Background: Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by musculoskeletal and cutaneous involvement. While TNF inhibitors (TNFi) are commonly used as first-line biologic therapies, treatment failure is frequent. IL-23 inhibitors (IL23i) represent an alternative mechanism of action (MoA), but direct real-world comparisons between these drug classes remain limited. Objectives: To compare the effectiveness of TNFi versus IL23i in real-life PsA patients. Design: This multicenter retrospective observational study is part of the BIRRA (BIologics Retention Rate Assessment) project. Consecutive patients with PsA—classified according to the CASPAR criteria—were screened across 29 Italian rheumatology referral centers. Methods: We analyzed 1418 therapeutic lines for PsA initiated between 2019 and 2024 across 29 Italian rheumatology centers. Treatment lines were categorized as TNFi or IL23i based on the drug’s MoA. Demographic, clinical, and treatment-related data were collected. The primary outcome was treatment retention, evaluated by Kaplan–Meier survival analysis. A Cox proportional hazards model adjusted for a propensity score (PS) was used to account for confounding factors. Results: Among 1418 prescriptions (1270 TNFi; 148 IL23i), IL23i lines were associated with older age, longer disease duration, higher baseline disease activity, and more prior biologic disease-modifying antirheumatic drugs exposure. Despite this, no significant difference in crude retention was observed. After PS adjustment, IL23i prescriptions showed significantly longer treatment retention than TNFi (hazard ratio 0.53; 95% confidence interval: 0.31–0.90; p = 0.02). Axial or mixed PsA phenotype and higher baseline Disease Activity in Psoriatic Arthritis score were associated with lower retention. Conclusion: In this real-world cohort, IL23i prescriptions demonstrated comparable treatment persistence compared to TNFi, even in more challenging clinical scenarios. These findings support the inclusion of IL23i as a valid therapeutic option in PsA. Prospective studies are needed to confirm their positioning in treatment algorithms.

Objective:To evaluate the real-world effectiveness of baricitinib (BARI) in rheumatoid arthritis (RA), compare outcomes in patients <65 years versus ≥65 years, and identify predictors of DAS28-ESR remission/low disease activity (LDA) at 6 and 12 months. Methods:Retrospective multicentre cohort (n=423). Baseline variables included age, sex, disease duration, and comorbidities. DAS28-ESR was recorded at baseline, 6 and 12 months; remission was defined as DAS28-ESR <2.6 and LDA as ≤3.2. Predictors of remission/LDA were assessed with multivariable logistic regression, reporting odds ratios (ORs), 95% confidence intervals (CIs), and p-values. Results:Median age was 60 years (IQR 50.5-69.5); 79% were female; median disease duration 76 months (IQR 31-157). Compared with patients <65, those ≥65 had longer disease duration (94 vs 65 months; p<0.05) and more diabetes (16% vs 5%), dyslipidaemia (47% vs 19%), and hypertension (62% vs 33%) (all p<0.05). Median DAS28-ESR fell from 5.42 (IQR 4.84-6.06) at baseline to 3.71 (2.83-4.59) at 6 months and 3.29 (2.42-4.19) at 12 months (global repeated-measures test significant). Remission+LDA was achieved by 135/421 (32.1%) at 6 months and 182/423 (43.0%) at 12 months; remission alone increased from 65/421 (15.4%) to 117/423 (27.7%). Age ≥65 was not associated with response (6 months: OR 0.71, 95% CI 0.44-1.14, p=0.16; 12 months: OR 0.83, 95% CI 0.55-1.24, p=0.37). ACPA positivity independently predicted remission/LDA (6 months: OR 2.32, 95% CI 1.43-3.77, p<0.05; 12 months: OR 1.71, 95% CI 1.12-2.59, p<0.05). Prior JAK inhibitor exposure was not associated with reduced response. Results were consistent in a per-protocol sensitivity analysis. Conclusion:In this large multicentre real-world cohort, BARI significantly reduced disease activity over 12 months, with comparable effectiveness across age groups. ACPA positivity emerged as an independent predictor of achieving remission/LDA, supporting its potential role in treatment stratification.

Background/Objectives: Systemic sclerosis (SSc) patients frequently develop osteoporosis; however, vertebral fracture risk factors remain poorly characterized. This study identifies general and SSc-specific predictors of vertebral fractures in SSc patients undergoing osteoporosis evaluation. Methods: This multicenter cross-sectional study enrolled consecutive SSc patients meeting ACR/EULAR 2013 criteria with suspected osteoporosis. Data included demographics, disease characteristics, bone density (DXA), and vertebral imaging. Stepwise logistic regression analyzed fracture associations (p ≤ 0.05 significant). Results: The majority of 103 enrolled patients were female and all were post-menopausal. The prevalence of osteoporosis was 52.4%, that of vertebral fractures was 38.8%, and that of osteopenia was 28.1%. General risk factor analysis identified family history of fragility fractures (OR 11.8, p = 0.008) and vertebral T-scores (OR 0.6, p = 0.049) as significant predictors. When adding SSc-specific factors, only family history (OR 13.8, p = 0.03) and gastrointestinal (GI) involvement (OR 4.8, p = 0.05) remained significant. Conclusions: Vertebral fractures in SSc patients are strongly linked to a family history of fractures. The suggestive association with GI involvement may imply a significant role for malabsorption-related metabolic impairment. Prioritizing bone density screening in SSc patients with GI symptoms may enable earlier intervention and reduce fracture risk.

Background:Real-world comparative data on treatment persistence of upadacitinib and tofacitinib in psoriatic arthritis remain limited. Because persistence reflects treatment durability, tolerability, and perceived benefit in routine practice, it may serve as a pragmatic measure of real-world effectiveness. Objective:This study aimed to compare real-world treatment persistence between upadacitinib and tofacitinib in patients with psoriatic arthritis and to identify predictors of treatment discontinuation using data from the Italian multicenter BIRRA cohort. Methods:In this retrospective, multicenter, observational study, PsA patients treated with UPA and/or TOFA were enrolled from 34 rheumatology centers. Baseline demographics, treatment details, and disease activity (DAPSA) were collected. Treatment persistence was evaluated using Kaplan-Meier survival analysis. Cox proportional hazards models identified predictors of discontinuation, including sex, age, treatment line, prescription year, concomitant csDMARDs/steroids, PsA subtype (peripheral, axial, or mixed), and prior or current JAK inhibitor (JAKi) use. Results:Among 181 enrolled patients (UPA n = 124; TOFA n = 57), retention rates at 6, 12, and 18 months were 86%, 68%, and 54% for UPA and 78%, 60%, and 60% for TOFA (p = 0.7). Concomitant csDMARD therapy (HR: 1.92; 95% CI: 1.04-3.54; p = 0.037) and later-line treatment (HR: 1.17; 95% CI: 1.01-1.35; p = 0.034) were independently associated with higher discontinuation risk. No statistically significant differences were observed between the two JAK inhibitors. Conclusion:UPA demonstrated a slightly longer persistence than TOFA, though the difference was not statistically significant after adjustment. Concomitant csDMARDs and later treatment lines significantly reduced persistence. These results suggest that PsA treatment retention may be influenced more by patient- and treatment-related factors than by the specific JAK inhibitor prescribed.

Interleukin-17 inhibitors (IL-17i) represent a key therapeutic option for psoriatic arthritis (PsA), but real-world evidence regarding the effectiveness of cycling strategies within this class is lacking. This study evaluated the real-world retention of IL-17i in PsA, focusing on whether prior IL-17i exposure affects subsequent IL-17i persistence. This multicentre, retrospective, observational study included consecutive patients with PsA treated with an IL-17i across 24 Italian rheumatology centres. The primary outcome was drug retention, analysed using Kaplan–Meier methods, with differences between IL-17i-naïve and IL-17i-experienced patients assessed with the log-rank test. Secondary outcomes included baseline clinical characteristics and predictors of discontinuation. A total of 868 patients were included (59.3

We appreciate the interest of Joaquin et al in our recent study on the treatment persistence of ixekizumab in psoriatic arthritis. In response, we clarify that our study utilized prospectively collected real-world clinical data from a multicenter observational cohort, rather than administrative databases. We emphasize the importance of persistence, as assessed through the Drug Retention Rate (DRR), a validated measure in observational studies of biologic therapies. The DRR reflects a complex interplay of factors, including efficacy, safety, and patient choice, making it a valuable indicator of therapeutic performance. We agree that adherence is an interesting topic, but argue that its absence does not invalidate persistence data. Our study was designed to evaluate treatment persistence, not behavioural pharmacology. We believe that our methodological rigor, real-world design, and consistency with international literature make our data a reliable reference for understanding ixekizumab persistence in routine clinical pratice.

Real-world evidence on 12-month outcomes of guselkumab (GUS) in psoriatic arthritis (PsA) remains limited. This multicenter observational study aimed to identify predictors of 12-month DAPSA remission (DAPSA < 4) in patients with PsA treated with GUS. Secondary objectives were to assess remission rates and changes in disease activity at 6 and 12 months. We screened all patients with PsA initiating GUS across 26 Italian rheumatology centers. Data collected included demographics, disease activity measured by DAPSA, and psoriasis (PsO) extent classified as 0%, < 10%, 10-20%, or > 20% body surface area. A multivariable logistic regression model restricted to patients with an evaluable 6-month assessment was used to identify predictors of 12-month DAPSA remission. Covariates included age, sex, smoking status, body mass index, disease duration, number of prior advanced therapies, axial involvement, and 6-month articular and/or cutaneous response. Articular response was defined as DAPSA remission (DAPSA < 4), and cutaneous response as improvement by at least one PsO body surface area severity category. A two-sided p value < 0.05 was considered statistically significant. Of 278 initiators, 199 were evaluable at 6 months. At month 6, 18 patients had a combined articular and cutaneous response, 9 had an articular-only response, 74 had a cutaneous-only response, and 98 had no response. In intention-to-treat analyses, DAPSA remission was achieved by 12% at 6 months and 20% at 12 months; corresponding per-protocol rates were 16% and 30%. Median DAPSA decreased from 27.0 at baseline to 11.9 at 6 months and 8.6 at 12 months. In multivariable analysis, combined response (OR 64.6, 95% CI 5.7-731.2), joint-only response (OR 16.9, 95% CI 4.4-65.2), and skin-only response (OR 2.5, 95% CI 1.04-6.2) were associated with 12-month DAPSA remission. In routine practice, 6-month response status stratified the probability of 12-month DAPSA remission. Early articular remission and combined articular-cutaneous response showed the strongest associations, whereas skin-only improvement was a modest but statistically significant predictor and should not be interpreted as a strong determinant of later articular remission.

The efficacy and safety of filgotinib (FIL) for the treatment of patients with rheumatoid arthritis (RA) have been evaluated in a number of randomized controlled trials. However, there is a scarcity of real-world studies evaluating the effectiveness, persistence, tolerability, and safety of FIL in everyday clinical practice. This study aimed to assess the effectiveness and retention rate of FIL in a real-world cohort of patients with RA. A multicenter retrospective cohort study of patients with RA treated with FIL was conducted in 27 Italian tertiary referral rheumatology centers. The drug retention rate (DRR) was estimated by the Kaplan–Meier method, while multivariate Cox regression was used to detect potential factors affecting drug survival and persistence in therapy. Disease activity score (DAS28-CRP) was assessed at baseline and after 6 and 12 months. We enrolled 204 patients (80

Objectives:Guselkumab is a biologic disease-modifying antirheumatic drug (bDMARD) with proven efficacy for psoriatic arthritis (PsA) in randomized controlled trials. Evidence of its effectiveness from clinical practice remains limited. We evaluated the real-world effectiveness of guselkumab for PsA (primary objective) and identified factors influencing clinical outcomes. Methods:This retrospective, observational, multicentre study enrolled consecutive patients with PsA prescribed guselkumab for joint involvement at 26 Italian rheumatology referral centres. Baseline data included patient history, PsA subtype, treatment history and disease activity. Treatment effectiveness was assessed with Kaplan-Meier curves; Cox proportional hazards analysis identified factors associated with treatment persistence. Results:The study included 278 patients (median age: 57 years [interquartile range, IQR: 50-63]; 64.4% female); median observation 10.7 months (IQR: 5.3-15.9; total: 3332.6 patient-months). Retention rates at 6, 12 and 24 months were 90.4%, 80.0% and 67.8%, respectively. Reasons for discontinuation included primary inefficacy (48% of 54 cases), secondary inefficacy (41%) and skin/mucosal intolerance (4%). Statistically significant factors (P < 0.05) influencing treatment persistence included sex, smoking, concurrent conventional synthetic DMARDs (csDMARDs), corticosteroid use, year of prescription and axial or enthesitic involvement. Conclusions:Approximately two-thirds of PsA patients treated with guselkumab remained on therapy after 2 years. Adverse events motivated <10% of discontinuations. Effectiveness was higher in patients with enthesitic or axial PsA and in those without concurrent corticosteroids or csDMARDs, confirming the effectiveness and safety of guselkumab as an optimal choice for monotherapy, particularly in PsA patients with enthesitis, with or without joint impairment, and/or axial involvement.

Objective Dose reduction of biologic drugs in patients with psoriatic arthritis (PsA) who are in Minimal Disease Activity (MDA) is now considered a feasible option. This study evaluated which baseline clinical and ultrasonographic (US) factors may be predictive of disease activity after anti-TNF-α spacing. Methods This observational, prospective, multicentre, 12-month study enrolled consecutive adult patients with PsA taking TNF-α inhibitors and in stable MDA who accepted to reduce their dose therapy by doubling the administration interval. Data collection included demographics, personal history, clinical disease characteristics, and joints and entheses US features. Patients maintaining the MDA were compared with those who experienced a disease flare during the 12 months of follow-up. The statistical analysis included the comparison between groups and the search of the factors associated with persistence of MDA. Results Of the evaluable 72 patients (29 females and 43 males), 55 (76.4%) maintained a state of MDA while 17 (23.6%) experienced a disease relapse. Baseline values of DAPSA<2 and of BASDAI<1.5, and lower BASDAI and DAS28 values were significantly associated with maintenance of MDA. The multivariate analysis showed that baseline values of DAPSA<2 and of BASDAI<1.5 were predictive of persistence of MDA. Baseline US findings were not associated with the outcome of disease activity. Conclusions In this study, anti-TNF-α spacing proved to be feasible in most of the PsA patients in a stable MDA. The only factor predictive of persistence of remission was a very low clinical disease activity at baseline.

The increase in biological disease-modifying antirheumatic drugs for psoriatic arthritis (PsA) made it possible to consider different mechanisms of action (MoA) after the failure of the first advanced-line therapy. However, there is still a lack of real-world evidence comparing the cycling (re-administration of a similar MoA) and the swap strategy. This retrospective observational study aims to evaluate the retention rate, as a proxy for effectiveness, of second-line therapeutic options after the failure of a TNF inhibitor (TNFi) by comparing cycling versus swap strategies. PsA patients who failed the first-line TNFi and subsequently received either a TNFi or IL-17i were retrospectively selected from 25 centers. We collected demographic and disease-related data (disease duration, clinical phenotype, Disease Activity in Psoriatic Arthritis score), concomitant use of conventional synthetic disease-modifying antirheumatic drugs. Patients were categorized into cycling (second TNFi) (CG) or swapping (switch to IL-17i) (SG) groups. Kaplan-Meier survival curves were used to evaluate the retention rate, and a Cox regression analysis was performed to identify risk factors influencing treatment retention. In CG and SG there were 275 and 177 patients, respectively. Retention rate in SG was higher than in CG (p < 0.001). Treatment interruption predictors were cycling strategy (p < 0.001), Disease Activity in Psoriatic Arthritis (p = 0.013), prescription year (p = 0.016), axial (p = 0.013), mixed involvement (p = 0.001). The swap strategy showed higher treatment retention than cycling in PsA patients who failed the first-line TNFi. This finding supports the hypothesis that changing MoA may improve the chances of selecting the most effective PsA treatment. Not applicable.

IXE (Ixekizumab) is a monoclonal antibody targeting interleukin-17A (IL17A) which has demonstrated significant efficacy and safety in the management of psoriatic arthritis (PsA) in randomized controlled trials (RCTs). However, available data on long-term persistence of therapy are scarce. Methods: This multi-center study aimed to evaluate the drug retention rate (DRR) of IXE in a real-world setting and to identify key factors influencing treatment persistence. 195 patients with PsA treated with IXE between 2018 and 2024 were included. The primary outcome was DRR, calculated at 360, 720, and 1080 days after treatment initiation. Clinical and demographic factors were analyzed as potential predictors of IXE treatment permanency. Results: IXE retention rates were 66% at 360 days, 49% at 720 days, and 39% at 1080 days. Low baseline disease activity was a strong predictor of higher retention (HR 0.24, 95% CI: 0.09–0.62, p = 0.003), while younger age was significantly associated with improved persistence (HR 0.98, 95% CI: 0.96–1.00, p = 0.045). Conversely, patients with both axial and peripheral joint involvement were more likely to discontinue therapy (HR 1.78, 95% CI: 1.04–3.06, p = 0.036), as were those receiving IXE as a second- or third-line therapy (HR 1.17, 95% CI: 1.02–1.33, p = 0.021). Conclusions: This multicenter real-world study confirms the long-term retention rate of IXE in PsA. The findings highlight key factors influencing treatment persistence and provide valuable insights to optimize patient management. Further real-world research is needed to better understand the therapeutic performance of IXE in different patient populations.

Introduction: Upadacitinib (UPA) is an oral Janus kinase inhibitor (JAKi) recently approved for the treatment rheumatoid arthritis (RA) treatment. Although registrational studies have demonstrated the efficacy of UPA in RA, data on the long-term retention rate of this drug are still lacking. Objective: The objective of his study was to evaluate the real-world retention rate of UPA in patients with RA, analyze possible reasons for treatment discontinuation, and attempt to identify independent factors possibly associated with persistence of UPA treatment Methods: We conducted a multicenter retrospective observational study of patients with RA referred to tertiary rheumatology hospitals in Italy. One-hundred-eleven consecutive patients who received UPA in different lines of treatment were enrolled. Clinical history, previous treatments, and RA disease activity at baseline were recorded. The retention rate of UPA was assessed by Kaplan-Meier curve study. Cox proportional regression analysis was also performed to study the effect of independent factors on UPA therapy retention rate including age, sex, smoking habit, presence of anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF), disease duration, disease activity, line of treatment and concomitant treatments. Results: Analysis of demographic data revealed an M:F ration of 28:83, a median age of 58 years with an interquartile Range (IQR) of 50-65 years, and a median disease duration 78 months (IQR: 40-167) . The median observation period was 6.0 months (IQR 3.2-10.0). Most patients were on monotherapy or receiving concomitant steroids (55.0% and 58.6%, respectively). The UPA retention rate at 6 and 12 months was 90.4% and 74.7%, respectively. Reasons for treatment discontinuation included lack of efficacy (8/19), lost of efficacy (6/19) infections (3/19) and cancer onset (2/19). Other factors affecting the rate of UPA maintenance were duration of illness and RA seropositivity. Conclusion: The high retention rate of UPA indirectly suggests the good efficacy and acceptable safety profile of this drug in RA therapy. From our study data, we conclude that UPA could be an appropriate choice in most patients with RA, even after failure of previous lines of treatment. We also found that the drug had a higher retention rate in patients with seropositive RA than in their seronegative counterparts.

BACKGROUND:Upadacitinib (UPA) is a selective, reversible Janus kinase inhibitor (JAKi) approved for the treatment of RA. However, there is still no solid evidence on the long-term efficacy of UPA in treated patients. The purpose of this study was to determine the efficacy of UPA to obtain remission or low disease activity (LDA) in a series of UPA patients in patients with RA after 6 and 12 months of treatment in a real-world setting. METHODS:A series of 111 consecutive patients treated with UPA in 23 rheumatology centers were enrolled. Personal history, treatment history and disease activity at baseline, after 6 and 12 months were recorded. Intention-to-treat (ITT) and per-protocol (PP) analyses assessed achievement of remission or LDA or defined as DAS28 <2.6 and ≤3.2, respectively. Logistic regression analysis examined the role of several independent factors on the reduction of disease activity after 6 months of treatment. RESULTS:Of the initial group of 111 subjects at baseline, 86 and 29 participants completed clinical assessments at 6 and 12 months. According to ITT analysis, the rates of remission and LDA were 18% and 18% at 6 months and 31.5% and 12.5% at 12 months, respectively. PP analysis showed higher rates of remission and LDA at 6 (23.3% and 19.8%) and 12 months (55.2% and 20.7%). Results of multivariate logistic regression analysis indicated that a low DAS28 score (P=0.045) was the only predictor of achieving remission at 6 months. None of the baseline factors predicted remission/LDA at 6 months. CONCLUSIONS:RA patients treated with UPA achieved a significant rate of disease remission or LDA in a real-world setting. The 6-month response was found to depend only on the baseline value of DAS28, while it was not influenced by other factors such as disease duration, line of treatment or concomitant therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or corticosteroids.

Background and Objectives: The treatment landscape for Rheumatoid Arthritis (RA) has evolved significantly with the introduction of Janus kinase inhibitors (JAKi), such as Tofacitinib (TOFA), which offer a new therapeutic option for patients who have failed or are intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Safety concerns, particularly related to cardiovascular and cancer risks, prompted a need for additional investigation in real-world clinical settings. This study aimed to evaluate the long-term effectiveness and predictors of response to TOFA in two subpopulations of RA patients, categorized by differing cardiovascular risk profiles. Materials and Methods: This was a retrospective, multicenter observational study conducted as part of the BIRRA project, involving 23 Italian rheumatological referral centers. A total of 213 patients diagnosed with RA and treated with TOFA were included, with data collected on baseline demographics, clinical history, disease activity, and comorbidities. Patients were divided into high-risk and low-risk cardiovascular groups based on age (≥65 years) and the presence of at least one cardiovascular risk factor. Disease activity was assessed at baseline, 6 months, and 12 months using DAS28-ESR and DAS28-CRP. Treatment response was evaluated using intention-to-treat (ITT) and per-protocol (PP) approaches. Predictors of low disease activity (LDA) and remission were assessed through logistic regression, and clustering analyses were used to identify subgroups of patients with different therapeutic responses. Results: The study included 213 patients, with 129 classified as high-risk. For the overall cohort, patients achieving LDA and remission at 6 months were 20% and 12%, respectively, for the ITT analysis, and 29% and 14% for the PP analysis. At 12 months, 26% of patients reached LDA, and 17% achieved remission according to ITT, while for the PP analysis, these rates were 30% and 19%, respectively. No significant differences in remission or LDA rates were observed between the high-risk and low-risk groups. In the high-risk subgroup, 17% of patients reached LDA and 9% achieved remission at 6 months (ITT analysis), while these rates increased to 22% and 13%, respectively, in the PP analysis. At 12 months, 22% achieved LDA and 13% achieved remission in the ITT analysis, while 28% and 17% did so in the PP analysis. The reduction in DAS28-ESR and DAS28-CRP scores was significant (p < 0.001) across all time points for both high-risk and low-risk patients. Logistic regression analyses revealed that none of the baseline characteristics—including age, sex, comorbidities, rheumatoid factor, anti-citrullinated protein antibody (ACPA) positivity, initial disease severity, or treatment history—were significant predictors of remission or LDA at 6 or 12 months. The clustering analysis suggested that older patients, particularly those with worse baseline DAS28 scores, tended to show a less favorable response to treatment, potentially indicating impacts of age-related factors such as immunosenescence on therapeutic outcomes. Conclusions: Tofacitinib demonstrated similar effectiveness in both high- and low-risk cardiovascular subgroups of RA patients, with significant reductions in disease activity observed at both 6 and 12 months. Despite safety concerns related to cardiovascular risk, TOFA remained an effective treatment option across patient subgroups, with no significant differences in remission or LDA rates based on cardiovascular risk profiles. Age appeared to negatively impact treatment response, highlighting the role of immunosenescence in RA management. These findings support the use of TOFA as a personalized therapeutic option for RA, emphasizing the need for careful evaluation of cardiovascular and age-related risks in clinical decision-making.

Background/Objectives: The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA), and filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US Food and Drug Administration (FDA) raised concerns about the safety of TOFA after its approval. This prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA use, then extended a third warning to all JAKi in patients at high risk of developing serious adverse effects (SAE). These include thrombosis, major adverse cardiac events (MACE), and cancer. The purpose of this work was to analyze how the first two safety warnings from the EMA affected the prescribing of JAKi by rheumatologists in Italy. Methods: All patients with rheumatoid arthritis who had been prescribed JAKi for the first time in a 36-month period from 1 July 2019, to 30 June 2022 were considered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi prescription had occurred before the EMA’s first safety alert (1 July–31 October 2019, Group 1), between the first and second alerts (1 November 2019–29 February 2020, Group 2), or between the second and third alerts (1 March 2021–30 June 2021, Group 3). The percentages and absolute changes in the patients prescribed the individual JAKi were analyzed. Differences among the three groups of patients regarding demographic and clinical characteristics were also assessed. Results: A total of 864 patients were prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 in Group 2, and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In the first group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second group, the most prescribed JAKi was BARI (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third group, BARI was still the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%), and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). The number of patients who were prescribed BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). In contrast, the number of patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). Conclusions: These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers as favorable in terms of the risk/benefit ratio, and their use gradually increased at the expense of the other molecules.

Background: Since 2022 clinicians have been consistently aware by the European Medical Agency (EMA) of prescribing Jak-inhibitors (JAKi) after assessing a risk/benefit ratio, especially in patients with rheumatoid arthritis (RA)1. Nevertheless, during the last years, uptake of selective JAKis has consistently increased, although limited data regarding differences between selective and unselective JAKis are available to date. Objectives: To assess differences between selective and unselective JAKIs in terms of discontinuation's rate. Methods: In this retrospective study, all patients with RA treated with JAKis were prospectively enrolled from 22 Italian centres since 2017. Selective JAKi included filgotinib and upadactinib, whereas unselective JAKIs included tofacitinib and baricitinib. Reasons of discontinuation rates were: primary and secondary inefficacy, remission, adverse events [deaths, infections, onset of major cardiovascular events-(MACEs)-, deep vein thrombosis-(DVT)-, pulmonary embolism-PE, cancers]. The following variables were collected at JAKi's first prescription: sex, age, disease duration (years), smoking, BMI, comorbidities (diabetes, hypertension, dyslipidaemia, cancer, major cardiovascular events-MACEs), positive RF/ACPA, associated cDMARDs, prednisone and prednisone dosage (mg/day), previous use of JAKi, time to discontinuation (days), reasons of discontinuation, discontinuation rates for each JAKi, line of treatment, DAS28-ESR, b/tsDMARDS naïve patients. Results: 693 patients were included in study. 395 (57%) patients received baricitinib, 150 (21.7%) tofacitinib, 94 (13.6%) upadacitinib and 54 (7.8%) filgotinib. The majority of patients were treated with unselective JAKi (78.6% vs 21.4% of selective JAKi). 157 (22.7%) patients discontinued JAKI after a median time of 334 days (IQR 152-869). Details of discontinuation rates for each drug are reported in Table 1. Reasons of discontinuation were primary inefficacy (n=55, 7.9%), secondary inefficacy (n=29, 4.2%), infections (n=9, 1.3%), PE/DVT (n=6, 0.9%), cancer (n=6, 0.9%), deaths (n=2, 0.3%), and other causes (n=7, 3.5%) including remission status in 1 patient. No MACEs were observed in this cohort during the follow up period, although 348 patients (50.2%) had at least one comorbidity at baseline. Notably, both VZV infection (n=3) and DVT/PE (N=6) occurred in patients on treatment with baricitinib. Among 157 patients who discontinued JAKi, a statistical difference between selective and unselective JAKIs was found (15.9% on selective JAKi vs. 84.1% on unselective JAKI, p value <0.001 at log-rank test, Figure 1). Finally selective JAKi were withdrawn before unselective JAKi (median 173 days, IQR 129-22 vs median 401.5 days, IQR 173.5-981). Conclusion: In this real-world cohort, only a minority of patients discontinued JAKi (22.7%). Primary and secondary inefficacy were the most common reasons of JAKi's withdrawal. All TVP/PE and VZV infections occurred in the baricitinib group, probably due to different overall time of drug's exposition. Finally, selective JAKis were discontinued earlier than unselective JAKi. REFERENCES: [1] Smolen JS, et al. Ann Rheum Dis 2023. Acknowledgements: NIL. Disclosure of Interests: Maddalena Larosa UCB, ABBVIE, AMGEN, Dario Camellino AStrazeneca, Boerhinger Ingelheim GSK, and Janssen, Andrea Becciolini: None declared, Eleonora Di Donato: None declared, Giuditta Adorni: None declared, Gianluca Lucchini: None declared, Daniele Santilli: None declared, Eugenio Arrigoni: None declared, Elena Bravi: None declared, Ilaria Platè: None declared, Alessandra Bezzi: None declared, Alessandra Bezzi: None declared, Maria Cristina Focherini: None declared, Fabio Mascella: None declared, Vincenzo Bruzzese: None declared, Palma Scolieri: None declared, Simone Parisi: None declared, Maria Chiara Ditto: None declared, Enrico Fusaro: None declared, Viviana Ravagnani: None declared, Guido Rovera: None declared, Alessia Fiorenza: None declared, Rosetta Vitetta: None declared, Antonio Marchetta: None declared, Alessandro Volpe: None declared, BERND RAFFEINER: None declared, Eleonora Celletti: None declared, Myriam Di Penta: None declared, Emanuela Sabatini: None declared, Francesco Cipollone: None declared, Francesca Ometto: None declared, Cecilia Giampietro: None declared, Valeria Nucera: None declared, Aurora Ianniello: None declared, Francesca Serale: None declared, Marta Priora: None declared, Dilia Giuggioli: None declared, Carlo Salvarani: None declared, Gilda Sandri: None declared, Federica Lumetti: None declared, FRANCESCO MOLICA COLELLA: None declared, Veronica Franchina: None declared, Aldo Molica Colella: None declared, Patrizia Del Medico: None declared, Rosalba Caccavale: None declared, Marino Paroli: None declared, Giulio Ferrero: None declared, Natalia Mansueto: None declared, Romina Andracco: None declared, Matteo Colina: None declared, Simone Bernardi: None declared, Francesco Girelli: None declared, Antonella Farina: None declared, Roberta Foti: None declared, Francesco De Lucia: None declared, Giorgio Amato: None declared, Rosario Foti: None declared, Alberto Lo Gullo: None declared, Mirco Magnani: None declared, Olga Addimanda: None declared, Massimo Reta: None declared, Alarico Ariani AMGEN, JANSSEN.

Background Janus kinase (JAK) inhibitors have been approved for the treatment of Rheumatoid Arthitis (RA) and other systemic or organ-specific autoimmune diseases. Sustained remission or low disease activity are target treatments recomended by European League Against Rheumatism (EULAR) in RA patients [1]. Upadacitinib (UPA), a reversible, oral JAK inhibitor, has been engineered to have a greater selectivity for JAK1 vs JAK2, JAK3, and tyrosine kinase. In the Phase 3 SELECT clinical trial program, UPA has been shown to be effective and well tollerate in patients with RA [2]. However, data on the use of UPA in real-world clinical practice are limited. Objectives To evaluate UPA effectiveness in RA patients and to report the main reasons of suspension and the most relevant factor related to treatment persistence. Methods In 25 Italian rheumatological referral centers, all RA consecutive patients who received UPA were enrolled. Anamnestic data, treatment history and RA disease activity at baseline were recorded.The 6 and 12 months UPA retention rate was assessed with the Kaplan-Meier curve methods. The Cox analysis investigated the effect of age, sex, smoke habit, ACPA/RF presence, disease duration, DAS28-CRP, line of treatment, concomitant csDMARD treatment on UPA retention rate. A p-value < 0.05 was considered statistically significant. Results The one-hundred-eleven enrolled patients median age 57 (IQR 50-65 yrs); M:F 28:83; disease duration 78 (IQR 40-170 months). The median observation period was 6.1 (IQR 3.2-10.2) months. The observation lasted 812 patients-months. The majority of patients (54.0%) were in mono-therapy and received steroids (respectively 54.0% and 58.6%) (Table 1).The UPA retention rate at 6, 12 months was, respectively 90.4% and 74.7% (Figure 1). The main discontinuation reason was lack of efficacy (42% of interruptions), cancer onset and infections (both 11%). No thromboembolic events were reported.According to the Cox analysis, no one of the above mentioned parameters were associated to high risk of treatment interruption. Conclusion UPA effectiveness appears to be confirmed. The safety profile of UPA 15 mg in real-world practice is consistent with data from Phase 3 SELECT trials, with no new safety signals. References [1]Smolen JS, et al. Ann Rheum Diseases 2023;82:3-18.[2]Burmester GR et al.Lancet 2018; 23;391(10139):2503-2512 Acknowledgements: NIL. Disclosure of Interests None Declared.Figure 1Table 1Baseline characteristics UPACharacteristicsValueM:F28:83Age, median [IQR] yrs58 [50-65]Smokers, n (%) (**)YesFormerNo16 (16,5)17 (17,5)64 (66,0)Body Mass Index, median [IQR] kg/m^2 (*)24,7 [22,4-27,7]Disease Duration, median [IQR], months78 [40-170]RF positivity, n (%)72 (64,9)ACPA positivity, n (%)68 (61,3)SJC, median [IQR]4 [3-8]TJC, median [IQR]8 [5-11]ESR, median [IQR], mm/h32 [20-53]CRP, median [IQR], mg/dl1,2 [0,5-3,3]VAS Patient (0-100), median [IQR]70 [50-80]DAS28, median [IQR]5,5 [4,9-5,9]Line of treatment, [IQR]3 [2-4]Concomitant csDMARDs use, n (%)MTXLFNSSZHCQ41 (36,9)3 (2,7)1 (0,9)5 (4,5)Concomitant steroids use, n (%)65 (58,6)Steroids dose (PDN-Eq), median, mg/die5 [5-6]Prior bDMARDs use, n (%)TNFiIL6iIL1iCD20iCD80i53 (47,7)13 (11,7)02 (1,8)11 (9,9)Prior tsDMARDs use, n (%)BaricitinibTofacitinib9 (8,1)2 (1,8)Concomitant relevant disease, n (%)DiabetesHypercholesterolemiaMACEArterial HypertensionCancer12 (10,8)23 (20,7)5 (4,5)34 (30,6)4 (3,6)

Background: Tofacitinib (TOFA) was the first Janus kinase inhibitor (JAKi) to be approved for the treatment of rheumatoid arthritis (RA). However, data on the retention rate of TOFA therapy are still far from definitive. Objective: The goal of this study is to add new real-world data on the TOFA retention rate in a cohort of RA patients followed for a long period of time. Methods: A multicenter retrospective study of RA subjects treated with TOFA as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) was conducted in 23 Italian tertiary rheumatology centers. The study considered a treatment period of up to 48 months for all included patients. The TOFA retention rate was assessed with the Kaplan–Meier method. Hazard ratios (HRs) for TOFA discontinuation were obtained using Cox regression analysis. Results: We enrolled a total of 213 patients. Data analysis revealed that the TOFA retention rate was 86.5% (95% CI: 81.8–91.5%) at month 12, 78.8% (95% CI: 78.8–85.2%) at month 24, 63.8% (95% CI: 55.1–73.8%) at month 36, and 59.9% (95% CI: 55.1–73.8%) at month 48 after starting treatment. None of the factors analyzed, including the number of previous treatments received, disease activity or duration, presence of rheumatoid factor and/or anti-citrullinated protein antibody, and presence of comorbidities, were predictive of the TOFA retention rate. Safety data were comparable to those reported in the registration studies. Conclusions: TOFA demonstrated a long retention rate in RA in a real-world setting. This result, together with the safety data obtained, underscores that TOFA is a viable alternative for patients who have failed treatment with csDMARD and/or biologic DMARDs (bDMARDs). Further large, long-term observational studies are urgently needed to confirm these results.