Kristina Forslind

EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis

Objective To develop evidence-based recommendations on the use of imaging of the joints in the clinical management of rheumatoid arthritis (RA). Methods The task force comprised an expert group of rheumatologists, radiologists, methodologists and experienced rheumatology practitioners from 13 countries. Thirteen key questions on the role of imaging in RA were generated using a process of discussion and consensus. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, dual-emission x-ray absorptiometry, digital x-ray radiogrammetry, scintigraphy and positron emission tomography. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. The experts used the evidence obtained from the relevant studies to develop a set of 10 recommendations. The strength of recommendation was assessed using a visual analogue scale. Results A total of 6888 references was identified from the search process, from which 199 studies were included in the systematic review. Ten recommendations were produced encompassing the role of imaging in making a diagnosis of RA, detecting inflammation and damage, predicting outcome and response to treatment, monitoring disease activity, progression and remission. The strength of recommendation for each proposition varied according to both the research evidence and expert opinion. Conclusions Ten key recommendations for the role of imaging in the management of RA were developed using research-based evidence and expert opinion.

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial

BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis. METHODS We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3-4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004. FINDINGS 487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10-2.30], p=0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group. INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs. FUNDING Swedish Rheumatism Association, Schering-Plough.

Influence of gender on assessments of disease activity and function in early rheumatoid arthritis in relation to radiographic joint damage

Objective: To evaluate gender differences in score on 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) and Signals Of Functional Impairment (SOFI) and to relate these scores to radiographic joint destruction. Methods: In all, 549 patients with early RA (62% women) from the BARFOT (for “Better Anti-Rheumatic FarmacOTherapy”) study were included. At baseline, 1, 2 and 5 years DAS28, HAQ and SOFI scoring, and radiographs of hands and feet were performed. The radiographs were scored using the van der Heijde–Sharp score. Results: In women the DAS28 was significantly higher than in men due to higher scores for general health and tender joints. Likewise, HAQ and VAS pain were rated significantly higher in women. The SOFI score was worse in men during the first 2 years, depending on higher upper limb scores. Total Sharp score (TotSharp), erosion score and joint space narrowing score did not differ between the sexes at any time point. The DAS28 area under the curve (AUC) correlated significantly with TotSharp at 5 years in both genders (r = 0.316, r = 0.313) mainly owing to swollen joints and erythrocyte sedimentation rate (ESR). The SOFI AUC correlated significantly with TotSharp in women (r = 0.135 to 0.220) but not in men. Conclusions: Despite a similar degree of radiographic joint destruction women had, compared with men, worse scores for DAS28 and HAQ, possibly due to higher pain perception and less muscular strength and perhaps because men overestimate their functional capacity.

In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial

Objective To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis (RA; symptom duration <1 year) who had initially responded well to methotrexate monotherapy. Methods In the SWEFOT trial, all 487 patients started methotrexate (target dose 20 mg/week). After 3–4 months, 147 had low disease activity, 28-joint based disease activity score (DAS28) ≤3.2. These patients were not randomly selected but were followed in regular care for 2 years. Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp (SvdH) score were analysed. Results The majority of the 147 patients continued on methotrexate monotherapy. After 1 and 2 years, DAS28 remission was achieved in 59.6% and 71.8% and mean observed DAS28 values were 2.53 and 2.25, respectively. Despite the favourable clinical course, a proportion of the patients progressed radiographically with a mean (SD) increase in the SvdH score after 2 years of 3.90 (6.84). There was no significant difference in progression between patients in DAS28 remission versus not in remission (p=0.73). At baseline, approximately half the patients had no radiographic damage, while after 2 years the proportion was approximately 20%. Conclusion Most early RA patients who achieve low disease activity after 3–4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up, and additional treatment is needed infrequently. Some radiological progression occurs in most patients, and may be marked or severe in some, even despite sustained DAS28 remission. Close monitoring for radiological progression is thus warranted.

Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: results from the SWEFOT trial

Objectives Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. Methods Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. Results Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). Conclusions In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. Trial registration number WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.

Hand bone loss measured by digital X-ray radiogrammetry is a predictor of joint damage in early rheumatoid arthritis.

Objective: The aim of this study was to evaluate whether loss of bone measured by digital X-ray radiogrammetry (DXR) of hands early in the course of rheumatoid arthritis (RA) may predict future radiographic joint damage after 1 and 2 years. Methods: A total of 166 patients with early RA, who were part of the Better Anti-Rheumatic FarmacOTherapy (BARFOT) low-dose prednisolone study, were included. The patients had been randomized to treatment with 7.5 mg prednisolone daily or no prednisolone when they started with their first disease-modifying anti-rheumatic drug (DMARD) therapy. Radiographs of hands and feet were taken at baseline and after 1 and 2 years and assessed by the van der Heijde modified Sharp (vdH-S) score. Hand bone density (HBD) was measured on the same radiographs by DXR. Changes in HBD and hand bone loss (HBL) were calculated. HBL was defined as a change in DXR bone mineral density (DXR-BMD) during the first year by more than 0.0048 g/cm2. Results: HBL was found in 64% of the patients. Patients with HBL had radiological progression significantly more often than patients without (80% vs. 57%, p=0.012). Patients not treated with prednisolone had HBL more often than patients with this treatment (83% vs. 44%, p=0.001). In multiple regression analyses, HBL and change in DXR-BMD during the first year proved to be independent predictors of radiological progression. Conclusions: Loss of bone measured by DXR was found to be an independent predictor of radiological joint damage and may thus be an additional tool in the process of treatment decision in early RA.

Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial

Objectives To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. Methods In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. Results 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12–63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. Conclusions In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. Trial registration number NCT00764725.

Early increase in serum-COMP is associated with joint damage progression over the first five years in patients with rheumatoid arthritis

BackgroundCurrently available biomarkers for the early tissue process leading to joint damage in rheumatoid arthritis are insufficient and lack prognostic accuracy, possibly a result of variable activity of the disease over time. This study represents a novel approach to detect an altered activity of the disease process detected as increasing serum-COMP levels over a short time and whether this would correlate with joint damage progression over the first 5 years of disease.MethodsIn all, 349 patients from the Swedish BARFOT early RA study were examined. Serum-COMP was analysed by ELISA at diagnosis and after 3 months. Based on changes in serum-COMP levels, three subgroups of patients were defined: those with unchanged levels (change ≤ 20%) (N=142), decreasing levels (> 20%) (N=173) and increasing levels (> 20%) (N=34). Radiographs of hands and feet were obtained at inclusion, after 1, 2 and 5 years and scored according to Sharp van der Heijde (SHS). Radiographic progression was defined as increase in SHS by ≥5.8.ResultsThe group of patients with increasing COMP levels showed higher median change in total SHS and erosion scores at 1, 2 and 5 year follow-up compared with the groups with stable or decreasing COMP levels. Furthermore, the odds ratio of radiographic progression was 2.8 (95% CI 1.26-6.38) for patients with increasing COMP levels vs. patients with unchanged levels.The group of patients with increasing COMP levels had higher ESR at inclusion but there were no baseline differences between the groups for age, gender, disease duration, disease activity (DAS28), function (HAQ), CRP, nor presence of rheumatoid factor or anti-CCP. Importantly, neither did changes over the 3-month period in DAS28, HAQ, ESR nor CRP differ between the groups and these variables did not correlate to joint damage progression.ConclusionIncreasing serum-COMP levels between diagnosis and the subsequent 3 months in patients with early RA represents a novel indicator of an activated destructive process in the joint and is a promising tool to identify patients with significant joint damage progression during a 5-year period.

Short-Time In Vitro and In Vivo Precision of Direct Digital X-ray Radiogrammetry

Digital X-ray radiogrammetry (DXR) calculates peripheral bone mineral density (BMD) from hand radiographs. The aim of this study was to examine in vitro and in vivo precision for the new direct digital version of DXR, a development of the conventional DXR. The in vitro precision for direct DXR was tested on 4 different X-ray equipment, based on 31 radiographs of the same phantom. The in vivo precision was based on duplicate hand radiographs from both hands in 39 individuals. For the 4 X-ray equipment, in vitro precision ranged from 0.14% to 0.30%, expressed as coefficient of variations (CV%) and from 0.0012 to 0.0028 g/cm2, expressed as smallest detectable difference (SDD). The precision was correlated to the resolution of the radiographic equipment (r=0.95, p=0.05). The corresponding values for the in vivo precision for mean values of both hands were: CV%=0.46%; SDD=0.0046 g/cm2, and least significant change (LSC%)=1.28%. The DXR-BMD for 1 of the X-ray equipment differed 1.1% from the overall mean. The precision for direct DXR was highly satisfactory both in vitro and in vivo. DXR-BMD values may differ between the radiographic equipment, and follow-up measurements should be performed with the same X-ray equipment.

The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor

Objective Anti-carbamylated protein (anti-CarP) antibodies are reported to associate with more radiographic progression within the total rheumatoid arthritis (RA) population and anti-citrullinated peptide antibody (ACPA)-negative subgroup. We explored the association of anti-CarP with radiographic progression in RA and aimed to replicate the association and evaluate the added value of anti-CarP antibodies in relation to ACPA and rheumatoid factor (RF). Methods 576 Swedish and 628 Dutch patients with RA (2394 and 3247 sets of radiographs, respectively) were longitudinally studied. Replication was restricted to the Swedish patients. In both cohorts, the association of anti-CarP with radiographic progression was determined in strata of patients with similar ACPA and RF status; results of both cohorts were combined in fixed-effect meta-analyses. The net percentage of patients for whom the radiographic progression in 5 years was additionally correctly classified when adding anti-CarP to a model including ACPA and RF was evaluated. Results Anti-CarP associated with radiographic progression in the total Swedish RA population (beta=1.11 per year, p=8.75×10−13) and in the ACPA-negative subgroup (beta=1.14 per year, p=0.034). Anti-CarP associated with more radiographic progression in the strata of ACPA-positive/RF-negative, ACPA-negative/RF-positive and ACPA-positive/RF-positive patients with RA (respective p values 0.014, 0.019 and 0.0056). A model including ACPA and RF correctly classified 54% and 57% of the patients; adding anti-CarP to this model did not increase these percentages (54% and 56% were correctly classified). Conclusions Anti-CarP antibodies associated with more severe radiographic progression in the total and ACPA-negative RA population. Anti-CarP-positivity had a statistically significant additive value to ACPA and RF, but did not improve correct classification of patients.