients with SLE (ACR/EULAR 2019 criteria) and HC with similar demographic characteristics were recruited. Demographic, clinical, clinimetric, serological and therapeutic data were collected (Table 1). CDs were screened with the MoCA test performed by certified personnel (altered if<26/30). A neuropsychologist explored deficits in 8 cognitive domains with a battery of neuropsychological tests. Depressive symptoms were evaluated with the Center for Epidemiologic Studies Depression Scale CES-D, (altered if>15) and fatigue with FACIT-F (altered if<30).Results:Ninety-nine patients and 36 HCs were enrolled (Table 1). MoCA test was altered in 44 SLE and 7 HCs (44.4% VS 19.4%, p=0.008). MoCA values in SLE correlated significantly with the alterations found in the battery test in the domains of memory, executive functions, complex attention and problem solving (Rey Immediate Words p=0.014; Recognition p=0.043, Stroop Test p=0.010, FAB p =0.005, Digit Symbol p=0.018). High MoCA scores correlated with the absence of CDs (mean 26.86±1.86, p=0.012). At least one subjective cognitive symptom was reported by 31/57 SLE and 13/36 HC but no correlation was found with the MoCA alterations, while a correlation emerged with the CES-D values (p=0.002) and fibromyalgia (p=0.003). At multivariate analysis after correction for age, gender, level of education, disease duration, fibromyalgia, dyslipidemia, SLEDAI-2K, anti-RibP titre, the factors that influenced MoCA were male gender (β=-0.206, p=0.014), education <8 years (β=0.444, p<0.001), dyslipidemia (β=-0.205, p=0.016), and antiRib-P (β=-0.221, p=0.008).Conclusion:MoCA test is useful for screening but not for diagnosis of CDs in SLE patients. Low level of education, male gender, dyslipidemia and anti-Rib-P titer were factors independently associated with MoCA alterations. No correlation between subjective cognitive symptoms with MoCA alterations was found, while a correlation emerged with CES-D values and fibromyalgia.REFERENCES:NIL.Table 1.Demographics, clinics, clinimetrics, serological, therapeutics characteristics of the cohortsVariablesSLE (N=99)HC (N=36)Gender, F (%)92 (92.9%)34 (94.4%)Age, mean (SD)43.6 (±12.36)40 (±14.2)Education ≤8 years, N (%)29 (29.3%)4 (11.1%)Disease duration years, median (IQR)10.3 (3.3-18.2)-Neuropsychiatric Lupus, N (%)19 (19.2%)-Dyslipidemia, N (%)22 (22.5%)9 (25%)Hypertension, N (%)33 (33.7%)4 (11.1%)Smoking, N (%)17 (17.5%)8 (23.5%)MoCA test, mean (SD)25.3 (±3.05)27 (±2.9)>=1 cognitive domain altered N (%)17 (53%)-CES-D altered (>15), N (%)46 (46.5%)14 (38.9%)CES-D, median (IQR)16 (9-21.8)13 (7-17.3)FACIT altered (<30), N (%)23 (44.2%)8 (22.2%)FACIT, median (IQR)33 (25-40)42.5 (33.8-47)Subjective cognitive symptoms N (%)31 (54.4%)13 (36.1%)Fibromyalgia, N (%)21 (21.2%)-SLEDAI-2K, median (IQR)2 (0-5.5)-PGA, median (IQR)0.2 (0-0.8)-SLICC-DI, median (IQR)0.0 (0-1)-LLDAS, N (%)58 (58.3%)-Anti-dsDNA, median (IQR)9.2 (2.2-36.8)-C3, median (IQR)89 (73-97.5)-Anti-phospholipids, N (%)29 (30.5%)-Anti Rib-P, N (%)20 (21.3%)-PDN dose mg/die, median (IQR)4.6 (2.5-7.5)-Hydroxychloroquine, N (%)78 (78.8%)-Immunosuppressors, N (%)80 (80.8%)-Acknowledgements:NIL.Disclosure of Interests:Elisabetta Chessa: None declared, cristina serafini: None declared, Alberto Floris: None declared, Maria Maddalena Angioni: None declared, MATTIA CONGIA: None declared, Alessandro Mathieu: None declared, Alberto Cauli: None declared, Mauro Giovanni Carta: None declared, Matteo Piga AstraZeneca, GSK, Otsuka, Roche, AstraZeneca, GSK.

This study is primarily aimed at assessing serum changes on a large panel of proteins in patients with chronic back pain following spa therapy, as well as evaluating different spa therapy regimens as a preliminary exploratory clinical study. Sixty-six patients with chronic back pain secondary to osteoarthritis were randomly enrolled and treated with daily mud packs and bicarbonate-alkaline mineral water baths, or a thermal hydrotherapy rehabilitation scheme, the combination of the two regimens or usual medication only (control group), for two weeks. Clinical variables were evaluated at baseline, after 2 and 12 weeks. One thousand serum proteins were tested before and after a two-week mud bath therapy. All spa treatment groups showed clinical benefit as determined by improvements in VAS pain, Roland Morris disability questionnaire and neck disability index at both time points. The following serum proteins were found greatly increased (≥2.5 fold) after spa treatment: inhibin beta A subunit (INHBA), activin A receptor type 2B (ACVR2B), angiopoietin-1 (ANGPT1), beta-2-microglobulin (B2M), growth differentiation factor 10 (GDF10), C-X-C motif chemokine ligand 5 (CXCL5), fibroblast growth factor 2 (FGF2), fibroblast growth factor 12 (FGF12), oxidized low density lipoprotein receptor 1 (OLR1), matrix metallopeptidase 13 (MMP13). Three proteins were found greatly decreased (≤0.65 fold): apolipoprotein C-III (Apoc3), interleukin 23 alpha subunit p19 (IL23A) and syndecan-1 (SDC1). Spa therapy was confirmed as beneficial for chronic back pain and proved to induce changes in proteins involved in functions such as gene expression modulation, differentiation, angiogenesis, tissue repair, acute and chronic inflammatory response.

BackgroundSex hormones have effects on the development, progression and severity of SLE, prevalently affecting women (F:M=9:1). The neuroprotective, neurotrophic and anti-inflammatory properties of a class of progesterone-derived NeuroActive Steroids (NASs), prompted numerous investigations about the potential of these GABAA receptor allosteric modulators. However, no data about NASs on neuropsychiatric SLE (NPSLE) are available.ObjectivesThis exploratory pilot study aims to delve into a new unexplored landscape by assessing circulating NASs levels in NPSLE patients.MethodsA cohort of 16 SLE patients without NP manifestations and 16 with new onset NP diffuse symptoms was enrolled. Mood disorders and cognitive dysfunction were defined according to the Center for Epidemiologic Studies Depression Scale (CES-D) and a battery of neuropsychological tests, respectively, interpreted by a neuropsychologist. A group of 8 healthy controls (HCs) matched for mean age and gender ratio was also recruited. Exclusion criteria: ongoing contraceptive or hormonal treatment; glucocorticoid pulse or treatment variations 6-month before blood collection; anxiolitic, anticonvulsivant, antiepilettic drug intake; gonadal-adrenal surgical intervention or pathologies. Data regarding demographics, SLEDAI andSLICC organ damage index (SDI) were collected. NASs serum levels and their precursor were measured by ELISA assay, as listed: Progesterone, Diidroepiandrosterone (DHEA), Diidroepiandrosterone-Sulphate (DHEA-S), Allopregnanolone. To appreciate differences between groups, women’s fertile or menopausal subgroups were formed and p-value <0.05 has been set.ResultsTable 1 reports on data from the whole cohort. Progesterone levels in fertile women were significantly higher in the NPSLE versus HCs group (p=0.011). The Progesterone-direct metabolite, Allopregnanolone, was significantly increased in NPSLE compared to both groups of fertile SLE (p=0.026) and HCs females (p=0.027). Inversely, low levels of DHEA and DHEA-S in SLE patients versus HCs (p=0.025 and p=0.005) were found. Looking for NP symptoms, DHEA titer inversely correlates with cognitive deficit diagnosis (p=0.04), while depression diagnosis (62.5% of NPSLE cohort) correlates with Allopregnanolone levels (p=0.042). Moreover, depression severity measured by the CES-D score correlates with Progesterone (r=0.550, p=0.041) and Allopregnanolone (r=0.712, p=0.004; Figure 1). At multivariate analysis after correction for age, disease duration, SLEDAI and SDI, Allopregnanolone confirmed its independent correlation (β=0.712, p=0.004) with depression severity.ConclusionIn this pilot study, we describe for the first time the unbalanced levels of the most potent neuroactive steroid Allopregnanolone in SLE fertile patients with new onset neuropsychiatric diffuse manifestations. Moreover, in NPSLE patients, the diagnosis of cognitive deficit associates with circulating DHEA low levels and that of depression associates with Allopregnanolone high levels, significantly correlated also with the severity of this manifestation. Since the appropriate NASs balance is needed for optimal brain and neuroimmune function, our preliminary observations – that needs to be validated in an extended cohort - open a new perspective in the field, where the circulating NASs assessment in NPSLE patient could be a new promising diagnostic and preclinical research strategy.Table 1.Demographic and clinical characteristics of the participantsNPSLE (16)SLE (16)HC (8)Age mean (DS)48.2 (15.9)42.1 (10.8)49 (16)Gender (F, %)100100100Fertile (%)505050Menopausal (%)505050Disease duration, yrs median (IQR)6(2.3-9.3)6.7(3.0-10.4)-SLEDAI median (IQR)5 (1.8-11)2 (0-4)-Dose PDN mg/daily median (IQR)9.5 (5.1-14.6)3.8 (3.2-7)-Cognitive disorder (%)50--Major depression (%)62.5--Figure 1.Median value of NASs circulating levels on NPSLE/SLE/HCs fertile and menopausal female. *pvalue ≤ 0,05; ** pvalue ≤ 0,01AcknowledgementsAll staff of the Rheumatology Unit of the AOU of Cagliari, patients and volunteer donors.Disclosure of InterestsMaria Maddalena Angioni: None declared, Elisabetta Chessa: None declared, alessandra perra: None declared, elisa pintus: None declared, Alberto Floris: None declared, MATTIA CONGIA: None declared, Mauro Giovanni Carta: None declared, Alberto Cauli: None declared, Matteo Piga Speakers bureau: GSK, Consultant of: GSK, GALAPAGOS, ASTRAZENECA.

Background:Anifrolumab (ANI) is a fully human monoclonal antibody against the type I interferon receptor that has recently been approved for the treatment of moderate to severe Systemic Lupus Erythematosus (SLE) as an add-on treatment to standard of care. Data from randomized controlled trials have demonstrated its efficacy and safety, but real-world data are still limited, especially regarding the impact of this new drug on patients’ quality of life (QoL).Objectives:To evaluate the effect of ANI therapy on QoL and disease burden in a multicentric cohort of refractory SLE patients.Methods:Consecutive adult SLE patients (2019 EULAR/ACR criteria) were prospectively enrolled at ANI prescription. Data on demographic features, medical history, previous therapies and SLICC-DI were collected from clinical charts at enrolment. Patients’ assessments were performed at the first ANI infusion and subsequently after one, three and six months of treatment. At each time-point, the clinical evaluation included SLEDAI-2K, SLE-DAS, Physician Global Assessment, number of tender and swollen joints and cutaneous activity and damage assessed using the Cutaneous LE Disease Area and Severity Index (CLASI-A for activity and -D for damage). Patients’ perspective was assessed by self-administration of validated Patient Reported Outcomes (PROs): Lupus Impact Tracker (LIT) to assess the overall impact of SLE on patients’ QoL, Functional Assessment of Chronic Illness Therapy – Fatigue scale (FACIT-F) to measure self-reported fatigue and its impact on daily activities and, in a subgroup of patients with mucocutaneous involvement, Skindex-16 which is a specific PRO to investigate the impact of the skin disease in symptom, emotional and functioning spheres.Results:Twenty-five patients (96% female, 92% Caucasian) with a median age of 45 years (IQR 37-58) and a median disease duration of 11 years (IQR 7.5-21.5) were enrolled. In the whole cohort, 24 patients (96%) had a history of articular involvement, 23 (92%) of mucocutaneous involvement, 16 (64%) of haematological involvement, 7 (28%) of lupus nephritis, 5 (20%) of serositis and 4 (16%) of neuropsychiatric involvement. At baseline, 23 patients (92%) were on concomitant steroid therapy (median prednisone daily dose 7.5 mg, IQR 5-10), 19 (76%) on hydroxychloroquine and 23 (92%) on immunosuppressive treatment (10 methotrexate, 9 mycophenolate mofetil, 3 azathioprine, 1 cyclosporine). Active disease manifestations at the time of ANI prescription were in most cases mucocutaneous (18/25, 72%), followed by articular (10/25, 40%) and haematological (5/25, 20%) involvement.As reported in Table 1, after ANI start, all the disease activity measures showed a progressive improvement over time. A significant correlation was observed between LIT and joint count and Skindex-16 and CLASI-A at baseline (r≥0.464, p≤0.026 for LIT; r≥0.731, p≤0.04 for Skindex-16). During follow-up, LIT and Skindex-16 exhibited progressively and significantly improved scores, while no changes were observed in FACIT-F scores. Notably, Skindex-16 was significantly improved as early as 4 weeks after the first drug infusion (symptoms p=0.028, emotions p=0.03, functioning p=0.05), while LIT reached statistical significance after 12 weeks of treatment (p=0.046), maintaining in both cases the result achieved over time (Figure 1).Conclusion:Our preliminary data show that ANI not only allows a rapid clinical improvement of SLE activity, but also of QoL as shown by the significant amelioration of PROs from the very first months of treatment. Further long-term studies on larger cohorts are needed to confirm and corroborate these results.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Interstitial lung disease (ILD) is common in systemic sclerosis (SSc) and remains the leading cause of death. Gastroesophageal reflux disease (GERD) is frequent in SSc and has recently been recognized as an independent predictive factor for ILD progression. However, the characteristics of SSc patients with GERD and ILD are unknown, as well as predictive factors for the progression of ILD in this population.Objectives:We aimed (1) to analyze the prevalence of GERD in SSc-ILD patients in the EUSTAR database, (2) to assess the association of GERD with disease characteristics in SSc-ILD patients and (3) to identify the predictive factors for ILD progression in SSc patients with GERD.Methods:SSc-patients from the EUSTAR database fulfilling the ACR/EULAR criteria for SSc, with ILD confirmed on high-resolution computed tomography (HRCT) and available data on GERD were included. GERD was diagnosed if reflux/dysphagia was present at least once since the baseline visit. The longitudinal study included patients with at least two visits 12±3 months apart. Disease characteristics in patients with and without GERD were compared at baseline. The progression of lung fibrosis was defined as an FVC% decline of ≥ 10% or an FVC% decline of 5-9% in association with a DLCO% decline of ≥ 15% between two visits. Progression-free survival was defined as the time from baseline visit until ILD progression and/or death. Multivariable logistic regression was performed to identify factors associated with GERD in SSc-ILD patients at baseline. Prognostic factors for ILD progression, death and a combined outcome of death and ILD progression in SSc-ILD patients with GERD were tested by multivariate Cox proportional hazards regression. Multiple imputation was used to impute missing data.Results:5462 SSc patients with ILD at baseline were included. GERD was reported in 4400 (80.6%) of the SSc-ILD patients. Patients with GERD were more often female, had a longer disease duration, more frequent diffuse cutaneous subset, musculoskeletal and intestinal symptoms as compared to patients without GERD. Additionally, they had more severe lung involvement with more severe respiratory symptoms, lower FVC, lower DLCO and worse performances at 6-minute walking test as compared to patients without GERD (Table 1). The diffuse cutaneous subtype (OR: 1.43 [1.18-1.72], p < 0.001), lower DLCO (OR: 0.99 [0.99-1.00], p = 0.018) and treatment with ILD modifying drugs (OR: 1.97 [1.65-2.37], p < 0.001) were independently associated with GERD at baseline. Of the SSc-ILD patients with GERD, 1747 were included in the longitudinal analysis. Over a mean follow-up of 3.3 years, progression was observed in 34.8% of SSc-ILD patients with GERD. An older age (HR: 1.02 [1.01-1.02], p < 0.001), female sex (HR: 1.37 [1.07-1.75], p = 0.013) and the use of ILD modifying drugs (immunosuppressive and/or antifibrotic therapies) (HR: 1.41 [1.09-1.82], p = 0.009) were independent predictors for ILD progression in SSc-ILD patients. In total, 199 deaths were recorded over a mean follow-up of 5.9± 3.7 years. The use of PPI, as a surrogate marker of more persistent and severe GERD, independently predicted death (HR: 2.30 [1.52-3.48], p < 0.001) and the combined outcome of death and ILD progression (HR: 1.28 [1.04-1.56], p = 0.017) (Figure 1).Conclusion:GERD is common in SSc-ILD patients and is associated with more severe lung involvement. The risk of ILD progression is increased in older patients and women with GERD and SSc-ILD, suggesting special attention to these populations. Current PPI use predicts death and ILD progression, supporting the hypothesis of the deleterious nature of persistent reflux in SSc-ILD progression and prognosis.REFERENCES:NIL.Acknowledgements:EUSTAR collaborators.Disclosure of Interests:Eliane Roth: None declared, Cosimo Bruni Consulting for Boehringer Ingelheim., Research grants from Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Foundation for research in Rheumatology (FOREUM), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis Foundation for Bio-medical Research, EMDO Foundation. Educational grants from AbbVie and Wellcome Trust. Congress participation support from Boehringer Ingelheim., Liubov Petelytska: None declared, Patricia Carreira Patricia E Carreira has received fees for conferences and advisory boards (last 5 years): Janssen, Lilly, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Boehringer Ingelheim, Abbie, Sanofi Genzyme, Mitsubishi Tanabe, Patricia E Carreira has received fees for conferences and advisory boards (last 5 years): Janssen, Lilly, VivaCell, Emerald Health Pharmaceuticals, Gesynta Pharma, Boehringer Ingelheim, Abbie, Sanofi Genzyme, Mitsubishi Tanabe, Jeska K. de Vries-Bouwstra Speaker fees from Dutch Society (payments made to institution), Boehringer Ingelheim (payments made to institution)., Consulting fees from Boehringer Ingelheim, Jansen-Cilag and Abbvie (payments made to institution), JdVB has received grant/research support to her institution from ReumaNederland (Dutch patient Society for Rheumatology), Nationale Vereniging voor mensen met lupus, APS, sclerodermie en MCTD (Dutch patient society), ARCH (Autoimmune Research and Collaboration Hub; Dutch interdisciplinary society for patients and caregivers), Janssen-Cilag, and Boehringer IngelheimJanssen-Cilag (payments made to institution)., Alexandra Balbir-Gurman Speaker for (pharmaceutical) companies Boehringer Ingelheim, Abbvie, Pfizer, Sanofi, Janssen, Scientific grant from Abbvie, Vasiliki Liakouli: None declared, Gianluca Moroncini: None declared, Christina Bergmann Consulting fees from Janssen and Boehringer-Ingelheim, not related to the content of this work., Luc Mouthon: None declared, Christopher P Denton: None declared, Maria De Santis consulting for Boehringer Ingelheim., Research grant from Gruppo Italiano Lotta alla Sclerodermia (GILS). Congress participation support from Abbvie, Lilly, Janssen, Grunenthal, Galapagos, Novartis, Alberto Cauli: None declared, Paul Hasler: None declared, Vera Bernardino Speaker fees from Astrazeneca and GSK., Marie-Elise Truchetet: None declared, Madelon Vonk received speaker fees from Boehringer Ingelheim, Bristol-Myers Squibb, GSK, Janssen Pharmaceutical Companies of Johnson & Johnson, MSD, Novartis, and Roche; served as a data safety monitoring board member at Corbus; and is treasurer of EUSTAR and steering committee member of the ERN ReCONNET., received consulting fees from Boehringer Ingelheim and Janssen Pharmaceutical Companies of Johnson & Johnson, received research grants from Boehringer Ingelheim, Ferrer, Galapagos and Janssen Pharmaceutical Companies of Johnson & Johnson, Francesco Del Galdo has received fees and research support from: Abbvie, Argenx, Arxx, AstraZeneca, Boehinger-Ingelheim, Chemomab, GSK, Janssen, IAG, Merck, Mitsubishi-Tanabe, Novartis., has received fees and research support from: Abbvie, Argenx, Arxx, AstraZeneca, Boehinger-Ingelheim, Chemomab, GSK, Janssen, IAG, Merck, Mitsubishi-Tanabe, Novartis., Anna-Maria Hoffmann-Vold Boehringer Ingelheim, Boehringer Ingelheim, Janssen, Medscape, Merck Sharp & Dohme, Novartis and Roche, ARXX, BMS, Boehringer Ingelheim, Genentech, Janssen, Medscape, Merck Sharp & Dohme and Roche, Boehringer Ingelheim, Janssen, Oliver Distler OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years:4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Co-founder of CITUS AG., OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Co-founder of CITUS AG., OD has/had consultancy relationship with and/or has received research funding from and/or has served as a speaker for the following companies in the area of potential treatments for systemic sclerosis and its complications in the last three calendar years: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Argenx, Arxx, AstraZeneca, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, Horizon, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Orion, Prometheus, Redxpharma, Roivant, Topadur and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143). Co-founder of CITUS AG., Muriel Elhai: None declared.

The most important goal of therapy in psoriatic arthritis (PsA) is to reach the remission state of disease. Nowadays, data on molecular players of clinical remission and effective disease inactivation are scarce: gene expression analysis could highlight markers characteristic of PsA remission state. Our aim was to analyze the gene expression profile of patients with clinically inactive (drug-induced remission) PsA versus healthy controls and PsA active state. From a cohort of 300 patients affected by PsA according to CASPAR criteria, we selected 40 patients (peripheral arthritis subset) with >1-year remission by TNFα antagonism assessed by DAPSA ≤ 4 (R) and 40 PsA with active disease state by DAPSA > 14 score (no bDMARDs ongoing) (A), and 40 healthy controls (HC) matching for mean age and gender ratio. Both PsA groups were not on corticosteroid treatment. Each condition has been profiled first using pooled RNAs from peripheral blood (biological duplicates) by Affymetrix Human GeneChip HTA 2.0. To identify a transcript as differentially expressed in both duplicates, a fold change (FC) 1.5 and p-value 0.05 has been set. Then, from the comparative list of differential expressed genes (DEGs) in R vs HC state, coding mRNAs were selected and interactions analyzed by STRING software, biological functions and annotations by Gene Onthology (GO). From these analysis, 12 genes were validated in the whole PsA cohort (R+A) and HCs, by quantitative real-time PCR (RT-qPCR) in triplicate (TaqMan chemistry, GAPDH housekeeping, 2–ΔΔCt for relative quantification, FC cutoff ±1.5 for differential analysis). The transcriptomic analysis generated 3 comparative lists of mRNAs (R vs HC= 125; R vs A= 1184; A vs HC= 378 transcripts). Then, we focused on remission state analyzing the mRNAs list R vs HC. Filtering data for coding DEGs, was made a list of 24 genes further analyzed for functions and interactions: STRING analysis created one interactions network and GO highlighted in which biological processes these DEGs are involved (Fig panels 1A, 1B). Validation analysis by rt-qPCR in the PsA cohort (R+A) and HCs confirmed the downregulation of c-FOS and the upregulation of CCDC50 (alias YMER) genes in the R vs HC conditions (pvalue= 0.004). The dysregulation of further genes in other comparisons was measured, as shown in Tab and Fig panel 1C. Observing the amount of DEGs, is evident that the drug-induced remission state is more similar to healthy condition, however this trend of “similarity” does not mean “identical”. The bioinformatic analysis showed that DEGs in the R vs HC conditions are primarily involved in biological processes related to immune system as well as correlates in an interactions network. Our molecular characterization of clinical remission revealed that effective disease inactivation appears to be molecularly-driven by two key genes, c-FOS and CCD50 (YMER), both involved in the NF-κB signalling pathway modulation. [Display omitted] Coding DEGs mis-regulated in the remission state. Differentially expressed genes (DEGs) in the Remission (R) state vs Healthy Controls (HC) analyzed for multiple-proteins interaction by STRING software V10.5 (panel A) and biological functions by Gene Set Enrichment Analysis (panel B). DEGs validations by RT-qPCR, confirmed the CCD50 and c-FOS dysregulation in the R state (panel C, RQ= Relative Quantification, t test RvsHC pvalue=0,004). DEGs by RT-qPCR. Validated differentially expressed genes (DEGs) in the remission (R) state vs healthy controls (HC) selected from the microarray analysis comparative list (FC cutoff ±1.5). Differential analysis (40 R vs 40 HC vs 40 Active) was made by FoldChange (FC) cutoff ±1.5 (overexpressed ≥ 1.5; - 1.5 ≥ downregulated). None declared GENE SYMBOLGene chip Array R vs HCRemission vs HCActive vs HCRemission vs ActiveALPL-1.7-1.11.3-1.25ANPEP-1.681.01.1-1.1BPI-1.57-1.11.27-1.5CCDC501.51.5-1.251.8CEACAM8-2.3-1.21.2-1.5CHI3L1-1.59-1.1-1.0-1.0DEFA1B-2.3-1.41.9-2.7FCAR-1.56-1.11.1-1.3FOS-1.51-2.0-1.5-1.4KLRB11.52-1-1.61.6PADI2-1.54-1.11.0-1.1TNFSF14-1.511.11.2-1.1