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Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren’s syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P=0.02, OR=1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P=0.03, OR=1.53), pSS (P=0.016, OR=1.69), and RA (P=0.0001, OR=2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.

Immune thrombocytopaenic purpura (ITP) is an autoimmune systemic disease detectable by the presence of low blood platelets count (<105/µl) and the production of autoantibodies against glycoproteins expressed on the platelet surface. The clinical course is often acute, and life-threatening events may occur especially in children, with 52% of paediatric patients recovering either spontaneously or after treatment. A chronic ITP evolution is observed in 64% of adults, of whom 12% will develop an overlapping autoimmune disease. Several microbial agents such as CagA-positive Helicobacter pylori or Candida albicans and a number of viruses including CMV, EBV or HIV can potentially trigger ITP through molecular mimicry. Moreover, ITP improves after treatment of the underlying infection. Similarly, vaccines such as MMR may prompt ITP (IRR 5.48, 1.61–18.64, p < 0.006). Early recognition of the underlying microbial trigger and the removal of modifiable aetiopathogenetic factors should be integrated as a complementary treatment strategy in all patients who do not readily improve with standard ITP care.

Background Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. Methods Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. Results PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. Conclusions Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.

BackgroundThe distal interphalangeal joint (DIP), the extensor tendon enthesis and fingernail, in psoriatic arthritis (PsA) represent a very interesting site where the dermatologic, synovial, and entheseal features of the disease merge. The nail-enthesis complex (NEC) can be well analysed with ultrasound (US), and the nailfold is the ideal site to assess angiogenesis, another typical feature of psoriatic synovitis, with both power Doppler (PD) and nailfold videocapillaroscopy (NVC). Studies have shown that PsA patients may have differences in the structure of the nail complex and capillaries compared with healthy individuals. No study has combined the two techniques.ObjectivesTo evaluate the ability of combined US examination of the NEC and NVC to differentiate PsA from psoriasis (PSO), rheumatoid arthritis (RA), and healthy subjects (HC).MethodsTwenty age- and sex-matched subjects per group were consecutively enrolled. Each subject was blindly assessed and underwent US of the NEC, NVC, and clinical examination. For the US examination, the nail plate, matrix, and bed were assessed in grayscale (GS) and with PD according to the Brown University Nail Enthesis Scale (BUNES)[1]. For the nail plate, the Wortsman[2] classification was also evaluated. The thickness of the nail plate, matrix, and nail bed were measured. Mean values of 10 digits were used for the analysis. Capillary density, number of microhaemorrhages, tortuous capillaries, ectasia, and ramified capillaries were assessed at NVC. Mean values were calculated for II-V digits in both hands. After excluding subjects with missing values, differences among groups were analysed with Kruskal-Wallis test. US and NVC variables were then included in a K-Means clustering model. The number of clusters was determined using the elbow method. Factor analysis was performed to explain the clustering results. The number of factors was selected using the Scree plot method.ResultsThe BUNES GS total score, the BUNES GS score for the plate, and the Wortsman score were significantly lower in HC compared to all other groups. BUNES GS for the plate was higher in PSO than in HC. The number of tortuous capillaries was higher in PsA than in PSO and HC, but not in RA. The clustering model identified five clusters (Figure 1A), showing good separation of PsA and HC. PSO were distributed from cluster 2 to cluster 5 and RA among all clusters. At factor analysis (Figure 1B), all US GS variables loaded on factor 1, US PD variables loaded on factor 2, matrix and bed thickness loaded on factor 3, and number of tortuous capillaries and ectasias loaded on factor 4. Loadings of Factor 5 and 6 were below 0.5.ConclusionThe results of this pilot study confirm that PsA patients have significant changes in the structure of the NEC compared with healthy subjects. However, most of these changes do not appear to be specific to PsA, as they are also found in PSO and, most surprisingly, in RA where DIP joint involvement is not present. Interestingly, PsA patients appear to have higher numbers of tortuous capillaries compared with PSO and HC, consistent with increased angiogenesis in the synovium. The combined evaluation seems to provide a good distinction between PsA and HC. Not surprisingly, PSO patients clustered closer to PsA (although with significant overlap with HC), which may be due to subclinical involvement. RA patients are distributed among all clusters and have alterations similar to those of PsA. This study does not provide a clear explanation for this phenomenon, and further studies are needed. This pilot study allowed us to identify US and NVC features that can be selected and applied in a prospective study that includes early undifferentiated arthritides and new-onset PSO, to understand whether the observed differences occur early in the disease and whether changes occur during the course of the disease. A larger sample size could also improve the accuracy of the clustering model.References[1]Cunha JS et al. doi:10.3899/jrheum.170146[2]Wortsman X et al. doi:10.1016/j.det.2006.03.014Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Primary Sjögren’s syndrome (pSS) prevalence is highly variable ranging from 0.02% to 3.5% according to classification criteria, study geographical setting, data collection and study design. The largest population-based studies estimate a prevalence range from 0.01% to 0.05%. Moreover, due to chronic course and concomitant comorbidities, pSS is associated with remarkable costs and work disability as direct consequence of the disease, of delayed disease diagnosis as well reduced physical function. To date, real-world data on pSS prevalence and economic burden in the Italian population have not been evaluated.Objectives:To estimate pSS prevalence and its direct burden on the Italian National Health Service (INHS), in terms of healthcare delivered and costs, by the analysis of an Italian administrative healthcare data system.Methods:A retrospective analysis by the cross linkage of the administrative healthcare data collected by the Fondazione Ricerca e Salute’s database (~5 million inhabitants/year, about 8% of the Italian population beneficiary of the INHS care) and by local and regional Health Authorities (HAs) was performed. People with at least one in-hospital primary or secondary diagnosis of pSS (ICD-9-CM code: 710.2) or with the disease waiver claim (code: 030) in 2018 were identified as affected by pSS. Demographic data, mean healthcare consumptions, drugs supplied, local outpatient specialist services and direct costs at one year following index date (first in-hospital diagnosis/disease waiver claim) were analysed through an individual direct matched pair case-control analysis (age, sex, local HA of residency).Results:The study included 1.746 pSS cases and 1.746 matched controls with 3.8/10,000 inhabitants identified as affected by pSS in Italy in 2018 (females 93.6%, mean age 61±13 years). In the year following index date, 53.7% of cases and 42.7% of controls received ≥1 drug (p<0.001); mean per capita cost was €501 and €161, respectively (p<0.01). Immunosuppressants accounted for the highest cost of the total expenditure per case (€ 75/501; 15.0%), followed by antiacids (€ 34/501; 6.7%) and ophtalmologics (€ 24/501; 4.7%). At least one hospitalization occurred to 7.8% of cases and 3.9% of controls (p<0.001) with mean per capita costs of €416 and €129, respectively (p=0.46). The most common hospitalization cause among cases was “diffuse diseases of connective tissue” (34/1,746; 1.9%). Finally, at least one outpatient specialist service was performed in 49.8% of cases, mainly for laboratory tests (43.2%) and general examinations (37.1%), and in 30.6% of controls (p<0.001); mean per capita costs were €200 and €75, respectively (p<0.01). Overall, in the year following index date, the INHS spent € 1,171 per case and € 372 per control (p < 0.01) (Figure 1).Conclusion:The study allowed to estimate for the first time the prevalence of pSS in a very large representative Italian sample population. In line with previous population-based studies, disease prevalence resulted 3.8 per 10,000 inhabitants, which may be consistent with an orphan disease. Moreover, in comparison to the general population, pSS exerts a considerable impact on healthcare system with about threefold higher burden in terms of healthcare resource consumption and direct INHS costs related to both disease issues and comorbidities. These findings confirm the need for a multidisciplinary approach to pSS by the Italian HAs, encompassing all aspects of patient care, by including early diagnosis, access to INHS health services and long-term follow-up.Figure 1.Integrated healthcare costs incurred by the Italian National Health Service.REFERENCES:NIL.Acknowledgements:We thank the Italian Association of people with Sjögren’s syndrome (A.N.I.Ma.S.S. ODV - Associazione Nazionale Italiana Malati Sindrome Sjögren) for the unconditional support.Disclosure of Interests:None declared.

Background:Platelets (PLT) exert an immunomodulating activity in multiple normal biological processes, such as damage repair and defence against infections. It has been clearly demonstrated that they play a significant role in promoting and supporting inflammatory and autoimmune diseases, such as rheumatoid arthritis (RA). However, the knowledge on the mechanisms through which PLT are involved in these processes are very limited.Objectives:The purpose of this study was to in vitro investigate the effect of PLT on T helper (Th)17 axis biology in RA patients in comparisonto healthy subjects and their contribution to the pathogenesis of the disease.Methods:CD3+ T cells were isolated and PLT ultrapurified from peripheral blood of a cohort of patients with RA diagnosed according to 2010 ACR/EULAR classification criteria, with at least moderate disease activity (DAS28-CRP>3.2) and no ongoing b/tsDMARD treatment and of a group of age and sex-matched healthy controls (HC). T cells and PLT were co-cultured at a ratio of 1:100. Both homologous (i.e., T cells and PLT from the same subject) cultures and cross-cultures (i.e., T cell from RA patient with PLT from HC and vice versa) were set up, in order to investigate whether any observed effect was caused by T cells or PLT. Cultures were carried out in the presence of anti-CD3 and anti-CD28 antibodies. At day 5, cells were harvested and the percentage of Th17 cells (CD4+IL-17A+ of CD3+) in the presence or absence of PLT was assessed by flow cytometry. T cell proliferation was evaluated at day 5 upon carboxyfluorescein succinimidyl ester (CFSE) staining, using flow cytometry and assessment of proliferation index (PI). The concentration of IL-17A in culture supernatants was also estimated at day 5 by ELISA. RNA sequencing and transcriptome analysis was performed after 18h of culture on paired T cell and T cell+PLT samples.Results:Twelve patients with RA and twelve HC were enrolled.In the presence of PLT, a reduction of % Th17 cells was observed in HC at day 5 (7.5 ± 1.2% vs 3.9 ± 1.1%, p=0.016) (Figure 1A). In RA samples, no effect was observed in %Th17 cells (4.3 ± 0.6% vs 5.1 ± 0.9%, p=0.313) (Figure 1B), while there was a reduction of T cell proliferation in both RA and HC (Figure 1C–F). A significant increased concentration of IL-17A in the supernatants of cultures of both HC (6.9 ± 7.6 ng/ml vs 14.8 ± 13.9 ng/ml, p=0.008) and RA samples (3.7 ± 3.8 ng/ml vs 11.3 ± 7.9 ng/ml, p=0.004) was observed in the presence of PLT (Figure 1G and H).Overall, the results of homologous and cross-cultures did not show significant differences, thus RNA sequencing was performed on homologous cultures only.Following transcriptome analysis, 149 and 50 differentially expressed genes specific for RA and HC PLT:T cell co-culture samples were identified, respectively. Gene-set and pathway enrichment analysis revealed significant deregulation of the Th17 pathway (FDR=0.019) associated with a significant upregulation of IL-17A, IL-17F, CCL20 (p<0.05, |fold-change|>2) in RA T vs. PLT:T cell samples (Figure 2), while no corresponding significant changes were observed in HC samples.Conclusion:The results of this study provide indications that PLT may exert a pro-inflammatory effect in RA by upregulating the transcription of Th17-pathway related genes resulting in maintenance of a Th17 cellular response that is, instead, downregulated in HC. These data, together with the absence of an increased proliferation of Th17 cells, suggest that PTL effects are mostly exerted on a differentiation level. The apparently contrasting results of IL-17 secretion can be explained by the well-known potent and unspecific initial stimulating effect of PLT on the secretion of stored intracellular IL-17, together with other cytokines, upon contact with T cells.REFERENCES:[1] Zhu L. et al. J. Thromb. Haemost. 2014[2] Tan, S. et al. Platelets. 2022Figure 1.Figure 2.RA-specifically enriched KEGG pathways in PLT:T cell cultures. (A) Protein-protein-interaction network of differentially expressed genes involved in the pathways (B) Bar diagram depicting the -log2(false discovery rate, FDR) of significance of enrichment of each pathway.Acknowledgements:NIL.Disclosure of Interests:Giacomo Cafaro Janssen, Eli-Lilly, Maria-Ioanna Christodoulou: None declared, Sabrina Cipriani: None declared, Manuela Sebastiano: None declared, Carlo Perricone: None declared, Onelia Bistoni: None declared, Roberto Gerli: None declared, Elena Bartoloni: None declared

Adenosine deaminase 2 deficiency (DADA2) is a rare monogenic vasculopathy caused by loss-of-function homozygous or compound heterozygous mutations in ADA2, formerly CECR1 (cat eye syndrome chromosome region 1) gene. The DADA2 phenotype is widely heterogeneous, and patients may present with fever, weight loss, livedo reticularis/racemosa, digital ischemia, cutaneous ulceration, peripheral neuropathy, abdominal pain, bowel perforation, and portal or nephrogenic hypertension. More specific manifestations include early-onset ischemic or hemorrhagic stroke, mild immunodeficiency and hypogammaglobinemia, cytopenia, and vision disturbances. Herein, we present the case of a young male with vasculitis associated with DADA2. The presence of HLA-B51 and the clinical features of this patient raised the question of similarities between ADA2 deficiency, Behçet’s disease, and NOD2-associated diseases. Treatment of this rare monogenic disease is challenging and based on small case series. The long-term experience of this patient proved the difficulties of prednisone tapering and the lack of satisfactory therapeutic strategies.

Background:Primary Sjögren’s syndrome (pSS) is characterized by a highly heterogeneous phenotype driven by different clinical manifestations and by an unpredictable course. Moreover, up to 15% of patients may develop systemic manifestations and about 45% accumulate permanent damage after 5-10 years of disease. However, no study evaluated damage at longer follow-up nor analysed disease phenotypes which, at baseline, may identify patient clusters at higher risk to accrue irreversible damage.Objectives:To evaluate features and factors associated with damage accrual and to identify disease-related variables and phenotypes at higher risk to develop damage at 15 years.Methods:A cohort of pSS patients fulfilling the 2002 AECG and/or 2016 ACR/EULAR classification criteria and with at least 15 years of regular follow-up (no gaps longer than 18 months between two visits) was retrospectively included. Demographic, clinical and serological parameters, disease activity by ESSDAI, Charlson Comorbidity Index, disease damage by SSDDI and treatments were recorded every 5 years from diagnosis to 15-year follow-up. Changes of continuous and polytomous variables among timepoints was evaluated by Friedman’s test. Dichotomous variables were compared among timepoints by Cochran Q test, followed by pairwise analysis by McNemar test, when appropriate. Significant variables at univariate analysis were include in a multivariable logistic regression analysis model with wild bootstrapping to account for collinearity and heteroscedasticity. Unsupervised agglomerative hierarchical clustering analysis was performed building the model based on SSDDI and the scores of its domains at 15 years. Disease characteristics at baseline were subsequently compared among the clusters.Results:A total of 102 pSS patients (97% female, mean age at diagnosis 45±12 years, mean disease duration 20±5 years) were included. Damage significantly increased from 1 (0-1.25) at 5 years, to 1 (0-2) at 10 years, and to 1 (0-3) at 15 years (p <0.001 for omnibus test and for all pairwise comparisons) (Figure 1). ESSDAI score significantly reduced from 5 (3-8) at baseline, to 3 (2-6.25) at 5 years, 3 (2-7) at 10 years, and to 3 (1-7.25) at 15 years (p<0.001 for omnibus test; at pairwise analysis differences were significant between baseline and each of the other timepoints). At linear regression analysis, ESSDAI at baseline significantly predicted damage at 15 years (β = 0.496, p<0.001, CI 0.154 - 0.368), independently from age at diagnosis and comorbidities. Among ESSDAI domains, lymphadenopathy was an independent predictor of damage at 15 years (β = 0.274, p = 0.034, CI 0.255 – 3.331). Finally, the hierarchical clustering model based on SSDDI domains at 15 years identified five patient clusters with distinct damage patterns: Cluster 1 (C1) included almost all patients with salivary flow impairment and extra-glandular damage, C2 included patients with structural damage (loss of teeth and ocular damage) without salivary or tear flow impairment, C3 included patients who developed lymphoproliferative disease, C4 patients with isolated tear flow impairment and C5 patients with no damage (Figure 2).Conclusion:This multi-centre study outlines for the first time damage trajectories at 15 years of follow-up in a multi-center Italian pSS cohort. In our cohort, damage progressively builds up over at least 15 years. However, progression pattern is different among damage domains. The largest damage burden develops by year 5. Disease activity at baseline along with lymphadenopathy, independent of other disease features and comorbidities, significantly predict damage, strengthening the importance of early disease activity control to prevent damage. Interestingly, we identified 5 patient clusters with distinct damage patterns which, if reproduced in larger cohorts, may allow to tailor clinical and therapeutic approach to the disease since diagnosis and to reduce long-term damage accrual and, consequently, associated morbidity and mortality.REFERENCES:NIL.Figure 1.SSDDI score at 5, 10 and 15 years.Figure 2.Heatmap of clusters detected by the agglomerative hierarchical clustering model.Acknowledgements:NIL.Disclosure of Interests:None declared.

BackgroundSjögren’s syndrome (SS) represents a chronic autoimmune disorder characterized by a relatively benign course. However, up to 40% of SS patients develop systemic extra-glandular involvement which, in turn, may lead to long-term damage accrual. Few studies assessed damage accrual in SS with a follow-up ranging from 5 to 10 years. Knowledge of long-term risk of damage and awareness of factors contributing to damage accrual in SS represent important issues to identify patients requiring a closer follow-up and to better stratify therapy.ObjectivesTo examine disease damage progression every 5 years until 20 years of follow-up and disease related features associated with higher damage score at 20 years in a multicenter SS cohort.MethodsA cohort of 252 SS patients fulfilling the 2002 AECG and/or 2016 ACR-EULAR classification criteria was retrospectively analysed. The following variables were collected at diagnosis and every 5-year timepoints until 20 years: demographic, clinical and serologic parameters; disease activity by ESSDAI; Charlson Comorbidity Index (CCI); disease damage by SSDDI and treatments. Patients were grouped according to damage degree at 20 years: “low/no damage”, LND (SSDDI ≤ 1) and “moderate/high damage”, MHD (SSDDI ≥ 2). Continuous variables were compared by Mann-Whitney U test and categorical variables by Chi-squared test of Fisher’s exact test, as appropriate. Significant variables at univariate analysis were include in a multivariable logistic regression analysis model with wild bootstrapping to account for collinearity and heteroscedasticity.ResultsA total of 50 patients (mean age at diagnosis 44±12 years, mean disease duration 24±5 years) had 20 year follow-up. Mean SSDDI increased from 1.2 (±1.5) at 5 to 1.5 (±1.7) at 10 years and from 1.54 (±1.7) at 15 to 2.04 (±2.2) at 20 years. Oral/ocular damage, peripheral nervous (PN) involvement and lymphoproliferative disease mainly contributed to damage accrual. Mean ESSDAI reduced from 6.4 (±3.7) at baseline to 4.9 (±5.4) and mean CCI increased from 1.6 (±0.8) to 3.5 (±1.6) at 20 years. At univariate analysis, MHD patients had significant higher median ESSDAI at all timepoints and CCI at 5 and 20 years, higher frequency of parotid swelling at 5 years (35% vs 7%, p=0.021), low C4 (30% vs 3%, p=0.012) at 15 years and monoclonal component at 20 years (30% vs 7%, p=0.047) and lower of arthritis at 10 years (0% vs 23%, p=0.033) in comparison to LND. Patients with MHD had higher prevalence of glucocorticoid (GC) use at 20 years in comparison to LND (75% vs 27%, p=0.001). Multivariable logistic regression analysis model was able to correctly classify 87.5% of patients. None of the included parameters was independent predictor of outcome variable, likely due to a non-linear relationship among variables and the low subject number included.ConclusionThis is the first study exploring disease damage at 20 year follow-up in SS patients. Notably, damage occurs early, increases already in the first 5-10 years and is mainly driven by oral and ocular damage, PN involvement and lymphoma. Higher disease activity at baseline and during follow-up and higher GC use, also reflecting a more active disease, represent two important variables contributing to damage. Thus, controlling disease activity since diagnosis and minimizing steroid prescription may reduce long-term damage accrual. Among disease-related features, appearance of parotid swelling in the first 5 years requires awareness. Surely, further studies are needed to identify, at diagnosis, patient phenotype at higher risk of long-term damage.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Clinical remission is the main target in the management of Rheumatoid Arthritis (RA) patients. Different indexes are used to assess remission, among which the Boolean-based and index-based remission definitions (the latter using the simplified or clinical disease activity index SDAI, CDAI) and the less stringent Disease Activity Score on 28 joints (DAS28).Whatever the clinical remission definition applied, it frequently don‘t reflect a “complete” remission condition, indeed several authors found residual active synovitis at ultrasonography (US) and its presence is predictive of disease relapses. There is no consensus yet about which target joints should be included in the US assessment of RA patients in clinical remission, and consequently, several sets of joints have been evaluated so far.We have previously demonstrated that the US evaluation of only 4 target joints (wrists and II metacarpophalangeal (MCP) joints) allows to reach a high sensitivity in detecting subclinical active synovitis in RA patients in clinical remission. Upadacitinib is a selective JAK1 inhibitor that achieved significantly higher remission rates than adalimumab and abatacept in RA patients, however, real-life data are still scarce. Here we present the 24-weeks data of the UPAdacitinib Rheumatoid Arthritis REmission UltraSonography (UPARAREMUS) study.Objectives:The primary end-point of the study was the proportion of patients achieving “complete” remission at week 24. Secondary end-points were the proportion of patients achieving clinical remission with each composite measure (CDAI, DAS28crp, and SDAI) at week 12 and 24 the changes from baseline to week 12 and week 24 in the DAS28crp, CDAI, and SDAI.Methods:This is a longitudinal multicenter observational study, enrolling bio-naïve and bio-inadequate responders RA patients. Clinical assessment of disease activity and US of 4 target joints (wrists and II MCF bilaterally) were performed at baseline, week 12 and 24. US was carried ou by experts rheumatologists who had passed an inter-observer reliability test. US-detected synovitis and PD synovitis were scored according to a 0-3 semi-quantitative simplified score. Clinical remission was defined as: DAS28crp<2.6 or CDAI≤2.8 or SDAI≤3.3. US remission was defined as the absence of PD signal ≥ 2 in one target joints, or PD≥1 in two target joints. “Complete” remission was defined as clinical remission plus US remission. Median values at baseline, at week-12 and week-24, in the DAS28crp, CDAI and SDAI were calculated and compared using the Wilcoxon non-parametric test. Proportions, medians, and interquartile ranges were calculated as appropriate and logistic regression was used to evaluate if there were baseline factors associated with complete remission, adjusting for the effect of confoundersResults:A total of 60 RA patients were enrolled (clinical and demographic characteristics are resumed in Figure 1).After 12 weeks and 24 weeks respectively, 40% and 63.6% of patients achieved complete remission (Figure 2). The following parameters were associated with complete remission: being bio-naïve and having a shorter disease duration, although at multivariate analysis significant OR was found only for being bio-naïve [(aOR 4.09 (95%CI 1.05-15.9) p=0.04]. After 12 weeks, 45% of patients achieved clinical remission with at least one of the remission indices, three out of these patients did not reach US remission (13%). At 24 weeks, the percentage of patients achieving clinical remission improved to 65.4% and the proportion of patients w/o an associated US remission further decrease to 3%.A significant reduction in disease activity was registered during the follow-up with each composite measure (Figure 2).Conclusion:UPARAREMUS is the first study evaluating the efficacy of upadacitinib in reaching both clinical and US remission in RA patients. A 24-weeks upadacitinib treatment led to complete remission in a high percentage of enrolled patients. The only baseline parameter associated with a higher chance of reaching complete remission at multivariate analysis was being bio-naïveFigure 1.Baseline characteristics of enrolled rheumatoid arthritis (RA) patientsREFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Andrea Picchianti-Diamanti This is an Investigator Initiated Study externally supported by Abbvie, Maria Sofia Cattaruzza: None declared, Simonetta Salemi: None declared, Roberta Di Rosa: None declared, Giorgio Sesti: None declared, Maria Sole Chimenti: None declared, Arianna D’Antonio: None declared, Bruno Frediani: None declared, Caterina Baldi: None declared, Gloria Crepaldi: None declared, Michele Maria Luchetti: None declared, Valentino Paci: None declared, Alen Zabotti: None declared, Ivan Giovannini: None declared, Marco Canzoni: None declared, Gian Domenico Sebastiani: None declared, Chiara Scirocco: None declared, Carlo Perricone: None declared, Bruno Laganà: None declared, Annamaria Iagnocco: None declared.