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Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis. [ABSTRACT FROM AUTHOR]

The emergence of biologics with different modes of action (MoAs) and therapeutic targets has changed treatment patterns in patients with inflammatory rheumatic diseases. While tumour necrosis factor inhibitors (TNFis) are often utilized as the first biologic disease-modifying antirheumatic drug, some patients may not respond adequately (primary failure), fail to sustain response over time (secondary failure), or experience intolerable adverse events. Whether these patients would benefit more from cycling to a different TNFi or switching to a biologic with a different MoA is still unclear. We discuss here treatment outcomes of TNFi cycling versus MoA switching after treatment failure with a first TNFi in patients with inflammatory rheumatic diseases, focusing specifically on rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and juvenile idiopathic arthritis. Treatment guidelines for these patients are ambiguous and, at times, contradictory in their recommendations. However, this is due to a lack of high-quality head-to-head data to definitively support cycling between TNFis after failure to a first-line TNFi over switching to a different MoA. [ABSTRACT FROM AUTHOR]

Objective. Oral Janus kinase inhibitors ( JAKis) represent an effective strategy for rheumatoid arthritis (RA) treatment. A previous study supported that tofacitinib (TOF) is associated with higher incidence of cardiovascular (CV) and neoplastic events compared to tumor necrosis factor inhibitors. Given the apparent discrepancy between these data and real-world experience, we aimed to investigate the safety and efficacy of the available JAKis in a multicenter cohort. Methods. We retrospectively evaluated patients with RA who ever received 1 JAKi (TOF, baricitinib [BAR], upadactinib [UPA], filgotinib [FIL]) from 4 tertiary care centers in Milan, Italy. Outcomes related to JAKi safety were recorded, particularly major CV events as well as adverse events of special interest (AESIs), which included serious infections, opportunistic infections, venous thromboembolism, herpes zoster infections, liver injury, malignancies, and deaths; retention rates were also calculated. Further analyses included patients fulfilling the risk factors suggested to influence TOF safety. Results. Six hundred eighty-five patients were included and received BAR (48%), TOF (31%), UPA (14%), or FIL (7%) as first-line innovative treatment prior to a biologic. Of a total of 1137 patient-years of observation, we recorded 1 stroke and 123 (18%) AESIs, including 3 deaths, all a result of severe infections. Among patients with a higher CV risk, we observed a higher frequency of AESIs (23%). Conclusion. Our real-world data confirm that JAKis are effective and carry a low risk of AESIs, especially in patients who do not display CV risk factors at baseline. Our study could not identify differences between JAKis. Different safety profiles should be defined in larger prospective cohorts. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic inflammatory arthritis, such as rheumatoid arthritis (RA) and spondyloarthritis (SpA), often have a significant impact on bone tissue, where bone is not just a passive target but actively contributes to the disease progression. This review explores the pathogenic mechanisms involving bone, highlighting the complex molecular interactions between bone cells and the immune system, a field known as osteoimmunology. It discusses the unique processes of bone erosion and systemic bone loss in RA and SpA, as well as abnormal bone formation in SpA. Several rheumatologic diseases are primarily distinguished by their involvement of bone tissue, which not only serves as a mere target of the condition but often plays a pivotal role in its pathogenesis. This scenario is particularly prominent in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Given the immunological and systemic nature of these diseases, in this review, we report an overview of the pathogenic mechanisms underlying specific bone involvement, focusing on the complex interactions that occur between bone tissue's own cells and the molecular and cellular actors of the immune system, a recent and fascinating field of interest defined as osteoimmunology. Specifically, we comprehensively elaborate on the distinct pathogenic mechanisms of bone erosion seen in both rheumatoid arthritis and spondyloarthritis, as well as the characteristic process of aberrant bone formation observed in spondyloarthritis. Lastly, chronic inflammatory arthritis leads to systemic bone involvement, resulting in systemic bone loss and consequent osteoporosis, along with increased skeletal fragility. [ABSTRACT FROM AUTHOR]

Objective: To evaluate in patients with rheumatoid arthritis (RA) the impact of EMA recommendations on the real-life prescription of JAK inhibitors (JAKis) and the use of the Expanded Risk Score in RA (ERS-RA) to quantify the risk of major adverse cardiac events (MACE). Methods: We conducted a retrospective analysis of real-life RA patients treated with JAKis. Patients were classified as ineligible for JAKis if they fulfilled EMA criteria (>65 years-old, history of malignancy, or increased risk of venous thromboembolic events [VTE] or MACE including smoking). Risk of MACE was defined according to ORAL Surveillance trial inclusion criteria (ORALSURV) or by using the ERS-RA. Results: Of 194 patients enrolled, 57.9% were classified as ineligible according to EMA definition (ORALSURV criteria). The most frequent reason for ineligibility was increased MACE risk (70.2%), followed by age>65 (34.2%), smoking (30.7%), and increased risk of VTE (20.2%) or malignancy (7%). The use of the ERS-RA reduced the rate of patients carrying an increased CV risk to 18.6% (p<0.001 versus ORALSURV), leading to 46.4% overall ineligible patients. Over a drug-exposure of 337 patient/years, we observed 2 VTE, one MACE (non-fatal stroke), and one solid malignancy (all in the group of patients classified as ineligible according to both the definitions). Conclusions: Rigorous application of EMA indications in clinical practice could result in the exclusion of a large proportion of RA patients from treatment with JAKis. A proper quantification of the risk for MACE by dedicated tools as ERS-RA is advocated to better tailor the management of RA. [ABSTRACT FROM AUTHOR]

Objectives The primary endpoint of the pivotal phase III study of infliximab (IFX) s.c. demonstrated non-inferiority of s.c. to i.v. IFX, based on 28-joint DAS-CRP (DAS28-CRP) improvement at week (W) 22 (NCT03147248). This post-hoc analysis investigated whether numerical differences in efficacy outcomes at W30/54 were statistically significant, using conservative imputation methods. Methods Patients with active RA and inadequate response to MTX received IFX i.v. 3 mg/kg at W0 and W2 (induction) and were randomized (1:1) to IFX s.c. 120 mg every 2 weeks or i.v. 3 mg/kg every 8 weeks thereafter (maintenance). Patients randomized to IFX i.v. switched to IFX s.c. from W30–54. This post-hoc analysis compared efficacy outcomes for s.c. and i.v. groups pre-switch (W30) and post-switch (W54) using last observation carried forward (LOCF) and non-responder imputation (NRI) methods. Results Of 343 randomized patients, 165 (IFX s.c.) and 174 (IFX i.v.) were analysed. At W30, significantly improved outcomes were identified with s.c. vs i.v. IFX for DAS28-CRP/DAS28-ESR/Clinical Disease Activity Index (CDAI)/Simplified Disease Activity Index (SDAI) scores (LOCF); ACR/good EULAR responses, DAS28-CRP/Boolean remission, and DAS28-CRP/DAS28-ESR/CDAI/SDAI low disease activity and remission (LOCF and/or NRI); and minimal clinically important difference in HAQ score (LOCF and NRI). After switching to IFX s.c. from IFX i.v. fewer significant between-group differences were identified at W54. Conclusion IFX s.c. showed improved efficacy at W30 compared with IFX i.v. and the reduced between-group difference in efficacy outcomes at W54 after switching supports the results suggesting benefits of IFX s.c. compared with IFX i.v. at W30. Trial registration ClincialTrials.gov, http://clinicaltrials.gov , NCT03147248, https://clinicaltrials.gov/ct2/show/NCT03147248. [ABSTRACT FROM AUTHOR]

To our knowledge, no studies so far have investigated the role of pizza and its ingredients in modulating disease activity in rheumatoid arthritis (RA). We assessed this question via a recent cross-sectional study including 365 participants from Italy, the birthplace of pizza. Multiple robust linear and logistic regression models were fitted with the tertile consumption categories of each available pizza-related food item/group (i.e., pizza, refined grains, mozzarella cheese, and olive oil) as independent variables, and each available RA activity measure (i.e., the Disease Activity Score on 28 joints with C-reactive protein (DAS28-CRP), and the Simplified Disease Activity Index (SDAI)) as the dependent variable. Stratified analyses were carried out according to the disease severity or duration. Participants eating half a pizza >1 time/week (vs. ≤2 times/month) reported beneficial effects on disease activity, with the significant reductions of ~70% (overall analysis), and 80% (the more severe stratum), and the significant beta coefficients of −0.70 for the DAS28-CRP, and −3.6 for the SDAI (overall analysis) and of −1.10 and −5.30 (in long-standing and more severe RA, respectively). Among the pizza-related food items/groups, mozzarella cheese and olive oil showed beneficial effects, especially in the more severe stratum. Future cohort studies are needed to confirm this beneficial effect of pizza and related food items/groups on RA disease activity. [ABSTRACT FROM AUTHOR]

Rheumatoid Arthritis (RA) is a systemic disease with many different clinical phenotypes. RA could be classified according to disease duration, seropositivity for rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA), joint subtype, clinical behaviourbehavior and many other subgroups. In this review, we summarize and discuss the multifaceted aspects of RA, focusing on the relationship between autoimmunity status and clinical outcome, achievement of remission and influence on treatment response, from the 2022 International GISEA/OEG Symposium. [ABSTRACT FROM AUTHOR]

Few observational studies investigated the relationship between single food groups and disease activity in rheumatoid arthritis (RA). Within a recent Italian cross-sectional study (365 patients, median age: 58.46 years, 78.63% females), we focused on two food groups, olive oil and nuts, representing vegetable sources of fatty acids. Disease activity was measured with Disease Activity Score on 28 joints based on C-reactive protein (DAS28-CRP) and the Simplified Disease Activity Index (SDAI). Robust linear and logistic regression models included tertile-based consumption categories of each food group and several confounders. Stratified analyses were performed by disease severity or duration. Higher consumption of both food groups exerted a favorable effect on disease activity, significant only for olive oil (Beta: −0.33, p-value: 0.03) in the linear regression on the overall sample. This favorable effect was stronger in the more severe or long-standing forms of RA (p-value for heterogeneity <0.05, especially for disease severity). Significant ORs were as low as ~0.30 for both food groups, strata (i.e., more severe and long-standing RA), and disease activity measures. Mean DAS28-CRP significantly decreased by ~0.70 for olive oil and ~0.55 for nuts in the two strata; mean SDAI significantly decreased by 3.30 or more for olive oil in the two strata. Globally, the beta coefficients doubled, and the ORs halved (in absolute values) for both food groups, reaching significance in 12 of the 16 available models fitted to the more severe or long-standing RA strata. More compromised forms of RA may benefit from increasing consumption of olive oil, olives, and nuts. [ABSTRACT FROM AUTHOR]

Objectives: To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA).Methods: This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022.Results: Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission.Conclusion: The results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA. [ABSTRACT FROM AUTHOR]

Objectives: To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).Methods: SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.Results: Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.Conclusion: The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation. [ABSTRACT FROM AUTHOR]

Clinical joint examination is the cornerstone for evaluation of patients with RA. However, since large discrepancies have been shown even between experienced rheumatologists in evaluation of joint inflammation, and tender joints may have limited value in reflecting inflammation, US has in recent decades been introduced in the clinical assessments of RA patients. US has high accordance with other imaging modalities and enables detection of clinically difficult pathologies and contributes to assessments of joints difficult to evaluate clinically. However, there is no general agreement on the optimal use of US in rheumatology, and the prevalence of machines as well as the level of experience differs greatly between countries. In addition, standardized use of US in treat-to-target follow-up of RA patients was found not to have any added value. Thus, how to use US in monitoring of RA patients is open for debate. The present article will discuss the pros and cons for using US in the clinical setting. [ABSTRACT FROM AUTHOR]

Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules′ interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health. [ABSTRACT FROM AUTHOR]

The first subcutaneous (SC) formulation of infliximab CT-P13 has been authorized for the treatment of rheumatoid arthritis (RA) in Europe in 2019. Later, in 2020, approved indications were extended also to ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease (CD) and ulcerative colitis (UC). The present review provides summary of the key features of SC infliximab, with particular focus on pharmacokinetic profile, clinical development program in comparison with the intravenous (IV) formulation, and the latest evidence in the literature. We conclude that SC infliximab represents a new and promising approach in the treatment of patients with RA, offering an optimized clinical profile and a more practical option in comparison to the IV formulation. Nevertheless, SC formulation can improve the use of national health systems resources (e.g., through the time of healthcare workers not having to supervise infusions) and facilitate social distancing measures during the COVID-19 pandemic, as the patient can self-inject the medicine at home without going to the hospital. The limitations of the SC infliximab are mainly due to the limited experience of use in clinical practice and the absence of long-term drug retention data. [ABSTRACT FROM AUTHOR]

Tofacitinib is an oral Janus kinase (JAK) inhibitor indicated for the treatment of rheumatoid arthritis (RA). The efficacy and safety/tolerability of tofacitinib have been extensively evaluated as monotherapy and combination therapy in multiple, randomised, multicentre studies in patients with RA. Tofacitinib as monotherapy (as first- and second-line treatment) or as combination with methotrexate (MTX) or other csDMARDs as second- and third-line treatment is effective and generally well tolerated in patients with RA. This article focuses on recent real-world evidence investigating the effectiveness, treatment persistence and safety/tolerability of tofacitinib in patients with RA. With this purpose, a literature review was conducted from April 2018 up to October 2020 for the effectiveness, persistence and safety of tofacitinib for the treatment of RA, primarily focusing on real-world studies. These retrospective and prospective and observational studies demonstrate the effectiveness of tofacitinib, thus supporting pivotal data from the clinical trial programme. Treatment persistence was generally comparable to that of biologic disease-modifying anti-rheumatic drugs. Safety findings in these observational studies were consistent with the known safety profile of the approved dose of 5 mg twice daily. [ABSTRACT FROM AUTHOR]

Introduction: Coronavirus disease 2019 (COVID-19) pandemic raises a great challenge in the management of patients with rheumatoid arthritis (RA), which are generally more susceptible to infection events because of the autoimmune condition itself and the treatment with immunomodulatory drugs. The use of disease-modifying anti-rheumatic drugs (DMARDs), including biologics and targeted-synthetic DMARDs, has aroused particular interest because of both their immunosuppressive effects and their hypothetical potential in COVID-19 treatment. Areas covered: For this narrative review, a literature search was conducted between December 2019 and February 2021 on PubMed including epidemiological studies, gathering the main evidence available to date about the impact of COVID-19 on RA patients and the influence of anti-rheumatic drugs on patients' susceptibility to this infection. We also summarize the recommendations from the international guidelines on the management of rheumatic diseases and treatments in this pandemic context, especially focused on RA. Expert opinion: About a year after the outbreak of the pandemic, we are able to answer some of the most relevant questions regarding patients with RA and their management in this pandemic context. Our efforts must now be directed toward consolidating the currently available data with more rigorous studies and facing new issues and challenges including, foremost, vaccination. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis. This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and Abstract archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety. [ABSTRACT FROM AUTHOR]

Janus Kinase inhibitors (JAKi) have been approved for the treatment of Rheumatoid Arthritis (RA) for several years. They are the first oral advanced treatment with efficacy similar to, if not greater than, biologic agents. Recently, concerns over their safety was raised by the results from Oral Surveillance trial suggesting that tofacitinib, one of the JAKi, was associated with higher cardiovascular adverse events and malignancies than TNF inhibitors (TNFi). Since then, regulatory authorities have added warnings to the labels of JAKi. On this purpose, whether rheumatologists should use JAKi as first line advance treatment has become a controversial topic. Some rheumatologists have argued that biologics should be first line advance treatment since there are extensive effectiveness and safety data. In addition, with the advent of biosimilar drugs, they are the most cost-effective treatment. On the other hand, JAKi are very efficacious and are generally safe apart from older and high-risk patients. When TNFi are contraindicated and in certain RA patients ,especially when an oral drug is preferable, JAKi have significant advantage providing patients are involved in the decision-making process. • Biologics have extensive effectiveness and safety data in RA. • Biologics especially biosimilars, are highly cost-effective. • JAKi are very efficacious and have shown superiority to TNF inhibitors in randomized control trials • JAKi are generally safe apart from older and high-risk patients. • When TNF inhibitors are contraindicated and/or an oral drug is preferred JAKi can be used as first line treatment providing patients are informed of the risk and are involved in the decision-making process. [ABSTRACT FROM AUTHOR]

Emerging literature suggests that diet plays an important modulatory role in rheumatoid arthritis (RA) because diet is an environmental factor that affects inflammation, antigen presentation, antioxidant defense mechanisms and gut microbiota. Patients with RA frequently ask their doctors about which diets to follow, and even in the absence of advice from their physicians, many patients are undertaking various dietary interventions. Given this background, the aim of this review is to evaluate the evidence to date regarding the ideal dietary approach for management of RA in order to reduce the counteracting inflammation, and to construct a food pyramid for patients with RA. The pyramid shows that carbohydrates should be consumed every day (3 portions of whole grains, preferably gluten free), together with fruits and vegetables (5 portions; among which fruit, berries and citrus fruit are to be preferred, and among the vegetables, green leafy ones.), light yogurt (125 ml), skim milk (200 ml), 1 glass (125 ml) of wine and extra virgin olive oil; weekly, fish (3 portions), white meat (3 portions), legumes (2 portions) eggs (2 portions), seasoned cheeses (2 portions), and red or processed meats (once a week). At the top of the pyramid, there are two pennants: one green means that subjects with RA need some personalized supplementation (vitamin D and omega 3) and one red means that there are some foods that are banned (salt and sugar). The food pyramid allows patients to easily figure out what to eat. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this economic evaluation was to compare the cost per responder between upadacitinib and abatacept (intravenous [iv] or subcutaneous [sc]) in patients with moderate-to-severe Rheumatoid Arthritis (RA) in Italy. Methods: The clinical efficacy was assessed based on SELECT-CHOICE study results. The clinical efficacy of upadacitinib and abatacept (iv or sc) was measured by Clinical Remission (CR), Low Disease Activity (LDA) and American College of Rheumatology response (ACR20, 50 and 70). The treatment cost was based on the number of administrations dispensed at 12 or 24 weeks. The cost per responder was adopted as a cost-effectiveness indicator. Results: Independent of the clinical efficacy measure used and the duration of treatment considered, the cost per responder was consistently lower for upadacitinib compared to abatacept (iv or sc) across all clinical measures. For example, considering the CR at 24 weeks, the cost per responder for upadacitinib was € 9,417 compared to € 17,817 for abatacept sc or to € 23,110 for abatacept iv. The differences in the cost per responder between upadacitinib and abatacept (iv or sc) increased when higher ACR response levels were considered. Conclusions: These results suggested that upadacitinib is a cost-effectiveness option compared to abatacept (iv or sc) from the perspective of the Italian National Health Service in patients with moderate-to-severe Rheumatoid Arthritis in Italy. [ABSTRACT FROM AUTHOR]

There are few comparative data for tumor necrosis factor inhibitors in patients with rheumatoid arthritis (RA). Historical data for reference product/biosimilar intravenous infliximab, or adalimumab and etanercept, were pooled and compared with phase 3 study results for a subcutaneous (SC) formulation of the infliximab biosimilar CT-P13, in a systematic review and meta-analysis (PROSPERO: CRD42019149621). The authors identified 13 eligible controlled trials that randomized over 5400 participants to prespecified treatments of interest. Comparison with pooled historical data suggested a numerical advantage for CT-P13 SC over intravenous infliximab for almost every prespecified efficacy outcome evaluated, including Disease Activity Score in 28 joints (C-reactive protein/erythrocyte sedimentation rate), Clinical/Simplified Disease Activity Index scores, American College of Rheumatology responses, and multiple measures of disease remission and low disease activity; for the majority of outcomes, there was no overlap in 95% confidence intervals between groups. A numerical advantage for CT-P13 SC was also observed for safety outcomes (adverse events, infections, and discontinuations). Similar, but less marked, trends were observed for comparison with historical efficacy and safety data for adalimumab/etanercept. CT-P13 SC offers an improved or similar benefit-to-harm ratio compared with infliximab (intravenous) and adalimumab/etanercept, for the treatment of moderate-to-severe RA. [ABSTRACT FROM AUTHOR]

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field.Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items.Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high.Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate the factors associated with early discontinuation (within one year) of etanercept (ETA) in rheumatoid arthritis (RA) patients who began ETA as first biologic disease-modifying antirheumatic drug (bDMARD) and who were entered into the Gruppo Italiano di Studio sulla Early Arthritis (Italian Group for the Study of Early Arthritis; GISEA) registry. Patients and methods: This registry-based cohort study included 477 RA patients (95 males, 382 females; median age 53 years; range 18 to 83 years) who began ETA as first bDMARD. Patient demographics, disease features and drugs were re-evaluated after 12 months. Baseline predictors of ETA discontinuation were estimated by univariate and multivariate analyses using Cox regression model. Results: Seventy patients (14.7%) discontinued ETA during the first year (for inefficacy in 55.8%, adverse events in 28.6%, and other reasons in 6.5%). Concurrent conventional synthetic DMARDs (csDMARDs) were reported in 54.3% of patients, mainly methotrexate (MTX), while 52.4% of subjects took low doses of glucocorticoids. Patients stopping ETA more frequently showed one or more comorbidities, mainly cardiovascular diseases (28.6% vs. 15.7% in patients stopping and continuing ETA, respectively, p=0.009). The presence of comorbidities and a combination therapy with csDMARDs other than MTX were independent factors associated with early discontinuation of ETA at multivariate Cox analysis. Conclusion: Although ETA demonstrated a high persistence in biologic-naïve RA patients, about 15% of patients discontinued the treatment within 12 months. The presence of comorbidities and a combination therapy with csDMARDs other than MTX were the main factors for an early withdrawal of the drug. [ABSTRACT FROM AUTHOR]

Objectives: To describe and explore differences in formal regulations around sick leave and work disability (WD) for patients with rheumatoid arthritis (RA), as well as perceptions by rheumatologists and patients on the system's performance, across European countries.Methods: We conducted three cross-sectional surveys in 50 European countries: one on work (re-)integration and social security (SS) system arrangements in case of sick leave and long-term WD due to RA (one rheumatologist per country), and two among approximately 15 rheumatologists and 15 patients per country on perceptions regarding SS arrangements on work participation. Differences in regulations and perceptions were compared across categories defined by gross domestic product (GDP), type of social welfare regime, European Union (EU) membership and country RA WD rates.Results: Forty-four (88%) countries provided data on regulations, 33 (75%) on perceptions of rheumatologists (n=539) and 34 (77%) on perceptions of patients (n=719). While large variation was observed across all regulations across countries, no relationship was found between most of regulations or income compensation and GDP, type of SS system or rates of WD. Regarding perceptions, rheumatologists in high GDP and EU-member countries felt less confident in their role in the decision process towards WD (β=-0.5 (95% CI -0.9 to -0.2) and β=-0.5 (95% CI -1.0 to -0.1), respectively). The Scandinavian and Bismarckian system scored best on patients' and rheumatologists' perceptions of regulations and system performance.Conclusions: There is large heterogeneity in rules and regulations of SS systems across Europe in relation to WD of patients with RA, and it cannot be explained by existing welfare regimes, EU membership or country's wealth. [ABSTRACT FROM AUTHOR]

Objectives This post hoc analysis of the TOZURA study programme evaluated the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or with concomitant conventional synthetic DMARDs (csDMARDs) in patients with RA categorized by baseline glucocorticoid (GC) use. Methods TOZURA was a multinational, open-label, single-arm, common-framework study programme (11 protocols, 22 countries) in patients with moderate to severe RA in whom csDMARDs or biologic therapies had failed or who were MTX naïve. Patients received once-weekly TCZ-SC 162 mg for ⩾24 weeks as monotherapy or in combination with csDMARDs and/or oral GC use (⩽10 mg/day prednisone or equivalent), which was to be continued unchanged for 24 weeks. Treatment subgroups were defined by baseline GC use and analysed for efficacy and safety. Results Of 1804 patients who received TCZ-SC, 145 received monotherapy + GC, 208 received monotherapy without GC, 730 received combination therapy + GC and 721 received combination therapy without GC. The median GC dose in both GC subgroups was 5 mg/day. The proportion of patients who achieved clinical remission, defined as DAS in 28 joints using ESR <2.6, increased similarly from baseline to week 24 in all subgroups. Improvements in patient-reported outcomes were similar in all subgroups. Overall adverse event profiles were generally similar between subgroups, with some slight numerical differences between GC and non-GC subgroups. Conclusion The incremental efficacy benefits of TCZ-SC as monotherapy and in combination with csDMARDs were similar between patients with and without previous and continued oral GC treatment, with generally similar safety profiles. Trial Registration ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603, NCT02046616. [ABSTRACT FROM AUTHOR]

To assess, in a setting close to real life, the efficacy and safety of weekly subcutaneous tocilizumab (TCZ-SC) 162 mg, alone or with a conventional synthetic DMARD (csDMARD), in moderate-to-severe RA patients with inadequate response to DMARDs or anti-TNFα drugs. This national, multicenter, open-label, phase IIIb trial is part of an umbrella study (TOZURA). Patients were treated for 52 weeks followed by 8 weeks drug-free to evaluate immunogenicity. The primary end point was the Clinical Disease Activity Index (CDAI) change from baseline at weeks 2 and 24. Other efficacy parameters, including sleep quality, and the safety and immunogenicity were also assessed up to week 52. Of 288 patients enrolled in 43 Italian centers, 78.8% received TCZ-SC (86.8% females; mean age 54.7 ± 12.1 years; mean disease duration 7.8 ± 7.5 years; DMARD-IRs 94.7%). Of these, 78.0% completed the 52-week period and 52.0% received concomitant methotrexate. TCZ-SC yielded a significant reduction in median CDAI from baseline already at week 2, which progressed up to week 24 and remained stable thereafter (P < 0.0001 at each time point). A significant, rapid, and sustained improvement of the other efficacy variables was also observed. Patients were deemed as ready for home administration after a median of 2.0 (range 1-8) administrations, with a rate (since the last visit) of 80.6% and 95.5% at weeks 2 and 52, respectively. TCZ-SC displayed low immunogenicity and no unexpected toxicities. TCZ-SC, alone or with a csDMARD, yielded rapid and sustained efficacy in DMARD/anti-TNFα-IR RA patients, with acceptable toxicity. Home administration seems feasible. [ABSTRACT FROM AUTHOR]

The article discusses a study in which a panel of 15 Italian experts in rheumatoid arthritis treatment and management set up the Delphi process with tumor necrosis factor inhibitors (TNFi). The first phase outlined the definition of the four fields of investigation. The second phase concerned dose adjustments or interruption of TNFi in treated patients with a pre-specified outcome. The third phase focused on patients who have obtained a first TNFi but have failed to achieve a clinical response.

TNF inhibitors are biologic DMARDs approved for the treatment of active RA in mid-1990s. They still represent a valuable therapeutic option to control the activity, disability and radiographic progression of the disease. In the context of TNF inhibitors, there are currently several molecules and different administration routes that provide optimal treatment personalization, allowing us to respond to a patient's needs in the best possible way. The increasing use of TNF inhibitors has not only improved the management of RA, but it has also helped in our understanding of the pathogenetic mechanisms of the disease. This review focuses on the basis of this targeted therapy and on the knowledge gained from their use about therapeutic effects and adverse events. Effectiveness analysed from drug registries and safety issues are presented together with recent data on infections (in particular, Mycobacterium tuberculosis and hepatitis B), cancer (lymphoma, skin cancers) and cardiovascular risk. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCTs) represent the gold-standard of medical evidence to assess the efficacy and safety of therapeutic interventions. However, the need to minimize bias and ensure the correct design to explore the study aims often affects the generalizability of results. As a consequence, the evidence derived from the most rigorous research strategy available is not always representative of the real-world settings for which this evidence is ultimately intended. Observational studies, in contrast, although affected by a number of potential confounders, can more effectively capture treatment characteristics and safety issues that had not been identified by previous RCTs, owing to the short duration of follow-up or highly selective inclusion criteria. The aim of this review is to provide a comparative summary of the main advantages and pitfalls of RCTs and real-world data, emphasizing the need for a constant integration of all available levels of evidence to provide the best care for patients. [ABSTRACT FROM AUTHOR]

The article focuses on a study which aims at identifying factors that influence treatment adjustments and adoption of a treat-to-target (T2T) strategy in patients with rheumatoid arthritis (RA). It mentions introduction of biologic disease-modifying antirheumatic drugs (bDMARD) treatment in RA. It states that an aggressive therapy approach in early RA patients to prevent damage disease progression. It mentions use of methotrexate with glucocorticoids for treating RA.

Objectives. The aim of this pooled analysis of the TOZURA study programme was to evaluate the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) in patients with moderate to severe RA who had an inadequate response to csDMARD or anti-TNF agent therapy or who were MTX naive. Methods. TOZURA is a multinational, open-label, single-arm, common-framework, phase 4 study programme (11 protocols, 22 countries). Patients received TCZ-SC 162 mg each week for ≥24 weeks, administered at the investigator's discretion, as monotherapy or in combination with a csDMARD. Efficacy, safety and immuno-genicity were evaluated; propensity score-based matching was used for between-group comparisons. Results. Of 1804 patients, 353 (19.6%) received monotherapy and 1451 (80.4%) received combination therapy. The 28-joint DAS using ESR (DAS28-ESR) in both groups decreased significantly from baseline to week 24 (mean change: monotherapy -3.40, combination therapy -3.46), with no significant difference between groups (P = 0.46). The proportion of patients who achieved DAS28-ESR or Clinical Disease Activity Index remission or ACR 20/50/70/90 responses was similar between groups. Overall, 13.9% of patients withdrew--6.2% for safety reasons and 1.6% for insufficient therapeutic response; 5.8% of patients experienced one or more serious adverse events [14.6/100 patient-years (PY)]; six deaths occurred (0.64/100 PY). Conclusion. In a common framework of 11 studies in 22 countries, this phase 4 study programme confirmed TCZ-SC's known efficacy and safety profile with comparable effects as monotherapy and in combination with csDMARDs. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To evaluate the 2‐year retention rate of golimumab compared with etanercept and adalimumab as second‐line biologic agent in rheumatoid arthritis (RA) patients who failed a previous tumor necrosis factor inhibitor (TNFi). Methods: Data on RA patients treated with a second‐line subcutaneous TNFi were extracted from a multicentric Italian cohort (the LORHEN registry). The analysis was limited to etanercept, adalimumab and golimumab in the period when all were available in Italy (since October 2010). The 2‐year retention rate was calculated by Kaplan–Meier method and the comparative risk for discontinuation among individual TNFi was compared by a stratified log‐rank test. Results: One hundred and ninety‐five RA patients treated with etanercept (n = 76), adalimumab (n = 68) or golimumab (n = 51) were included in the analysis. The 2‐year retention rate (40% with a median time‐on‐drug of 12.9 months in the whole population) was significantly lower for adalimumab (31.2%, P = 0.018) and numerically lower for etanercept (39.8%, P = 0.068) compared with golimumab (53.4%) because of a higher discontinuation rate due to adverse events (P = 0.042 and P = 0.038 versus golimumab, respectively). Drug survival was greater in concomitant synthetic disease modifying anti‐rheumatic drug (sDMARD) users (44.2%) compared with TNFi monotherapy (22.5%, P = 0.036). No difference was found in survival analysis according to first‐line TNFi reason for discontinuation and pattern of TNFi switch (antibody‐receptor, antibody‐antibody or receptor‐antibody). Conclusions: Our real‐life data confirmed switching to a second TNFi as a good option for treating first‐line TNFi failures in RA, especially in combination with sDMARDs. Second‐line golimumab showed an overall better 2‐year drug survival compared with adalimumab and etanercept. [ABSTRACT FROM AUTHOR]

The purpose of the study was to estimate the clinical profile of naïve biological patients with rheumatoid arthritis (RA) starting adalimumab through 3-year calendar periods and their clinical outcomes such as drug survival and global clinical disease control (GCDC). RA patients starting adalimumab as first biological drug between 2003 and 2012 were subdivided in 3-year calendar periods. Survival on therapy was estimated using the Kaplan-Meier analysis. One and 2-year clinical response was assessed by calculating percentage of patients attaining GCDC (28-joint Disease Activity Score (DAS28) ≤ 2.6 + Health Assessment Questionnaire (HAQ) ≤ 0.5), low disease activity (DAS28 ≤ 3.2), remission (DAS28 ≤ 2.6) and good European League Against Rheumatism (EULAR) response. Multivariate regression models were used to assess baseline predictors of drug discontinuation or achievement of clinical remission. We recruited 1695 RA patients. Overall drug persistence at 3 years was 40.6 %, while the global rate of nonswitching patients was 54.7 %. Compared to 2003-2005, initiators in more recent years had a significantly lower 3-year crude drug retention rate (log rank, p < 0.0001) and a significantly higher rate of switching to alternative biologics (log rank, p < 0.0001). No difference in adverse events or effectiveness rate among the calendar periods was found. A substantial proportion of patients (up to 27 %) achieved GCDC at 2 years, regardless of the calendar period. In real-life setting, RA patients starting adalimumab in more recent years had a higher rate of drug discontinuation not related to ineffectiveness or side effects but to switching, probably due to a wider availability of biologics. A meaningful proportion of patients attained GCDC without any difference across calendar periods. [ABSTRACT FROM AUTHOR]

Objectives: To explore the influence of comorbidities on clinical outcomes and disease activity in rheumatoid arthritis (RA). Methods: In patients included in the cross-sectional observational multicenter international study COMORA, demographics, disease characteristics and comorbidities (hypertension, diabetes, hyperlipidemia, renal failure, ischemic heart disease, stroke, cancer, gastro-intestinal ulcers, hepatitis, depression, chronic pulmonary disease, obesity) were collected. Multivariable linear regression models explored the relationship between each comorbidity and disease activity measures: 28-swollen joint count (SJC), 28-tender joint count (TJC), erythrocyte sedimentation rate (ESR), patient’s and physician’s global assessment (PtGA, PhGA), patient reported fatigue and 28-Disease Activity Score (DAS28). Results are expressed as mean difference (MD) adjusted for the main confounders (age, gender, disease characteristics and treatment). Results: A total of 3,920 patients were included: age (mean ±SD) 56.27 ±13.03 yrs, female 81.65%, disease duration median 7.08 yrs (IQR 2.97–13.27), DAS28 (mean ±SD) 3.74 ± 1.55. Patients with diabetes had more swollen and tender joints and worse PtGA and PhGA (MD +1.06, +0.93, +0.53 and +0.54, respectively). Patients with hyperlipidemia had a lower number of swollen and tender joints, lower ESR and better PtGA and PhGA (MD -0.77, -0.56, -3.56, -0.31 and -0.35, respectively). Patients with history of ischemic heart disease and obese patients had more tender joints (MD +1.27 and +1.07) and higher ESR levels (MD +5.64 and +5.20). DAS28 is influenced exclusively by cardiovascular comorbidities, in particular diabetes, hyperlipidemia, ischemic heart disease and obesity. Conclusions: Cardiovascular comorbidities relate more than others with disease activity in RA. Diabetes and hyperlipidemia in particular seem associated with higher and lower disease activity respectively influencing almost all considered outcomes, suggesting a special importance of this pattern of comorbidities in disease activity assessment and clinical management. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease of unknown aetiology, leading to progressive damage of bone and cartilage with functional impairment and disability. Whilst the synovial membrane represents the epicentre of the immune-inflammatory process, there is growing evidence indicating the potential involvement of additional anatomical compartments, such as the lung, bone marrow, and secondary lymphoid tissues. Draining lymph nodes represent the elective site for tissue immune-surveillance, for the generation of adaptive immune responses and a candidate compartment for the maintenance of peripheral tolerance. Despite the precise role of the juxta- and extra-articular lymph node stations in the pathogenesis of RA remaining poorly defined, several lines of research exploiting new technological approaches are now focusing on their assessment as a potential new source of pathobiologic information, biomarkers, and complementary therapeutic targets. In this review we present an updated overview of the main concepts driving lymph node research in RA, highlighting the most relevant findings, current hypothesis, and translational perspectives. [ABSTRACT FROM AUTHOR]

Objective. The B cell chemoattractant chemokine ligand 13 (CXCL13) is emerging as a new biochemical marker in RA. This study was undertaken to dissect the relationship between CXCL13 expression levels in the synovium and clinico-pathological variables relevant to RA pathogenesis and outcome.Methods. Synovial tissues from 71 RA patients were evaluated by immunohistochemistry. Thirty paired samples were used for comparative gene expression analysis by quantitative real-time PCR. CXCL13 levels were analysed in relation to cellular, molecular and clinical features of inflammation, lymphocyte activation and joint damage.Results. In patients with early disease (<12 months duration), CXCL13 expression correlated significantly with synovial markers of local disease activity and systemic inflammation. Such correlation was less evident in established RA. Notably, the association with lymphocyte infiltration and with expression of B/T cell–related activation and proliferation genes, such as activation-induced cytidine deaminase, IFN-γ and IL-2, remained highly significant independent of disease duration and local disease activity. Patients featuring the highest levels of CXCL13 were more frequently ACPA positive and IgG ACPA titres were increased in the high CXCL13 expression group. Furthermore, the frequency of erosive disease on radiographs was significantly higher in the upper tertile of CXCL13 expression (P = 0.01 with adjustment for disease duration and ACPA). Accordingly, synovial CXCL13 and the local receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio significantly co-varied (ρ = 0.52, P < 0.01), independent of the level of local inflammation.Conclusion. Synovial CXCL13 appears to be a marker of a more severe pattern of RA disease, characterized by increased lymphocyte activation and bone remodelling beyond the level of conventional markers of inflammation. [ABSTRACT FROM PUBLISHER]