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Janus kinase (JAK) Inhibitors are the latest drug class of disease-modifying medication to emerge for the treatment of rheumatoid arthritis (RA). They are a small molecule-targeted treatment and are the first oral option to compare favourably to existing biologic disease-modifying anti-rheumatic drugs (DMARDs). Tofacitinib, baricitinib and upadacitinib are the first 3 JAK inhibitors to become commercially available in the field and are the core focus of this review. To date, they have demonstrated comparable efficacy to tumour necrosis factor (TNF) inhibitors in terms of American College of Rheumatology (ACR) response rates and disease activity (DAS28) scores with similar cost to the benchmark adalimumab. This narrative review article aims to synthesise and distil the key available trial data on JAK inhibitor efficacy and safety, along with their place in the ACR and European League Against Rheumatism (EULAR) guidelines for RA. The novel mechanism of action of the JAK/STAT pathway is highlighted along with the potential effects of modulating each pathway. The rapid onset of action, role in attenuation of central pain processing and effect on structural damage and radiographic progression are also all examined in detail. We also explore the latest meta-analyses and comparative performance of each of the 3 available JAKs in an effort to determine which is most efficacious and which has the most favourable safety profile. Post marketing concerns regarding thromboembolism risk and herpes zoster infection are also discussed. Additionally, we review the cost-benefit analyses of the available JAK inhibitors and address some of the pharmacoeconomic considerations for real-world practice in the UK and US by detailing the raw acquisition cost and the value they provide in comparison to the benchmark biologic adalimumab and the anchor DMARD methotrexate.

Background In psoriatic arthritis (PsA), growing evidence indicates sex-specific differences regarding clinical manifestation and treatment outcomes. Research has highlighted that females may be less likely to achieve treatment targets and are more prone to discontinuing therapy, though data on sex-specific adverse events is limited. This analysis investigates sex differences in treatment outcomes, persistence, discontinuation reasons, and adverse events during first-line b/tsDMARD therapy. Methods In this analysis bionaïve patients with PsA from the RABBIT-SpA register were included at the start of their first b/tsDMARD. Therapy persistence was estimated using the Cox-regression adjusted for age. Descriptive analyses were used to examine and compare sex–specific differences on reasons for therapy discontinuation. Results A total of 457 female patients and 343 male patients were included. Females exhibited more severe joint involvement and poorer patient-reported parameters, such as higher disease activity, more pain, and greater functional limitations. In contrast, males showed more pronounced skin involvement and a higher prevalence of nail psoriasis. Females had lower treatment persistence rates, both in the overall analysis of all first-line b/tsDMARDs and in subgroup analyses restricted to TNFi and IL17i therapies. At 12 months, 52% of females and 68% of males remained on their initial b/tsDMARD therapy. Notable sex differences were also observed in the reasons for therapy discontinuation: males more frequently discontinued due to lack of efficacy or remission, while females more often stopped treatment due to adverse events. Our safety analysis indicated that although female patients experienced a greater number of overall adverse events, males reported serious adverse events at twice the rate. Conclusions Our findings underscore the need for sex-specific treatment strategies and more comprehensive research into biological and sociocultural factors influencing therapy persistence and reasons for discontinuation in real-world settings. Tailored treatment strategies are needed with regard to biologic therapy to overcome worse therapeutic outcomes in female patients with PsA. Clinical trial number Not applicable.

Background This study evaluates patient-reported outcomes (PROs) in a double-blind, phase III study of baricitinib as monotherapy or combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with no or minimal prior conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and naïve to biological DMARDs. Methods Patients were randomized 4:3:4 to MTX administered once weekly ( N  = 210), baricitinib monotherapy (4 mg once daily (QD), N  = 159), or combination of baricitinib (4 mg QD) and MTX (baricitinib + MTX, N  = 215). PROs included the Patient’s Global Assessment of Disease Activity (PtGA), patient's assessment of pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), duration of morning joint stiffness (MJS), worst joint pain, worst tiredness, Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA), Short Form 36 version 2, Acute (SF-36); and EuroQol 5-Dimensions (EQ-5D) Health State Profile. Comparisons were assessed with analysis of covariance (ANCOVA) and logistic regression models. Results Compared to MTX, patients in both baricitinib groups reported greater improvement ( p  ≤ 0.01) in HAQ-DI, PtGA, pain, fatigue, worst join pain, SF-36 physical component score, and EQ-5D at weeks 24 and 52. For the SF-36 mental component score, patients in both baricitinib groups reported statistically significant improvements ( p  ≤ 0.01) at week 52 compared to MTX-treated patients. Statistically significant improvements ( p  ≤ 0.05) were observed with the WPAI-RA for the baricitinib groups vs. MTX at week 24 and for the WPAI-RA daily activity and work productivity measures for baricitinib + MTX at week 52. Conclusions In this study, baricitinib alone or in combination with MTX, when used as initial therapy, resulted in significant improvement compared to MTX in the majority of the pre-specified PRO measures. Trial Registration ClinicalTrials.gov, NCT01711359 . Registered on 18 October 2012.

Introduction: We aimed to investigate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the course and treatment of patients with inflammatory rheumatic musculoskeletal disease (iRMD) using biologic or targeted synthetic disease modifying and rheumatic drugs (b/tsDMARDs). Methodology: The study was carried out in two stages: in the first stage we investigated the delay of b/tsDMARD treatment in the first 3 months of the pandemic; in the second stage, we investigated all patients who decided to continue treatment after interruption in the 12-month period. Results: A total of 521 patients were included in the study. The iRMD diagnosis was listed as spondyloarthritis (SpA) (54.3%), rheumatoid arthritis (RA) (25.7%), psoriatic arthritis (PsA) (8.4%), vasculitis (6.1%), and others (5.4%). Concurrent use of hydroxychloroquine (hazard ratio [HR] = 1.49), iv bDMARD use (HR = 1.34), and a history of discontinuation of drug in the first 3 months of the pandemic (HR = 1.19) were determined as factors that reduced 12-month drug retention rates. The use of glucocorticoid (HR = 3.81) and having a diagnosis of interstitial lung disease/chronic obstructive lung disease (HR = 4.96) were found to increase the risk of being infected by SARS coronavirus 2 (SARS-CoV-2). Conclusions: It was shown that approximately 1/5 of iRMD patients using b/tsDMARDs delayed their treatment due to the fear of COVID-19 in the first three months of the pandemic process. However, with good communication with the patients, b/tsDMARD treatment was restarted and the 12-month drug retention status was quite high.

Introduction Noninfectious inflammation of the posterior eye segment represents an important cause of visual impairment. It often affects relatively young people and causes a significant personal and social impact. Although steroids and nonbiologic- Disease-Modifying Antirheumatic Drugs (nbDMARDs) are effective both in acute and long- lasting diseases, however they are increasingly being replaced by biologic (DMARDs). bDMARD. This article therefore aims to identify recent advances in the therapy of noninfectious posterior segment uveitis. Methods A Medline-search was conducted using the terms: nbDMARD, bDMARD, posterior uveitis, intermediate uveitis, treatment, corticosteroid. In addition, clinical studies were included as registered at ClinicalTrials.gov. Results Currently two major lines of treatments can be identified: (1) the intraocular application of anti-inflammatory agents and (2) the introduction of new agents, e.g., (bDMARDs) and small-molecule-inhibitors. Whereas intravitreal treatments have the advantage to avoid systemic side effects, new systemic agents are progressively earning credit on the basis of their therapeutic effects. Conclusion Even when current treatment strategies are still hampered by the limited number of randomized controlled trials, promising progress and continuous efforts are seen.

The treatment of inflammatory arthritides has been changed dramatically in the past two decades with the introduction of the biological (b) disease-modifying anti-rheumatic drugs (DMARDs) as well as the targeting synthetic (ts) DMARDs that can be used as monotherapy or in combination with conventional synthetic (cs) DMARDs. The concept of treat to target (T2T) and tight control monitoring of disease activity represents a therapeutic paradigm of modern rheumatology. In rheumatoid arthritis (RA), this treatment approach has proven to be effective in many clinical trials and is now a well-established approach. The most common treatment strategies rely on the combination of csDMARDs (mainly methotrexate, sulfasalazine and hydroxychloroquine). This comes from different studies which compare the outcomes of combination therapies versus csDMARD monotherapy or versus methotrexate plus biologics in early RA patients. Here, we review the literature of the most important T2T studies for RA patients. The results showed that a tight control strategy appears to be more important than a specific drug to control RA. T2T approach aiming for remission or low disease activity can be achieved in early RA patients using less expensive drugs in comparison to newer drugs and this may need to be recognised in the future recommendations for the management of RA.Key Points• Tight-control and treat-to-target (T2T) strategies are the cornerstone in achieving remission or low disease activity in rheumatoid arthritis (RA)• A plethora of clinical trials has confirmed the efficacy of csDMARDs when the tight-control and T2T strategies are applied• T2T and tight-control strategies are a less expensive option in comparison to newer drugs and may be recognised in the future recommendations for the management of RA.• Treatment decisions and strategies are more important than just the drugs.

Background The current EULAR definition of difficult-to-treat rheumatoid arthritis (D2T-RA) identifies patients with active disease refractory to multiple treatments at a single time point, without considering the persistence of this condition over time. The study aimed to assess difficult-to-treat rheumatoid arthritis (D2T-RA) over 12 months, considering persistence over time rather than a single time point, in a real-life cohort. Methods In a single-center real-life cohort, demographic and clinic data were cross-sectionally collected for each patient at baseline and retrospectively over the previous 12 months bimonthly. For each timepoint, the prevalence of D2T-RA patients was calculated, and patients meeting the EULAR definition for at least 6 months were defined as persistent D2T-RA (pD2T-RA). Finally, the clinical characteristics associated with the time-based definition of pD2T-RA were analyzed. Results Among 610 adult RA patients, 104 were refractory to ≥ 2 treatments. Initially, 41.3% met D2T-RA criteria, but only 27.9% fulfilled persistent D2T-RA (pD2T-RA) criteria over 6 months. The pD2T-RA group was associated with male gender, higher HAQ and Charlson Comorbidity Index scores, more failed treatments, and use of non-NSAID analgesics. Logistic regression linked pD2T-RA to higher SDAI and CRP values, and the use of glucocorticoids or analgesics. Chronic use of glucocorticoids was strongly associated with pD2T-RA. Conclusions The application of a temporal criterion allowed for the selection of a subgroup of pD2T-RA patients who differ from those who meet the definition of D2T-RA only episodically. Chronic use of glucocorticoids was the factor most strongly associated with pD2T-RA status. Key messages What is already known about this subject? Since the institution of the D2T-RA definition, many efforts have been made to characterize this subpopulation's prevalence as well as clinical and demographical features. However, no studies have so far faced the temporal maintenance of the D2T-RA status. What does this study add? A definition of persistent or episodic D2T-RA is proposed according to the temporal trajectory of D2T-RA status, resulting in approximately 27% of D2T-RA patients persistently fulfilling the pD2T-RA definition. At each single time point, one-third of D2T-RA patients are represented by episodic D2T-RA patients. How might this impact on clinical practice? Persistent D2T-RA definition may serve to further homogenize the D2T-RA population.

The goal of this narrative review was to provide current data on psoriatic arthritis (PsA) therapeutic strategies, supporting treatment decisions with a domain-based approach. This narrative review of treatment strategies for PsA focused on several disease domains (ie, peripheral arthritis, enthesitis, axial disease, dactylitis, skin and nail disease), as well as the so-called “related conditions” of uveitis, Crohn's disease, and ulcerative colitis. We searched PubMed, EMBASE, international guidelines, and recent congress abstracts. Currently, multiple approved treatment options offer a wide range of options, such as tumor necrosis factor (TNF) inhibitors; inhibitors of interleukin-17 (IL-17), IL-12/23 (IL-12/23), IL-23 (IL-23), and Janus kinase; the phosphodiesterase 4 inhibitor apremilast; and the T-cell modulator abatacept. However, no treatment option shows clear superiority concerning efficacy on peripheral arthritis and dactylitis over the others, whereas limited evidence suggests that the IL-17 inhibitor ixekizumab and the IL-12/23 inhibitor ustekinumab may be superior to TNF inhibitors in treating enthesitis. Recent data on enthesitis have also shown promising results for methotrexate. Treatment of axial PsA is mostly derived from axial spondyloarthritis, and more data are needed focusing on this specific subgroup of PsA patients. Thus far, the most important finding from the only randomized controlled trial in this specific population is that the IL-17 inhibitor secukinumab was superior to placebo in terms of clinical and radiologic end-points in axial PsA. Regarding psoriatic skin involvement, head-to-head trials in PsA as well as skin psoriasis showed the superiority of IL-17, IL-23, and IL-12/23 inhibitors over TNF inhibitors. When treating PsA with concurrent uveitis, according to the existing data, monoclonal TNF inhibitor antibodies should be preferred. In PsA and concomitant inflammatory bowel disease, treatment decisions must include the consideration of which specific type of inflammatory bowel disease (Crohn's disease or ulcerative colitis) is present, as some of the agents either lack data or are ineffective in treating these 2 conditions. In both types, IL-17 inhibitors should be avoided. When determining treatment strategy, comorbidities should be carefully assessed, and the corresponding risk profile of the respective treatment modalities should be taken into consideration. There are many approved therapeutic options for treating patients with PsA, and additional emerging treatment options are in the pipeline. Individualized treatment decisions for each patient, depending on the leading disease phenotype, underlying comorbidities, and patient preferences, should be made based on shared decision-making.

Data regarding malignancy risk amongst rheumatoid arthritis (RA) patients using biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) was conflicting, and real-world Taiwanese data was lacking. To compare the malignancy risk and to investigate factors associated with malignancies amongst RA patients initiating b/tsDMARDs. Nationwide, population-based, retrospective cohort study. We conducted a retrospective cohort study using the Taiwan National Health Insurance Research Database from 2001 to 2020. Adult patients with newly diagnosed, biologic-naïve RA were included if they initiated b/tsDMARDs, and those with prior malignancies were excluded. The primary outcome was the first diagnosis of malignancies after b/tsDMARD initiation. Time-dependent Cox proportional hazards models were performed to evaluate malignancy risk across different b/tsDMARDs and to identify independent risk factors. A total of 8732 adult RA patients were included. Over both 5-year and extended 18-year follow-up periods, there was no statistically significant difference in malignancy risk amongst the four treatment groups (tumour necrosis factor inhibitors (TNFis), tocilizumab, abatacept and tsDMARDs). Independent associated factors included male gender, older age at b/tsDMARD initiation, chronic lung diseases including chronic obstructive pulmonary disease and higher-dose corticosteroid prescription. Use of conventional DMARDs and more frequent ambulatory follow-up were associated with a lower risk. In this Taiwanese nationwide RA cohort, b/tsDMARD class demonstrated no difference in malignancy risk within 5 years after their initiation. Clinicians should instead focus on individual associated factors, particularly male gender, older age at b/tsDMARD initiation, chronic lung diseases and higher-dose corticosteroid exposure, while optimising the protective role of conventional DMARDs and regular follow-up for better disease control.

Background/Objectives: The combination of denosumab treatment with biological disease-modifying antirheumatic drugs (bDMARDs) or targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) in patients with inflammatory rheumatic diseases (IRD) may raise safety concerns for clinicians, particularly regarding infections. In this study, we investigated whether the risk of infection increases in patients who receive bDMARDs or tsDMARDs for IRD and are simultaneously treated with denosumab for osteoporosis (OP). Methods: As a control group, we evaluated patients receiving bDMARDs or tsDMARDs concomitantly with zoledronic acid (ZA), which is not clearly associated with infections. A total of 88 patients—including 30 patients receiving bDMARDs or tsDMARDs with ZA and 58 patients receiving bDMARDs or tsDMARDs with denosumab—met the criteria and were included in this study. The groups were compared in terms of the ratio/risk of serious infections requiring hospitalisation and infections requiring outpatient treatment after applying the inverse probability of treatment weighting (IPTW) to the control for confounding factors. The Cox proportional hazards regression model was used to compare the risks of infection, taking confounding factors into account. Results: The mean age of patients in the ZA group was 59.07 years (±SD: 13.65), while that of patients in the denosumab group was 69.93 years (±SD: 11.72). Comorbidities occurred more frequently in the denosumab group (n = 44, 75.86%) than in the ZA group (n = 14, 46.66%). The median duration of medication use in the denosumab group was 24 months (minimum: 6 months; maximum: 72 months). The median duration of medication use in the ZA group was 24 months (minimum: 12 months; maximum: 60 months). When comparing the groups regarding the risk of infection, denosumab was not associated with an increased risk of either a serious infection requiring hospitalisation (Hazard Ratio (HR): 0.37; 95% Confidence Interval (CI): 0.14–0.94) or an infection requiring outpatient treatment (HR: 0.29; 95% CI: 0.12–0.71). Conclusions: In conclusion, the combination of denosumab treatment with bDMARD or tsDMARD treatments is safe for short-term use.