OBJECTIVE: We investigated the effectiveness and safety of very low-dose (<5 mg daily) glucocorticoids (GCs) in patients with RA treated with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs).
METHODS: In this prospective cohort study, we included all RA patients who started their first b/tsDMARDs at our institution between 2015 and 2020 and were monitored every 6 months for 3 years. Relationships between exposure to very low-dose GCs and disease activity were examined through multivariable logistic regression and repeated-measures analysis of variance. The impact of very low-dose GCs on safety was also evaluated.
RESULTS: We enrolled 229 RA patients, of whom 68% were prescribed very low-dose GCs and 32% received no GCs. After three years on b/tsDMARDs, 32% had never abandoned, 20% had gone on and off, and 23% had permanently discontinued very low-dose GCs, while 25% had never taken GCs. Shorter disease duration at b/tsDMARD initiation was the single modifiable predictor of very low-dose GCs cessation (OR 1.1, 95% CI 1.03-1.14 for any 1-year decrease; p= 0.001). A significant association existed between ongoing utilization of very low-dose GCs and persistent moderate disease activity. Use of very low-dose GCs was associated with hypertension (20% vs 11%) and myocardial infarction (2.3% vs 0%).
CONCLUSIONS: A substantial proportion of RA patients treated with b/tsDMARDs continue to receive very low-dose GCs without significantly improving disease control. However, this appears to increase cardiovascular morbidity.

BACKGROUND: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population.
METHODS: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed.
RESULTS: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation.
CONCLUSIONS: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient\'s baseline anti-HBs titre and type of therapy.

OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

Sarcopenia is a syndrome defined by generalized and progressive loss of skeletal muscle mass, strength, and function. Besides affecting elderly population, it is actually common among inflammatory rheumatic diseases (IRD) patients. We performed a systematic literature review with a meta-analysis to investigate the influence of biologic and target synthetic disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) on sarcopenia in IRD. A systematic search has been performed on Pubmed, Scopus, and Web of science. Studies characteristics were collected. Assessment tools were body composition (total lean mass (TLM) and percentage, appendicular skeletal mass (ASM), fat-free mass and index (FFM and FFMI), skeletal mass index (SMI) and segmental lean mass (SLM)), and muscle strength and physical performance tests. Treatment effect defined the difference in change from baseline to the end of follow-up treatment was divided by the pooled SD of the difference. Twenty-two studies on 778 patients receiving bDMARDs/tsDMARDs and 157 controls were reviewed. They investigated rheumatoid arthritis (RA) (N = 14), spondyloarthritis (SpA) (N = 6), psoriatic arthritis (N = 1), and both RA and SpA (N = 1). tsDMARDs were used in one study with no effect on sarcopenia. Ten studies demonstrated that bDMARDs increased significantly muscle measures in 347 patients (44.6%) with a significant increase in TLM (6/15 studies; 57.4%), FFMI (4/6 studies; 59.9%), ASM (2/5 studies; 17.6%), SMI (2/5 studies; 18.1%), and SLM (2/2 studies; 3.6%). bDMARDs showed also a positive effect on handgrip strength in 1/3 of studies (45.2%) and on physical performance in 1/2 of studies (61%). In 1/5 of comparative studies, IRD patients on bDMARDs showed significantly higher increase of TLM in comparison to controls naïve bDMARDs. Regarding diagnosis, positive effect of bDMARDs was seen in 67.4% in SpA versus 49.3% in RA, with a significant increase of TLM, ASM and FFMI in 59.4%, 100%, and 65.2% in SpA versus 54.9%, 24.1%, and 54.8% in RA, respectively. Meta-analysis assessed the effect of bDMARD on TLM in 10 studies. There was no statistically significant difference [SMD - 0.10 (95% Confidence Interval - 0.26 - 0.06; tau2 = 0). Heterogeneity across studies was null, and the 95% confidence interval (index of precision) was equal to the 95% predictive interval. The first systematic literature review showed that bDMARDs have a significant improve effect in nearly half of RA and SpA patients on muscle mass and muscle strength, assessed separately. However, the meta-analysis concluded that bDMARDs have no significant effect on TLM.

Background: Biologic (bDMARD) and targeted synthetic (tsDMARD) disease-modifying anti-rheumatic drugs have broadened the treatment options and are increasingly used for patients with psoriatic arthritis (PsA). These agents block different pro-inflammatory cytokines or specific intracellular signaling pathways that promote inflammation and can place patients at risk of serious infections. We aimed to review the incidence of opportunistic infections (OIs) in patients with PsA who were treated with these agents. Methods: We searched PubMed and EMBASE through 14 April 2022 for randomized clinical trials evaluating bDMARD or tsDMARD in the treatment of PsA. Trials were eligible if they compared the effect of a bDMARD or tsDMARD with placebo and provided safety data. We used the Revised Cochrane risk-of-bias tool to assess the risk of bias among trials, and stratified the studies by mechanism of action (MOA) of the agents studied. Results: We included 47 studies in this analysis. A total of 17,197 patients received at least one dose of an agent of interest. The cumulative incidence of OIs by MOA was as follows: 1) JAK inhibitors: 2.72% (95% CI: 1.05%-5.04%), 2) anti-IL-17: 1.18% (95% CI: 0.60%-1.9%), 3) anti-IL-23: 0.24% (95% CI: 0.04%-0.54%), and 4) anti-TNFs: 0.01% (95% CI: 0.00%-0.21%). Based on their MOA, these agents are known to increase the risk of certain serious infections. The cumulative incidence of herpes zoster infection following treatment with JAK inhibitors (JAKi) was 2.53% (95% CI: 1.03%-4.57%) and the cumulative incidence of opportunistic Candida spp. infections following treatment with anti-IL-17, was 0.97% (95% CI: 0.51%-1.56%). Conclusion: The overall incidence of OIs among patients with PsA who were treated with biologic and targeted synthetic agents is low. However, careful monitoring is warranted for specific OIs such as herpes zoster infection following JAKi treatment, mucocutaneous candidiasis following anti-IL-17 treatment, and Mycobacterium tuberculosis infection following anti-TNF treatment.

BACKGROUND: RA-BE-REAL has the overall aim of defining a profile of patients with rheumatoid arthritis (RA) starting baricitinib or any other targeted synthetic (ts) or any biologic (b) disease-modifying antirheumatic drug (DMARD) for the first time, and the primary objective of estimating time until discontinuation from any cause (excluding sustained response) of the initial treatment.
METHODS: RA-BE-REAL is an ongoing, prospective, observational, 36-month study in patients with RA initiating treatment with baricitinib (cohort A) or any other tsDMARD or any bDMARD (cohort B) for the first time. The primary objective is to assess the time until treatment discontinuation from any cause (excluding sustained response) at 24 months, (i.e., the rate of discontinuation of initial baricitinib or ts/bDMARD). Patient profiles of each cohort are described and compared. Post-baseline data are descriptively analyzed. This manuscript presents baseline and interim (6-month) outcomes for European patients with RA participating in the global RA-BE-REAL study.
RESULTS: Data from 1074 patients (cohort A: 509; cohort B: 565) were analyzed. For cohorts A and B, respectively, the 6-month cumulative incidence (95% confidence interval) of treatment discontinuation was 16.5 (12.9-21.1) and 23.3 (19.1-28.2), and the proportions of patients achieving remission were 25.6% and 18.5%. At baseline, mean patient age was 59.1 and 57.0 years (p = 0.010) and mean disease duration was 10.0 and 8.9 years (p = 0.047), respectively. The proportions of patients exposed to ts/bDMARDs at any time before study entry were 51.9% and 39.1%, and the proportions of patients initiated on monotherapy were 50.9% and 31.2%, respectively.
CONCLUSIONS: In real-world settings, patients with RA initiating treatment with baricitinib were older and had longer disease duration than those initiating treatment with any other tsDMARD or any bDMARD. Initial descriptive data regarding treatment discontinuation (including reasons for discontinuation), effectiveness, and treatment patterns will be enriched as the study progresses.

BACKGROUND: In patients with rheumatoid arthritis (RA), attaining remission or low disease activity (LDA), as recommended by the treat-to-target approach, has shown to yield improvement in symptoms and quality of life. However, limited evidence from real-world settings is available to support the premise that better disease control is associated with lower healthcare costs. This study fills in evidence gaps regarding the cost of care by RA disease activity (DA) states and by therapy.
METHODS: This retrospective cohort study linked medical and prescription claims from Optum Clinformatics Data Mart to electronic health record data from Illumination Health over 1/1/2010-3/31/2020. Mean annual costs for payers and patients were examined, stratifying on DA state and baseline use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologics, and targeted synthetic (ts)DMARDs. Subgroup analysis examining within-person change in costs pre- and post-initiation of new therapy was also performed. Descriptive statistics, means, and boot-strapped confidence intervals were analyzed by DA state and by RA therapy. Furthermore, multivariate negative binomial regression analysis adjusting for key baseline characteristics was conducted.
RESULTS: Of 2339 eligible patients, 19% were in remission, 40% in LDA, 29% in moderate DA (MDA), and 12% in high DA (HDA) at baseline. Mean annual costs during follow-up were substantially less for patients in remission ($40,072) versus those in MDA ($56,536) and HDA ($59,217). For patients in remission, csDMARD use was associated with the lowest mean annual cost ($25,575), tsDMARD was highest ($75,512), and tumor necrosis factor inhibitor (TNFi) ($69,846) and non-TNFi ($57,507) were intermediate. Among new TNFi (n = 137) and non-TNFi initiators (n = 107), 31% and 26% attained LDA/remission, respectively, and the time to achieve remission/LDA was numerically shorter in TNFi vs. non-TNFi initiators. For those on biologics, mean annual within-person medical and inpatient costs were lower after achieving LDA/remission, although pharmacy costs were higher.
CONCLUSIONS: Cost of care increased with increasing DA state, with patients in remission having the lowest costs. Optimizing DA has the potential for substantial savings in healthcare costs, although may be partially offset by the high cost of targeted RA therapies.

UNASSIGNED: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses.
UNASSIGNED: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated.
UNASSIGNED: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0-1.5h and mean t1/2 was 7.4-13.0h for all doses. In the multiple-dose period, median tmax was 1.5-2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of >150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death.
UNASSIGNED: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses.
UNASSIGNED: NCT04143477.

The management of psoriatic arthritis (PsA) has long been equated with that of rheumatoid arthritis (RA), particularly because methotrexate (MTX) was found efficient in RA in the 1990s. However, results of collective evidence-based medicine, included and argued in this narrative review, do not currently support the use of MTX as first-line therapy in severe PsA. A recent Cochrane systematic review examining the efficacy of MTX in PsA concluded that low-dose MTX was only slightly more effective than placebo. Questions about a structural effect of MTX in PsA remains non-elucidated. Even if tolerance data on MTX are more consensual and adverse events generally non-severe, subjective side effects such as fatigue might lead to MTX withdrawal based on the patient\'s decision. PsA patients with axial disease, radiographic lesions, and extensive and disabling skin or joint involvement should receive early treatment with targeted therapy and no longer with MTX. Finally, the usefulness of MTX combined with targeted therapies is limited. MTX does not affect efficacy but only seems to increase the therapeutic maintenance of monoclonal TNF inhibitors. This narrative review may help clarify the place of MTX in PsA management. It allows for reflection on the evolution of current concepts and practices.

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