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Objective: The randomised placebo-controlled GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) trial evaluated the benefits and harms of prednisolone 5 mg/day added to standard care for 2 years in patients aged 65+ years with rheumatoid arthritis (RA). Here, we studied disease activity, flares and possible adrenal insufficiency after blinded withdrawal of study medication., Methods: Per protocol, patients successfully completing the 2-year trial period linearly tapered and stopped blinded study medication in 3 months. We compared changes in disease activity after taper between treatment groups (one-sided testing). Secondary outcomes (two-sided tests) comprised disease flares (DAS28 (Disease Activity Score 28 joints) increase >0.6, open-label glucocorticoids or disease-modifying antirheumatic drug (DMARD) increase/switch after week 4 of tapering) and symptoms/signs of adrenal insufficiency. In a subset of patients from 3 Dutch centres, cortisol and ACTH were measured in spot serum samples after tapering., Results: 191 patients were eligible; 36 met treatment-related flare criteria and were only included in the flare analysis. Mean (SD) DAS28 change at follow-up: 0.2 (1.0) in the prednisolone group (n=76) vs 0.0 (1.2) in placebo (n=79). Adjusted for baseline, the between-group difference in DAS28 increase was 0.16 (95% confidence limit -0.06, p=0.12). Flares occurred in 45% of prednisolone patients compared with 33% in placebo, relative risk (RR) 1.37 (95% CI 0.95 to 1.98; p=0.12). We found no evidence for adrenal insufficiency., Conclusions: Tapering prednisolone moderately increases disease activity to the levels of the placebo group (mean still at low disease activity levels) and numerically increases the risk of flare without evidence for adrenal insufficiency. This suggests that withdrawal of low-dose prednisolone is feasible and safe after 2 years of administration., Competing Interests: Competing interests: AAHA: None declared. MB: Novartis, Pfizer. LH: None declared. DO-B: AbbVie, Boehringer Ingelheim, Sandoz, EwoPharma, BMS, Alfą Sigma, Pfizer, Eli Lilly, Nordic Pharma. RB: UCB, Galapagos, Pfizer, Janssen. MRK: None declared. JAPdS: None declared. ENG: None declared. RK: None declared. CA: None declared. PB: None declared. HR: AbbVie, Amgen, Galapagos, Novartis, Amgen. ZS: AbbVie, Bristol-Myers, Pfizer, MSD, Lilly, Novartis, Gedeon Richter. FB: AbbVie, AstraZeneca, Gruenenthal, Horizon Therapeutics, Mundipharma, Pfizer, Roche. PM: None declared. WL: Pfizer, Galapagos, Lilly, Amgen, UCB. YS: None declared. MC: BMS, AMGEN, Pfizer, Celgene, Horizon. MMtW: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Low-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear., Methods: The GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL)., Results: We randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p<0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare., Conclusion: Add-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm., Trial Registration Number: NCT02585258., Competing Interests: Competing interests: Maarten Boers: Novartis. Linda Hartman: none. Daniela Opris-Belinski: Abbvie, Pfizer, MSD, Novartis, Eli Lilly, Ewo Pharma, UCB. Reinhard Bos: none. Marc R. Kok: none. José A.P. da Silva: none. Eduard N. Griep: none. Ruth Klaasen: none. Cornelia F. Allaart: none. Paul Baudoin: none. Hennie G. Raterman: AbbVie, Amgen, Celgene, Roche, Sandoz, Sanofi Genzyme, UCB. Zoltan Szekanecz: none. Frank Buttgereit: Abbvie, AstraZeneca, Gruenenthal, Horizon Therapeutics, Mundipharma, Pfizer, Roche. Pavol Masaryk: none. L. Thomas Klausch: none. Sabrina Paolino: none. Annemarie M. Schilder: Eli Lilly, Novartis, Genzyme. Willem F. Lems: Pfizer, Galapagos, Lilly, Amgen, UCB. Maurizio Cutolo: none., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Suboptimal medication adherence is a serious problem in the treatment of chronic inflammatory diseases. To measure medication adherence, electronic monitoring is regarded as superior to pill count. GLORIA is an ongoing two-year trial on the addition of low-dose (5 mg/d) prednisolone or placebo to standard care in older people (65+ years) with RA. During the entire trial, adherence is measured with electronic caps, and with pill counts. The objective is to describe medication adherence patterns, and to compare the adherence results of the two methods., Methods: The recorded adherence patterns of patients (blinded for treatment group) were classified according to descriptive categories. The cutoff for good adherence was set at 80% of prescribed pills taken., Results: Trial inclusion closed in 2018 at 451 patients, but trial follow-up is ongoing; the current dataset contains adherence data of 371 patients. Mean number of recorded 90-day periods per patient was 4 (range 1-8). Based on pill count over all periods, 90% of the patients had good adherence; based on cap data, only 20%. Cap data classified 30% of patients as non-user (<20% of days an opening) and 40% as irregular user (different adherence patterns, in or between periods)., Conclusion: In our trial of older people with RA, the majority appeared to be adherent to medication according to pill count. Results from caps conflicted with those of pill counts, with patterns suggesting patients did not use the bottle for daily dispensing, despite specific advice to do so., Trial Registration: NCT02585258. ClinicalTrials.gov (https://www.clinicaltrials.gov/)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: U-Act-Early was a 2-year, randomized placebo controlled, double-blind trial, in which DMARD-naïve early RA patients were treated to the target of sustained remission (SR). Two strategies initiating tocilizumab (TCZ), with and without methotrexate (MTX), were more effective than a strategy initiating MTX. The aim of the current study was to determine longer-term effectiveness in daily clinical practice., Methods: At the end of U-Act-Early, patients were included in a 3-year post-trial follow-up (PTFU), in which treatment was according to standard care and data were collected every 3 months during the first year and every 6 months thereafter. Primary end point was disease activity score assessing 28 joints (DAS28) over time. Mixed effects models were used to compare effectiveness between initial strategy groups, correcting for relevant confounders. Between the groups as randomized, proportions of patients were tested for DMARD use, SR and radiographic progression of joint damage., Results: Of patients starting U-Act-Early, 226/317 (71%) participated in the PTFU. Over the total 5 years, mean DAS28 was similar between groups (P > 0.20). During U-Act-Early, biologic DMARD use decreased in both TCZ initiation groups and increased in the MTX initiation group, but during follow-up this trend did not continue. SR was achieved at least once in 99% of patients. Of the 226 patients, only 30% had any radiographic progression over 5 years, without significant differences between the groups., Conclusion: Although in the short-term the strategies initiating TCZ yielded the most clinical benefit, in the longer-term differences in important clinical outcomes between the strategies disappeared, probably due to continuation of the treat-to-target principle., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Assessment of disease activity is a critical component of tight-control, treat-to-target treatment strategies of rheumatoid arthritis (RA). Recently, the HandScan has been validated as a novel method for objectively assessing RA disease activity in only 1.5 min, using optical spectral transmission (OST) in hands and wrists. We describe the protocol of a randomized controlled clinical trial (RCT) to investigate whether HandScan-guided treatment aimed at 'HandScan remission' (HandScan arm) is at least as effective as and more cost-effective than clinically guided treatment aimed at ACR/EULAR 2011 Boolean remission (DAS arm)., Methods/design: The study is a multi-center, double-blind, non-inferiority RCT of 18 months duration. Patients ≥ 18 years with newly diagnosed, disease-modifying antirheumatic drug (DMARD)-naïve RA according to the ACR 2010 classification criteria, will be randomized to the DAS arm or the HandScan arm. The efficacy of the arms will be compared by evaluating Health Assessment Questionnaire (HAQ) scores (primary outcome) after 18 months of DMARD therapy, aimed at remission. The equivalence margin in HAQ scores between study arms is 0.2. Secondary outcomes are differences in cost-effectiveness and radiographic joint damage between treatment arms. The non-inferiority sample size calculation to obtain a power of 80% at a one-sided p value of 0.05, with 10% dropouts, resulted in 61 patients per arm. In both arms, DMARD strategy will be intensified monthly according to predefined steps until remission is achieved; in both arms DMARDs and treatment steps are identical. If sustained remission, defined as remission that persists consistently over three consecutive months, is achieved, DMARD therapy will be tapered., Discussion: The study protocol and the specifically designed decision-making software application allow for implementation of this RCT. To test a novel method of assessing disease activity and comparing (cost-)effectiveness with the contemporary method in treat-to-target DMARD strategies in early RA patients., Trial Registration: Dutch Trial Register, NTR6388. Registered on 6 April 2017 ( NL50026.041.14 ). Protocol version 3.0, 19-01-2017.

Objective: To determine the impact of stopping tumor necrosis factor inhibitor (TNFi) treatment on patient-reported outcomes (PROs) of physical and mental health status, health utility, pain, disability, and fatigue in patients with established rheumatoid arthritis (RA)., Methods: In the pragmatic, 12-month POET trial, 817 RA patients with ≥6 months of remission or stable low disease activity were randomized 2:1 to stopping or continuing TNFi. In case of flare, TNFi was restarted at the discretion of the rheumatologist. PROs were assessed every 3 months., Results: TNFi was restarted within 12 months in 252 of 531 patients (47.5%) in the stop group. At 3 months, mean PRO scores were significantly worse in the stop group, and a larger proportion of patients experienced a minimum clinically important difference (MCID) on all PROs. Effect sizes (ES) were strongest for health utility (ES -0.24) and pain (ES -0.30). Mean scores improved again after this point, but disability scores remained significantly different at 12 months. After 12 months, the relative risk of experiencing an MCID ranged from 1.16 for mental health status to 1.58 for fatigue. Mean PRO scores for patients restarting TNFi within 6 months were no longer significantly different from those that did not restart TNFi at 12 months., Conclusion: Stopping TNFi had a significant negative short-term impact on a broad range of PROs. Long-term negative consequences appeared to be limited, and outcomes in patients needing to restart TNFi within the first 6 months tended to be restored at 12 months., (© 2017, American College of Rheumatology.)

Objective: There is increasing evidence that adipocytokines may exert proinflammatory and destructive effects in rheumatoid arthritis (RA). Hence, the authors investigated the relationship between adipocytokines and several features associated with RA (inflammation, joint destruction and cardiovascular disease), as well as the effect of treatment with a tumour necrosis factor inhibitor or glucocorticoids (GCs) hereupon., Methods: Serum levels of adiponectin, leptin, resistin, visfatin, vaspin and lipids were determined in a well-defined cohort of patients with RA before and after 16 weeks of adalimumab treatment (adalimumab cohort). The same parameters were analysed in two other cohorts of patients with RA before and after 2 weeks of high-dose prednisolone (high GC cohort) and before and after 22 weeks of treatment with a combination regimen with tapered high-dose prednisolone (COBRA -GC cohort). Radiographs of hands and feet (adalimumab and COBRA-GC cohorts) were assessed at baseline and after treatment., Results: Treatment with adalimumab or GC showed opposing effects on vaspin and visfatin levels. Lipid levels improved after several months of adalimumab or GC treatment; in the adalimumab cohort, this was related to reduced visfatin levels, independent of C reactive protein levels. After long-term adalimumab or GC treatment, resistin levels declined, which was associated with a decrease in inflammation markers. In the adalimumab cohort, baseline resistin levels were predictive of baseline radiological damage, independent of anticitrullinated peptide antibodies status or C reactive protein levels., Conclusion: Changes in serum adipocytokine levels were treatment specific, further strengthening the role of visfatin and resistin in several disease manifestations of RA.

Objective: It remains unclear whether autoantibodies are useful biomarkers to tailor the choice of biological treatment in RA. We investigated the relationship between the presence and levels of different RF and ACPA isotypes and the response to TNF blockade in an exploratory study., Methods: A total of 101 active RA patients were prospectively treated with infliximab (3 mg/kg). Changes in disease activity were monitored by the 28-joint DAS (DAS-28). Serum levels of different isotypes [immunoglobulins M, G and A (IgM, IgG and IgA)] of RF and anti-citrullinated peptide antibodies were measured by ELISA., Results: The mean DAS-28 decreased from 5.9 (1.1) at baseline to 4.0 (1.3) at Week 16 of infliximab treatment (P < 0.001). High baseline levels of different isotypes of RF (all P < 0.008), ACPA IgM (P = 0.008) and ACPA IgG (P = 0.07) were associated with an absolute decrease in DAS-28 after TNF blockade. This relationship persisted after adjusting for DAS-28 at baseline. However, the different isotypes of baseline RF and ACPA levels accounted for only a small proportion of variance in treatment response (RF: R² between 7 and 12% and ACPA: R² between 4 and 7%). The simultaneous presence of all three isotypes of RF or ACPA had no additive value., Conclusion: Presence as well as the titres of RF and IgM ACPA at baseline are significantly correlated with better response to infliximab treatment. However, this correlation is not strong enough to allow a reliable prediction in individual patients. Trial Registration. ISRCTN Register, http://www.controlled-trials.com/isrctn/, ISRCTN36847425.

Objective: Adipose tissue has immunomodulating effects in rheumatoid arthritis (RA), although the exact role is, at present, unclear. The purpose of this study was to determine whether body mass index (BMI) affects response to infliximab in RA patients investigated prospectively., Methods: In 89 patients with active RA, the BMI was calculated before initiation of infliximab treatment (3 mg/kg intravenously). After 16 weeks of treatment, changes in disease activity were assessed with the Disease Activity Score in 28 joints (DAS28)., Results: The mean ± SD BMI was 26 ± 5 kg/m(2) (range 17-42). The BMI correlated positively with the DAS28 at baseline (r = 0.34, P = 0.001). Since selection of study patients according to DAS28 values could influence the clinical response to tumor necrosis factor (TNF) blockade due to regression to the mean because the clinical response is itself based on the change in the DAS28 values, analysis of covariance was used to correct for the baseline DAS28. A highly significant, negative association between the BMI and the absolute decrease in the DAS28 after 16 weeks (P = 0.001) was found also when adjusted for anti-citrullinated protein antibodies., Conclusion: Although the infliximab dosage is based on body weight, RA patients with a high BMI responded less well to infliximab, a finding that held true when adjusted for the baseline DAS28 or anti-citrullinated protein antibody status. These results support the notion that adipose tissue may be involved in the pathophysiology of RA and could have implications for other immune-mediated inflammatory conditions treated with TNF antagonists., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Some patients with rheumatoid arthritis (RA) exhibit lymphocyte aggregates in the synovium. This study was undertaken to address whether the presence of lymphocyte aggregates before treatment could serve as a biomarker for the clinical response to tumor necrosis factor (TNF) blockade, and to confirm whether the aggregation of synovial lymphocytes is reversible after anti-TNF treatment., Methods: Synovial tissue biopsy samples were obtained from 97 patients with active RA before the initiation of infliximab treatment. Lymphocyte aggregates in the synovial tissue were counted and also graded for size. Logistic regression analysis was performed to identify whether the presence of lymphocyte aggregates could be a predictor of the clinical response at week 16. Furthermore, the effects of TNF blockade on lymphocyte aggregates were compared between patients with RA and patients with psoriatic arthritis (PsA)., Results: Fifty-seven percent of RA synovial tissue samples contained lymphocyte aggregates, and 32% of the patients had large aggregates. Aggregates were found in 67% of clinical responders compared with 38% of nonresponders. The presence of aggregates at baseline was a highly significant predictor of the clinical response to anti-TNF treatment (R(2) = 0.10, P = 0.008). Positivity for lymphocyte aggregates increased the power to predict the clinical response (R(2) = 0.29), when analyzed in a prediction model that included baseline disease activity evaluated by the Disease Activity Score in 28 joints, anti-cyclic citrullinated peptide antibody positivity, and synovial TNFalpha expression. There was a reduction in lymphocyte aggregates after anti-TNF antibody therapy in both RA and PsA., Conclusion: RA patients with synovial lymphocyte aggregates have, on average, a better response to infliximab treatment than those with only diffuse leukocyte infiltration. Moreover, the aggregation of synovial lymphocytes is reversible after anti-TNF antibody treatment.

Objective: To explore the effects of anti-tumour necrosis factor (TNF)alpha antibody therapy on bone mineral density (BMD) of the lumbar spine and femur neck in patients with rheumatoid arthritis (RA)., Methods: A total of 50 patients with active RA (DAS28> or =3.2) who started adalimumab (40 mg subcutaneously/2 weeks) were included in an open label prospective study. All patients used stable methotrexate and were allowed to use prednisone (< or =10 mg/day). The BMD of the lumbar spine and femur neck was measured before and 1 year after start of treatment., Results: Disease activity at baseline (28-joint Disease Activity Score (DAS28)) and disease duration were inversely correlated with femoral neck BMD and lumbar spine BMD (p<0.05). Mean BMD of lumbar spine and femur neck remained unchanged after 1 year of adalimumab therapy (+0.3% and +0.3%, respectively). Of interest, a beneficial effect of prednisone on change in femur neck BMD was observed with a relative increase with prednisone use (+2.5%) compared to no concomitant prednisone use (-0.7%), (p = 0.015)., Conclusion: In contrast to the progressive bone loss observed after conventional disease-modifying antirheumatic drug therapy, TNF blockade may result in an arrest of general bone loss. Consistent with previous observations, the data also suggest that the net effect of low-dose corticosteroids on BMD in RA may be beneficial, possibly resulting from their anti-inflammatory effects.