Favourable effect of a 'second hit' after 13 weeks in early RA non-responders: the Amsterdam COBRA treat-to-target randomized trial.

OBJECTIVE: The aim of this study was to investigate the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA. METHODS: Early RA patients were classified as being at high or low risk of worsening RA based on disease activity and prognostic factors. High-risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, MTX increasing to 25 mg/week), and low-risk patients received MTX monotherapy increasing to 25 mg/week. The primary outcome (target) was DAS44 < 1.6 or EULAR good response at 26 weeks. At 13 weeks, non-responders were randomized to (open-label) intensification [high-risk patients: prednisolone 60 mg/day tapered to 7.5 mg/day, addition of SSZ (2 g/day) and HCQ (400 mg/day); low-risk patients: prednisolone 30 mg/day tapered to 7.5 mg/day] or continuation. RESULTS: In the high-risk group (n = 150), 110 patients (73%) reached the target at 13 weeks, and 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n = 16), and after 26 weeks, 12 (80%) vs 7 (44%) of these, respectively, reached the target [difference: 36%, (95% CI 2%, 71%); P = 0.04]. In the low-risk group (n = 40), 17 (43%) reached the target. Non-responders were randomized to intensification (n = 8) or continuation (n = 7); 4 vs 3, respectively, reached the target.Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup of that group. Serious adverse events were rare. Protocol violations were frequent and mostly led to mitigation of actual treatment intensification. CONCLUSION: Initial combination therapy was very successful in high-risk RA, and early intensification was beneficial in patients not reaching the strict target. The low-risk group was too small for drawing conclusions. In routine practice, adherence to early intensification based on strict targets is difficult. TRIAL REGISTRATION: Netherlands Trial Register (NTR), NL4393, https://www.trialregister.nl/.

Development of prediction models to select older RA patients with comorbidities for treatment with chronic low-dose glucocorticoids.

OBJECTIVE: To develop prediction models for individual patient harm and benefit outcomes in elderly patients with RA and comorbidities treated with chronic low-dose glucocorticoid therapy or placebo. METHODS: In the Glucocorticoid Low-dose Outcome in Rheumatoid Arthritis (GLORIA) study, 451 RA patients ≥65 years of age were randomized to 2 years 5 mg/day prednisolone or placebo. Eight prediction models were developed from the dataset in a stepwise procedure based on prior knowledge. The first set of four models disregarded study treatment and examined general predictive factors. The second set of four models was similar but examined the additional role of low-dose prednisolone. In each set, two models focused on harm [the occurrence of one or more adverse events of special interest (AESIs) and the number of AESIs per year) and two on benefit (early clinical response/disease activity and a lack of joint damage progression). Linear and logistic multivariable regression methods with backward selection were used to develop the models. The final models were assessed and internally validated with bootstrapping techniques. RESULTS: A few variables were slightly predictive for one of the outcomes in the models, but none were of immediate clinical value. The quality of the prediction models was sufficient and the performance was low to moderate (explained variance 12-15%, area under the curve 0.67-0.69). CONCLUSION: Baseline factors are not helpful in selecting elderly RA patients for treatment with low-dose prednisolone given their low power to predict the chance of benefit or harm. TRIAL REGISTRATION: https://clinicaltrials.gov; NCT02585258.

[18F]Fluoride PET provides distinct information on disease activity in ankylosing spondylitis as compared to MRI and conventional radiography.

PURPOSE: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. METHODS: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. RESULTS: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. CONCLUSION: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. CLINICAL TRIAL REGISTRATION: NL43223.029.13 registered at 02-05-2013.  https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A.

Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial.

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.

High-intensity versus low-intensity resistance training in patients with knee osteoarthritis: A randomized controlled trial.

OBJECTIVES: To assess whether (i) high-intensity resistance training (RT) leads to increased muscle strength compared to low-intensity RT in patients with knee osteoarthritis (OA); and (ii) RT with vitamin D supplementation leads to increased muscle strength compared to placebo in a subgroup with vitamin D deficiency. DESIGN: Randomized controlled trial. SETTING: Outpatient rehabilitation centre. SUBJECTS: Patients with knee OA. INTERVENTIONS: 12 weeks of RT at high-intensity RT (70-80% of 1-repetition maximum (1-RM)) or low-intensity RT (40-50% of 1-RM) and 24 weeks of vitamin D (1200 International units vitamin D3 per day) or placebo supplementation. MAIN MEASURES: Primary outcome measure was isokinetic muscle strength. Other outcome measure for muscle strength was the estimated 1-RM. Secondary outcome measures were knee pain and physical functioning. RESULTS: 177 participants with a mean age of 67.6 ± 5.8 years were included, of whom 50 had vitamin D deficiency. Isokinetic muscle strength (in Newton metre per kilogram bodyweight) at start, end and 24 weeks after the RT was 0.98 ± 0.40, 1.11 ± 0.40, 1.09 ± 0.42 in the high-intensity group and 1.02 ± 0.41, 1.15 ± 0.42, 1.12 ± 0.40 in the low-intensity group, respectively. No differences were found between the groups, except for the estimated 1-RM in favour of the high-intensity group. In the subgroup with vitamin D deficiency, no difference on isokinetic muscle strength was found between the vitamin D and placebo group. CONCLUSIONS: High-intensity RT did not result in greater improvements in isokinetic muscle strength, pain and physical functioning compared to low-intensity RT in knee OA, but was well tolerated. Therefore these results suggest that either intensity of resistance training could be utilised in exercise programmes for patients with knee osteoarthritis. No synergistic effect of vitamin D supplementation and RT was found, but this finding was based on underpowered data.

Muscle weakness is associated with non-contractile muscle tissue of the vastus medialis muscle in knee osteoarthritis.

BACKGROUND: Quadriceps weakness is assumed to be associated with compositional properties of the vastus medialis muscle in patients with knee osteoarthritis (OA). METHODS: The aim was to determine the association of non-contractile muscle tissue in the vastus medialis muscle, measured with routine MRI, with muscle extensor strength in patients with knee OA. Sagittal T1-weighted 3T MRI of 94 patients with knee OA, routinely acquired in clinical practice were used for analysis. Using the MRI's, the amount of non-contractile muscle tissue in the vastus medialis muscle was measured, expressed as a percentage of (non)-contractile tissue, dichotomized into a low and a high non-contractile percentage group. Muscle strength was assessed by isokinetic measurement of knee extensors and by conduction of the Get-Up and Go (GUG) test. In regression analyses, associations of percentage of non-contractile muscle tissue with muscle strength and GUG time were determined and controlled for sex, age, BMI and radiographic severity. RESULTS: A high percentage of non-contractile muscle tissue (> 11.2%) was associated with lower muscle strength (B = -0.25, P = 0.006) and with longer GUG time (B = 1.09, P = 0.021). These associations were specifically confounded by sex and BMI, because these two variables decreased the regression coefficient (B) with > 10%. CONCLUSIONS: A high percentage of non-contractile muscle tissue in the vastus medialis muscle measured by clinical T1-weighted 3T MRI is associated with muscle weakness. The association is confounded by sex and BMI. Non-contractile muscle tissue seems to be an important compositional property of the vastus medialis muscle underlying quadriceps weakness.

Association of altered folylpolyglutamate synthetase pre-mRNA splicing with methotrexate unresponsiveness in early rheumatoid arthritis.

OBJECTIVES: An efficient pharmacological response to MTX treatment in RA patients relies on the retention and accumulation of intracellular MTX-polyglutamates catalysed by the enzyme folylpolyglutamate synthetase (FPGS). We recently identified a partial retention of FPGS intron 8 (8PR) as a prominent splice variant conferring FPGS dysfunction and decreased MTX polyglutamylation in acute lymphoblastic leukaemia. Here, we explored the association between FPGS 8PR levels and lack of MTX responsiveness in RA patients. METHODS: Thirty-six patients undergoing MTX treatment were enrolled from the Combinatie behandeling Reumatoide Artritis (COBRA)-light trial. RNA was isolated from blood samples at baseline, 13 weeks and 26 weeks of therapy, from patients in either COBRA-light (n = 21) or COBRA (n = 15) treatment arms. RT-qPCR analysis was used to assess RNA levels of FPGS 8PR over wild-type FPGS (8WT). RESULTS: In the COBRA-light treatment arm, higher baseline ratios of 8PR/8WT were significantly associated with higher 44-joint disease activity score (DAS44) at 13 and 26 weeks. Higher baseline ratios of 8PR/8WT also trended towards not obtaining low disease activity (DAS <1.6) and becoming a EULAR non-responder at 13 and 26 weeks. In the COBRA-treatment arm, a significant association was observed between high baseline 8PR/8WT ratios and higher DAS44 score at 26 weeks. Higher 8PR/8WT ratios were associated with non-response at week 26 based on both low disease activity and EULAR criteria. CONCLUSION: This study is the first to associate alterations in FPGS pre-mRNA splicing levels with reduced responsiveness to MTX treatment in RA patients. TRIAL REGISTRATION: ISRCTN55552928.

Medication adherence in older people with rheumatoid arthritis is lower according to electronic monitoring than according to pill count.

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/).

Peripheral quantitative computed tomography in the assessment of bone mineral density in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients.

INTRODUCTION: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. METHODS: Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. RESULTS: We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p<0.017 after Bonferroni's correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. CONCLUSIONS: BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Development and Validation of a Sensitive UHPLC-MS/MS-Based Method for the Analysis of Folylpolyglutamate Synthetase Enzymatic Activity in Peripheral Blood Mononuclear Cells: Application in Rheumatoid Arthritis and Leukemia Patients.

BACKGROUND: Folylpolyglutamate synthetase (FPGS) is a crucial enzyme in both cellular folate homeostasis and the intracellular retention of folate analogue drugs such as methotrexate (MTX), which is commonly used for the treatment of (pediatric) leukemia and the anchor drug in rheumatoid arthritis (RA) treatment. To date, assessment of FPGS catalytic activity relies on assays using radioactive substrates that are labor-intensive and require relatively large numbers of cells. Here, we describe a nonradioactive, ultra-high-performance liquid chromatography-tandem mass spectrometer (UHPLC-MS/MS)-based method allowing for sensitive and accurate measurements of FPGS activity in low cell numbers (ie, 1-2 × 10) of biological specimens, including leukemic blast cells of acute lymphoblastic leukemia patients and peripheral blood mononuclear cells of patients with RA. METHODS: The UHPLC-MS/MS assay was validated with 2 CCRF-CEM human leukemia cells, one proficient and one deficient in FPGS activity. Linearity of time and protein input were tested by measuring FPGS activity at 30-180 minutes of incubation time and 10-300 mcg protein extract. In addition, FPGS enzyme kinetic parameters were assessed. RESULTS: The FPGS enzymatic assay showed a linear relation between FPGS activity and protein input (R ≥ 0.989) as well as incubation time (R ≥ 0.996). Moreover, the UHPLC-MS/MS method also allowed for evaluation of FPGS enzyme kinetic parameters revealing Km values for the substrates MTX and L-glutamic acid of 64 µmol/L and 2.2 mmol/L, respectively. The mean FPGS activity of acute lymphoblastic leukemia blast cells (n = 4) was 3-fold higher than that of CCRF-CEM cells and 44-fold and 88-fold higher than that of peripheral blood mononuclear cells from MTX-naive (n = 9) and MTX-treated RA patients (n = 6), respectively. CONCLUSIONS: Collectively, given its sensitivity with low cell numbers and avoidance of radioactive substrates, UHPLC-MS/MS-based analysis of FPGS activity may be eligible for routine therapeutic drug monitoring of MTX in RA and leukemia for therapy (non)response evaluations.

Outcome measures for adherence data from a medication event monitoring system: A literature review.

WHAT IS KNOWN: Currently, medication bottles with an electronic cap are frequently used to measure medication adherence. This system is termed medication event monitoring system (MEMS). To our knowledge, the optimal method to summarize data from MEMS has not yet been determined. OBJECTIVE: Look for best practices on how to quantify adherence data from MEMS. METHODS: Review of PubMed, Embase and Cochrane databases for the articles on medication adherence with MEMS. RESULTS: Of 1493 identified articles, 207 were included in this review. The MEMS cap was used for a median of 3 months (IQR: 4; range: 1 week to 24 months) in various health conditions. Many different outcome measures were used. Most studies computed an adherence score, expressed as the percentage of days on which the correct dose of medication was taken. The threshold to mark people as adherent was most frequently, arbitrarily, set at 80% (range: 67%-95%). We found no data to support a specific threshold. DISCUSSION: Although the commonly used definition of adherence has face validity, we found no validation studies, and not all studies used the same cut-off for adherence. Ideally, a cut-off should be defined and validated in the context of the specific drug and its pharmacokinetic and dynamic characteristics, and perhaps other contextual factors, rather than generically. In addition, there was large heterogeneity in the definition of what "correct intake" of medication is. WHAT IS NEW AND CONCLUSION: Outcome measures for MEMS data lacked standardization, and no demonstrable effort to validate any definition against a relevant clinical outcome is available. Consensus on the definition of adherence is urgently needed.

What have we learned from BeSt?

BACKGROUND: How have the long term outcomes of RA improved in the last decade? METHODS: Patients with DMARD naïve RA were randomized to 4 treatment strategies: 1. sequential DMARD monotherapy, 2. step-up combination therapy, 3. initial combination therapy including prednisone or 4. including infliximab. Treatment-to-target was aimed at DAS≤2.4 (three-monthly calculations). Functional ability (HAQ), radiologic damage progression (Sharp/vanderHeijde Score) and overall survival were reported. RESULTS: Patients in arms 3 and 4 showed earlier clinical improvement. Up to 50% achieved DAS-remission (<1.6), up to 29% achieved drug free remission. Damage progression was well suppressed (median after 10years in completers 2 SHS points), functional ability approached normality (mean HAQ 0.6). There was no increased mortality (Standardized Mortality Ratio 1.16, 95% CI 0.92-1.46). CONCLUSIONS: Early treatment determines early clinical improvement, treatment-to-target determines long term outcomes. Prevention of relevant radiologic damage progression and disability, drug free remission and normalized survival are realistic goals.

TNF inhibitor treatment is associated with a lower risk of hand osteoarthritis progression in rheumatoid arthritis patients after 10 years.

Objective: To investigate the effect of TNF inhibitors (TNFis) on incidental and progressive hand OA in recent-onset RA patients after a 10 year follow-up. Methods: Radiographs of 262 RA patients (mean age 52 years, 66% women) from the BeSt study were scored for osteophytes in DIP/PIP joints using the Osteoarthritis Research Society International atlas (0-3; summed score 0-54) and according to the Kellgren-Lawrence (KL) score (0-4; summed score 0-72) at baseline and 10 year follow-up. TNFi treatment was assessed on visits every 3 months. Associations between TNFi treatment and hand OA were analysed on the patient and joint level using generalized linear models and generalized estimating equations, respectively. Results: Fifty-eight percent of the patients were treated with TNFi, with a median duration of 42 months. A total of 143 patients (55%) had hand OA in any IP joint at baseline based on the Osteoarthritis Research Society International osteophyte score. On the patient level, TNFi treatment duration did not affect incidental hand OA. However, every month of TNFi treatment resulted in a reduced relative risk (RR) of hand OA progression in DIP joints [relative risk (RR) 0.987 (95% CI 0.978, 0.996)] but not in PIP joints. On the joint level, the effect on hand OA progression was observed in DIP joints [RR 0.996 (95% CI 0.991, 1.000)] but not in PIP joints. The results from the KL score analyses were comparable to the osteophyte score. Conclusion: TNFi treatment was associated with a reduced risk on radiographic hand OA progression in DIP joints but not in PIP joints after 10 years. Although the effect sizes are small, these results provide evidence for influence of TNF-α in hand OA pathogenesis.

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.

Muscle wasting in male TNF-α blocker naïve ankylosing spondylitis patients: a comparison of gender differences in body composition.

Objective: To assess gender differences in body composition (BC) in a cohort of AS patients naïve to TNF-α blockers. Methods: Patients included fulfilled the Modified New York criteria for AS. Demographic information and disease activity measures (ASDAS and BASDAI) were reported. BC was measured by whole body DXA. Body fat percentage (BF%), fat mass index (FMI), fat free mass index (FFMI) and android/gynoid fat ratio were reported and compared between men and women and with the reference population (percentiles). Results: Seventy consecutive patients were included; 60% were men. Demographic variables were similar, except for dyslipidaemia (57.1% of men; 14.3% of women). Women had significantly more fat (BF%, FMI), and less muscle (FFMI) than men, but below the median of the reference population. Male AS patients had a markedly low FFMI (31.7th percentile) compared with the reference population. In the whole group, after multivariate analysis, an ASDAS CRP >3.5 was related to lower fat free mass content. In men, a significant relationship between having a high disease activity (ASDAS, BASDAI) and lower BF% or FMI percentile was found, but in women it was the opposite. Conclusion: Muscle wasting, measured as low FFMI compared with the reference population, was found in male TNF-α blocker naïve AS patients, especially in those with active disease. Women had higher volumes of body fat than men, but near the median of the reference population. The relationships between fat content and disease activity support the complex association between adipose tissue and inflammation.

Similar efficacy and safety of initial COBRA-light and COBRA therapy in rheumatoid arthritis: 4-year results from the COBRA-light trial.

Objective: To assess the efficacy and safety of initial COBRA-light vs COBRA therapy in RA patients after a 4-year follow-up period. Methods: In the COBRA-light trial, 162 consecutive patients with recent-onset RA were randomized to either COBRA-light (prednisolone and MTX) or COBRA therapy (prednisolone, MTX and SSZ) for 1 year. After 1 year, treatment was continued without protocol, and adjusted by the treating physician according to clinical judgement, preferably with a treat-to-target strategy. Four years after trial initiation, all patients were invited to participate in the COBRA-light extension study, in which patients were interviewed and physically examined, patient reported outcomes were assessed, radiographs were made and clinical records were examined for comorbidities and medication use. Results: In the extension study, 149 out of 162 (92%) original trial patients participated: 72 COBRA-light and 77 COBRA patients. Initial COBRA-light and COBRA therapy showed similar effect on disease activity, physical functioning, radiological outcome and Boolean remission over the 4-year follow-up period. In addition, both treatment groups showed similar survival and major comorbidities, although the power to detect differences was limited. Besides protocolled differences in prednisolone, MTX and SSZ use, the use of other synthetic and biologic DMARDs and intra-articular and intramuscular glucocorticoid injections was similar in both treatment groups over the 4-year period. Conclusion: Early RA patients initially treated with COBRA-light or COBRA therapy had similar efficacy and safety outcomes over a 4-year follow-up period.

Cardiovascular risk management in rheumatoid arthritis patients still suboptimal: the Implementation of Cardiovascular Risk Management in Rheumatoid Arthritis project.

Objective: To assess the 10-year cardiovascular (CV) risk score and to identify treatment and undertreatment of CV risk factors in patients with established RA. Methods: Demographics, CV risk factors and prevalence of cardiovascular disease (CVD) were assessed by questionnaire. To calculate the 10-year CV risk score according to the Dutch CV risk management guideline, systolic blood pressure was measured and cholesterol levels were determined from fasting blood samples. Patients were categorized into four groups: indication for treatment but not treated; inadequately treated, so not meeting goals (systolic blood pressure ⩽140 mmHg and/or low-density lipoprotein ⩽2.5 mmol/l); adequately treated; or no treatment necessary. Results: A total of 720 consecutive RA patients were included, 375 from Reade and 345 from the Antonius Hospital. The mean age of patients was 59 years (s.d. 12) and 73% were female. Seventeen per cent of the patients had a low 10-year CV risk (<10%), 21% had an intermediate risk (10-19%), 53% a high risk (⩾20%) and 9% had CVD. In total, 69% had an indication for preventive treatment (cholesterol-lowering or antihypertensive drugs). Of those, 42% received inadequate treatment and 40% received no treatment at all. Conclusion: Optimal CV risk management remains a major challenge and better awareness and management are urgently needed to reduce the high risk of CVD in the RA population.

Analgesic use in patients with knee and/or hip osteoarthritis referred to an outpatient center: a cross-sectional study within the Amsterdam Osteoarthritis Cohort.

Although analgesics are widely recommended in current guidelines, underuse and inadequate prescription of analgesics seem to result in suboptimal treatment effects in patients with knee and/or hip osteoarthritis (OA). This study aimed (i) to describe the use of analgesics; and (ii) to determine factors that are related to analgesic use in patients with knee and/or hip OA referred to an outpatient center. A cross-sectional study with data from 656 patients with knee and/or hip OA referred to an outpatient center (Amsterdam Osteoarthritis (AMS-OA) cohort) was conducted. Self-reported use of analgesic (yes/no) was administered and subdivided into acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs, including coxibs) and opioids. Logistic regression analyses were performed to analyze the association between analgesic use and disease-related, predisposing and enabling factors. Analgesic use was reported by 63% of the patients, with acetaminophen, NSAIDs and opioid use reported by 50, 30 and 12%, respectively. Factors related to analgesic use were higher pain severity, longer duration of symptoms, higher radiographic hip OA severity, overweight/obesity and psychological distress. These factors explained 21% of the variance of analgesic use. More than one-third of patients with established knee and/or hip OA referred to an outpatient center did not use any analgesics. Although multiple, mostly disease-related associated factors were found, analgesic use remained predominantly unexplained. Our study seems to indicate that prescription of analgesics should be guided more dominantly by clinical symptoms and needs, and preceded by a thorough shared decision-making process between patient and physician.