Effect of initiating biologics compared to intensifying conventional DMARDs on clinical and MRI outcomes in established rheumatoid arthritis patients in clinical remission: Secondary analyses of the IMAGINE-RA trial.

OBJECTIVES: To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. METHOD: One-hundred patients with established RA, Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as 'in clinical remission') who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models. RESULTS: Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0-2.6), HAQ score (0.08, 0.03-0.1), MRI combined inflammation (2.5, 0.9-4.1), and SDAI scores (2.7, 1.9-3.5). CONCLUSIONS: Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01656278.

Scoring magnetic resonance imaging (MRI) inflammation and structural lesions in sacroiliac joints of patients with axial spondyloarthritis: assessment of all MRI slices of the cartilaginous compartment versus standardized six or five slices.

Objectives: The Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joint (SIJ) scoring system assesses six or five (6/5) semicoronal magnetic resonance imaging (MRI) slices for inflammation/structural lesions in patients with axial spondyloarthritis (axSpA). However, the cartilaginous SIJ compartment may be visible in a few additional slices. The objective was to investigate interreader reliability, sensitivity to change, and classification of MRI scans as positive or negative for various lesion types using an 'all slices' approach versus standard SPARCC scoring of 6/5 slices.Method: Fifty-three axSpA patients were treated with the tumour necrosis factor inhibitor golimumab and followed with serial MRI scans at weeks 0, 4, 16, and 52. The most anterior and posterior slices covering the cartilaginous compartment and the transitional slice were identified. Scores for inflammation, fat metaplasia, erosion, backfill, and ankylosis in the cartilaginous SIJ compartment were calculated for the 'all slices' approach and the 6/5 slices standard.Results: By the 'all slices' approach, three readers scored mean 7.2, 7.7, and 7.0 slices per MRI scan. Baseline and change scores for the various lesion types closely correlated between the two approaches (Pearson's rho ≥ 0.95). Inflammation score was median 13 (interquartile range 6-21, range 0-49) for 6/5 slices versus 14 (interquartile range 6-23, range 0-69) for all slices at baseline. Interreader reliability, sensitivity to change, and classification of MRI scans as positive or negative for various lesion types were similar.Conclusion: The standardized 6/5 slices approach showed no relevant differences from the 'all slices' approach and, therefore, is equally suited for monitoring purposes.

Structural progression rate decreases over time on serial radiography and magnetic resonance imaging of sacroiliac joints and spine in a five-year follow-up study of patients with ankylosing spondylitis treated with tumour necrosis factor inhibitor.

OBJECTIVE: To investigate temporal changes in structural progression assessed by serial conventional radiography and magnetic resonance imaging (MRI) of the sacroiliac joints (SIJs) and spine in patients with ankylosing spondylitis (AS) treated with tumour necrosis factor (TNF) inhibitor for 5 years. METHOD: Forty-two patients were included and 33 patients were followed for 5 years in a prospective investigator-initiated study. Conventional radiographs were required four times and MRI seven times. The modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS); Spondyloarthritis Research Consortium of Canada (SPARCC) MRI SIJ and Spine Inflammation, and SPARCC MRI SIJ Structural Score (SSS) for Fat, Erosion, Backfill, and Ankylosis; and the Canada-Denmark MRI scores for Spine Inflammation, Fat, Erosion, and New Bone Formation (NBF) were applied. RESULTS: Compared with baseline, MRI Inflammation had decreased significantly at week 22 (spine)/week 46 (SIJ) and thereafter. MRI SIJ Fat (from week 22), SIJ Ankylosis, Spine NBF, and mSASSS had increased significantly at week 46 and thereafter. SIJ Erosion had decreased from year 2. The annual progression rate in mSASSS was significantly higher during weeks 0-46 compared to week 46 to year 3. In multivariate regression analyses, baseline SIJ Inflammation and Backfill were independent predictors of 5 year progression in SIJ Ankylosis. Spine Erosion predicted progression in Spine NBF. Longitudinally, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, MRI Spine Inflammation, Fat, and Erosion scores were significantly associated with mSASSS. SIJ Inflammation, Fat, Erosion, and Backfill scores were longitudinally associated with SIJ Ankylosis. Structural progression was not associated with body mass index, smoking, or Assessment of SpondyloArthritis international Society Non-Steroidal Anti-Inflammatory Drug Index. CONCLUSION: In a 5 year follow-up study of patients with AS treated with TNF inhibitor, structural progression decreased over time.

Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage.

OBJECTIVES: To investigate the multi-biomarker disease activity (MBDA) score by comparison with imaging findings in an investigator-initiated rheumatoid arthritis (RA) trial (HURRAH trial, NCT00696059). METHOD: Fifty-two patients with established RA initiated adalimumab treatment and had magnetic resonance imaging (MRI), ultrasonography (US), computed tomography (CT), and radiography performed at weeks 0, 26, and 52. Serum samples were analysed using MBDA score assays and associations between clinical measures, MBDA score, and imaging findings were investigated. RESULTS: The MBDA score correlated significantly with MRI synovitis (rho = 0.65, p < 0.001), MRI bone marrow oedema (rho = 0.36, p = 0.044), and US power Doppler (PD) score at week 26 (rho = 0.35, p = 0.039) but not at week 0 or week 52. In the 15 patients who had achieved a Disease Activity Score based on C-reactive protein (DAS28-CRP) < 2.6 at week 26, MRI and/or US detected subclinical inflammation and 13 (87%) had a moderate/high MBDA score. For the cohort with available data, none of the four patients in MBDA remission (score ≤ 25) at week 26 had progression of imaging damage from baseline to week 52 whereas progression was observed in three out of nine (33%) and seven out of 21 (33%) patients with moderate (30-44) and high (> 44) MBDA scores, respectively. CONCLUSIONS: In this cohort, the MBDA score correlated poorly with MRI/US inflammation. However, the MBDA score and MRI/US were generally concordant in showing signs of inflammation in most patients in clinical remission during anti-tumour necrosis factor (anti-TNF) therapy. MBDA scores were elevated in all patients with structural damage progression.

Pattern of bone erosion and bone proliferation in psoriatic arthritis hands: a high-resolution computed tomography and radiography follow-up study during adalimumab therapy.

OBJECTIVES: To investigate the pattern and development of bone erosion and proliferation in patients with psoriatic arthritis (PsA) during treatment with adalimumab, using high-resolution computed tomography (CT) and conventional radiography. METHOD: Forty-one biologic-naïve PsA patients were initiated with adalimumab 40 mg subcutaneously every other week. CT and radiography of the 2nd-5th metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints were conducted at baseline (n = 41) and after 24 weeks (n = 32). Changes in bone erosion and proliferation are described and the imaging modalities compared. RESULTS: Ninety percent of bone erosions detected by CT were located in the metacarpal heads, and most frequently in the 2nd-3rd MCP joints. Radial (37%) and ulnar (31%) surfaces were more frequently eroded than dorsal (10%) and palmar (22%) sites. Using CT, bone proliferations were located primarily on the sides of the distal part of the DIP joints (43% of all proliferations), but also proximally in DIP (17%) and MCP joints (27%). For bone erosions and proliferations, respectively, radiography showed a low sensitivity (17% and 26%), but a high specificity (98% and 95%) and accuracy (93% and 87%), with CT as the gold standard reference. Neither CT nor radiography revealed statistically significant changes in bone erosion or proliferation scores between baseline and follow-up. CONCLUSIONS: Patterns of bone erosion and proliferation in PsA hands were revealed in more detail by CT than by radiography. No overall progression or repair could be detected during adalimumab treatment with either of the methods.

Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept.

We present a case of toxic hepatitis related to infliximab treatment in a 38-year-old woman with rheumatoid arthritis (RA). The patient had previously been treated with different disease-modifying drugs (DMARDs) alone or in combination but had never revealed signs of liver dysfunction. Due to high disease activity, treatment with infliximab (3 mg/kg i.v.) was initiated in combination with methotrexate (MTX) (25 mg/week) and folic acid (5 mg/week). The patient stopped MTX and folic acid on her own initiative after 3 weeks due to improvement of joint symptoms. After seven infusions, progressive elevations of the transaminases up to five times the upper normal limit were noted and treatment with infliximab was terminated. Serological tests for viral and autoimmune hepatitis and for ANA and anti-dsDNA were all negative. Specific infliximab antibodies could not be detected. Ultrasound of the liver was normal. Liver biopsy showed late signs of acute toxic hepatitis without MTX-related fibrosis. This is one the first cases that convincingly demonstrates that infliximab treatment may cause toxic hepatitis. Moreover, the case suggests a lack of hepatic cross-toxicity between infliximab and etanercept as the patient continued with etanercept without new episodes of liver dysfunction.

Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure.

OBJECTIVE: With computed tomography (CT) and radiography, to investigate if repair of bone erosions, defined as regression of erosion scores, occurs during adalimumab treatment of patients with rheumatoid arthritis (RA). METHODS: Fifty-two patients with RA, naïve to biological agents, with at least two low-grade radiographic erosions in the wrist or metacarpophalangeal (MCP) joints in the same (index) hand, initiated adalimumab 40 mg subcutaneously every other week. Thirty-five patients completed the study (median age 61 years (interquartile range 46-68), disease duration 8 years (3-15)). CT of the index wrist and MCP joints 2-5 and radiographs of hands and forefeet were obtained at baseline, 6 and 12 months. Images were evaluated by investigators blinded to chronology and clinical data, and assessed according to Sharp/van der Heijde (radiographs) and OMERACT RA MRI scoring (CT) methods. RESULTS: Disease activity score, C-reactive protein, tender and swollen joints count and Health Assessment Questionnaire score had all decreased at 6 and 12 months (wilcoxon signed-ranks test p<0.001). No significant change in any imaging parameters of joint destruction was observed at 6 and 12 months. High intrareader agreements were reached (mean intraobserver intraclass coefficients: 0.96 (CT) and 0.97 (radiography)). The number of patients with change scores exceeding the smallest detectable change (SDC) was comparable on CT and radiography, as were the proportions of patients progressing/regressing. Decreased erosion scores at 12 months were registered in 1.6% and 1.8% of sites assessed on CT and radiography, respectively. CONCLUSION: Repair of erosions in adalimumab-treated patients with RA is rare, but erosive regression, exceeding the SDC, on CT and radiography occurred. The very limited overall erosive progression supports the view that joint destruction is minimal during adalimumab treatment of patients with RA.

The Bath metrology index as assessed by a trained and an untrained rater in patients with spondylarthropathy: a study of intra- and inter-rater agreements.

The Bath ankylosing spondylitis metrology index (BASMI; range 0-10) has gained widespread use in daily clinical practice as an objective measure of spinal stiffness not only in patients with ankylosing spondylitis (AS) but also in patients with other spondylarthropathies (SpA). We examined intra-rater and inter-rater reproducibility of BASMI scoring in 30 Danish patients with SpA (median age 40 years, range 22-56 years) fulfilling the European Spondylarthropathy Study Group criteria, 25 of them satisfying the modified New York Criteria for AS. Measurements were performed twice on two different days (median interval 7 days, range 4-11) by a trained physiotherapist (PT) and by an untrained nurse who had undergone a single 1-h training session with the PT. The median BASMI score obtained by the PT on the two test days was 3.5 (range 1-8) and 3.0 (range 1-8), respectively (NS). Test-retest BASMI scores from the PT were significantly correlated (r(s) = 0.95, p < 0.0001). The 95% likely range for the difference between a patient's BASMI scores from two tests was +/-1.4 corresponding to a minimal detectable difference of +/-2 in the individual patient as the scale consists of intervals of 1. Similar results were achieved by the nurse. BASMI scores obtained by the two raters were significantly inter-correlated (r(s) = 0.95, p < 0.0001). The mean difference between paired BASMI scores obtained by the nurse and the PT on test day 1 was -0.2 with a minimal detectable difference of +/-2. A similar result was found using data from test day 2. In conclusion, a change in BASMI less than 2 may be due solely to expected random measurement error. A single 1-h training session allowed an untrained nurse to obtain BASMI results almost identical to those of an experienced PT.

Bone status in rheumatoid arthritis assessed at peripheral sites by three different quantitative ultrasound devices.

Rheumatoid arthritis (RA) is characterized by periarticular and generalized loss of bone mass. Quantitative ultrasound (QUS) has been introduced as a method for the assessment of bone status and fracture risk. In this cross-sectional study bone status was assessed by QUS at different peripheral sites in 27 women with RA (mean disease duration 15 years) and in 36 healthy women matched for age, height and weight. Speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz) and stiffness of the calcaneus were assessed by a Lunar Achilles device. Amplitude-dependent SOS (Ad-SOS, m/s) of the second to fifth phalanx was measured by a DBM Sonic 1200, and SOS of the distal forearm and third phalanx was measured by a Omnisense multisite scanner. Bone mass (g/cm2 or g) of the hip, spine, distal forearm and total body was measured by dual-energy X-ray absorptiometry. QUS values were significantly reduced in RA at most sites ( p<0.005-0.001), but between-group differences were small, and large overlaps between the groups were noticed. After correction for bone mass, the observed differences remained statistically significant for the calcaneus and distal radius ( p<0.05). Independent associations between ultrasound measures and markers of disease activity were not demonstrated. In conclusion, bone status as assessed by QUS was compromised in RA, but whether ultrasound transmission may serve as a marker of disease progression and fracture risk in the individual patient remains to be clarified in prospective studies.

Bone quality and bone mass as assessed by quantitative ultrasound and dual energy x ray absorptiometry in women with rheumatoid arthritis: relationship with quadriceps strength.

OBJECTIVE: To examine relationships of bone quality as assessed by quantitative ultrasound (QUS) and bone mineral density (BMD, g/cm(2)) with quadriceps strength (QS) in women with rheumatoid arthritis (RA). METHODS: Sixty seven women with RA according to the 1987 American College of Rheumatology (ACR) criteria were examined. Mean (SD) age was 62 (13) years, mean disease duration 15 years. Most were or had been receiving glucocorticoid treatment. Calcaneal bone quality expressed as speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz), and stiffness was measured by QUS. BMD of the femoral neck, spine, and distal forearm was measured by dual energy x ray absorptiometry (DXA). Maximal voluntary isokinetic quadriceps strength (Nm) was assessed by isokinetic dynamometry. Pain was recorded on a visual analogue scale (VAS), disability was scored by the Stanford Health Assessment Questionnaire (HAQ), and the degree of physical impairment was expressed by the Steinbrocker index (SI). RESULTS: In multiple regression analyses, QS predicted SOS, BUA, and stiffness (r(partial) ranging from 0.36 to 0.45, p<0.005) and femoral neck BMD (r(partial)=0.30, p<0.05) independently of age, height, weight, disease duration, HAQ, VAS, SI, and cumulative steroid dose. BMD of the spine and distal forearm was not associated with QS. After adjustment for covariates, women with subnormal BMD of the femoral neck (T score <-1), had a 20% lower QS than those with normal BMD (p<0.0001). CONCLUSIONS: Calcaneal bone quality and femoral neck BMD were associated with QS in women with RA. This finding indicates that physical activity including muscle strengthening exercises may play a part in the prevention of bone loss in these patients.

Associations of isokinetic knee extensor and flexor strength with steroid use and walking ability in women with rheumatoid arthritis.

Seventy-five women with rheumatoid arthritis according to the 1987 criteria of the American Rheumatism Association were examined. Mean age was 61.9 +/- 12.5 years, mean disease duration 14 years. Sixty-three were or had been on steroids (median cumulative prednisolone dose 2.5 g). Maximal voluntary knee extensor and flexor strength (Nm) was assessed at 30 degrees/s by an isokinetic dynamometer. Walking ability was expressed as walking and stair-climbing time (s). Markers of disease activity included number of swollen and tender joints, pain as recorded by the patients on a visual analogue scale (VAS), and disability as scored by the Stanford Health Assessment Questionnaire (HAQ). Muscle strength, walking time (50 m) and stair-climbing time were reduced on average by 30%, and increased by 28% and 54% (p<0.0001), respectively, compared to 67 age-, weight- and height-matched healthy women. Associations between muscle strength and cumulative or current steroid dose were not found after correction for age and disease duration. Significant linear correlations were found between knee extensor strength and walking time (r =-0.78, p<0.0001) and stair-climbing time (r = -0.76, p<0.0001). Similar correlations were found for flexor strength. The correlations remained significant (Rpartial ranging from -0.64 to -0.69, p<0.0001) in multiple regression analyses adjusting for age, height, weight, disease duration, number of swollen and tender joints, and VAS and HAQ scores. In conclusion, negative effects of steroids on muscle strength were not demonstrated. Leg muscle strength is an important and independent determinator of walking ability in RA.

Effects of silicone breast prostheses on the assessment of body composition by dual-energy X-ray absorptiometry.

We examined the influence of silicone breast prostheses on body composition as assessed by dual-energy X-ray absorptiometry (DXA). Eighteen women were measured with and without a pair of silicone breast prostheses placed on the upper part of the trunk simulating endogenous implants. Bone area, bone mineral content (BMC), areal bone mineral density (BMD), lean tissue mass (LTM) and fat tissue mass (FTM) of the total body and of the subregions of the body, i.e. the head, trunk, arms and legs, were measured by a Norland XR-36 DXA scanner. After application of the silicone prostheses, bone area, BMC and BMD of the total body significantly increased by an average of 3.7, 6.6 and 3.4% (P<0.0001), respectively. Total body LTM and FTM were not affected. In the trunk region, changes were more pronounced. Trunk BMC, for example, was overestimated by 17.9% (P<0. 0001). The prostheses also influenced measurements of truncal soft tissue composition, with a small but statistically significant overestimation of both LTM (1.1%) and FTM (2.1%) (P<0.05). No changes in bone mass and soft tissue composition were seen in the head, arms and legs. Activation of a high-density detection software utility provided by the manufacturer had no influence on any of the measurements. We conclude that silicone breast prostheses affect the assessment of body composition by DXA.

Quadriceps strength in women with a previous hip fracture: relationships to physical ability and bone mass.

Associations between physical ability, level of current physical activity and bone mass were examined in 47 elderly women (mean age 80 years) who had suffered from a hip fracture 3-36 months (mean 17 months) previously. Measures of physical ability included isokinetic quadriceps strength of both the non-fractured and fractured leg, and walking and stair climbing speed. An estimate of current physical activity was made using the Northwick Park activity index questionnaire specifically designed for hip fracture patients. Bone mineral density of the spine and hip (Ward's triangle, femoral neck and trochanter) was assessed by dual energy X-ray absorptiometry. Relationships between the measured parameters were analysed using multiple regression analyses, taking into account the confounding effects of age, height, weight and months since fracture. Quadriceps strength of the fractured leg was on average 18% lower than that of the contralateral leg (p < 0.001). Quadriceps strength of the fractured leg proved to be the most robust predictor of walking speed (Rpartial = 0.69, p < 0.0001), stair climbing speed (Rpartial = 0.46, p < 0.001) and the activity index (Rpartial = 0.56, p < 0.0001). Bone mineral density was independently predicted only by body weight (Rpartial range: 0.45-0.72, p < 0.001), not by any of the parameters of physical ability or by the Northwick Park activity index. In conclusion, quadriceps strength is markedly affected in women with a previous hip fracture and is associated with walking ability and level of physical activity. This study showed that bone mass is linked to body weight, not to physical ability and activity. Thus, the main benefit of muscle strengthening exercises in these women may be to promote mobility.

Relationships between bone mineral density, serum vitamin D metabolites and calcium:phosphorus intake in healthy perimenopausal women.

OBJECTIVES: To determine the relationships between serum vitamin D metabolites, bone mass, and dietary calcium and phosphorus in a cohort of 510 healthy Danish perimenopausal women. DESIGN: A population-based cross-sectional study. SUBJECTS: A total of 510 healthy women aged 45-58 years, with amenorrhoea for 3-24 months. None of the women was using hormone replacement therapy. MEASUREMENTS: Measurements of total bone mineral content and regional bone mineral density were performed by dual-energy X-ray absorptiometry. Analyses of serum levels of 25-OHD and 1,25-(OH)2D, intact PTH, ionized calcium and phosphate, as well as biochemical markers of bone turnover in blood and urine. Assessment of calcium and phosphorus intake using dietary records. RESULTS: A consistent inverse relationship between serum 1,25-(OH)2D and bone mineral content/ density was found in whole-body mineral content (P = 0.001), spine (P = 0.005) and femoral neck (P<0.05). There was a positive relationship between levels of 1,25-(OH)2D and biochemical bone markers, indicating that high levels of 1,25-(OH)2D are accompanied by increased bone turnover. The dietary calcium:phosphorus ratio was inversely related to serum 1,25-(OH)2D (P = 0.04) and positively related to bone mineral density (P<0.0005). No relationships could be detected between levels of PTH, serum ionized calcium and phosphate, and serum vitamin D metabolites. CONCLUSION: Within normal physiological range, elevated levels of 1,25-(OH)2D were associated with decreased bone mineral density and content, reduced calcium:phosphorus ratio in the diet and increased bone turnover.

Early changes in muscle strength after total knee arthroplasty. A 6-month follow-up of 30 knees.

We studied 30 patients with arthrosis in one knee operated on with a cemented (n 26) or an uncemented total knee arthroplasty (TKA) (n 4). Full weight-bearing from the first postoperative day was allowed in all patients, and they received standard postoperative physiotherapy. 1 week prior to surgery, and after 3 and 6 months, isokinetic and isometric muscle strength in both legs were measured, using a Cybex 6000 dynamometer. Isokinetic tests showed a bilateral, significant, and progressive increase (30-53%) in flexor muscle strength most pronounced in the operated legs. Isokinetic extensor strength increased significantly (14-18%) in the operated legs, while in the contralateral legs, a limited increase was found. Isometric flexion strength significantly decreased in the operated knees (17%). Isometric extension strength showed a temporary decrease at 3 months, which returned to the preoperative level. No significant change in isometric strength was observed in the contralateral legs. The knee pain during the muscle strength measurements decreased significantly from the preoperative level, which may indicate that the substantial pain relief within 3 months after a TKA is an important factor for evaluation of muscle strength.