Chronotherapy with low-dose modified-release prednisone for the management of rheumatoid arthritis: a review

To date, rheumatoid arthritis (RA) remains a debilitating, life-threatening disease. One major concern is morning symptoms (MS), as they considerably impair the patients’ quality of life and ability to work. MS change in a circadian fashion, resembling the fluctuations of inflammatory cytokines such as interleukin-6, whose levels are higher in RA patients compared to healthy donors. Conversely, serum levels of the potent anti-inflammatory glucocorticoid cortisol are similar to that of healthy subjects, suggesting an imbalance that sustains a pro-inflammatory state. From a therapeutic point of view, administering synthetic glucocorticoids (GCs) to RA patients represents an optimal strategy to provide for the inadequate levels of cortisol. Indeed, due to their high efficacy in RA, GCs remain a cornerstone more than 60 years after their first introduction, and despite the development of a wide range of targeted agents. However, to improve safety, low-dose GCs have been introduced, that have demonstrated high efficacy in reducing disease activity, radiological progression, and improving patients’ signs and symptoms especially in early RA when added to conventional disease-modifying antirheumatic drugs. A further improvement has been provided by the development of modified-release prednisone, which, by taking advantage of the circadian fluctuations of inflammatory cytokines, cortisol and MS, is given at bedtime to be released approximately 4 hours later. Several studies have already demonstrated the efficacy of this agent on disease activity, MS, and quality of life in the setting of established RA. Moreover, preliminary studies have shown that this new formulation not only has no impact on the adrenal function, but likely improves it. This review is a comprehensive, updated summary of the current evidence on the use of GCs in RA, with focus on the efficacy and safety of low-dose prednisone and modified-release prednisone, the latter representing a rational, cost-effective, and tailored approach to maximize the benefit/risk ratio in RA patients

Baseline Ultrasound Assessment Improves the Response to Apremilast in Patients with Psoriatic Arthritis: Results from a Multicentre Study

ound: Psoriatic arthritis (PsA) phenotypes show different responses to the many available drugs. For a tailored medicine, it is important to choose the most effective treatment according to patients’ characteristics. Apremilast is recommended in PsA with moderate activity. In clinical practice, the most suitable PsA patients for apremilast are those affected by the peripheral oligoarticular arthritis. However, it is not so straightforward to definitely identify this phenotype. Musculoskeletal ultrasound (MUS) is a good tool for detecting the joints actually involved by PsA. The aim of this study is to verify if MUS assessment is useful in selecting the best PsA responders to apremilast. Methods: The following data of all consecutive PsA patients from 15 centres were recorded: anamnestic data, disease activity, PsA phenotype, apremilast treatment duration and reason of suspension. MUS assessment before apremilast treatment was the criteria which clustered patients in two groups. Apremilast retention rate estimate the drug’s effectiveness. The Cox analysis revealed the risk factors associated with treatment persistence. Mann-Whitney U and Chi-squared tests assessed the intergroup differences. Results: Only 40% of 356 patients (M:F: 152/204; median age 60 yrs) received MUS examination. In MUS group the moderate disease (median DAPSA 22.9 vs 26.9; p=0.0006) and the oligo-articular phenotype (63.6% vs 36.1%, p<0.0001) were more common. The retention rate was higher in MUS group (HR 0.55 IC95% 0.32-0.94; p=0.03). Conclusion: In apremilast treated PsA patients, baseline MUS assessment is related to an increased retention rate. MUS may identify patients’ characteristics favourable to apremilast response

Predictors of DAPSA Response in Psoriatic Arthritis Patients Treated with Apremilast in a Retrospective Observational Multi-Centric Study (2023-02-07)

Background: To date, only a few real-world-setting studies evaluated apremilast effectiveness in psoriatic arthritis (PsA). The aims of this retrospective observational study are to report long-term Disease Activity Index for Psoriatic Arthritis (DAPSA) response of apremilast in PsA patients and to analyze the predictors of clinical response. Methods: All PsA consecutive patients treated with apremilast in fifteen Italian rheumatological referral centers were enrolled. Anamnestic data, treatment history, and PsA disease activity (DAPSA) at baseline, 6 months, and 12 months were recorded. The Mann–Whitney test and chi-squared tests assessed the differences between independent groups, whereas the Wilcoxon matched pairs signed-rank test assessed the differences between dependent samples. Logistic regressions verified if there were factors associated with achievement of DAPSA low disease activity or remission at 6 and 12 months. Results: DAPSA low disease activity or remission rates at 6 and 12 months were observed, respectively, in 42.7% (n = 125) and 54.9% (n = 161) patients. Baseline DAPSA was inversely associated with the odds of achieving low disease activity or remission at 6 months (odds ratio (OR) 0.841, 95% confidence interval (CI) 0.804–0.879; p < 0.01) and at 12 months (OR 0.911, 95% CI 0.883–0.939; p < 0.01). Conclusions: Almost half of the PsA patients receiving apremilast achieved DAPSA low disease activity or remission at 6 and 12 months. The only factor associated with achievement of low disease activity or remission at both 6 and 12 months was baseline DAPSA

Influence of safety warnings on the prescribing attitude of JAK 2inhibitors for rheumatoid arthritis in Italy

The Janus kinase inhibitors (JAKi) tofacitinib (TOFA), baricitinib (BARI), upadacitinib (UPA) and 74 filgotinib (FILGO) are effective drugs for the treatment of rheumatoid arthritis. However, the US 75 Food & Administration (FDA) raised concerns on the safety of TOFA after its approval. This 76 prompted the European Medicines Agency (EMA) to issue two safety warnings for limiting TOFA 77 use then extended in a third warning to all Jaki in patients at high risk of developing serious adverse 78 events (SAE). These included thrombosis, major adverse cardiac events (MACE) and cancer. Thepurpose of this work was to analyze how the first two safety warnings from EMA affected the pre- 80 scribing of Jaki by rheumatologists in Italy. All patients with rheumatoid arthritis who had been 81 prescribed JAKi for the first time in a 36-month period from July 1, 2019, to June 30, 2022 were con- 82 sidered. Data were obtained from the medical records of 29 Italian tertiary referral rheumatology 83 centers. Patients were divided into three groups of 4 months each, depending on whether the JAKi 84 prescription had occurred before the EMA's first safety alert (July 1-October 31, 2019, Group 1), 85 between the first and second alerts (November 1, 2019-February 29, 2020, Group 2), or between the 86 second and third alerts (March 1, 2021-June 30, 2021, Group 3). Percentage and absolute changes in 87 patients prescribed the individual JAKi were analyzed. Differences among the three Groups of pa- 88 tients in demographic and clinical characteristics were also assessed. A total of 864 patients were 89 prescribed a JAKi during the entire period considered. Of these, 343 were identified in Group 1, 233 90 in Group 2 and 288 in Group 3. An absolute reduction of 32% was observed in the number of patients 91 prescribed a JAKi between Group 1 and Group 2 and 16% between Group 1 and Group 3. In contrast, 92 there was a 19% increase in the prescription of a JAKi in patients between Group 2 and Group 3. In 93 the first Group, BARI was the most prescribed drug (227 prescriptions, 66.2% of the total), followed 94 by TOFA (115, 33.5%) and UPA (1, 0.3%). In the second Group, the most prescribed JAKi was BARI 95 (147, 63.1%), followed by TOFA (65, 27.9%) and UPA (33, 11.5%). In the third Group, BARI was still 96 the most prescribed JAKi (104 prescriptions, 36.1%), followed by UPA (89, 30.9%), FILGO (89, 21.5%) 97 and TOFA (33, 11.5%). The number of patients prescribed TOFA decreased significantly between 98 Group 1 and Group 2 and between Group 2 and Group 3 (p ˂ 0.01). Patients who were prescribed 99 BARI decreased significantly between Group 1 and Group 2 and between Group 2 and Group 3 (p 100 ˂ 0.01). In contrast, patients prescribed UPA increased between Group 2 and Group 3 (p ˂ 0.01). 101 These data suggest that the warnings issued for TOFA were followed by a reduction in total JAKi 102 prescriptions. However, the more selective JAKi (UPA and FILGO) were perceived by prescribers 103 as favorable in terms of risk/benefit ratio and their use gradually increased at the expense of the 104 other molecules

Ixekizumab Retention Rate and Predictors of Treatment Persistence in Psoriatic Arthritis: Results of an Italian Multicenter Study

XE (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. Keywords: biologic treatment; comparative effectiveness; interleukin 17 inhibitor; ixekizumab; psoriasis; psoriatic arthritis

The Italian Society for Rheumatology guidelines on reproductive health in patients with rheumatic diseases

Objective. To date, there is no shared national guideline in Italy for the management of reproductive health in rheumatic diseases (RHRD). The Italian Society for Rheumatology has committed to developing clinical practice recommendations to provide guidance on both management and treatment regarding RHRD in Italy. Methods. Using the GRADE-ADOLOPMENT methodology, a systematic literature review was conducted to update the scientific evidence that emerged after the publication of the reference recommendations from the American College of Rheumatology. A multidisciplinary group of 18 clinicians with specialist experience in rheumatology, allergy and clinical immunology, internal medicine, nephrology, gynecology and obstetrics, and neonatology, a professional nurse, a clinical psychologist, and a representative from the National Association of Rheumatic Patients discussed the recommendations in collaboration with the evidence review working group. Subsequently, a group of stakeholders was consulted to examine and externally evaluate the developed recommendations. Results. Recommendations were formulated for each area of interest: contraception, assisted reproductive technology, preconception counseling, and use of drugs before, during, and after pregnancy and during breastfeeding, considering both paternal and maternal exposure. Conclusions. The new SIR recommendations provide the rheumatology community with a practical guide based on updated scientific evidence for the management of RHRD

Transcriptomic profile comparison of monocytes from rheumatoid arthritis patients in treatment with methotrexate, anti-TNFa, abatacept or tocilizumab.

It is well documented that patients affected by rheumatoid arthritis (RA) have distinct susceptibility to the different biologic DMARDs available on the market, probably because of the many facets of the disease. Monocytes are deeply involved in the pathogenesis of RA and we therefore evaluated and compared the transcriptomic profile of monocytes isolated from patients on treatment with methotrexate alone or in combination with tocilizumab, anti-TNFα or abatacept and from healthy donors. Whole-genome transcriptomics yielded a list of regulated genes by Rank Product statistics and DAVID was then used for functional annotation enrichment analysis. Last, data were validated by qRT-PCR. Abatacept, tocilizumab and anti-TNFa cohorts were separately compared with methotrexate, leading to the identification of 78, 6, and 436 differentially expressed genes, respectively. The upper-most ranked genes were related to inflammatory processes and immune responses. Such an approach draws the genomic profile of monocytes in treated RA patients and lays the basis for finding gene signature for tailored therapeutic choices

Transcriptomic profile comparison of monocytes from rheumatoid arthritis patients in treatment with methotrexate, anti-TNFa, abatacept or tocilizumab

It is well documented that patients affected by rheumatoid arthritis (RA) have distinct susceptibility to the different biologic DMARDs available on the market, probably because of the many facets of the disease. Monocytes are deeply involved in the pathogenesis of RA and we therefore evaluated and compared the transcriptomic profile of monocytes isolated from patients on treatment with methotrexate alone or in combination with tocilizumab, anti-TNFα or abatacept and from healthy donors. Whole-genome transcriptomics yielded a list of regulated genes by Rank Product statistics and DAVID was then used for functional annotation enrichment analysis. Last, data were validated by qRT-PCR. Abatacept, tocilizumab and anti-TNFa cohorts were separately compared with methotrexate, leading to the identification of 78, 6, and 436 differentially expressed genes, respectively. The upper-most ranked genes were related to inflammatory processes and immune responses. Such an approach draws the genomic profile of monocytes in treated RA patients and lays the basis for finding gene signature for tailored therapeutic choices.</jats:p

Effectiveness of SB4 Transition from Originator Etanercept in Rheumatoid Arthritis and Axial Spondyloarthritis: A Subgroup Analysis from the BENEFIT Study

Objectives: The pan-European BENEFIT study of patients with stable rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) who transitioned from reference etanercept to SB4 found no clinically meaningful changes in disease control after transition. The analysis aims to illustrate the peculiarities of the Italian cohort of patients compared with the whole population to provide a more real-life approach to the data for the Italian rheumatologists, ruling out possible local confounding factors. Methods: A prospective study for up to 6 months following transition was conducted. Outcome measures of interest include clinical characteristics at time of transition and disease activity scores (Disease Activity Score-28 [DAS28] for RA, Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] for axSpA) over time and safety. Results: One-hundred and eleven subjects (out of the 557 in total enrolled in the study) were derived from 8 Italian sites, including 79 with RA and 32 with axSpA. In both cohorts, the efficacy was maintained at 3 months and 6 months from the transition to the biosimilar with no significant change in mean DAS28 and BASDAI scores: at the end of the 6 months of observation the mean DAS28 and BASDAI was similar to baseline (confidence interval [CI] -0.22, 0.22), while the mean variation of the BASDAI was -0.14. Of note, 100.0% (95% CI 89.1, 100.0) in the axSpA and 90.8% (95% CI 81.5, 95.5) in the RA cohort of patients continued to receive SB4 at month 6 (binary variable with 95% Clopper-Pearson CI). Conclusions: Italian patients with stable RA or axSpA who transitioned from originator Etanercept to SB4 maintained clinical response at 6 months post-transition. Both the cohorts are representative of typical patients with long-standing established diagnoses. Most of the patients transitioned to the same dose regimen of biosimilar as that received for the originator, and the regimen remained unchanged at 6 months, supporting the effectiveness of the transition

Effectiveness of SB4 transition from originator etanercept in rheumatoid arthritis and axial spondyloarthritis: A subgroup analysis from the BENEFIT study

Abstract Objectives The pan-European BENEFIT study of patients with stable rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) who transitioned from reference etanercept to SB4 found no clinically meaningful changes in disease control after transition. The analysis aims to illustrate the peculiarities of the Italian cohort of patients compared with the whole population to provide a more real-life approach to the data for the Italian rheumatologists, ruling out possible local confounding factors. Methods A prospective study for up to 6 months following transition was conducted. Outcome measures of interest include clinical characteristics at time of transition and disease activity scores (Disease Activity Score-28 [DAS28] for RA, Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] for axSpA) over time and safety. Results One-hundred and eleven subjects (out of the 557 in total enrolled in the study) were derived from 8 Italian sites, including 79 with RA and 32 with axSpA. In both cohorts, the efficacy was maintained at 3 months and 6 months from the transition to the biosimilar with no significant change in mean DAS28 and BASDAI scores: at the end of the 6 months of observation the mean DAS28 and BASDAI was similar to baseline (confidence interval [CI] −0.22, 0.22), while the mean variation of the BASDAI was −0.14. Of note, 100.0% (95% CI 89.1, 100.0) in the axSpA and 90.8% (95% CI 81.5, 95.5) in the RA cohort of patients continued to receive SB4 at month 6 (binary variable with 95% Clopper-Pearson CI). Conclusions Italian patients with stable RA or axSpA who transitioned from originator Etanercept to SB4 maintained clinical response at 6 months post-transition. Both the cohorts are representative of typical patients with long-standing established diagnoses. Most of the patients transitioned to the same dose regimen of biosimilar as that received for the originator, and the regimen remained unchanged at 6 months, supporting the effectiveness of the transition. </jats:sec