Long-term mortality in treated-to-target RA and UA: results of the BeSt and IMPROVED cohort.

OBJECTIVES: To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA). METHODS: The BeSt (BehandelStrategieën) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)≤2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed. RESULTS: Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy. CONCLUSIONS: After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor.

Glucocorticoids, Inflammation and Bone.

The current review on glucocorticoids (GCs), inflammation and bone is focused on three aspects: (1) the mutual effects between GCs, inflammation and bone in inflammatory rheumatic diseases, (2) current views on fracture risk assessment in patients using GCs and (3) non-pharmacological and pharmacological treatment to prevent fractures in GC-using patients with inflammatory rheumatic diseases. The use of GCs results in increased risk for fractures due to both direct and indirect negative effects of GCs on bone mass, and on bone and muscle strength. However, also the underlying inflammatory rheumatic disease is associated with the increased bone loss and fracture risk due to the chronic inflammation itself, and due to disability/immobility caused by active disease or joint destruction. The rapid and strong anti-inflammatory effect of GCs in patients with rheumatoid arthritis seems to balance the negative effects of GCs on bone in the early, active phase of the disease. Recently, an update of the American College of Rheumatology guidelines for prevention and treatment of GC-induced osteoporosis was published with renewed recommendations. To prevent fractures, general measures, including treatment of the underlying inflammatory disease adequately (even with GCs when indicated), a healthy lifestyle, including adequate calcium and vitamin D supplementation, and regular weight bearing exercises are important. In rheumatic patients with high fracture risk using GCs, especially when the cumulative dose is high and/or the underlying inflammatory disease is active, treatment with anti-osteoporotic drugs, usually an oral bisphosphonate, is indicated.

Changes in body weight and body composition in patients with active rheumatoid arthritis aged 65+ treated with 2-year low-dose add-on prednisolone in the randomised double-blind placebo-controlled GLORIA trial.

OBJECTIVES: To investigate the effect of 2 years of add-on prednisolone 5 mg/day on body weight and composition in patients with active rheumatoid arthritis (RA) aged 65+ and the relation with disease activity. METHODS: The Glucocorticoid Low-dose Outcome in RheumatoId Arthritis trial, a pragmatic, placebo-controlled, double-blind, randomised controlled trial investigated the balance of benefit and harm of 2 years of prednisolone 5 mg/day added to standard care in 451 patients with active RA aged 65+. In the current study, 449 patients were included, and body weight and Disease Activity Score of 28 Joints were measured at baseline and after 3, 6, 12, 18 and 24 months. In 57 patients, body composition was assessed at baseline and after 2 years with dual-energy X-ray absorptiometry. Data were analysed with longitudinal mixed models. RESULTS: The mean (95% CI) change in body weight was 0.9 (0.3 to 1.6) kg in the prednisolone group and -0.4 (-1.1 to 0.2) kg in the placebo group (difference 1.3 (0.5-2.2), (p<0.01)). The treatment effect was independent of disease activity suppression and comprised mostly increase in (appendicular) lean mass after 2 years. There was no significant increase in total fat mass, nor redistribution of fat mass from peripheral to central tissues. CONCLUSIONS: Patients with active RA aged 65+ treated with prednisolone 5 mg/day for 2 years gained about 1 kg in weight, compared with minimal-non-significant-weight loss on placebo. Our data suggest that the small increase in weight is mostly lean mass, rather than increase or redistribution of fat mass traditionally associated with glucocorticoid treatment.

Frequency of joint inflammation is associated with local joint damage progression in rheumatoid arthritis despite long-term targeted treatment.

OBJECTIVES: To investigate whether in rheumatoid arthritis (RA) frequency of local joint inflammation is associated with radiographic joint damage progression in that joint. METHODS: Data from 473 patients with RA and available radiographs from the BeSt study were used. Patients were treated to target (Disease Activity Score of ≤2.4) for a median of 10 years. At each study visit every 3 months, joints were assessed for swelling and tenderness. Radiographs of hands and feet were made yearly. A generalised linear mixed model was used to assess the association between the percentage of study visits at which clinical inflammation was observed in a joint (cumulative inflammation) and radiographic joint damage in that same joint. Clinical inflammation was primarily defined as joint swelling (with or without joint tenderness). For secondary analyses, we also investigated joint tenderness without joint swelling. Damage was measured as the percentage of the maximum possible Sharp-Van der Heijde score in a particular joint. RESULTS: Cumulative local joint swelling was associated with local progression of radiographic damage in the same joint (ß=0.14, 95% CI 0.13 to 0.15). This association was also found in a subset of joints that were swollen at least once. Cumulative local joint tenderness without concurrent local joint swelling was less strongly associated with local radiographic joint damage progression (ß=0.04, 95% CI 0.03 to 0.05). CONCLUSIONS: In RA, long-term cumulative local joint inflammation is associated with joint damage progression in the same joint.

The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study.

OBJECTIVE: To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. METHODS: 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤ 2.4 during ≥ 6 months taper to maintenance dose; if DAS <1.6 during ≥ 6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. RESULTS: After 5 years, 48% of patients were in clinical remission (DAS <1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2-5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. CONCLUSION: Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.

Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis.

INTRODUCTION: To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years. METHODS: In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years. RESULTS: 68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage. CONCLUSIONS: In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.