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1.  Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis 
Introduction
To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years.
Methods
In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years.
Results
68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage.
Conclusions
In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.
doi:10.1186/ar3025
PMCID: PMC2911882  PMID: 20482894
2.  Radiographic Severity of Rheumatoid Arthritis in African-Americans: Results from the CLEAR Registry 
Arthritis care & research  2010;62(5):624-631.
Objective
To describe radiographic changes in African-Americans with rheumatoid arthritis (RA) from the CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) Registry, a multicenter observational study.
Methods
Self-declared African-American patients, were enrolled in CLEAR I, a longitudinal cohort of early RA (disease duration <2 years) from 2000 to 2005; or in CLEAR II, a cross-sectional cohort (any disease duration), from 2006 to the present. Demographic and clinical data were obtained, and sets of hand/wrist and foot radiographs were scored using the modified Sharp/van der Heijde scoring system.
Results
A total of 357 and 418 patients, respectively, have been enrolled into CLEAR I and CLEAR II. We report here an interim analysis of radiographic severity in these patients. For the CLEAR I cohort, 294 patients had a mean radiographic score of 2.89 at the baseline visit; 32.0% showed either erosions (25.9%) or joint space narrowing (JSN) (19.4%). At the 36-month visit the mean score was 5.65; 44.2% had erosions, 41.5% JSN and 55.4% had either. Among those patients without radiographic damage at baseline, 18.9% had progressed at the 36-month visit, compared to 57.1% of those with baseline damage (p<0.0001). For the CLEAR II cohort, 167 patients with RA of any duration, 65.3% exhibited joint erosions, 65.3% JSN and 74.8% exhibited either. The mean radiographic score was 33.42.
Conclusion
This is the largest radiographic study of African American RA patients. Damage occurs early in the disease and is associated with radiographic progression at 3 years of disease duration. The CLEAR Registry will provide a valuable resource for future analyses of genetic, clinical, and environmental factors associated with radiographic severity of RA in African-Americans.
doi:10.1002/acr.20040
PMCID: PMC3052790  PMID: 20461784
3.  Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(11):1508-1512.
Objectives
Osteoporosis is a well‐known extra‐articular phenomenon in patients with uncontrolled, long‐standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease‐related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA.
Methods
BMD of the total hip and the lumbar spine was measured using dual‐energy x ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score ⩽−2.5 SD and reduced BMD as Z score ⩽−1 SD. Multivariate logistic regression analyses were performed to detect associations of osteoporosis and reduced BMD with disease activity, functional disability, joint damage (Sharp–van der Heijde score) and demographic factors.
Results
Osteoporosis and reduced BMD were found in the spine and/or the hip in 11% and 25%, respectively, of the patients. Longer symptom duration and presence of rheumatoid factor (RF) were the only RA‐specific markers for osteoporosis and reduced BMD. Further, postmenopausal status in women, a low body mass index, familial osteoporosis, and, remarkably, male gender, were independently associated with osteoporosis and reduced BMD.
Conclusion
In patients with recently diagnosed active RA who had never been treated with DMARDs or corticosteroids, BMD seems to be well‐preserved and predominantly related to demographic factors. Longer symptom duration and a positive RF, but not higher disease activity or more joint damage, were related to osteoporosis and reduced BMD.
doi:10.1136/ard.2007.070839
PMCID: PMC2111640  PMID: 17456523
early rheumatoid arthritis; bone mineral density; osteoporosis
4.  A high serum level of eotaxin (CCL 11) is associated with less radiographic progression in early rheumatoid arthritis patients 
Introduction
Prognosis in rheumatoid arthritis (RA) is difficult to assess. The aim of this study was to examine whether serum levels of a spectrum of cytokines were predictive of radiographic progression in early RA patients.
Methods
A total of 82 early RA patients (disease duration < 1 year) were followed for 12 months. Clinical assessments, X-rays of hands and magnetic resonance imaging (MRI) of the dominant wrist were assessed at baseline and after 3, 6 and 12 months. The X-rays were scored according to the van der Heijde modified Sharp score (vdHSS). Cytokine analyses were performed with multiplex technology. Associations between cytokines and radiographic progression were examined by logistic regression.
Results
In all, 49% of the patients developed radiographic progression. The median (interquartile range (IQR)) baseline eotaxin level (pg/ml) was significantly lower in patients with (193 (119 to 247)) than without progression (265 (166 to 360)). In the univariate logistic regression analyses, eotaxin was negatively associated to radiographic progression, and this association was maintained in the multivariate model with an odds ratio (OR) (95% confidence interval (CI)) for progression of 0.58 (0.41 to 0.82) per 50 pg/ml increase in eotaxin level. None of the other measured cytokines showed any association to radiographic progression.
Conclusion
This study raises the hypothesis that high serum levels of eotaxin predict less radiographic progression in early RA patients.
doi:10.1186/ar2381
PMCID: PMC2453772  PMID: 18312691
5.  One year outcome of undifferentiated polyarthritis 
Annals of the Rheumatic Diseases  2002;61(8):700-703.
Objective: To identify variables that can predict a progressive outcome after one year of follow up in patients presenting with undifferentiated polyarthritis (UPA) at an early arthritis clinic.
Methods: New patients with arthritis in two or more joints of less than three years' duration were categorised at entry as UPA or as rheumatoid arthritis (RA) based on the clinical diagnosis of the rheumatologist. Outcome variables after one year were radiographic damage (Sharp/van der Heijde score) and functional status (Health Assessment Questionnaire: HAQ score). A progressive disease at one year was defined as radiographic progression ≥4, or one year radiographic damage ≥10, or HAQ score ≥1. The baseline variables of patients with UPA with a progressive or mild outcome were compared.
Results: 280 patients (70% women; median age 56 years (range 18–90), median duration of symptoms 3.5 months) were included. 203 (72%) patients were clinically diagnosed as having RA and 77 (27%) as having UPA. The group of patients with progressive UPA (n=32 (42%)) had a significantly higher mean age, prevalence of arthritis of the hands, and disease activity (DAS28) at the first visit compared with the patients of the mild UPA group (n=45 (58%)). The RA group had significantly more frequent serum IgM-RF positivity, higher mean disease activity (DAS28) and mean C reactive protein concentration, more frequent symmetric arthritis, and arthritis in more than three joint groups than the progressive UPA group. Six (19%) of the progressive UPA group versus eight (4%) of the RA group did not receive disease modifying antirheumatic drugs during the first year.
Conclusions: After one year of follow up, 32 (42%) of the patients with UPA had a progressive disease. A progressive outcome was associated with older age, higher disease activity, and arthritis of the hands at baseline. To avoid undertreatment of patients with UPA, treatment should be based on severity rather than on diagnosis.
doi:10.1136/ard.61.8.700
PMCID: PMC1754180  PMID: 12117675
6.  Study of active controlled monotherapy used for rheumatoid arthritis, an IL‐6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader‐blinded randomised controlled trial of tocilizumab 
Annals of the Rheumatic Diseases  2007;66(9):1162-1167.
Objective
To evaluate the ability of tocilizumab (a humanised anti‐IL‐6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.
Methods
In a multi‐centre, x ray reader‐blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease‐modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.
Results
Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.
Conclusion
Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
doi:10.1136/ard.2006.068064
PMCID: PMC1955155  PMID: 17485422
7.  Serial determination of cyclic citrullinated peptide autoantibodies predicted five-year radiological outcomes in a prospective cohort of patients with early rheumatoid arthritis 
The objective of this study was to evaluate the potential of serially determined anti-cyclic citrullinated peptide (CCP) antibodies for predicting structural joint damage in patients with early rheumatoid arthritis (RA), compared to a single baseline determination. Ninety-nine RA patients with disease durations of less than one year and no history of disease-modifying antirheumatic drug therapy were followed prospectively for at least five years. Anti-CCP2 concentrations were measured using a second-generation ELISA. Sharp scores as modified by van der Heijde were determined on hand and foot radiographs. Anti-CCP2 antibodies were detected in 55.5% of patients at baseline and 63.6% at any time during the first three years. Presence of anti-CCP2 at any time during the first three years was associated with radiographic damage at baseline (odds ratio (OR), 3.66; 95% confidence interval (95% CI) 0.99–13.54) and with five year progression of the total Sharp score (OR, 3.17; 95% CI, 1.3–7.7), erosion score (OR, 5.3; 95% CI, 1.4–19.2) and joint space narrowing score (OR, 2.8; 95% CI, 1.15–6.8). The presence of anti-CCP2 or IgM RF at baseline did not predict these outcomes. Patients with negative anti-CCP2 tests throughout follow-up had less radiographic progression than patients with increasing anti-CCP2 concentrations; they did not differ from patients with decreasing anti-CCP2 antibody levels. HLADRB1* typing showed that progression of the mean modified Sharp score was not correlated with the presence of the shared epitope alleles. In conclusion, serially determined anti-CCP2 antibodies during the first three years of follow-up performs better than baseline determination for predicting radiographic progression in patients with early RA.
doi:10.1186/ar1896
PMCID: PMC1526612  PMID: 16469118
8.  Long term evaluation of radiographic disease progression in a subset of patients with rheumatoid arthritis treated with leflunomide beyond 2 years 
Annals of the Rheumatic Diseases  2004;63(6):737-739.
Methods: Patients treated with leflunomide for >2 years in one of three phase III trials and subsequent extensions, for whom paired, evaluable radiographs at baseline and study end point were available, were included. Radiographs of hands and feet were assessed according to the modified Sharp/van der Heijde scoring method, for erosion, joint space narrowing, and total score. Changes from baseline were assessed, and a predicted yearly progression rate estimated for each patient.
Results: 128 of the original 824 patients were included, with mean disease duration 5.1 years and mean leflunomide treatment duration 4.3 years until the final x ray examination. The mean change from baseline in total score was 8.6 with yearly adjusted rate 1.9, and the median change was 2 with yearly adjusted rate 0.5, compared with 7.9 and 4.9, respectively, before leflunomide treatment. After treatment, the rate improved in 92/128 (72%) patients and deteriorated in 21/128 (16%). In 42 (33%) patients who had a total score >0 at baseline, no radiographic progression occurred after leflunomide treatment.
Conclusions: In a subset of patients who continued treatment long term, leflunomide treatment reduced the rate of radiographic damage.
doi:10.1136/ard.2003.010983
PMCID: PMC1755041  PMID: 15140783
9.  Clinical predictors of erosion-free status in rheumatoid arthritis: a prospective cohort study 
Rheumatology (Oxford, England)  2011;50(8):1473-1479.
Objective. Treatment algorithms in RA include factors associated with poor prognosis; however, many patients remain erosion free despite years of disease. Our objective was to characterize the group of RA patients without erosions and identify its clinical predictors.
Methods. Our study was conducted within a prospective observational cohort of RA patients recruited from the outpatient practice of an academic medical centre. We studied patients with bilateral hand radiographs at cohort baseline and 2-year follow-up assessed with Sharp/van der Heijde scores (SHS). The primary outcome was erosion-free status at baseline and 2-year follow-up. We assessed baseline values of the following as potential correlates: age at RA onset, gender, RA duration, BMI, 28-joint DAS (DAS-28), CRP, anti-CCP status, tender and swollen joint counts, functional status [multidimensional HAQ (MDHAQ)], tobacco use and RA treatments. Variables with P ≤ 0.25 in the univariate analyses were assessed using backward selection in multivariable logistic regression models.
Results. Of the 271 subjects included, 21% (n = 56) were considered erosion free. Forty-six per cent (n = 26) of this group was anti-CCP positive compared with 56% (n = 121) in subjects with erosions present. Mean RA duration for erosion-free subjects was 3.9 years compared with 4.6 years in erosive subjects. Treatments for RA did not differ between the two groups. In the multivariable-adjusted analysis, significant predictors of erosion-free status were younger age at onset and shorter RA duration.
Conclusion. In our cohort, 21% of subjects were erosion free at baseline and 2 years. Few baseline clinical characteristics significantly predicted erosion-free status.
doi:10.1093/rheumatology/ker129
PMCID: PMC3133482  PMID: 21447567
Rheumatoid arthritis; Disease progression; Prognosis
10.  Associations between the PTPN22 1858C→T polymorphism and radiographic joint destruction in patients with rheumatoid arthritis: results from a 10‐year longitudinal study 
Annals of the Rheumatic Diseases  2007;66(12):1604-1609.
Objective
To investigate whether the PTPN22 1858T risk variant is associated with the rate of radiographic progression in rheumatoid arthritis (RA).
Methods
A longitudinally followed cohort of 238 Norwegian patients with RA (the EURIDISS cohort) was genotyped for the PTPN22 1858C→T polymorphism. Radiographic damage was assessed by hand radiographs at baseline and after 1, 2, 5 and 10 years, and the radiographs were scored with the Sharp method modified by van der Heijde (Sharp–van der Heijde score) by a single experienced reader. Baseline serum levels of rheumatoid factor and anti‐cyclic citrullinated peptide autoantibodies were also examined.
Results
The reported association between RA susceptibility and carriage of the T allele (34.4% in patients vs 21.4% in controls; odds ratio 1.92, 95% confidence interval 1.36 to 2.71, p = 0.0002) was confirmed. An association between annual progression rate of Sharp–van der Heijde score and T‐allele carriers (p = 0.01),was also found, which was also present when only patients positive for the shared epitope were analysed (p = 0.03). This association was also maintained in multivariate analyses adjusting for shared epitope and demographic variables.
Conclusions
An association between the PTPN22 risk variant and increased progression rate for structural damage was found. The results indicate that the PTPN22 gene may not only be associated with disease susceptibility, but also with disease progression.
doi:10.1136/ard.2006.067892
PMCID: PMC2095332  PMID: 17472988
rheumatoid arthritis; PTPN22; longitudinal study; radiographic damage; genetic predisposition
11.  Disease activity score-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis: data from the GUEPARD trial and ESPOIR cohort 
Annals of the Rheumatic Diseases  2011;70(4):611-615.
Objectives
To compare the efficacy of disease activity score in 28 joints (DAS28ESR)-driven therapy with anti-tumour necrosis factor (patients from the GUEPARD trial) and routine care in patients with recent-onset rheumatoid arthritis (patients of the ESPOIR cohort).
Results
After matching GUEPARD and ESPOIR patients on the basis of a propensity score and a 1:2 ratio, at baseline all patients had comparable demographic characteristics, rheumatoid factor, anticyclic citrullinated peptide antibody positivity and clinical disease activity parameters: erythrocyte sedimentation rate, C-reactive protein, mean DAS (6.26±0.87), Sharp/van der Heijde radiographic score (SHS), health assessment questionnaire (HAQ). Disease duration was longer in GUEPARD patients (5.6±4.6 vs 3.5±2.0 months, p<0.001). After 1 year, the percentage of patients in remission with an HAQ (<0.5) and an absence of radiological progression was higher in the tight control group (32.3% vs 10.2%, p=0.011) as well as the percentage of patients in low DAS with an HAQ (<0.5) and an absence of radiological progression (36.1% vs 18.9%, p=0.045). However, there was no difference in the decrease in DAS, nor in the percentage of EULAR (good and moderate), ACR20, ACR50 and ACR70 responses. More patients in the tight control group had an HAQ below 0.5 (70.2% vs 45.2%, p=0.005). Overall, pain, patient and physician assessment and fatigue decreased more in the tight control group. The mean SHS progression was similar in the two groups as was the percentage of patients without progression.
Conclusions
In patients with recent onset active rheumatoid arthritis, a tight control of disease activity allows more patients to achieve remission without disability and radiographic progression.
doi:10.1136/ard.2010.137695
PMCID: PMC3048626  PMID: 21242235
12.  Prognostic factors for remission in early rheumatoid arthritis: a multiparameter prospective study 
Annals of the Rheumatic Diseases  2004;63(6):675-680.
Objective: To determine prognostic factors for remission in early rheumatoid arthritis.
Methods: 191 patients with rheumatoid arthritis whose disease duration was less than one year were followed up prospectively for five years. Remission, defined by a disease activity score (DAS) of <1.6, was used as the outcome measure. Baseline clinical, laboratory, genetic, and radiographic data (with radiographic scores determined by Sharp's method, modified by van der Heijde) were obtained.
Results: 48 patients (25.1%) fulfilled the remission criteria at the three year follow up visit, and 30 (15.7%) at three and five years. On univariate analysis by Fisher's exact test, remission at three years and persistent remission at five years were closely correlated with baseline DAS values, C reactive protein level, Ritchie score, health assessment questionnaire score, duration of morning stiffness, and to a lesser extent baseline total radiological scores and rheumatoid factor negativity. No significant correlation was found with sex, age, extra-articular manifestations, erythrocyte sedimentation rate, anti-cyclic citrullinated protein antibodies, anti-keratin antibodies, anti-HSP 90, anticalpastatin antibodies, antinuclear antibodies, or HLA-DRB1* genotypes. Logistic regression analysis showed that the baseline independent variables predictive of remission were low DAS, Ritchie score, morning stiffness duration, and total radiographic score.
Conclusions: Baseline prognostic factors for remission in early rheumatoid arthritis were mainly clinical markers of disease activity and radiological scores.
doi:10.1136/ard.2003.010611
PMCID: PMC1755028  PMID: 15140774
13.  Radiological damage in patients with rheumatoid arthritis on sustained remission 
Annals of the Rheumatic Diseases  2006;66(3):358-363.
Objective
To assess the radiological damage progression in patients with recent rheumatoid arthritis in sustained remission.
Methods
A cohort of 191 patients with active early (<1 year) rheumatoid arthritis was prospectively assessed at baseline, 3 and 5 years by the Disease Activity Score (DAS) and the Sharp–van der Heijde Score (SHS) for radiographic damage. Patients in remission (DAS<1.6) at the 3‐year and 5‐year time points were compared with patients with a persistently active rheumatoid arthritis by Wilcoxon's signed rank test.
Results
57 patients died, were lost to follow‐up or had incomplete data; 30 (15.7% of those who completed) patients were in remission at 3 and 5 years. The SHS in these two groups was not significantly different at baseline (p = 0.15), but was lower in the remission group at 5 years (p = 0.0047). The median (IQR) radiographic score increased from 0.5 (0–7) at baseline to 2.5 (0–14) after 5 years for the remission group (p = 0.18) and from 2 (0–7) to 13 (3–29) in the group with active rheumatoid arthritis (p<0.001). 5 (16.7%) patients in remission had relevant progression of radiographic damage (ie, progression >4.1 points) and 6 (20%) presented new erosions in a previously unaffected joint between the third and the fifth years.
Conclusion
Patients with early rheumatoid arthritis in sustained remission did not present statistically significant radiographic degradation at the group level; nevertheless, 16.7% of these patients did present degradation. Absence of progression should be part of the remission definition in rheumatoid arthritis.
doi:10.1136/ard.2006.057497
PMCID: PMC1856000  PMID: 16935911
14.  PADI4 and HLA-DRB1 Are Genetic Risks for Radiographic Progression in RA Patients, Independent of ACPA Status: Results from the IORRA Cohort Study 
PLoS ONE  2013;8(4):e61045.
Introduction
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease influenced by both genetic and environmental factors, leading to joint destruction and functional impairment. Recently, a large-scaled GWAS meta-analysis using more than 37,000 Japanese samples were conducted and 13 RA susceptibility loci were identified. However, it is not clear whether these loci have significant impact on joint destruction or not. This is the first study focused on the 13 loci to investigate independent genetic risk factors for radiographic progression in the first five years from onset of RA.
Methods
Sharp/van der Heijde score of hands at 5-year disease duration, which represents joint damage, were measured retrospectively and used as an outcome variable in 865 Japanese RA patients. Genetic factors regarded as putative risk factors were RA-susceptible polymorphisms identified by the Japanese GWAS meta-analysis, including HLA-DRB1 (shared epitope, SE), rs2240340 (PADI4), rs2230926 (TNFAIP3), rs3093024 (CCR6), rs11900673 (B3GNT2), rs2867461 (ANXA3), rs657075 (CSF2), rs12529514 (CD83), rs2233434 (NFKBIE), rs10821944 (ARID5B), rs3781913 (PDE2A-ARAP1), rs2841277 (PLD4) and rs2847297 (PTPN2). These putative genetic risk factors were assessed by a stepwise multiple regression analysis adjusted for possible non-genetic risk factors: autoantibody positivity (anti-citrullinated peptide antibody [ACPA] and rheumatoid factor), history of smoking, gender and age at disease onset.
Results
The number of SE alleles (P = 0.002) and risk alleles of peptidyl arginine deiminase type IV gene (PADI4, P = 0.04) had significant impact on progressive joint destruction, as well as following non-genetic factors: ACPA positive (P = 0.0006), female sex (P = 0.006) and younger age of onset (P = 0.02).
Conclusions
In the present study, we found that PADI4 risk allele and HLA-DRB1 shared epitope are independent genetic risks for radiographic progression in Japanese rheumatoid arthritis patients. The results of this study give important knowledge of the risks on progressive joint damage in RA patients.
doi:10.1371/journal.pone.0061045
PMCID: PMC3620057  PMID: 23577190
15.  Anticitrullinated protein/peptide antibody assays in early rheumatoid arthritis for predicting five year radiographic damage 
Annals of the Rheumatic Diseases  2003;62(2):120-126.
Objective: To study the value of antibodies to citrullinated proteins/peptides for predicting joint outcomes in patients with recent onset rheumatoid arthritis (RA).
Methods: 191 patients with RA onset within the past year were followed up prospectively for five years. Serum samples obtained from 145 patients at baseline before disease modifying antirheumatic drug treatment were examined using three anticitrullinated protein/peptide antibody assays: antiperinuclear factor (APF) by indirect immunofluorescence (IIF), antikeratin antibodies (AKA) by IIF, and anti-cyclic citrullinated peptide (CCP) antibodies by enzyme linked immunosorbent assay (ELISA). Radiographs of the hands and feet taken at baseline and after three and five years were evaluated using Sharp scores modified by van der Heijde.
Results:Anti-CCP ELISA was positive in 58.9% of patients. APF/anti-CCP agreement was 77%. The likelihood of a total Sharp score increase after five years was significantly greater among patients with anti-CCP antibodies (67%; odds ratio (OR) 2.5; 95% confidence interval (95% CI) 1.2 to 5.0) or APF (57%; OR 2.4; 95% CI 1.2 to 4.9) but not rheumatoid factor (RF; OR 0.7; 95% CI 0.3 to 1.5). Mean values for radiographic damage, erosion, and joint narrowing scores at the three times were significantly higher in patients with anti-CCP or APF than in those without. AKA did not significantly predict radiographic damage. In separate analyses of patients with and without RF, anti-CCP or APF was better than RF for predicting total joint damage and joint damage progression after five years.
Conclusion: Antibodies to citrullinated proteins/peptides determined early in the course of RA by APF IIF or anti-CCP ELISA are good predictors of radiographic joint damage. Further studies of clinical, laboratory, and genetic parameters are needed to improve RA outcome prediction in clinical practice.
doi:10.1136/ard.62.2.120
PMCID: PMC1754441  PMID: 12525380
16.  Level of radiographic damage and radiographic progression are determinants of physical function: a longitudinal analysis of the TEMPO trial 
Annals of the Rheumatic Diseases  2008;67(9):1267-1270.
Background:
Many studies have examined the relationship between long-term radiographic damage and physical function. However, it is not known if short-term radiographic progression is also associated with physical function.
Aim:
To investigate the longitudinal relationship between physical function and both the level of radiographic damage and the radiographic progression rate in patients with early or advanced active rheumatoid arthritis.
Methods:
The database for the 2-year Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) was used for this study. Physical function was measured by the Health Assessment Questionnaire (HAQ) score at baseline, 6 months and 1 and 2 years. Radiographs of the hands and feet, taken at the same time points, were scored by the van der Heijde-modified Total Sharp Score (TSS). The HAQ score was modelled using generalised mixed linear modelling by TSS or progression in TSS (interval 0–1 year and 1–2 years) adjusted for age, sex, treatment and disease activity.
Results:
After adjustment for age, sex and disease activity, both TSS and the change in TSS (progression rate) were significant determinants of the HAQ score. When radiographic progression was divided into four categories (negative, zero, minor and greater progression), results showed that HAQ scores tended to be higher with a higher rate of progression. Patients with negative progression scores had lower HAQ scores than patients with positive progression scores.
Conclusions:
Patients with greater radiographic damage, and those with recent radiographic progression, have a higher degree of disability.
doi:10.1136/ard.2007.081331
PMCID: PMC2571961  PMID: 18203764
17.  Infliximab in active early rheumatoid arthritis 
Annals of the Rheumatic Diseases  2004;63(2):149-155.
Objective: To examine the impact of the combination of infliximab plus methotrexate (MTX) on the progression of structural damage in patients with early rheumatoid arthritis (RA).
Methods: Subanalyses were carried out on data for patients with early RA in the Anti-TNF Therapy in RA with Concomitant Therapy (ATTRACT) study, in which 428 patients with active RA despite MTX therapy received placebo with MTX (MTX-only) or infliximab 3 mg/kg or 10 mg/kg every (q) 4 or 8 weeks with MTX (infliximab plus MTX) for 102 weeks. Early RA was defined as disease duration of 3 years or less; 82 of the 428 patients (19%) met this definition. Structural damage was assessed with the modified van der Heijde-Sharp score. The changes from baseline to week 102 in total modified van der Heijde-Sharp score were compared between the infliximab plus MTX groups and the MTX-only group.
Results: The erosion and joint space narrowing scores from baseline to week 102 in the cohort of patients with early RA decreased significantly in each infliximab dose regimen compared with the MTX-only regimen. Consistent benefit was seen in the joints of both hands and feet.
Conclusions: Infliximab combined with MTX inhibited the progression of structural damage in patients with early RA during the 2 year period of treatment. Early intervention with infliximab in patients with active RA despite MTX therapy may provide long term benefits by preventing radiographic progression and preserving joint integrity.
doi:10.1136/ard.2003.013961
PMCID: PMC1754899  PMID: 14722203
18.  Predictors of radiographic joint damage in patients with early rheumatoid arthritis 
Annals of the Rheumatic Diseases  2001;60(10):924-927.
OBJECTIVE—To determine factors at diagnosis, associated with radiographic damage at diagnosis and after one year, in patients with early rheumatoid arthritis (RA).
METHODS—New patients with early RA were followed up for one year. Possible prognostic factors were duration of complaints, morning stiffness, disease activity score (DAS28), functional status (Health Assessment Questionnaire (HAQ) score), rheumatoid factor (IgM RF), and C reactive protein (CRP). Outcome was defined as radiographic damage of the hands and feet (Sharp/van der Heijde score). For the statistical analysis, one way analysis of variance and a forward stepwise logistic regression model was used.
RESULTS—130 patients with RA (68% female; median age 64 years, range 21-86) were included. Despite the fact that the median duration of complaints was short (15 weeks, range 2-106) the radiographic damage at diagnosis was significantly correlated with the duration of complaints (p<0.05). Patients with a duration of complaints of >34 weeks had significantly more radiographic joint damage at diagnosis than patients with a shorter duration of complaints. Radiographic progression at one year was correlated with high radiographic joint damage, high CRP level, and a positive IgM RF at entry.
CONCLUSIONS—In early RA, the number of radiographic lesions was correlated with a longer duration of complaints at the first visit. Progression of these lesions was predicted by a high baseline joint damage, high CRP level, and a positive IgM RF. Further reduction of the delay in referral and early treatment may further decrease joint damage in patients with recent onset polyarthritis.


doi:10.1136/ard.60.10.924
PMCID: PMC1753390  PMID: 11557647
19.  Association of IL4R single-nucleotide polymorphisms with rheumatoid nodules in African Americans with rheumatoid arthritis 
Introduction
To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans.
Methods
Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors.
Results
Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score >0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj = 8.08 (95% confidence interval (CI): 1.60-40.89), P = 0.01 and ORadj = 2.97 (95% CI, 1.08 to 8.17), P = 0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj = 8.45 (95% CI, 1.57 to 45.44), P = 0.01, and ORadj = 3.57 (95% CI, 1.18 to 10.76), P = 0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj = 4.52 (95% CI, 1.20 to 17.03), P = 0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls.
Conclusions
We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.
doi:10.1186/ar2994
PMCID: PMC2911851  PMID: 20444266
20.  Exploratory analyses of the association of MRI with clinical, laboratory and radiographic findings in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2011;70(12):2126-2130.
Objectives
Evaluate relationships between MRI and clinical/laboratory/radiographic findings in rheumatoid arthritis (RA).
Methods
637 methotrexate-naive patients (GO-BEFORE) and 444 patients with active RA despite methotrexate (GO-FORWARD) were randomly assigned to subcutaneous placebo + methotrexate, golimumab 100mg + placebo, golimumab 50mg + methotrexate, or golimumab 100mg + methotrexate every-4-weeks. In GO-BEFORE(n=318) and GO-FORWARD(n=240) substudies, MRI of dominant wrist/metacarpophalangeal joints were scored for synovitis, bone oedema and bone erosion (RA MRI scoring (RAMRIS) system). Relationships between RAMRIS scores and serum C-reactive protein (CRP), 28-joint count disease activity score (DAS28–CRP) and van der Heijde modified Sharp (vdH-S) scores were assessed.
Results
Baseline and weeks 24/28 DAS28–CRP, CRP, and vdH-S generally correlated well with baseline and week 24 RAMRIS synovitis, oedema and erosion scores. Early (week 4) CRP changes correlated with later (week 12) RAMRIS synovitis/oedema change scores; earlier (week 12) changes in some RAMRIS scores correlated with later (weeks 24/28) changes in vdH-S. Significant correlations between RAMRIS change scores and clinical/radiographic change scores were weak.
Conclusions
MRI and clinical/laboratory/radiographic measures generally correlated well. Associations between earlier changes in CRP and later changes in RAMRIS synovitis/osteitis were observed. Changes in MRI and clinical/radiographic measures did not correlate well, probably because MRI is more sensitive than radiographs and more objective than DAS28–CRP.
doi:10.1136/ard.2011.154500
PMCID: PMC3212698  PMID: 21926186
21.  Profile and course of early rheumatoid arthritis in Morocco: a two-year follow-up study 
Background
This study aimed to establish the profile and the evolution of an early Rheumatoid arthritis (RA) cohort in the Moroccan population and also to search possible predictor factors of structural progression.
Methods
Patients with early RA (< 12 months) were enrolled in a 2-year follow-up study. Clinical, biological, immunogenetic, and radiographical data were analyzed at study entry and at 24 months. Presence of radiographic progression was retained when the total score was superior to the smallest detectable difference (SDD) calculated to be 5.4 according the Sharp/van der Heijde (SVDH) method.
Results
Fifty one patients (88.8% women, mean age of 46.9 [ 24-72 ] ± 10.8 years, mean disease duration of 24 [ 6-48 ] ± 13.9 weeks) were enrolled in this study. 68.6% were illiterate and 19.6% reported at least one comorbid condition. The mean delay in referral for specialist care was 140 [ 7-420 ] ± 43 days.
Thirteen patients (62.5%) were IgM or IgA RF positive. HLA-DRB1*01 and DRB1*04 alleles were present respectively in 11.8% and 45.1% of patients.
At baseline, 35.3% patients were taking corticosteroids and 7.8% were under conventional DMARDs.
At 24 months, 77.2% received a median dose of 5 mg/day of prednisone. Methotrexate (MTX) was the most frequently prescribed DMARD, being taken by 65.2% of patients. 13.6% of patients had stopped their DMARD because of socioeconomic difficulties.
Comparison of clinical and biologic parameters between baseline and 24 months thereafter revealed a significant global improvement of the disease status including morning stiffness, pain score, swollen joint count, DAS 28 and HAQ scores, ESR and CRP.
Sixteen patients (34.8%) were in remission at 2 years versus no patients at baseline; P < 0.001.
Forteen patients (27.5%) had at least one erosion at baseline. Radiographic progression occurred in 33.3% of patients and was associated in univariate analysis to swollen joint count (p = 0.03), total SVDH score (P = 0.04) and joint space narrowing score (P = 0.03). No independent factors of radiographic progression were shown by logistic regression.
Conclusions
These study reports, provided for the first time in Morocco, a developing African country, a large amount of information concerning the profile and the course of early RA.
Patients who were receiving, for most of them, Methotrexate in monotherapy and low doses of corticosteroids, showed an improvement of all clinic and biologic disease parameters. Moreover, DAS remission was obtained in one third of patients and two thirds of the cohort had no radiographic progression at 2 years. No predictor factors of radiographic progression were found out.
These results should be confirmed or not by a large unbiased RA cohort which will give more relevant information about early RA characteristics and its course and will constitute a major keystone of its management.
doi:10.1186/1471-2474-12-266
PMCID: PMC3239294  PMID: 22111841
22.  Pain and psychological health status over a 10‐year period in patients with recent onset rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(9):1195-1201.
Objective
To examine rheumatoid arthritis (RA) with short disease duration over 10 years, and to identify factors that are associated with the course of pain, depression and anxiety.
Methods
A cohort of 238 patients with RA (age 20–70 years, mean disease duration 2.3 years, 68% rheumatoid factor positive) was followed with assessments at baseline and after 1, 2, 5 and 10 years. Self‐reported health status was assessed by pain on a 100 mm visual analogue scale, the Arthritis Impact Measurement Scales (AIMS), the 28‐item version of General Health Questionnaires, and the Health Assessment Questionnaire. We also examined the erythrocyte sedimentation ratio, grip strength (kg) and radiographic progression of the hands (van der Heijde modified Sharp score). Repeated measures analyses of variance were used to explore the effect of time on measures of outcome among completers, whereas repeated measures analyses using a mixed model were applied to identify factors that were longitudinally associated with pain, depression and anxiety.
Results
At the various assessment points 30% had a visual analogue scale pain score of ⩾40 mm, 5–13% had an AIMS depression score of ⩾4.0 and 20–30% had an AIMS anxiety score of ⩾4.0. The perceived level of pain was explained longitudinally by anxiety, disease activity, physical function and female gender, depression by high disease activity and anxiety, whereas anxiety was explained by low disease activity and depression.
Conclusion
More patients had increased levels of anxiety (20–30%) than increased levels of depression (5–13%). Several factors, including anxiety, but not depression, were associated with the course of pain.
doi:10.1136/ard.2006.064287
PMCID: PMC1955161  PMID: 17392351
23.  Prevalence of osteoporosis and osteopenia among African Americans with early rheumatoid arthritis: the impact of ethnic-specific normative data. 
PURPOSE: To examine the prevalence of osteopenia and/or osteoporosis among African Americans with early rheumatoid arthritis (RA) and to assess the effect of using race/ethnicity-specific normative data. METHODS: Bone mineral density (BMD) of the hip and spine was assessed in African Americans with early RA. To examine the impact of using different normative data on disease classification, we calculated two sets of T scores, the first using sex-matched reference data from Caucasians and the second using data from African Americans. Osteoporosis was defined as a BMD at either site > or =2.5 SD below the young adult mean. Osteopenia was defined as a BMD > or =1 SD and <2.5 SD below this mean. RESULTS: Using Caucasian referent data, 33% (n=48) of patients had osteopenia or worse (n=48, 32.9%) and 5% (n=8) were osteoporotic. With the use of African-American normative data, 55% (n=94) were osteopenic or worse, and 16% (n=27) were osteoporotic. CONCLUSION: African Americans with RA are at risk of osteopenia and/or osteoporosis. Different diagnostic classifications may occur in this population based solely on the normative data used for assessing fracture risk. These results underscore the need for a standardized approach in defining osteopenia and osteoporosis in African Americans.
PMCID: PMC1364462  PMID: 16173331
24.  Prevalence of Osteoporosis and Osteopenia among African Americans with Early Rheumatoid Arthritis: The Impact of Ethnic-Specific Normative Data 
Purpose: To examine the prevalence of osteopenia and/or osteoporosis among African Americans with early rheumatoid arthritis (RA) and to assess the effect of using race/ethnicity-specific normative data.
Methods: Bone mineral density (BMD) of the hip and spine was assessed in African Americans with early RA. To examine the impact of using different normative data on disease classification, we calculated two sets of T scores, the first using sex-matched reference data from Caucasians and the second using data from African Americans. Osteoporosis was defined as a BMD at either site ≥2.5 SD below the young adult mean. Osteopenia was defined as a BMD ≥1 SD and <2.5 SD below this mean.
Results: Using Caucasian referent data, 33% (n=48) of patients had osteopenia or worse (n=48, 32.9%) and 5% (n=8) were osteoporotic. With the use of African-American normative data, 55% (n=94) were osteopenic or worse, and 16% (n=27) were osteoporotic.
Conclusion: African Americans with RA are at risk of osteopenia and/or osteoporosis. Different diagnostic classifications may occur in this population based solely on the normative data used for assessing fracture risk. These results underscore the need for a standardized approach in defining osteopenia and osteoporosis in African Americans.
PMCID: PMC1364462  PMID: 16173331
osteoporosis; osteopenia; African Americans; DXA; rheumatoid arthritis
25.  High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review 
Clinical Rheumatology  2012;31(11):1529-1535.
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. Decreased bone mineral density (BMD) is a common complication of AS, with a prevalence range of 19 to 62 %. Many studies have shown decreased BMD in AS with long disease duration, but only a few studies investigated BMD in early AS. The prevalence of decreased BMD in early disease stages of AS has not yet been clearly described, and for that reason, we reviewed the literature which describes the prevalence of decreased BMD in AS patients with a short disease duration (<10 years). In this review, we included articles which used the modified New York criteria for the diagnosis of AS, included patients with a disease duration of less than 10 years, and used the WHO criteria for osteopenia and osteoporosis. Decreased BMD was defined as a T score < −1.0, including both osteopenia and osteoporosis. For this review, only articles that acquired BMD data of lumbar spine and femoral neck by DXA were used. The literature search provided us 35 articles of which 7 matched all our criteria, and they will be further outlined in this review. The overall prevalence of decreased BMD of the articles reviewed is 54 % (n = 229/424) for lumbar spine and 51 % (n = 224/443) for femoral neck. The prevalence of osteopenia vs. osteoporosis for lumbar spine is 39 vs. 16 % and for femoral neck, 38 vs. 13 %. This review showed a high total prevalence of 51–54 % decreased BMD and 13–16 % osteoporosis in AS with a short disease duration. This high prevalence was not to be expected in a relatively young and predominantly male population. Further research is needed to determine the clinical relevance of this low BMD by investigating the relation between low BMD and vertebral and nonvertebral fractures at this early stage in AS.
doi:10.1007/s10067-012-2018-0
PMCID: PMC3483100  PMID: 22706444
Ankylosing spondylitis; Bone mineral density; Osteopenia; Osteoporosis; Vertebral fractures

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