Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved.
To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate ...(MTX)-based treatment strategy for tight control in early RA increases its effectiveness.
A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II Computer Assisted Management in Early Rheumatoid Arthritis trial-II). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169)
7 hospitals in the Netherlands.
236 patients with early RA (duration <1 year).
Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission.
The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment.
Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group.
A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible.
Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes.
Catharijne Foundation.
To study whether assessment of rheumatoid arthritis (RA) disease activity in individual patients using the disease activity score in 28 joints (DAS28) or other instruments excluding joints of feet ...may lead to misclassification of disease activity.
A cohort of RA patients was classified into three 'regional radiographic damage progression' groups: predominantly progression in feet, similar progression in hands and feet and predominantly progression in hands; both in early (0-2 years) and later (2-5 years) disease. Baseline and mean DAS28, individual DAS28 variables and tender joint counts (TJC) and swollen joint counts (SJC) of the feet were compared between groups. The longitudinal relation of DAS28 with radiographic damage was investigated using a mixed model analysis with rheumatoid factor status, baseline joint damage and TJC and SJC of the feet as covariates.
Early (n=265) and later (n=200) in the disease course, by definition, the classification procedure resulted in 25% as predominantly foot, 25% as predominantly hand and 50% as similar progressors. In early RA predominantly foot progressors had higher TJC and SJC of the feet compared with predominantly hand progressors (p<0.001), but DAS28 was similar. This was not seen in later disease. The longitudinal relation between DAS28 and radiographic progression was influenced by the region of progression (predominantly foot progressors vs others, p<0.001), suggesting that DAS28 underestimates disease activity in predominantly foot progressors. In this group, joint counts for the feet were independently related to radiographic progression.
DAS28 underestimates actual disease activity and expected joint damage of individual early RA patients predominantly with disease in the feet.
To explore the influence of tender points (TP) on the Disease Activity Score assessing 28 joints (DAS28) in patients with rheumatoid arthritis (RA).
In 200 consecutive patients with RA from the ...outpatient clinic, DAS28 and its components, tender and swollen joint counts (TJC, SJC, respectively), visual analog scale (VAS) for patient's general health (GH), and erythrocyte sedimentation rate (ESR), along with a tender point count (TPC) were assessed. Patients were categorized according to 4 TPC classes: zero, 1-5, 6-10, and ≥ 11 TP. The influence of TPC classes on DAS28 and its individual components was determined with Kruskal-Wallis tests and correlations between TP and DAS28 and its components were calculated.
In 196 eligible patients, 70% were female, mean age was 59 years, and median disease duration was 3.9 years; median DAS28 was 3.1; and 49% had active disease, defined as DAS28 > 3.2. In 15% of patients, the TPC was ≥ 11, in 12% 6-10, in 30% 1-5, and in 43% zero. TPC significantly influenced the DAS28 and its less objective components TJC and VAS-GH (i.e., based on patient's report), but not the more objective DAS28 components SJC and ESR (i.e., observer- and laboratory-based).
DAS28 is influenced by tender points, even in the non-fibromyalgia range, falsely suggesting higher disease activity and decreasing the sensitivity of the DAS28 criterion of low disease activity or remission. When applying DAS28-guided "tight control" or "treat-to-target" treatment strategies in RA, evaluation of not only the DAS28, but also its individual components along with a full joint and physical evaluation including assessment of TP is required to reliably estimate the individual's disease activity, which guides therapeutic decisions.
Objective
Although the Computer Assisted Management in Early Rheumatoid Arthritis Trial‐II (CAMERA‐II) showed favorable clinical effects in the most intensive methotrexate (MTX)–based strategy with ...prednisone (MTX ± prednisone) compared to that with placebo (MTX + placebo), this beneficial difference was only seen in 1 of the 3 analyses of remission. Our objective was to investigate whether the Continuity Rewarded (ConRew) score and a simple sum score would better reveal differences regarding remission between the 2 treatment arms of CAMERA‐II. Furthermore, we investigated whether the patient vector graph, which plots on patient level, would add visual information on remission compared to a conventional box plot only, which displays data on the group level.
Methods
The ConRew method, which awards continuous periods of remission with a higher score, was applied, in addition to a simple sum score of remission periods of 4 weeks. A patient vector graph was compared with box plots.
Results
Both the mean ± SD simple sum score and the ConRew score of remission were significantly higher (favorable) in the MTX + prednisone strategy group versus the MTX + placebo group, respectively: 9 ± 7 versus 12 ± 8; P = 0.003, and 23 ± 16 versus 17 ± 14; P = 0.004. The patient vector graphs show a visual pattern of more and longer periods of remission in the MTX + prednisone strategy and visually add information to the box plots.
Conclusion
The simple sum of remission periods, the ConRew score, and the patient vector graph add understanding and discrimination to the analysis of the remission outcome in CAMERA‐II.
To explore the relationship between rheumatoid arthritis (RA) disease activity and functional disability over time, considering indirect (predictive) and direct (concurrent) associations as well as ...the influence of radiographic joint damage and treatment strategy.
Functional disability Health Assessment Questionnaire (HAQ), disease activity 28-joint Disease Activity Score (DAS28), and radiographic joint damage Sharp/van der Heijde score (SHS) were measured in 4 consecutive randomized controlled trials with increasingly intensive (tight control) treatment strategies. Average followup time for the 3 cohorts was 97, 53, and 50 months, respectively. Next to current DAS28, the previous DAS28 was used to study the predictive effect of a change in DAS28 on progression of functional disability (HAQ). Finally, it was investigated whether SHS mediated the predictive effect of DAS28.
In patients treated with intensive treatment strategies, the progression of HAQ over time was statistically significantly less (p < 0.0001). The predictive influence of DAS28 on HAQ progression increased over the duration of the disease. SHS was not found to influence HAQ progression and did not mediate the predictive effect of DAS28. In the less intensively treated patients, the direct effect of disease activity decreased with disease duration, and contrarily, SHS did influence HAQ progression, but was not found to (fully) mediate the predictive effect of DAS28.
In patients with RA treated with modern treatment strategies, there is less functional decline over time. Further, disease activity does predict functional decline but joint damage does not. This might indicate that factors associated with cumulative disease activity but not visible on radiographs can influence functional decline in patients with RA. This further underlines the importance of disease activity as a treatment target in early RA and in established RA.
The aim of this study was to investigate whether serum biomarker levels of C2C, C1,2C, CS846, and CPII can predict the long-term course of disease activity and radiographic progression early in the ...disease course of rheumatoid arthritis (RA).
In patients in the CAMERA trial, levels of biomarkers were evaluated at baseline and after 1 year of treatment. Relations of (changes in) biomarker values with the mean yearly radiographic progression rate and mean disease activity over a 5-year period were evaluated by using regression analysis. The added predictive value of biomarkers over established predictors for long-term outcome was analyzed by multiple linear regression analysis.
Of 133 patients, serum samples were available at baseline and after 1 year of treatment. In the regression analysis C1,2C at baseline, the change in C2C, C1,2C, and the sum of the standardized changes in C2C + C1,2C scores were statistically significantly associated with the mean yearly radiographic progression rate; the change in CPII was associated with the mean disease activity over 5 years of treatment. In the multiple linear regression analysis, only the change in C1,2C was of added predictive value (P = 0.004) for radiographic progression. Explained variances of models for radiographic progression and disease activity were low (0.28 and 0.34, respectively), and the biomarkers only marginally improved the explained variance.
The change in C1,2C in the first year after onset of RA has a small added predictive value for disease severity over a 5-year period, but the predictive value of this biomarker combined with current predictive factors is too small to be of use for individual patients.
To compare two therapeutic strategies for patients with recent-onset rheumatoid arthritis.
Open, randomized clinical trial.
Outpatient clinics of six clinical centers.
238 consecutive patients with ...recently diagnosed rheumatoid arthritis.
Delayed or immediate introduction of treatment with slow-acting antirheumatic drugs (SAARDs).
Primary end points were functional disability, pain, joint score, and erythrocyte sedimentation rate at 6 and 12 months and progression of radiologic abnormalities at 12 months.
Statistically significant advantages at 12 months for patients receiving the SAARD strategy (immediate treatment with SAARDs) with regard to all primary end points that may be clinically important are indicated by the differences in improvements from baseline and their 95% CIs. These differences were 0.3 (95% CI, 0.2 to 0.6) for disability (range, 0 to 3), 10 mm (CI, 1 to 19 mm) for pain (range, 0 to 100 mm), 39 (CI, 4 to 74) for joint score (range, 0 to 534), and 11 mm/h (CI, 3 to 19 mm/h) for erythrocyte sedimentation rate (range, 1 to 140 mm/h), all in favor of SAARD treatment. The SAARD strategy also appears to be advantageous at 6 months. Radiologic abnormalities progressed at an equal rate in the SAARD and the non-SAARD groups; the difference in progression (range, 0 to 448) was 1 (CI, -3 to 5). Analyses were based on the intention-to-treat principle and thus included 29% of patients in the non-SAARD group who discontinued the non-SAARD treatment strategy; treatment was usually discontinued because of insufficient effectiveness. The SAARD strategy including two alternative SAARDs could not be continued by 8% of patients, usually because of adverse reactions.
Early introduction of SAARDs may be more beneficial than delayed introduction for patients with recently diagnosed rheumatoid arthritis.
This study was designed to investigate whether methotrexate (MTX), used in the treatment of rheumatoid arthritis (RA), affects proliferation and differentiation of human osteoblasts in culture. The ...effects of MTX were assessed by analyzing markers of proliferation and differentiation of human trabecular bone-derived osteoblast-like cells cultured in the presence or absence of 1,25-dihydroxyvitamin D3 (1,25OH2D3). Treatment of the osteoblastic cells with MTX resulted in a strong dose-dependent inhibition of cell proliferation with half maximal response at a dose of 30 nM. MTX did not interfere with cellular alkaline phosphatase (AP) activity, the number of cells expressing cytochemical AP, or basal osteocalcin production. Addition of 1,25(OH)2D3 to the cultures caused an enhanced AP expression and osteocalcin production coinciding with a decreased osteoblast proliferation. Coincubation of 1,25(OH)2D3 with MTX in doses > or = 100 nM further inhibited osteoblast growth and induced a significant stimulation of AP expression and activity, and production of osteocalcin above the values reached in the 1,25(OH)2D3 cultures. In conclusion, MTX proved to be a potent inhibitor of osteoblast proliferation but did not affect basal osteoblastic phenotypic expression. In the presence of the osteoblast differentiation-promoter, 1,25(OH)2D3, MTX further inhibited cell growth which was associated with enhanced AP activity and osteocalcin production. Thus, MTX may have profound effects on bone metabolism and remodeling by interfering with bone cell turnover.
Sleep disorders are linked to development of type 2 diabetes and increase the risk of developing diabetes complications. Treating sleep disorders might therefore play an important role in the ...prevention of diabetes progression. However, the detection and treatment of sleep disorders are not part of standardised care for people with type 2 diabetes. To highlight the importance of sleep disorders in people with type 2 diabetes, we provide a review of the literature on the prevalence of sleep disorders in type 2 diabetes and the association between sleep disorders and health outcomes, such as glycaemic control, microvascular and macrovascular complications, depression, mortality and quality of life. Additionally, we examine the extent to which treating sleep disorders in people with type 2 diabetes improves these health outcomes. We performed a literature search in PubMed from inception until January 2021, using search terms for sleep disorders, type 2 diabetes, prevalence, treatment and health outcomes. Both observational and experimental studies were included in the review. We found that insomnia (39% 95% CI 34, 44), obstructive sleep apnoea (55–86%) and restless legs syndrome (8–45%) were more prevalent in people with type 2 diabetes, compared with the general population. No studies reported prevalence rates for circadian rhythm sleep–wake disorders, central disorders of hypersomnolence or parasomnias. Additionally, several cross-sectional and prospective studies showed that sleep disorders negatively affect health outcomes in at least one diabetes domain, especially glycaemic control. For example, insomnia is associated with increased HbA
1c
levels (2.51 mmol/mol 95% CI 1.1, 4.4; 0.23% 95% CI 0.1, 0.4). Finally, randomised controlled trials that investigate the effect of treating sleep disorders in people with type 2 diabetes are scarce, based on a small number of participants and sometimes inconclusive. Conventional therapies such as weight loss, sleep education and cognitive behavioural therapy seem to be effective in improving sleep and health outcomes in people with type 2 diabetes. We conclude that sleep disorders are highly prevalent in people with type 2 diabetes, negatively affecting health outcomes. Since treatment of the sleep disorder could prevent diabetes progression, efforts should be made to diagnose and treat sleep disorders in type 2 diabetes in order to ultimately improve health and therefore quality of life.
Graphical abstract
Objective
To evaluate whether the clinical advantages observed after 1 year in a randomized controlled clinical trial, in which 2 treatment strategies were compared (the early disease‐modifying ...antirheumatic drug DMARD approach versus the pyramid approach), persist after 5 years.
Methods
In this study, 238 patients with recently diagnosed rheumatoid arthritis (RA) were randomized to either the pyramid group (n = 56) or the early DMARD group (n = 182). Patients assigned to the pyramid group received nonsteroidal antiinflammatory drugs for at least 1 year after inclusion (the mean ± SD lag time until first prescription of a DMARD was 14 ± 9 months). Patients in the early DMARD group were treated with a DMARD immediately after inclusion.
Results
After 5 years, data were available for 44 patients in the pyramid group (79%) and 145 patients in the early DMARD group (80%). No prolongation of the clinical advantages in favor of the early DMARD group, as observed after the first year, was demonstrated. Nevertheless, a significantly shorter delay time until complete response and a higher number of patients with overall clinically relevant improvement at several assessment points were observed in the early DMARD group compared with the pyramid group.
Conclusion
The clinical results in favor of the early DMARD group, as observed after the first year, were not as evident after 5 years. This indicates that a more aggressive treatment approach in early RA is required, and that treatment should be continued for a prolonged period of time, in order to maintain the advantages obtained in the first year.
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