Aage Vestergaard

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.

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.

Conventional radiography requires a MRI-estimated bone volume loss of 20% to 30% to allow certain detection of bone erosions in rheumatoid arthritis metacarpophalangeal joints

The aim of this study was to demonstrate the ability of conventional radiography to detect bone erosions of different sizes in metacarpophalangeal (MCP) joints of rheumatoid arthritis (RA) patients using magnetic resonance imaging (MRI) as the standard reference. A 0.2 T Esaote dedicated extremity MRI unit was used to obtain axial and coronal T1-weighted gradient echo images of the dominant 2nd to 5th MCP joints of 69 RA patients. MR images were obtained and evaluated for bone erosions according to the OMERACT recommendations. Conventional radiographs of the 2nd to 5th MCP joints were obtained in posterior-anterior projection and evaluated for bone erosions. The MRI and radiography readers were blinded to each others assessments. Grade 1 MRI erosions (1% to 10% of bone volume eroded) were detected by radiography in 20%, 4%, 7% and 13% in the 2nd, 3rd, 4th and 5th MCP joint, respectively. Corresponding results for grade 2 erosions (11% to 20% of bone volume eroded) were 42%, 10%, 60% and 24%, and for grade 3 erosions (21% to 30% of bone volume eroded) 75%, 67%, 75% and 100%. All grade 4 (and above) erosions were detected on radiographs. Conventional radiography required a MRI-estimated bone erosion volume of 20% to 30% to allow a certain detection, indicating that MRI is a better method for detection and grading of minor erosive changes in RA MCP joints.

Does low-field dedicated extremity MRI (E-MRI) reliably detect bone erosions in rheumatoid arthritis? A comparison of two different E-MRI units and conventional radiography with high-resolution CT scanning

Objectives: To compare the ability of two different E-MRI units and conventional radiography (CR) to identify bone erosions in rheumatoid arthritis (RA) metacarpophalangeal (MCP) and wrist joints with CT scanning as the standard reference method. Methods: 20 patients with RA and 5 controls underwent CR, CT and two E-MRI examinations (Esaote Biomedica Artoscan and MagneVu MV1000) of one hand during a 2-week period. In all modalities, each bone of the wrist and MCP joints was blindly evaluated for erosions. MagneVu images were also assessed for the proportion of each bone being visualised. Results: 550 bones were examined. CT, Artoscan, MagneVu and CR detected 188, 116, 55 and 45 bones with erosions, respectively. The majority were located in the carpal bones. The sensitivity of the Artoscan for detecting erosions was higher than that of the MagneVu and CR (MCP joints: 0.68, 0.54 and 0.57, respectively; wrists: 0.50, 0.23 and 0.29). Corresponding specificities for detecting erosions were 0.94, 0.93 and 0.99, respectively, in the MCP joints and 0.92, 0.98 and 0.98 in the wrist. The MagneVu allowed visualisation of 1.5 cm of the ventral-dorsal diameter of the bone. In the wrist, 31.6% of bones were visualised entirely and 37.9% of bones were 67–99% visualised. In MCP joints, 84.2% of bones were visualised entirely and 15.8% of bones were 67–99% visualised. Conclusion: With CT as the reference method for detecting erosions in RA hands, the Artoscan showed higher sensitivity than the MagneVu and CR. All imaging modalities had high specificities. The better performance of the Artoscan should be considered when selecting an imaging method in RA.

The limited value of routine chest X-ray in the follow-up of stage II breast cancer

In 280 patients with stage II breast cancer, chest X-ray was performed at 6 and 12 months and yearly thereafter to the 6th year or until recurrence, another cancer was detected, the patient refused further follow-up or died. Among 1289 scheduled chest X-rays, malignant changes were found in 20 patients, of which only 3 had pulmonary symptoms. In a further 14 patients malignant changes were suspected, but follow-up examinations could not prove malignancy. 26 patients presented within 12 months after the last scheduled X-ray with pulmonary symptoms and a work-up chest X-ray revealed malignant changes. Thus, in only 1.3% of the scheduled X-rays were unsuspected malignant changes diagnosed. Median survival of patients with malignant chest X-rays found at scheduled controls versus between scheduled controls did not differ significantly (P = 0.26). It is concluded that routine chest X-ray is not indicated in patients with stage II breast cancer.

QUALITY OF UROGRAPHY AND RENAL CLEARANCE OF IONIC AND NONIONIC CONTRAST MEDIA

Thomsen HS, Vcstergaard A, Dorph S. Quality of urography and renal clearance of ionic and nonionic contrast media. Invest Radiol 1992;27:40–44.The authors evaluated whether urographic quality correlated with patient hydration and the level of their renal function, depending on whether they received ionic or nonionic contrast media. One hundred patients with normal serum creatinine levels were randomly assigned to receive intravenous urography with either an ionic high-osmolar or a nonionic low-osmolar contrast medium. Patient hydration was evaluated by measuring urine osmolality in a sample voided just before the examination. The plasma concentration of iodine was determined in a single blood sample drawn approximately 3 hours later. From these determinations the plasma clearance of contrast medium was calculated. The urograms were assessed blindly with regard to nephrographic and pyelography opacification, as well as overall diagnostic quality. The clearance varied between 42 and 115 ml. x minutes−1 x 1.73 m−2. No systematic correlation or practical significance was found between the clearances and the urogram quality. A high urinary osmolality before the examination tended to improve quality with both media. It is not possible to assess glomerular filtration rate from nephrographic and pyelographic opacification, or from overall quality of routine urograms in patients with normal serum creatinine levels.

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.

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).

Uncoupling of collagen II metabolism in newly diagnosed, untreated rheumatoid arthritis is linked to inflammation and antibodies against cyclic citrullinated peptides

Objective. To investigate the relationship between markers of collagen II synthesis and degradation with disease activity measures, autoantibodies, and radiographic outcomes in a 4-year protocol on patients with early rheumatoid arthritis (RA) who are naïve to disease-modifying antirheumatic drugs. Methods. One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C-telopeptide of collagen II (CTX-II) were quantified at baseline by ELISA. PIIANP was also assayed at 2 and 4 years. Anticyclic citrullinated peptide (anti-CCP) was recorded at baseline. An uncoupling index for cartilage collagen metabolism was calculated from PIIANP and CTX-II measurements. Results. PIIANP was low at diagnosis and 4 years on (p < 0.001), irrespective of treatment and disease activity. PIIANP was lowest in anti-CCP positive patients (p = 0.006), and there was a negative correlation between PIIANP and anti-CCP titers (ρ = −0.25, p 0.002). CTX-II was increased (p < 0.001) and correlated positively with disease activity and radiographic progression, but not with anti-CCP (p = 0.93). The uncoupling index was not superior to CTX-II in predicting radiographic changes. Conclusion. These results suggest that cartilage collagen formation and degradation are unbalanced when RA is diagnosed. The different associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration by inhibiting collagen IIA formation. Trial registration j.nr NCT00209859.