Henrik Skjødt

MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA)

Objective: To identify predictors of radiographic progression in a 2-year randomised, double-blind, clinical study (CIMESTRA) of patients with early rheumatoid arthritis (RA). Methods: Patients with early RA (n = 130) were treated with methotrexate, intra-articular betamethasone and ciclosporin/placebo-ciclosporin. Baseline magnetic resonance imaging (MRI) of the wrist (wrist-only group, n = 130) or MRI of wrist and metacarpophalangeal (MCP) joints (wrist+MCP group, n = 89) (OMERACT RAMRIS), x-ray examination of hands, wrists and forefeet (Sharp/van der Heijde Score (TSS)), Disease Activity Score (DAS28), anti-cyclic citrullinated peptide antibodies (anti-CCP), HLA-DRB1-shared epitope (SE) and smoking status were assessed. Multiple regression analysis was performed with delta-TSS (0–2 years) as dependent variable and baseline DAS28, TSS, MRI bone oedema score, MRI synovitis score, MRI erosion score, anti-CCP, smoking, SE, age and gender as explanatory variables. Results: Baseline values: median DAS28 5.6 (range 2.4–8.0); anti-CCP positive 61%; radiographic erosions 56%. At 2 years: DAS28 2.0 (0.5–5.7), in DAS remission: 56%, radiographic progression 26% (wrist+MCP group, similar for wrist-only group). MRI bone oedema score was the only independent predictor of delta-TSS (wrist+MCP group: coefficient = 0.75 (95% CI 0.55 to 0.94), p<0.001; wrist-only group: coefficient = 0.59 (95% CI 0.40 to 0.77), p<0.001). Bone oedema score explained 41% of the variation in the progression of TSS (wrist+MCP group), 25% in wrist-only group (Pearson’s r = 0.64 and r = 0.50, respectively). Results were confirmed by sensitivity analyses. Conclusion: In a randomised controlled trial aiming at remission in patients with early RA, baseline RAMRIS MRI bone oedema score of MCP and wrist joints (and of wrist only) was the strongest independent predictor of radiographic progression in hands, wrists and forefeet after 2 years. MRI synovitis score, MRI erosion score, DAS28, anti-CCP, SE, smoking, age and gender were not independent risk factors. Trial registration number: NCT00209859.

Magnetic resonance imaging, radiography, and scintigraphy of the finger joints: one year follow up of patients with early arthritis

OBJECTIVES To evaluate synovial membrane hypertrophy, tenosynovitis, and erosion development of the 2nd to 5th metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints by magnetic resonance imaging in a group of patients with rheumatoid arthritis (RA) or suspected RA followed up for one year. Additionally, to compare the results with radiography, bone scintigraphy, and clinical findings. PATIENTS AND METHODS Fifty five patients were examined at baseline, of whom 34 were followed up for one year. Twenty one patients already fulfilled the American College of Rheumatology (ACR) criteria for RA at baseline, five fulfilled the criteria only after one years follow up, whereas eight maintained the original diagnosis of early unclassified polyarthritis. The following MRI variables were assessed at baseline and one year: synovial membrane hypertrophy score, number of erosions, and tenosynovitis score. RESULTS MRI detected progression of erosions earlier and more often than did radiography of the same joints; at baseline the MRI to radiography ratio was 28:4. Erosions were exclusively found in patients with RA at baseline or fulfilling the ACR criteria at one year. At one year follow up, scores of MR synovial membrane hypertrophy, tenosynovitis, and scintigraphic tracer accumulation had not changed significantly from baseline; in contrast, swollen and tender joint counts had declined significantly (p<0.05). CONCLUSIONS MRI detected more erosions than radiography. MR synovial membrane hypertrophy and scintigraphy scores did not parallel the changes seen over time in clinically assessed swollen and tender joint counts. Although joint disease activity may be assessed as quiescent by conventional clinical methods, a more detailed evaluation by MRI may show that a pathological condition is still present within the synovium.

Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study

Objective: To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study. Methods: 160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76–104 ciclosporine/placebo-ciclosporine was tapered to zero. Results: American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p =  0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp–van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent. Conclusion: Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.

Dynamic magnetic resonance imaging of the metacarpophalangeal joints in rheumatoid arthritis, early unclassified polyarthritis, and healthy controls

Objective. To introduce dynamic magnetic resonance imaging (MRI) as an indicator of inflammatory activity in the metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA) or early unclassified polyarthritis, and to compare the results with a healthy control group. Materials and Methods. We examined 42 RA and 23 early unclassified polyarthritis patients, and 12 healthy controls in a cross-sectional study. Dynamic MRI (repeated FLASH-MR images after injection of a contrast agent) was performed through the 2nd to the 5th MCP joint. Two methods for identification of the enhancing synovial membrane were compared: 1) outlining of enhancing synovial membrane on subtraction images and 2) automated recognition by principal component analysis (PCA). The early enhancement (EE) rate was calculated on the basis of the first method. Results. Method 1) and 2) were closely associated (P<0.00001). From the healthy control group, an upper limit (mean+2SD) of normal enhancement was established for the 2nd to 5th MCP joints, which served to identify abnormal EE rates in the corresponding joints of patients. The patients had higher EE rates in the 2nd to 5th MCP joints than had the healthy controls (P<0.01). There were no significant differences between the two patient groups (P>0.09). Conclusion. PCA seems to be a promising method for automated identification of enhancing tissue. EE rates of the finger joints may be useful in the assessment of the inflammatory activity in the joints of patients with RA and early unclassified polyarthritis and may reflect other aspects of disease activity than clinical evaluation.OBJECTIVE To introduce dynamic magnetic resonance imaging (MRI) as an indicator of inflammatory activity in the metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA) or early unclassified polyarthritis, and to compare the results with a healthy control group. MATERIALS AND METHODS We examined 42 RA and 23 early unclassified polyarthritis patients, and 12 healthy controls in a cross-sectional study. Dynamic MRI (repeated FLASH-MR images after injection of a contrast agent) was performed through the 2nd to the 5th MCP joint. Two methods for identification of the enhancing synovial membrane were compared: 1) outlining of enhancing synovial membrane on subtraction images and 2) automated recognition by principal component analysis (PCA). The early enhancement (EE) rate was calculated on the basis of the first method. RESULTS Method 1) and 2) were closely associated (P<0.00001). From the healthy control group, an upper limit (mean+2SD) of normal enhancement was established for the 2nd to 5th MCP joints, which served to identify abnormal EE rates in the corresponding joints of patients. The patients had higher EE rates in the 2nd to 5th MCP joints than had the healthy controls (P<0.01). There were no significant differences between the two patient groups (P>0.09). CONCLUSION PCA seems to be a promising method for automated identification of enhancing tissue. EE rates of the finger joints may be useful in the assessment of the inflammatory activity in the joints of patients with RA and early unclassified polyarthritis and may reflect other aspects of disease activity than clinical evaluation.

Short- and long-term efficacy of intra-articular injections with betamethasone as part of a treat-to-target strategy in early rheumatoid arthritis: impact of joint area, repeated injections, MRI findings, anti-CCP, IgM-RF and CRP

Objective To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA). Methods During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan–Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested. Results 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not. Conclusion In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Circulating levels of osteopontin, osteoprotegerin, total soluble receptor activator of nuclear factor-kappa B ligand, and high-sensitivity C-reactive protein in patients with active rheumatoid arthritis randomized to etanercept alone or in combination with methotrexate.

Objective: To determine whether circulating levels of osteopontin (OPN), osteoprotegerin (OPG), total soluble receptor activator of nuclear factor‐kappa B ligand (total sRANKL), and high‐sensitivity C‐reactive protein (hsCRP) change in patients with rheumatoid arthritis (RA) during immunosuppressive therapy. Methods: Twenty‐five active RA patients were randomized to treatment with either etanercept alone or in combination with methotrexate (MTX). The treatment response after 16 weeks was assessed using the European League Against Rheumatism (EULAR) response criteria. Blood samples were taken before the start of and every fourth week during the study. OPN, OPG, and total sRANKL were measured by enzyme‐linked immunosorbent assays (ELISAs) and hsCRP by highly sensitive turbidometry. Results: At baseline, OPN and hsCRP were significantly (p<0.001) elevated compared to healthy persons. Compared to baseline only hsCRP levels decreased significantly (p<0.05 to p<0.001) in the EULAR responders through the study. OPN remained significantly (p<0.05) elevated at 16 weeks in patients with a low disease activity score (DAS⩽3.2). Total sRANKL increased significantly (p<0.05) from baseline to week 12. No statistically significant changes were observed in the non‐responders. Conclusion: Active RA patients showed increased circulating levels of hsCRP and OPN, but only hsCRP decreased during etanercept therapy. Our findings suggest that OPN, OPG, total sRANKL, and hsCRP reflect different aspects of the inflammatory process in RA.

Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influence of alendronate and intra-articular glucocorticoid treatment. Post hoc analyses from the CIMESTRA trial

Objectives The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during 1 year of a treat-to-target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)). Patients and methods A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score ≤0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp-van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients. Results The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged −2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients (–1.8% and –2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0–19), non-alendronate: 0 (0–18)). Conclusions In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression.

Mannose-Binding Lectin Gene Polymorphisms Are Associated with Disease Activity and Physical Disability in Untreated, Anti-Cyclic Citrullinated Peptide-Positive Patients with Early Rheumatoid Arthritis

Objective. To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). Methods. Patients with early RA (n = 158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position −221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). Results. Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p = 0.02), and physical disability by HAQ (p = 0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. Conclusion. The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

Differentiation between early rheumatoid arthritis patients and healthy persons by conventional and dynamic contrast-enhanced magnetic resonance imaging

Objectives: To identify the magnetic resonance imaging (MRI) parameter that best differentiates healthy persons and patients with early rheumatoid arthritis (RA), and to investigated responsiveness to treatment of various MRI parameters. Method: Conventional MRI and dynamic contrast-enhanced (DCE)-MRI of the hand were performed once for 26 healthy persons, and before and after 6 and 12 months of disease-modifying anti-rheumatic drug (DMARD) treatment for 14 early RA patients, using a 1.0-T MRI unit. One-slice DCE-MRI was analysed using Dynamika version 4.2. The number of enhancing voxels (Nvoxel), the initial rate of enhancement (IRE), the maximum enhancement (ME), ME×Nvoxel, and IRE×Nvoxel were calculated for wrist and 2nd–5th metacarpophalangeal (MCP) joints. Conventional MR images were evaluated using the RA MRI scoring system (RAMRIS) synovitis score. Results: Using DCE-MRI, enhancement was demonstrated in 61.5% of healthy persons and in 91.7% of RA patients at baseline, with a median Nvoxel of 3 and 362, respectively. At baseline, all parameters were higher for patients than for healthy persons (all p ≤ 0.003). Only one patient had a baseline RAMRIS synovitis score below the 95th percentile of the healthy persons. The corresponding number of patients was 3 for Nvoxel, ME×Nvoxel and IRE×Nvoxel, and 10 for IRE and ME. The RAMRIS synovitis score and IRE showed the highest responsiveness, with a standardized response mean (SRM) of –1.00 and –0.88, respectively. Conclusions: The RAMRIS synovitis scoring of conventional MRI, and to a lesser extent the one-slice DCE-MRI parameters of synovial volume, differentiated early RA patients and healthy persons. The decrease in RAMRIS synovitis score, Nvoxel, and IRE showed sensitivity to change during treatment.

Circulating surfactant protein -D is low and correlates negatively with systemic inflammation in early, untreated rheumatoid arthritis

IntroductionSurfactant protein D (SP-D) is a collectin with immuno-regulatory functions, which may depend on oligomerization. Anti-microbial and anti-inflammatory properties have been attributed to multimeric SP-D variants, while trimeric subunits per se have been suggested to enhance inflammation. Previously, we reported low circulating SP-D in early rheumatoid arthritis (RA), and the present investigation aims to extend these data by serial SP-D serum measurements, studies on synovial fluid, SP-D size distribution and genotyping in patients with early RA.MethodsOne-hundred-and-sixty disease-modifying antirheumatic drug (DMARD) naïve RA patients with disease duration less than six months were studied prospectively for four years (CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) trial) including disease activity measures (C-reactive protein, joint counts and Health Assessment Questionnaire (HAQ) score), autoantibodies, x-ray findings and SP-D. SP-D was quantified by enzyme-linked immunosorbent assay (ELISA) and molecular size distribution was assessed by gel filtration chromatography. Further, SP-D Met11Thr single nucleotide polymorphism (SNP) analysis was performed.ResultsSerum SP-D was significantly lower in RA patients at baseline compared with healthy controls (P < 0.001). SP-D increased slightly during follow-up (P < 0.001), but was still subnormal at four years after adjustment for confounders (P < 0.001). SP-D in synovial fluid was up to 2.5-fold lower than in serum. While multimeric variants were detected in serum, SP-D in synovial fluid comprised trimeric subunits only. There were no significant associations between genotype distribution and SP-D. Baseline SP-D was inversely associated to CRP and HAQ score. A similar relationship was observed regarding temporal changes in SP-D and CRP (zero to four years). SP-D was not associated to x-ray findings.ConclusionsThis study confirms that circulating SP-D is persistently subnormal in early and untreated RA despite a favourable therapeutic response obtained during four years of follow-up. SP-D correlated negatively to disease activity measures, but was not correlated with x-ray progression or SP-D genotype. These observations suggest that SP-D is implicated in RA pathogenesis at the protein level. The exclusive presence of trimeric SP-D in affected joints may contribute to the maintenance of joint inflammation.Trial registration(j.nr NCT00209859).