Antifilaggrin antibodies in early rheumatoid arthritis may predict radiological progression

OBJECTIVE: To elucidate the possibility that autoantibodies to filaggrin, detected in patients with early RA (having a disease duration of not more than one year), may predict joint destruction assessed after five years of observation. METHODS: This is a 5 yr extension of a previous study (1) of 112 consecutive patients with early RA. Serum antifilaggrin autoantibodies were detected by immunoblotting (AFA) and by indirect immunofluorescence ("AKA"). DAS28, pain on a VAS. HAQ, and CRP were measured. Plain X-ray films were taken from hands and forefeet and a Larsen score was calculated. RESULTS: Ninety-two of the original 112 patients had baseline X-rays available and constituted the study material. At 5 year follow-up, 67 of these 92 have been assessed and for 63 of these X-rays were available. For the whole patient material, significant radiological progression, measured by Larsen scores, occurred while disease activity and function (pain VAS, DAS28, CRP, and HAQ) improved significantly over five years. The groups of patients having AFA or "AKA" at baseline had significantly (p=0.006 and p<0.001, respectively) higher Larsen scores five years later than the groups without these antibodies. No clear relation of these antibodies to disease activity or function was demonstrated, except that the group of patients with "AKA" had significantly higher median CRP (p=0,003) after five years. CONCLUSIONS: The present study shows that antifilaggrin autoantibodies may predict radiological progression. The prognostic value of these antibodies will be further evaluated in relation to other potential markers in a larger patient material.     

Hand bone densitometry in rheumatoid arthritis,a five year longitudinal study: an outcome measure and a prognostic marker

OBJECTIVE: To investigate whether hand bone mineral content (BMC) measurement is an outcome measure for RA and whether the early changes in hand BMC predict functional disability. METHODS: Tender and swollen joints in hands and body, HAQ score, Larsen score on hand radiographs, serum CRP, and hand BMC measurement by DXA were studied every six months for five years in 40 patients with early RA. At the final visit, patients completed the SF-36 and Duruoz hand function questionnaires. RESULTS: All patients completed two years and 29 completed five years' follow up. Hand BMC worsened over the first three years (percentage loss from baseline: mean (SD) -5.5 (7.2), -7.5 (8.4), -9.8 (9.4)) and stabilised over last two years (-9.9 (8.8), -10 (7.8)). Baseline disease activity and function correlated with hand BMC loss at five years (swollen joints in hands: r=-0.38, p=0.043; swollen joints in body: r=-0.47, p=0.01; HAQ: r=-0.52, p=0.004). Percentage change in hand BMC over five years correlated with SF-36 physical function (r=0.61, p<0.01), hand function (r=-0.64, p<0.01), HAQ score (r=-0.63, p<0.01) at five years. Relative risk of bad hand functional outcome at five years was significantly higher for patients with hand BMC loss of >/=1.17 g (smallest detectable difference) than for patients with less bone loss within the first six months (OR=6.9, 95% CI 1.3 to 34.5, p<0.02). CONCLUSION: Early loss of hand BMC in patients with RA is a composite marker of disease activity and functional status and can predict poor functional outcome.     

Leukocyte protein calprotectin and outcome in rheumatoid arthritis. A longitudinal study

OBJECTIVE: To determine if calprotectin is predictive for outcome in patients with rheumatoid arthritis (RA). METHODS: Fifty six RA in-patients with variable disease duration were prospectively followed for five years. Clinical and laboratory data were collected to assess disease activity. Health Assessment Questionnaire (HAQ) and radiographic scores (of hands and wrists) as described by Larsen were used as outcome measures. Plasma calprotectin levels were determined with ELISA technique. RESULTS: Significant correlations (r) were found cross-sectionally at follow-up between calprotectin concentration and other known parameters of disease activity and severity: CRP (r = 0.67). investigator's global assessment of disease activity (r = 0.57). Waaler titre (r = 0.50). HAQ score (r = 0.48) and number of swollen joints (r = 0.48). Calprotectin at baseline was not identified as an independent predictor for HAQ or radiographic progression in the multivariate analysis. CONCLUSION: The results confirm calprotectin as a good measure of disease activity and joint inflammation in RA. However, the level of calprotectin at baseline was not predictive for radiographic damage or functional impairment five years later.     

The relationship of serum calprotectin with disease activity,functional status,ultrasonographic findings and radiological damage in rheumatoid arthritis patients

Aim of the workTo measure the levels of serum calprotectin (CLP) in rheumatoid arthritis (RA) patients and to assess its association with disease activity, functional status, ultrasonographic findings, and radiological damage.Patients and methodsThis study included 47 RA patients and 33 controls. The erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide (anti-CCP), rheumatoid factor (RF), C-reactive protein (CRP), disease activity score (DAS28), health assessment questionnaire (HAQ), modified Larsen radiological score, musculoskeletal ultrasound and serum CLP levels were assessed.ResultsThe mean age of the patients was 42.5 ± 12.8 years; 34 females and 13 males (F:M 2.6:1) with a mean disease duration of 2.6 ± 1.1 years. RF was positive in 72%. CLP level was significantly increased in patients compared to control (2.78 ± 0.89 μg/ml vs. 0.84 ± 0.5 μg/ml; p < 0.001) and in those with activity (3.27 ± 0.75 μg/ml) compared to those in remission (1.92 ± 0.15 μg/ml). A significant correlation was detected between CLP and DAS28, ESR, CRP, HAQ, and modified Larsen scores (p < 0.001). On regression, tender and swollen joint counts, ESR, CRP, HAQ, modified Larsen, ultrasound 7 score and CLP level were significant predictors of activity but were insignificant on multivariate analysis. At a cut-off value of 2.35 μg /ml CLP can significantly differentiate active RA patients from those in remission (AUC 0.95; p < 0.001) at a sensitivity of 90%, specificity of 100%, and accuracy of 95%.ConclusionThe serum CLP levels were significantly high in RA patients and these high levels were associated with disease activity, functional status, ultrasonographic findings, and radiological damage.     

Predictive factors of 5-year health assessment questionnaire disability in early rheumatoid arthritis

OBJECTIVE: To determine prognostic factors of disability in early rheumatoid arthritis (RA) and to investigate the radiological and functional course of the disease. METHODS: A total of 191 patients with early RA (diagnosed for less than one year) according to American College of Rheumatology criteria were followed prospectively for 5 years. At baseline and at endpoint, Stanford Health Assessment Questionnaire (HAQ) scores and radiological scores (Sharp's score modified by van der Heijde) were performed. Correlations between numerous baseline data and HAQ score at endpoint were analyzed, using nonparametric tests. A multilinear regression model was performed to select independent prognostic factors of HAQ disability. RESULTS: During the 5-year followup, mean HAQ decreased from 1.3 (+/- 0.7) to 0.6 (+/- 0.6). There were 98 (65.3%) patients with a score > 1 point at baseline, but only 46 (27.4%) after 3 years and 34 (21.8%) after 5 years. Moreover, 90% of the patients had an improvement of the disability score. Final HAQ disability was associated with baseline values of HAQ score, Pain, Ritchie index, tender joint count, Disease Activity Score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and erosion. Multivariate analysis selected baseline HAQ score, Ritchie index, ESR, CRP, and presence of erosion as independent prognostic factors of HAQ disability. The probability cutoff in the logistic model was selected to minimize the sum of false positive and false negative values: negative predictive value = 92.71%, positive predictive value = 46.15%, p = 0.408. Sex, age, IgM and IgA rheumatoid factors, other tested autoantibodies, and HLA class II genes did not contribute significantly to prediction of the disability after 5 years. At baseline, mean scores were 3.6 units (+/- 7.7) for total radiological score, 1.7 (+/- 4.5) for erosion score, and 1.9 (+/- 3.7) for joint space narrowing score. After 5 years, they were 17.9 +/- 22.3, 6.9 +/- 9.5, and 11.0 +/- 15.4, respectively. No erosion was present at the start in 58.0% of patients, compared to 24.2% and 22.4% at 3 and 5 years. Global radiographic progression concerned 87 patients (55.8%) during the 5 years. CONCLUSION: During the first 5 years of RA, radiological damage increased progressively in half of the patients, whereas HAQ disability improved in most of them during the same period of time and could be predicted by baseline values of HAQ score, Ritchie index, ESR, CRP, and presence (or absence) of erosion.     

Radiographic damage of large joints in long-term rheumatoid arthritis and its relation to function

OBJECTIVE: To describe the extent of radiographic damage of large joints in long-term rheumatoid arthritis (RA) and its relationship to small joint involvement and physical function. METHODS: After 12 yr of follow-up, radiographs of all large joints (Larsen large joint score 0-60) of 105 recent RA patients were assessed. Correlations were evaluated between the Larsen large joint score and radiographic damage of the hands and feet as measured by the van der Heijde modification of the Sharp score (SHS) and the health assessment questionnaire (HAQ). We determined the relative contributions of radiographic damage of small and large joints, disease activity and psychological function to the HAQ. RESULTS: The median Larsen large joint score was 3. In 54% of the patients at least one large joint was erosive. The correlation of the Larsen score with the SHS and HAQ scores was 0.76 and 0.60, respectively. Disease activity and radiographic damage of the large joints were the major determinants of the HAQ score. CONCLUSION: Large joint involvement after 12 yr of follow-up is extensive and is associated with functional disability. Large joint involvement is closely associated with small joint involvement.     

Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis

OBJECTIVE: Expression and activation of matrix metalloproteinases such as MMP-3 (stromelysin-1) and MMP-1 (collagenase-1) are increased in patients with rheumatoid arthritis (RA). Previous negative reports of their value as predictors of joint damage may be due to the lack of a large longitudinal study of early RA patients. This study evaluated their use in assessing early untreated patients with RA and predicting subsequent joint damage. METHODS: Ninety-eight patients with early untreated RA of less than 12 months duration and 20 normal controls had baseline serum samples tested with a double-antibody enzyme-linked immunosorbent assay for each of MMP-1 and MMP-3. The subsequent changes in Larsen score (DeltaLarsen) and Health Assessment Questionnaire (DeltaHAQ) over the first 12 months were recorded. RESULTS: Baseline serum levels of MMP-3 and MMP-1 correlated significantly with baseline C-reactive protein (CRP) (r=0.42 and 0.49, P<0.001), DeltaHAQ (r=0.32 and 0.30, P<0.01) and DeltaLarsen (r=0.23 and 0.32, P<0.05) respectively. Analysis of the group of patients with a normal CRP at presentation (n=21) showed correlation of the baseline MMP-3 and MMP-1 with the presence of erosive disease during the first 12 months (r=0.52 and 0.65 respectively, P<0.05). Logistic regression analysis, in the patients who were non-erosive at presentation, showed that the strongest correlation with progression in Larsen score was the baseline MMP-3 level (r=0.30, P=0.01). CONCLUSIONS: Baseline serum MMP-1 and MMP-3 levels correlate with disease activity and predict functional and radiographic outcome in early untreated RA. They may have a particular value in predicting the progression of erosive disease in patients who are not erosive at presentation.     

Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers

OBJECTIVE: To evaluate the performance of biochemical and traditional markers in predicting radiographic progression in rheumatoid arthritis (RA). METHODS: One hundred thirty-two patients with early RA were treated with nonbiologic therapies for 2 years and studied longitudinally. Genomic DNA was analyzed for presence of the shared epitope. Levels of matrix metalloproteinases (matrix metalloproteinase 1 [MMP-1], MMP-13, and MMP-3), tissue inhibitor of metalloproteinases 1 (TIMP-1), and cartilage oligomeric matrix protein (COMP) were assessed in serially obtained serum samples. The presence of pyridinoline (Pyr), deoxypyridinoline, glycosylated Pyr (Glc-Gal-Pyr), and C-telopeptide of type II collagen (CTX-II) was assessed in urine samples. Radiographs obtained at entry and at 2 years were evaluated using the modified Larsen score. RESULTS: Baseline and 2-year radiographs were available from 118 patients. Larsen scores worsened during the 2 years in 50 patients, while 68 patients had no radiographic progression. Levels of a variety of biochemical markers, i.e., MMP-3, CTX-II, COMP, TIMP-1, Pyr, and Glc-Gal-Pyr, correlated significantly with radiographic progression at entry and longitudinally as assessed by area under the curve (AUC). By multivariate analysis, a model including MMP-3 and CTX-II was identified as providing the best prediction of radiographic progression at entry (predictive accuracy by receiver operating characteristic [ROC] AUC = 0.76 [95% confidence interval 0.66-0.85]), while a combination of MMP-3, CTX-II, and swollen joint count formed the best longitudinal AUC model (predictive accuracy by ROC AUC = 0.81 [95% confidence interval 0.73-0.89]). Patient-reported measures (Health Assessment Questionnaire, pain scores) were of limited use. In a subset of 50 patients who were treated with methotrexate (MTX) during the followup period, median serum MMP-3 levels decreased after the initiation of MTX therapy (P = 0.0003). CONCLUSION: These results indicate that biochemical markers are useful predictors of radiographic progression in RA and that serum MMP-3 levels decrease significantly with MTX therapy. Multivariate models that include MMP-3 and CTX-II perform better than existing traditional markers in predicting radiographic outcome in RA.     

What factors influence functional ability in patients with rheumatoid arthritis. Do they alter over time?

OBJECTIVES: To describe the changes in functional ability (FA) taking place over 5 yr in patients with rheumatoid arthritis (RA) starting disease-modifying anti-rheumatic drug (DMARD) therapy, to investigate the factors having most influence upon FA and to compare these factors at baseline and after 5 yr of treatment. METHODS: Three hundred and sixty-six patients with active RA were studied as part of a 5-yr randomized controlled study of DMARD therapy. FA was assessed by Health Assessment Questionnaire (HAQ) score every 6 months. Multiple linear regression was used to identify factors affecting FA at baseline and at 5 yr. The independent variables used were age, sex, visual analogue scale (VAS) pain, Ritchie articular index, C-reactive protein (CRP), Larsen score and log-transformed morning stiffness (EMS). RESULTS: Mean HAQ score was 1.64 at baseline, improved by 21% at 1 yr and gradually returned towards baseline levels by 5 yr. At baseline only 34% of variance in HAQ score could be explained; the most significant explanatory variables were the Ritchie articular index and CRP. At 5 yr the variance explained was 60%. The Ritchie articular index remained the strongest factor followed by VAS pain, log(10) EMS and Larsen score. CONCLUSIONS: Improvement in function did occur after commencement of the first DMARD therapy but was not maintained to 5 yr. The most consistent factor affecting function was joint tenderness. Global pain and duration of EMS were of lesser importance. Disease activity measures such as the CRP exerted an influence in the earlier, more active stages of disease: radiographic damage assumed greater importance as the arthritis progressed.     

Combination drug strategy in recent-onset rheumatoid arthritis suppresses collagen I degradation and is associated with retardation of radiological progression.

OBJECTIVE: To assess whether serum C-terminal cross-linking telopeptide of type I collagen (ICTP), a marker of type I collagen degradation, has any additional value in the assessment of treatment effect in patients with early rheumatoid arthritis (RA). METHODS: A total of 182 patients were randomized to treatment either with three disease-modifying anti-rheumatic drugs (DMARDs) and low-dose prednisolone (COMBI) or with a single DMARD with or without low-dose prednisolone (SINGLE). We investigated the prognostic value of serum ICTP level for the progression of joint destruction in X-rays (Larsen's score) from baseline to 2 years. RESULTS: There was a statistically significant decrease in serum ICTP levels from baseline to 1 year. At 6 months, the serum ICTP level was lower in the COMBI patients compared to that of the SINGLE cases (p = 0.008, after adjustment for baseline ICTP). When grouping the patients according to serum ICTP tertiles at 6 months, there was a statistically significant trend for increasing median change in Larsen score from baseline to 2 years from lowest to highest ICTP tertile in the SINGLE patients [p = 0.008, after adjustment for 28-joint Disease Activity Score (DAS28) score and RF status at baseline], while in the COMBI, the change remained low in all ICTP tertiles. CONCLUSIONS: The COMBI strategy for recent-onset RA results in early suppression of type I collagen degradation, which is reflected in radiological joint damage at 2 years. Serum ICTP at 6 months may be useful for identifying those RA patients whose treatment should be intensified to prevent further joint damage.     

Incidence of severe outcome in rheumatoid arthritis during 20 years

OBJECTIVE: Information from successive inception cohorts is needed to reveal changes in the endpoint severity of rheumatoid arthritis (RA). We assessed joint destruction and disability 8-20 years after the onset of RA to estimate the number of patients with severe disease at the endpoint. METHODS: Radiographs of the hands and feet were taken at onset and at 1, 3, 8, 15, and 20 years from entry among 103 patients with recent onset (< 6 mo) seropositive RA. The Larsen score of 0-100 of 20 joints of hands and feet, the Health Assessment Questionnaire (HAQ) index, and the number of large joint arthroplasties were used to assess severity. The cumulative number of patients with amyloidosis was recorded. RESULTS: The median progression of small joint destruction was 2-3% yearly. At the endpoint 36% of the patients had Larsen score 50-100 and 23% scored 67-100. The endpoint HAQ index was 2-3 in 16% of the 81 patients investigated. The number of large joint arthroplasties was 29 in 16 patients. A high Larsen score or HAQ was registered in 30 (29%) patients. The incidence of amyloidosis was 13.6%; at the end of the 20 year followup 9 of the 14 patients with amyloidosis had died. CONCLUSION: Our prospective 20 year RA study is the first epidemiological survey in which 20 year severity in RA has been determined by 4 clinical measures; these data will serve as a basis for discussion of methods and comparison with other cohorts in the future.     

A comparison of bone loss in early and late rheumatoid arthritis using quantitative phalangeal ultrasound

This study compares amplitude-dependent speed of sound (AD-SoS) measured by phalangeal ultrasonography in a group of 60 patients with early rheumatoid arthritis (RA) with those who had had the disease for more than 4 years. The mean duration of the early disease group was 1.4 years, and the mean of the established RA group was 14.6 years. Plasma viscosity (PV), C-reactive protein (CRP) and HAQ scores were obtained. Forty-nine patients with early RA had hand radiographs assessed by the Larsen score method. The DBM Sonic system was assessed on normal volunteers and a coefficient of variation of 0.88% obtained. A significant correlation was found between the left and right hands of the patients groups studied (r=0.84). The mean Z score of both hands was therefore used in comparing the two clinical groups. Results showed no correlation between CRP, PV and Z scores of AD-SoS. The HAQ scores showed a weak negative correlation, and there was no correlation between the Larsen score and Z score, or the number of swollen joints and Z score. However, the early and established groups with RA were significantly different (#E5/E5#=0.004). Within the early RA group the Z score for AD-SoS was lower in those with disease duration of less than 2 years (–1.71) than in those with disease duration of 2–4 years (–1.01). This suggests that bone loss in the fingers is greater in the first 2 years of disease than in the following 2 years, which might reflect an effect of treatment.     

An eight year prospective study of outcome prediction by antiperinuclear factor and antikeratin antibodies at onset of rheumatoid arthritis

OBJECTIVES: Antikeratin antibodies (AKA) and antiperinuclear factor (APF) are specific antibodies found very early in rheumatoid arthritis (RA). The objective of this eight year follow up study was to assess the value of early AKA and APF assays in predicting functional disability and cartilage damage. METHOD: In 2000, 64 patients tested for AKA and APF (antifilaggrin antibodies) between 1990 and 1993 during evaluation of early symmetric oligoarthritis or polyarthritis (suspected RA) were invited to participate in this non-concurrent cohort study. The Health Assessment Questionnaire (HAQ) score, disease activity score (DAS), and Larsen radiographic score were the primary evaluation criteria. RESULTS: Twenty nine patients were re-evaluated. Clinical and laboratory data obtained in 1993 were similar in this group and in the 35 other patients. Twenty five patients had received a diagnosis of RA. Nine (31%) were rheumatoid factor (RF) positive, nine (31%) were AKA positive, and six (21%) were APF positive during the first year of the disease. APF was correlated with the Larsen score (p=0.011) and DAS (p=0.035) evaluated after a mean disease duration of 8.55 years. All APF positive patients had erosive disease. AKA was correlated with the DAS (p=0.035). CONCLUSION: The presence of AKA or APF early in the course of RA was associated with the DAS or Larsen score eight years later. The number of patients was small, but the findings confirmed those of studies with shorter follow ups. Antifilaggrin antibodies should be included in the initial investigation of patients with RA and, when positive, should alert to a high risk of poor outcomes.     

Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis

OBJECTIVE: To further evaluate the roles of matrix metalloproteinase 1 (MMP-1), MMP-3, and tissue inhibitor of metalloproteinases 1 (TIMP-1) in the pathogenesis of joint inflammation and articular erosions in early inflammatory arthritis. METHODS: Untreated patients with joint symptoms for <2 years were evaluated at presentation and followed up prospectively for 18 months. Swollen joint count and serum levels of C-reactive protein (CRP) were determined every 6 months. Serum levels of MMP-1, MMP-3, and TIMP-1 were measured by double-antibody sandwich enzyme-linked immunosorbent assay at the same time intervals. The number of joint erosions in serial radiographs of the hands and feet was also recorded. Analysis of synovial fluid levels of MMPs and TIMP-1 at presentation was completed in some patients. RESULTS: Of 175 patients evaluated at baseline, 85 had rheumatoid arthritis (RA), 39 had seronegative spondylarthropathy, 38 had undifferentiated arthritis, and 13 had self-limiting arthritis. Of 164 patients with available radiographs of the hands and feet at presentation, 33 (20.1%) had joint erosions. Baseline levels of MMP-1, MMP-3, and TIMP-1 were significantly higher (P = 0.0001, P = 0.013, and P = 0.0001, respectively) and ratios of TIMP-1:MMP-1 and TIMP-1:MMP-3 were significantly lower (P = 0.0001 and P = 0.013, respectively) in RA versus non-RA patients. In RA patients, serum levels of CRP correlated with MMP-3 and TIMP-1 levels, but not with MMP-1 levels. The number of erosions at presentation correlated with baseline levels of both MMP-1 and MMP-3, but not with levels of TIMP-1. One hundred one patients were followed up for the next 18 months. The number of patients with erosions and the number of erosions per patient increased significantly during this period. Area under the curve (AUC) measurements of MMP-1 and TIMP-1 levels, but not of MMP-3 levels, yielded significantly higher values in RA than in non-RA patients. In RA patients, only the AUC level of MMP-3 correlated with the AUC CRP level (r = 0.67, P = 0.0001), while only the AUC level of MMP-1 correlated with the number of new joint erosions (r = 0.28, P = 0.034). CONCLUSION: These data suggest an uncoupling of the pathophysiologic mechanisms associated with joint inflammation and articular erosion. Treatments that inhibit the production and activity of MMP-1 may preferentially limit the formation of new joint erosions and improve the long-term functional outcome of some patients with inflammatory arthritis.     

Relation between body mass index and radiological progression in patients with rheumatoid arthritis

OBJECTIVE: To determine if there is an influence of body mass index (BMI) on the radiological progression in early and longer duration rheumatoid arthritis (RA). METHODS: Fifty-four patients with RA were observed in a progressive 2 year followup for radiological progression of joint damage. At the beginning of study, 27 (50%) patients had a duration of complaints less than 6 months, grouped as early RA. BMI at the beginning and end of the study were monitored, together with HLA-DRB1 alleles, initial joint erosions, duration of disease, age, sex, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Outcome was defined as radiographic damage according to yearly increase of Larsen score. RESULTS: Increased radiographic joint damage of patients was significantly correlated with lower BMI at the beginning of the study (r = 0.363, p < 0.05), the presence of initial joint erosions (r = 0.341, p < 0.01), ESR (r = 0.315, p < 0.05), and CRP at study entry (r = 0.427, p < 0.01). Patients with an increase of Larsen score > or = 5.8/year were found to have a lower weight at the beginning of their complaints (BMI 24.8 +/- 4.7 vs 27.8 +/- 3.8; p < 0.05) as well as after the time of observation (BMI 24.6 +/- 3.7 vs 27.6 +/- 4.9; p < 0.05). Stepwise logistic regression analysis revealed a BMI < 27 at the beginning of disease (beta = 2.04, p = 0.003, odds ratio = 7.69), the presence of HLA-DR4 shared epitope (beta = 1.76, p = 0.015, OR 5.82), and joint erosions at study entry (beta = 1.56, p = 0.044, OR 4.78) as significant predictors for rapid joint damage. CONCLUSION: Together with the presence of HLA-DR4 shared epitope and erosive disease at study entry, a low BMI at the beginning of RA was found in association with higher radiographic progression in RA. Accordingly, BMI could be of interest as a sensitive and inflammation-independent predictor for radiological outcome of RA.     

Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis

OBJECTIVE: An elevated acute-phase response is associated with increased radiologic damage in rheumatoid arthritis (RA), but development of damage in previously normal joints ("new joint involvement") has not previously been investigated. This study was undertaken to investigate the hypothesis that when there is suppression of disease activity as judged by the C-reactive protein level, new joint involvement is reduced to a greater extent than is progression in already damaged joints ("damaged joint progression"). METHODS: Three hundred fifty-nine patients with active RA were studied as part of a 5-year randomized, prospective, open-label study of disease-modifying antirheumatic drug therapy. Time-averaged CRP was calculated from samples obtained every 6 months, and patients were divided into groups with CRP values of <6, 6-<12, 12-<25, and > or =25 mg/liter. Radiographs of the hands and feet were scored by the Larsen method; a damaged joint was defined as one with a score of > or =2. RESULTS: The rank correlation between time-integrated CRP and increase in Larsen score was 0.50; the correlation increased to 0.59 for patients entering the study with disease duration of < or =2 years. The percentage of new joint involvement over 5 years varied markedly with time-integrated CRP, from 7.3% in the CRP <6 mg/liter group to 39.1% in the CRP > or =25 mg/liter group (5.4-fold increase). The percentage of damaged joint progression increased from 26.1% in the CRP <6 mg/liter group to 41.6% in the CRP > or =25 mg/liter group (1.6-fold increase). CONCLUSION: The results of this study provide further confirmation that high CRP levels over time are associated with greater radiologic progression. Although radiologic progression still occurred in both previously normal and damaged joints despite the presence of normal CRP levels, this consisted of proportionately less new joint involvement compared with damaged joint progression. These findings support the idea that disease-suppressive therapy should be instituted at an early stage in patients with RA, before erosive damage has occurred.     

Reduced bone mineral density in early rheumatoid arthritis is associated with radiological joint damage at baseline and after 2 years in women

OBJECTIVE: Data suggest that reduced bone mass may be associated with radiological damage in rheumatoid arthritis (RA). We investigated if patients with reduced bone mineral density (BMD) at onset of RA had more radiological damage at onset and after 2 years than patients with normal BMD. METHODS: BMD at lumbar spine and hip was measured in 204 patients with recent RA at presentation. At baseline and after 2 years, radiographs of hands and forefeet were evaluated according to the Larsen method. At the same time-points, Disease Activity Score (DAS 28) and functional disability (the Stanford Health Assessment Questionnaire, HAQ) were assessed. RESULTS: The 134 women and 70 men had a mean age of 55 and 61 years, respectively. Reduced bone mass (RBM, Z score < or = 1.0 SD) in at least one site was found in 46.0% of women and 62.5% of men. T and Z scores correlated significantly with Larsen scores both at baseline and after 2 years for the total patient cohort. Calculated separately for the sexes, significant correlations were found only for women. Women but not men with reduced bone mass and osteoporosis had higher Larsen scores at baseline and after 2 years than those without. From a stepwise multiple logistic regression analysis Z score trochanter and baseline C-reactive protein were selected as independent predictors of joint damage, measured as proportion over the median Larsen scores. This model could explain about 25% of the "variance" in outcome (Nagelkerke R2 = 0.27). CONCLUSION: Reduced BMD at onset of RA in women was associated with a higher Larsen score at baseline and after 2 years, indicating that the development of reduced bone mass and joint destruction in RA may have a common pathophysiological mechanism.     

Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) level in plasma is described as a marker for joint inflammation in rheumatoid arthritis (RA). METHODS: MCP-1 in plasma and synovial fluid (SF) was quantified by ELISA in 36 RA patients with synovitis of the knee at Day 1 and 30. Disease activity was assessed by the swollen joint count, Ritchie Articular Index (RAI), global assessment, pain on visual analog scale, Health Assessment Questionnaire, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). RESULTS: By linear regression analysis plasma MCP-1 levels correlated significantly with the swollen joint count (Day 1: R = 0.47, p = 0.005; Day 30: R = 0.53, p < 0.001) and the RAI (Day 1: R = 0.37, p = 0.03; Day 30: R = 0.41, p = 0.01). The correlations of swollen joint count and RAI with ESR and CRP were significant only on Day 30 for the ESR (R = 0.40, p = 0.02). No association was found between plasma MCP-1 levels and the ESR/CRP levels. MCP-1 levels in plasma in RA patients were elevated compared to controls (p < 0.001) and MCP-I levels in SF were higher than in plasma (p < 0.001). No correlation was found between SF MCP-1 levels and in vitro migration of mononuclear cells towards SF. MCP-1 appears to participate in the disease process in RA, and plasma MCP-1 may be useful in monitoring joint inflammation.     

Scores for functional disability in patients with rheumatoid arthritis are correlated at higher levels with pain scores than with radiographic scores

OBJECTIVE: To analyze correlations of functional disability scores with other measures of clinical status, in particular, Larsen radiographic scores and pain scores, in patients with rheumatoid arthritis (RA). METHODS: The functional capacity of 141 patients with RA (102 women, 39 men; median age 57 years; median disease duration 11.8 years; 83% rheumatoid factor positive) was assessed according to the Stanford Health Assessment Questionnaire (HAQ). Other variables studied included Larsen scores for radiographic damage of the small joints of the hands, wrists, and feet, pain scores by visual analog scale (VAS), Disease Activity Scores, general health scores by VAS, and Beck Depression Inventory (BDI) scores. RESULTS: The Spearman correlation coefficient comparing HAQ and Larsen scores was 0.277 (P = 0.001) and between HAQ and pain scores 0.652 (P < 0.001). In regression analysis, pain scores explained 41.4% of the variation in HAQ scores, normalized Larsen scores explained 7.3%, and BDI scores explained 5.5%; other variables were not significant in the model. CONCLUSION: Functional capacity scores of patients with RA are correlated at higher levels with pain scores than with radiographic scores of small joints.     

Radiological progression in early rheumatoid arthritis after DMARDS: a one-year follow-up study in a clinical setting

OBJECTIVE: To analyse the frequency and prognostic factors of radiographic progression in a series of Spanish patients with early rheumatoid arthritis (RA) after 1 yr of treatment with disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Sixty patients (47 females, 13 males) with RA with a disease duration shorter than 2 yr [mean (s.d.) duration 9.5+/-6.6 months] were treated with the same therapeutic protocol using gold salts as the first DMARD and methotrexate as a second option, and were followed up for 1 yr. Radiographic progression in the hands and feet (total radiographic Larsen score and the erosion joint count) was used as the outcome variable. Clinical, laboratory, immunogenetic and radiographic data were obtained at study entry. Disease activity and response to therapy were measured at 6 and 12 months. RESULTS: Erosive disease was found in 21.7% of patients at baseline and in 38.3% after 1 yr. Although a substantial reduction in disease activity was observed during the 1 yr follow-up [disease activity score (DAS28) 5.8+/-0.8 at entry and 3.9+/-1.3 at 12 months, P < 0.001], the Larsen score rose from 1.9+/-3.3 to 5.6+/-9.8 after 1 yr. In 26.6% of patients, a raised erosion joint count was observed after 1 yr. Radiographic progression in the total joint radiographic damage (increase in Larsen score of >or=2) was observed in 36.6%. In the multivariate analysis, baseline pain [visual analogue scale (VAS)] and the presence of two copies of the shared epitope were associated with radiographic progression in the erosion joint count. Disease duration before study entry, VAS pain and Larsen score at baseline were significant predictors of radiographic progression in total damage (Larsen score). Baseline radiographic damage had the highest positive predictive value for progression. CONCLUSIONS: Radiographic progression was observed in up to 36.6% of patients with early RA after 1 yr of DMARD therapy in spite of a significant reduction in disease activity. Baseline factors, such as VAS pain, disease duration until DMARD therapy, damage score at baseline and the presence of two copies of the shared epitope, were associated with radiographic progression.