Objectives To identify the predictive factors of MRI-determined structural progression in patients with rheumatoid arthritis (RA) in remission or with low disease activity (LDA).
Methods In this 1-year longitudinal study, patients with RA in clinical remission (disease activity score (DAS) 44≤1.6) or with LDA (1.6<DAS 44≤2.4) underwent low-field MRI of the dominant hand at baseline and at 6 and 12 months. MRI images were scored by the rheumatoid arthritis MRI system (RAMRIS) by rheumatologists blind to clinical and biological data. Structural progression was defined as a change in the RAMRISerosion score between baseline and 1 year greater than the smallest detectable difference. Predictive factors of structural disease progression were analysed by logistic and linear regression.
Results 85 patients with RA in remission (n=47) or with LDA (n=38) were included. Their mean age was 50±13 years, 81% were female, mean disease duration was 35±20 months, rheumatoid factor (RF)/anti-CCP positivity was 63%/64% and 77% had radiographic erosion. At baseline most patients showed inflammatory activity on MRI: 87% had at least one synovitis and 23% at least one location of bone marrow oedema (BME). BME at baseline was predictive of change in RAMRISerosion (OR 1.25, 95% CI 1.09 to 1.43, p=0.0013, area under the curve=0.78).
Conclusion BME is a predictive factor of MRI-determined structural progression in patients with RA in clinical remission or with LDA.
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The aim of rheumatoid arthritis (RA) treatment is to achieve remission and to stop the progression of structural damage.1,–,3 Patients in clinical remission or low disease activity (LDA) state may show structural progression on radiography.4 More sensitive tools than clinical examination and radiography are needed to identify RA patients in clinical remission or LDA state at risk of structural progression in order to adapt treatment. MRI, which has a high sensitivity for detecting inflammation and erosion, could be useful in this respect.
We performed a 1-year MRI follow-up study to determine the value of MRI for predicting structural progression in patients with RA in clinical remission or with LDA.
In this prospective longitudinal study, patients with RA in clinical remission (disease activity score (DAS) 44≤1.6) or with LDA (1.6<DAS 44≤ 2.4) were followed up over a 1-year period by MRI.
To be included in the study, patients had to have established RA according to the 1987 American College of Rheumatology (ACR) criteria, to have been diagnosed since 2000 and be in clinical remission or with LDA as defined above (DAS 44≤2.4, with scores obtained 2 months apart). RA treatment had to be stable for at least 2 months and include synthetic or biological disease-modifying antirheumatic drugs (DMARDs) or low-dose corticosteroids (<10 mg/day). Exclusion criteria were contraindication to gadolinium or MRI, modification of DMARD therapy in the previous 2 months and a significant comorbidity whose evolution or treatment could interfere with the protocol.
Assessment of clinical, biological and radiographic characteristics
The patient characteristics recorded at baseline were age, sex, disease duration, current therapy, patient's assessment of pain and disease activity on visual analogue scales (VAS), tender joint count and swollen joint count on 44 joints assessed by a trained rheumatologist who was blinded to other data, blood cell count, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) level, rheumatoid factor (RF) and anti-cyclic citrullinated protein antibodies (anti-CCP antibodies).
The DAS was calculated as described elsewhere.5 Baseline x-rays were scored according to the Sharp score modified by van der Heijde (SvH) by rheumatologists blind to the clinical, biological and MRI results. The disease was considered ‘erosive’ if the SvHerosion score was ≥1.
MRI of the dominant wrist and hand was performed with a 0.2 Tesla C scanner (ESAOTE Equipment, Genova, Italy) at baseline and at 6 and 12 months. 3DT1 pre-gasolinium and post-gadolinium injection and STIR sequences were obtained in coronal and axial planes according to the MRI OMERACT group recommendations. All MRI scores were obtained in the same chronological order at the end of the study by two independent and experienced rheumatologists (VF, FG) who were blind to the clinical, biological and radiographic data. One month later one of the readers (FG) who was blind to the clinical, biological and radiographic data and to the previous MRI scores re-scored all baseline MRI images to evaluate intrarater reliability. MRI images were scored by the Rheumatoid Arthritis MRI Scoring System (RAMRIS) according to the OMERACT recommendations.6
Statistical analysis was performed using SAS V.9.1 (SAS, Cary, North Carolina, USA). Intraclass correlation coefficients (ICC) and their 95% CIs were calculated using R 2.8 (package ‘psy’ from the website: cran.r-project.org/).
Sources of variability, reliability and RAMRIS estimates
The generalisability theory7 8 was used to determine sources of variability, intraclass correlation coefficients, best estimates of RAMRIS scores (RAMRISsynovitis, RAMRISerosion and RAMRISoedema) at baseline and the best estimate of the change in RAMRISerosion between baseline and 1 year (ΔeRAMRISerosion) (see details in online supplement).
MRI evidence of structural disease progression: definition and predictive factors
The best estimates of the ΔeRAMRISerosion and its standard deviation (SD) were evaluated by a mixed procedure and reflected structural progression of disease. Calculating the smallest detectable difference (SDD) allowed the definition of a new qualitative variable called ‘structural progression’ with three values: ‘progression’, ‘no progression’ and ‘improvement’. The search for predictive factors of structural progression seen on MRI involved multivariate logistic regression (variable to explain: structural progression) and linear regression (variable to explain: ΔeRAMRISerosion). Baseline explanatory variables were age, sex disease duration, ESR, CRP level, RF and anti-CCP antibody positivity, treatment, corticosteroid use and estimates of RAMRISsynovitis, RAMRISerosion and RAMRISoedema at baseline (see details in online supplement).
Qualitative data were presented as numbers and percentages and quantitative data as mean±SD or median (IQR) depending on the distribution. Comparisons of remission and LDA groups for qualitative variables were performed with the χ2 or exact Fisher tests and comparisons of quantitative variables used the Wilcoxon test; p<0.05 was considered statistically significant.
Patient characteristics at baseline
Eighty-five patients with RA in clinical remission (n=47) or with LDA (n=38) were included. The characteristics of the patients at baseline are shown in table 1.
MRI characteristics of patients in clinical remission or with LDA
Intra-rater and inter-rater reliabilities were good to excellent (intra-rater ICC 0.90 for erosion, 0.86 for oedema and 0.78 for synovitis; inter-rater ICC 0.84, 0.67 and 0.68, respectively; see table S1 in online supplement).
MRI characteristics at baseline
Most patients showed inflammatory activity on MRI: 74 patients (87%) had at least one area of synovitis and 20 (23%) had at least one area of bone marrow oedema (BME). The mean±SD estimates of RAMRISerosion, RAMRISoedema and RAMRISsynovitis were 10.65±7.65, 1.92±5.38 and 4.97±3.73, respectively. All patients had at least one erosion at baseline (RAMRISerosion ≥1). Figure 1 shows the frequencies of MRI abnormalities with regard to location.
Patients in clinical remission and with LDA did not differ in having at least one synovitis (p=0.33) or one location of BME (p=0.9) or in RAMRISerosion, RAMRISoedema or RAMRISsynovitis (9.6±6.5, 1.4±4.2 and 4.5±3.4 vs 11.9±8.8, 2.5±6.6 and 5.6±4.1).
MRI evidence of structural disease progression at 1 year
Four patients showed MRI evidence of structural progression of disease (ΔeRAMRISerosion >SDD), 79 had no progression and 2 showed improvement. The patients with improvement were in the remission group. Of the four patients with significant disease progression, one was in the remission group and three were in the LDA group. The mean ΔeRAMRISerosion estimate was 0.65±3.1, with no difference between the remission and LDA groups (0.2±1.86 vs 1.14±4.13, p=0.72; see figure S1 in online supplement).
Predictors of MRI evidence of structural disease progression
RAMRISoedema was found to be a predictive factor of structural progression. In logistic regression, baseline RAMRISoedema was associated with progression at 1 year (OR 1.25, 95% CI 1.09 to 1.43, p=0.0013, area under the curve=0.78; figure 2) and, in linear regression, baseline RAMRISoedema (p<0.0001) and sex (p=0.001) were significant predictors of ΔeRAMRISerosion.
Subclinical inflammation was observed on MRI in most patients in clinical remission or with LDA: 74 of the 85 patients (87%) had at least one synovitis and 20 (23%) had at least one location of BME.
These results are consistent with those of Brown et al who found that 36 of 41 (88%) patients with clinical remission according to the DAS28 and 36 of 38 (95%) of those in remission according to ACR criteria showed demonstrable synovitis on MRI.9 Other studies involving ultrasonography confirmed the presence of remaining inflammation despite clinical remission.10 11 Remission is assessed by clinical and biological features, which may be insufficient to assess inflammatory activity in patients with a low level of inflammation.
MRI subclinical inflammation may explain the remaining structural progression despite clinical remission. The search for predictive factors of structural progression for these patients is critical to modify treatment in order to prevent joint destruction. In the study by Brown et al, synovial hypertrophy, the presence of power Doppler signals on ultrasonography and MRI synovitis assessments in individual joints at baseline were significantly associated with radiographic evidence of structural disease progression in RA patients in clinical remission or with LDA at 1-year follow-up.9
In our study, RAMRISoedema was identified as a predictive factor of MRI structural disease progression on both logistic and linear regression. This finding confirms the role of BME in the occurrence of future bone erosions, even in patients in remission or with LDA.
MRI has been found to be a predictive factor for evidence of structural progression in active RA and in early RA.12,–,15 McQueen et al showed that BME corresponded to an aggregate of inflammatory cells and may correspond to a ‘pre-erosive’ lesion.16 MRI detection of persistent BME in patients in remission or with LDA should lead to adjustment of treatment and stop treatment tapering.
To our knowledge, this study is the first to include a large number of patients in DAS remission or with LDA with a 1-year MRI follow-up enabling the detection by MRI of predictive factors of structural progression.
However, the study has some limitations. A follow-up period of 1 year may be insufficient and may explain the small number of patients with progression. Further studies are therefore needed to confirm the role of MRI evaluation as a predictive factor of structural progression in patients with RA in clinical remission or with LDA.
MRI evaluation is a valuable imaging technique for monitoring patients with RA in clinical remission or with LDA. BME appears to be a predictive factor of MRI-determined structural progression.
Patient consent Written informed consent was obtained from all subjects before study inclusion.
Ethics approval This study was conducted with the approval of the URC Pitie Salpetriere, Paris, France.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed
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