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Objectives This 52-week, randomised, double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol (CZP) as add-on therapy to non-biologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with low to moderate disease activity, and stopping therapy in patients in sustained remission. Methods Patients were randomised 1:1 to CZP (400 mg at weeks 0, 2 and 4, then 200 mg every 2 weeks) or placebo (every 2 weeks) plus current non-biologic DMARDs. At week 24, patients who achieved the primary endpoint of Clinical Disease Activity Index (CDAI) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52. Results Of 194 patients (CZP=96; placebo=98), >90% had moderate disease activity at baseline. Significantly more CZP patients met the primary endpoint than placebo patients (week 20 and 24 CDAI remission rates: 18.8% vs 6.1%; p≤0.05). At week 24, 63.0% vs 29.7% of CZP versus placebo patients (p<0.001) achieved LDA. Disease activity score (ESR) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo (19.8% vs 3.1%; p≤0.01 and 14.6% vs 4.1%; p≤0.05). CZP patients reported improvements in physical function versus placebo (mean Health Assessment Questionnaire-Disability-Index change from baseline: CZP, −0.25 vs placebo, −0.03; p≤0.01). During the period following withdrawal of CZP or placebo, only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52, but CZP reinstitution allowed renewed improvement. Adverse and serious adverse event rates were comparable between CZP and placebo groups. Conclusions Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity, allowing low-disease activity or remission to be reached in a majority of the patients. However, the data suggest that CZP cannot be withdrawn in patients achieving remission. Trial registration number NCT00674362.

One major medical issue with regards to the overall rheumatoid arthritis(RA) related inflammation and RA- cardiovascular risk (CVR) is the presence of the metabolic syndrome which is thought to be a state of chronic inflammation. We will focus on : [1]. Prevalence of the metabolic syndrome (MetS) in RA and of its principal components on the inflammatory status of RA.[2]. Influence of the MetS and of its componenets on the outcome of RA under conventional treatments and under biologics therapy.[3]. Gene expression in adipocytes vs house keeping gene [4]. Perspectives for a better therapeutic approach. We analyzed three cohorts of patients (564 RA (346 early RA-ERA patients, 218 long standing RA-LSRA with severe disease requiring biologic treatment), 452 SLE patients and 296 SSc patients. The Metabolic syndrome was defined according to the American Heart Association/Updated NCEP criteria (1). BMI was categorized into 3 classes, i.e <25 kg/m2 (normal weight), 25-30 kg/m2 (overweight), and >30 kg/m2 (obese). Gene expression profile was looked for in fat adipocytes in culture after four passages and after stimulation. The prevalence of MetS in the ERA cohort was 25.3%; and 12.5 % were obese. In LSRA the MetS was present in 27% and 12.8% were obese; in SLE patients MetS was observed in 31.3%. and 10% were obese. In the SSc MetS was observed in 14.2% and the prevalence of obesity was 10.4%. At baseline in ERA patients ESR and CRP, but not DAS, were significantly higher than in MetS negative patients. When following longitudinally ERA patients, all treated aiming at remission, we observed that MetS at baseline did not change the major outcome (CDAI or DAS remission); BMI did influence the major outcome: overweight and obese patients reached a lower rate of remission, with DAS and CDAI criteria, at 6 and 12 month follow-up visits (sustained DAS remission at 12th month: 49.1% in normal, 28.7% in overweight, 34.1% in obese, p=0.008; CDAI remission at 12th month: 50%, 37.1%, 31% in normal, overweight and obese, respectively, p=0.07). An higher percentage of obese and overweight ERA patients were under anti-TNF treatment after 12 months of follow-up (28.1% of obese, 28.8% of overweight, 16.2% of normal weight). The independent variables associated with the probability of being in anti-TNF therapy at 12th month follow-up were : age <55 years (OR: 2.7 (1.4-5.3)), baseline DAS≥3.7 (OR: 2.27 (1.19-4.34) and BMI≥25 (OR: 2.36 (1.21-4.59)). In LSRA patients with MetS at baseline had a lower chance of achieving both a Good EULAR response at 12 months (26.1 % vs 50 %, p =0.001) and a DAS remission (20.3 vs 32.4 %, p =0.06). In LSRA the independent predictors of “not obtaining Good Response at the 12th month of anti-TNF therapy” were the presence of hyperglicemia (OR (95%CI): 2.78 (1.06-7.14)), and hypertension (OR (95%CI): 3.03 (1.51-5.88)) in addition to an HAQ>1.5 (OR (95%CI): 2.22 (1.01-4.55)) at baseline. TNF, IL6, IL1, BAFF, BAFF-R and FcR genes were all expressed in adipocytes, and more particularly the PEDF gene was at least 3 fold higher in obese fat biopsies. Data show that MetS is present in a quarter of all RA either early or LSRA. In early RA it does not seem to influence the outcome, yet one of its component, i.e. obesity plays a negative role in the achievement of a major outcome. In LSRA MetS influences the achievement of both DAS remission and Good EULAR response. Obesity plays a crucial role in negatively influencing the outcome in ERA. Gene expression analysis has shown that a biomarker of obesity, namely PEDF, which exerts anti-inflammatory and anti-angiogenic effects, appears to be a possible biomarker for assessing a therapeutic intervention. Certainly the data at hand suggest that obesity and MetS should become usual targets for therapy in the RA population along with the targeted therapy strategies aiming at remission to avoid the overall CV risk Alberti KGGM, et al. Circulation. 2009;120:1640-1645 Disclosure of Interest G. Ferraccioli Grant/research support from: Pfizer, Roche

Objective: To formulate EULAR recommendations for the management of early arthritis. Methods: In accordance with EULAR’s “standardised operating procedures”, the task force pursued an evidence based approach and an approach based on expert opinion. A steering group comprised of 14 rheumatologists representing 10 European countries. The group defined the focus of the process, the target population, and formulated an operational definition of “management”. Each participant was invited to propose issues of interest regarding the management of early arthritis or early rheumatoid arthritis. Fifteen issues for further research were selected by use of a modified Delphi technique. A systematic literature search was carried out. Evidence was categorised according to usual guidelines. A set of draft recommendations was proposed on the basis of the research questions and the results of the literature search.. The strength of the recommendations was based on the category of evidence and expert opinion. Results: 15 research questions, covering the entire spectrum of “management of early arthritis”, were formulated for further research; and 284 studies were identified and evaluated. Twelve recommendations for the management of early arthritis were selected and presented with short sentences. The selected statements included recognition of arthritis, referral, diagnosis, prognosis, classification, and treatment of early arthritis (information, education, non-pharmacological interventions, pharmacological treatments, and monitoring of the disease process). On the basis of expert opinion, 11 items were identified as being important for future research. Conclusions: 12 key recommendations for the management of early arthritis or early rheumatoid arthritis were developed, based on evidence in the literature and expert consensus.

To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics’ registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p < 0.0001) and 24 months (52.3 vs 33.3 and 34.4%, respectively; p < 0.01). A similar pattern was observed in later lines. The most common AEs reported were infections, reactions to biologics (more frequent among TNFi-treated patients), increased transaminase (more frequent among TCZ-treated patients), and cardiovascular events. In clinical practice, TCZ induced a rapid and long-lasting remission and in a higher percentage of patients compared to abatacept and TNFi, with a good safety profile.

BackgroundIn the age of targeted-synthetic disease-modifying antirheumatic drugs (tsDMARDs), filgotinib represents the last JAK inhibitor available in Europe for rheumatoid arthritis (RA). Filgotinib is characterized by predominantly inhibition of JAK1 and its efficacy and safety have been highlighted by phase 2/3 studies, but no real-life data in RA are currently available.ObjectivesThe aim of this study was to evaluate the effectiveness and safety profile of filgotinib in real-life setting in RA patients included in Italian GISEA (Group for the Study of Early Arthritis) registry.MethodsFor this study, data from RA patients treated with filgotinib recorded in Italian GISEA registry were analysed. Disease activity scores and patients reported outcomes (PROs) were compared at baseline and six months follow-up using paired t-tests. The retention rate was estimated by the Kaplan-Meier method, while a cox regression model was used to search for possible factors influencing drug survival.ResultsOne hundred and seventy-nine patients (female 89.4%, age 57.8±12 years, FR/ACPA+ 64.3%, current/former smoker 31.8%) included in GISEA registry started filgotinib for active RA. Most patients were taking filgotinib as second (23.5%) or further (43%) b/tsDMARDs line of treatment. Filgotinib was used in monotherapy in 66.5% of patients, while 52% were not on treatment with glucocorticoids (GCs) at baseline. All demographic and clinical data are reported in Table 1. A follow-up visit was available for 122 patients (mean time of first follow-up visit: 4±2 months). As shown in table 1, we observed a decrease of all disease activity scores and PROs. At first follow-up visit, 67.8% of patients were in remission/low disease activity according to CDAI and 65.4% according to SDAI. Kaplan-Meyer analysis highlighted that drug persistence was similar either in monotherapy or combination therapy (Figure 1a), and irrespective of GCs at baseline (Figure 1b). However, a better persistence was observed in RA patients on first line treatment with filgotinib (Figure 1c). Thirty-five patients stopped filgotinib during follow-up, 10 for lack of efficacy, 4 for loss of efficacy, 4 for adverse events, while for the remaining cases the cause of drug discontinuation was unknown. No major cardiovascular events were reported. Finally, univariate Cox-regression model showed that b/tsDMARD naïve patients had a lower risk of drug discontinuation (naïve vs other lines: HR 0.37, 95%CI 0.20-0.86).ConclusionIn Italian real-life setting, filgotinib confirms a good effectiveness and safety profile.Table 1.Demographic and disease characteristics at baseline and at first follow-up visit (T1) of RA patients treated with Filgotinib.Variablesbaseline (n. 179)T1 (n. 122)Agemean (SD), years57.8 (12.7)58 (12.6)Gendern. (%), femalen. (%), man160 (89.4)19 (10.6)110 (90.2)12 (9.8)BMIn. (%), underweightn. (%), heathy weightn. (%), overweightn. (%), obese4 (3.8)50 (48.1)21 (20.2)29 (27.9)4 (5.3)36 (47.4)15 (19.7)21 (27.6)Smokersn. (%), currently smokern. (%), former smokern. (%), never smoker13 (13.8)17 (18)64 (68.1)8 (13.5)12 (20.3)39 (66.1)IgG RF/ACPA +n. (%)74 (64.3)54 (71.1)VAS painmean (SD)63.1 (29.1)35 (30.7)***VAS PtGAmean (SD)60 (26.7)35 (29)***VAS PhGAmean (SD)44 (25.4)20.9 (23)***TJC28mean (SD)5.4 (5)2.7 (3.8)**SJC28mean (SD)3.3 (3.5)1.3 (2.2)***DAS28-ESRmean (SD)4.6 (1.3)3.3 (1.4)**CDAImean (SD)19.1 (11.3)9.6 (9.5)**SDAImean (SD)20.5 (12)10.3 (10)**HAQ-DImean (SD)1.3 (0.7)0.9 (0.7)***glucocorticoidn. (%)86 (48)47 (38.5)**Prednisone (equivalent), mg/diemean (SD)5.8 (3.7)3.4 (2.6)*csDMARD (in corso)n. (%)60 (33.5)31 (25.4)b/tsDMARD linen. (%), 1^ linen. (%), 2^ linen. (%), 3^ line or others60 (33.5)42 (23.5)77 (43)/Mean time of first follow-up visit: 4±2 months*p<0.05, **p<0.01, ***p<0.001Figure 1.Survival analysis in RA patients treated with Filgotinib.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:Nowadays, numerous therapeutic options are available for patients with rheumatoid arthritis (RA), and the number of patients achieving remission has significantly increased. However, some patients have a disease defined by EULAR as “difficult-to-treat”1 (D2T), which today represents a new challenge for rheumatologists.Objectives:The primary objective was to evaluate the characteristics of the D2T-RA population recorded in the Italian GISEA registry undergoing treatment with b/tsDMARDs. The secondary objective was to assess the effectiveness and changes at 6 and 12 months in disease outcomes, stratifying the analysis by different mechanisms of action.Methods:For this study, data from RA patients treated with b/tsDMARDs recorded in the Italian GISEA registry from January 2017 to December 2023 were analyzed. Disease activity scores and patient-reported outcomes (PROs) were recorded at baseline, and at six- and twelve-month follow-up. D2T-RA patients were defined by meeting these three criteria: 1) failure of ≥ 2 b/tsDMARDs (with different mechanisms of action); 2) signs suggestive of active/progressive disease (at least moderate disease activity according to disease activity scores and/or glucocorticoid treatment ≥ 7.5 mg/day prednisone or equivalent); 3) patient VAS (Visual Analogue Scale) pain and/or PtGA (Patient Global Assessment) and/or PhGA (Physician Global Assessment) > 20. The retention rates were estimated using the Kaplan-Meier method and compared with log-rank test, while repeated measures ANOVA (Analysis of Variance) was used to assess changes in disease activity and PROs during follow-up.Results:The GISEA cohort included 5251 treatment lines with b/tsDMARDs. We were able to assess the D2T category for 3439 cases at the start of a new treatment. Overall, 1060 (30.8%) patients met all three criteria for D2T-RA, while 2379 (69.2%) patients were not categorized as D2T. Table 1 reports the demographic and clinical characteristics of D2T-RA patients. Patients with D2T-RA showed higher disease activity and PRO scores at baseline. Notably, JAK inhibitors (JAKis) were used more frequently in D2T-RA patients (48.8%) compared to non-D2T-RA patients (33.3%, p<0.05).Globally, the 5-year survival rate was significantly lower for D2T-RA patients compared to those with non-D2T-RA (47.5% vs 62.5%, p<0.001). No significant differences in persistence were observed among the classes of b/tsDMARDs used in D2T-RA (log-rank test: 6.76, p=0.15), with a 5-year survival rate of 38.7% for abatacept, 41.2% for TNFi, 48.1% for IL6r inhibitors, 62.3% for anti-CD20, and 49.6% for JAK inhibitors. Figure 1 shows changes from baseline in disease activity scores and VAS pain in D2T-RA according to b/tsDMARD class. DAS28-ESR was reduced in all b/tsDMARD classes, except for TNFi. CDAI was reduced in all b/tsDMARD classes without any differences among the classes. VAS pain was reduced in all classes. For VAS pain, we observed a significant difference between abatacept and JAK inhibitors, with JAK inhibitors showing greater reduction in VAS pain (p<0.05). Also filgotinib, the latest JAK inhibitor approved onto the market, exhibited a significant decrease on pain perception at both time points.Figure 1.Conclusion:Our study provides a snapshot of D2T-RA patients within the GISEA registry. All currently used b/tsDMARDs appear to be effective in this patient cohort. The higher efficacy of JAK inhibitors, particularly in managing pain symptoms in these patients, warrants further investigation.REFERENCES:[1] Nagy G, Roodenrijs NMT, Welsing PM, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2021 Jan;80(1):31-35.Acknowledgements:We thank Ing. Massimiliano Dellisanti Fabiano Vilardi for his valuable contribution to database creation and management.Disclosure of Interests:None declared.

Background:Long-term observational data on the real-life use of JAK inhibitors (JAKis) for rheumatoid arthritis (RA) and their comparison with biological drugs are still very limited. Large population-based registries have been increasingly used to investigate the performance of targeted drugs in a real-life setting.Objectives:The aim of this study is to evaluate and compare the 3-year retention rate of JAKis, TNF inhibitors (TNFis) and biologic drugs with other mechanisms of action (OMAs) in the large cohort of RA patients included in the Italian national GISEA registry.Methods:Data of all RA patients treated with targeted synthetic or biologic drugs were prospectively collected in the Italian multicentric GISEA registry. The analysis was limited to patients who started a first- or second-line targeted drug in the period after the first JAKi was marketed in Italy (1st December 2017). The 3-year retention rate was calculated by the Kaplan-Meier method and compared between different drug classes by a log-rank test. A descriptive analysis of reasons for discontinuation was performed.Results:The study population included 1027 RA patients (79.8% females, mean age [±SD] 56.9 [±13.5] years, mean disease duration 9.8 [±9] years, mean baseline SDAI 17.5 [±11.9], ACPA positive 67.4%, RF positive 62.7%) who received JAKis (baricitinib or tofacitinib, n=297), TNFis (n=365), or OMAs (n=365) as first or second targeted drug. Main baseline characteristics of study population were overall well balanced between treatment groups. Retention rate was numerically but not statistically higher (p=0.18) in patients treated with JAKis compared with TNFis or OMAs (80.6, 78.9 and 76.4% at 1 year and 73, 56.8 and 63.8% at 3 years, respectively) (Figure 1). Drug survival was significantly higher in patients receiving concomitant methotrexate (MTX) compared with monotherapy only in TNFis (66.8 vs 47.1%, p=0.04) but not in JAKis (76.1 vs 70.1%, p=0.54) and OMAs (66.1 vs 61.9%, p=0.41) group. Therapy was discontinued in a total of 211 patients because of ineffectiveness (n=107), adverse events (n=88), or compliance/other reasons (n=16). The most frequent reason for treatment withdrawal was ineffectiveness in both JAKis (n=30 out of 56) and TNFis (n=45 out of 74) groups, whereas OMAs were discontinued more frequently because of adverse events (n=41 out of 81).Conclusion:Our data confirmed in a real-life setting a favorable 3-year retention rate of all available targeted mechanisms of action for RA therapy. As expected, concomitant MTX significantly impacted persistence on therapy of TNFis only. Discontinuations of JAKis for adverse events were infrequent overall, confirming the safety profile observed in randomized clinical trials.Figure 1.Three-year retention rate by treatment group[Figure omitted. See PDF]Disclosure of Interests:None declared

Background:cytokine dysregulation plays an important role in the pathogenesis of Lupus Nephritis (LN) representing an attractive field of research aiming to find new pathways for new targeted therapies. IL-17, IL-23 axis seems to have a great influence in the development of LN.Objectives:to evaluate the strongest prognostic factors in a cohort of patient with LN focusing on of the impact of IL-17, IL 23 axis as new pathogenetic pathway on renal outcome.Methods:91 patients with active LN at disease onset or disease flare were enrolled. Laboratory, immunological and disease activity data were collected at the baseline and at 6(T6),12(T12),24(T24) months and at the last follow-up(FU). 84 renal biopsies were evaluated according to ISN/RPS classification, assessing the activity and chronicity indexes and the active interstitial infiltrate using the BANFF score system. Baseline serum levels of IL-17 and IL-23 were assessed by ELISA in 37 patients.Results:among the 84 renal biopsies evaluated 77% belonged to class III and IV according to ISN/RPS; 41,8% of patients had an active interstitial infiltrate<5%, 35.2% between 5% and 25% and 15,4% above 25%. Regarding immunological data 35,2% of patients revealed a seropositivity for antiphospholipid antibodies(APL+). The median serum level of IL-17 and IL-23 were 0.12±0.15 pg/ml and 27.7±9.12 pg/ml respectively. Using the ROC curves analysis we found a cut off value of 25.89 pg/ml for IL-23 for remission at T6. Among the 10 patients with a IL-23 level above this cut-off none achieved remission at T6 and the univariate analysis shows that a serum level of IL-23 above the defined cut-off was associated with an active interstitial infiltrate>5% at renal biopsy and with the development of persistent proteinuria. The analysis of IL-17 could not let us to find a cut off value for renal damage progression since a too much high number of patients had a null value. Nevertheless patients with more elevated serum levels of IL-17 at the baseline showed more elevated level of interstitial infiltrate at renal biopsy and a worse renal outcome overall. Finally we conducted an univariate and multivariate analysis for each renal outcome considered. We found that an inflammatory interstitial infiltrate>5% at renal biopsy and APL+ were associated with worse renal outcome in terms of early and persistent remission, chronic damage, persistent proteinuria, and renal flare both in univariate and multivariate analysis. Higher serum level of IL-23 was associated with persistent proteinuria, renal flare and tended to be associated to chronic renal damage and persistent renal activity.Conclusion:interstitial inflammatory infiltrate and APL+ represent in our study the strongest predictors of worse renal outcome. An higher serum level of IL-23 was found to be a negative prognostic factor pointed out the possibility to consider the IL-17-IL 23 axis as a biomarkers of a more aggressive renal disease.Disclosure of Interests:None declared

Steroids are the standard treatment for polymyalgia rheumatica. The efficacy of the candidate drug methotrexate has not yet been demonstrated in controlled studies. To compare the efficacy and safety of prednisone plus methotrexate and prednisone alone in patients with polymyalgia rheumatica. Multicenter randomized, double-blind, placebo-controlled trial. 5 Italian rheumatology clinics. 72 patients with newly diagnosed polymyalgia rheumatica. The proportion of patients no longer taking prednisone, the number of flare-ups, and the cumulative prednisone dose after 76 weeks. Prednisone dosage (25 mg/d) was tapered to 0 mg/d within 24 weeks and was adjusted if flare-ups occurred. Oral methotrexate (10 mg) or placebo, with folinic acid supplementation (7.5 mg), was given weekly for 48 weeks. Twenty-eight of 32 patients in the methotrexate group and 16 of 30 patients in the placebo group were no longer taking prednisone at 76 weeks (P = 0.003). The risk difference was 34 percentage points (95% CI, 11 to 53 percentage points). Similar results were obtained after adjustment for C-reactive protein level and duration of symptoms in a multivariate model. Fifteen of 32 patients in the methotrexate group and 22 of 30 patients in the placebo group had at least 1 flare-up by the end of follow-up (P = 0.04). The median prednisone dose was 2.1 g in the methotrexate group and 2.97 g in the placebo group (P = 0.03). The rate and severity of adverse events were similar. Follow-up was short, and a high dose of folinic acid and a relatively high starting dosage of prednisone were used. Ten of 72 patients (14%) discontinued treatment or were lost to follow-up. Prednisone plus methotrexate is associated with shorter prednisone treatment and steroid sparing. It may be useful in patients at high risk for steroid-related toxicity.

Rheumatoid arthritis is the most common autoimmune arthritis in adult population. This disease is characterized by joint damage and systemic involvement that lead to general physical and mental impairment with consequent worsening of quality of life. Rheumatoid arthritis is also associated with a large economic burden to healthcare systems. The evidence from the literature indicates that, despite available treatments, several unmet needs still interfere with rheumatoid arthritis management. Based on this evidence, some of the unmet medical needs currently present in the management of the rheumatoid arthritis were identified and a Delphi questionnaire was submitted to 60 Italian Rheumatologists. The aim of this Delphi was to achieve a broad consensus on the most relevant unmet needs identified, in order to present the Italian reality in view of the availability of new molecules that could provide an effective therapeutic option in the treatment of patients with rheumatoid arthritis.