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1.  Defining cut-off values for disease activity states and improvement scores for patient-reported outcomes: the example of the Rheumatoid Arthritis Impact of Disease (RAID) 
Arthritis Research & Therapy  2012;14(3):R129.
The Rheumatoid Arthritis Impact of Disease (RAID) is a patient-reported outcome measure evaluating the impact of rheumatoid arthritis (RA) on patient quality of life. It comprises 7 domains that are evaluated as continuous variables from 0 (best) to 10 (worst). The objective was to define and identify cut-off values for disease activity states as well as improvement scores in order to present results at the individual level (for example, patient in acceptable state, improved patient).
Patients with definite active RA requiring anti-tumour necrosis factor (anti-TNF) therapy were seen at screening, baseline and after 4 and 12 weeks of etanercept therapy. Answers to "Gold standard" questions on improvement (MCII: Minimum Clinically Important Improvement) and an acceptable status (PASS: Patient Acceptable Symptom State) were collected as well as the RAID score and Disease Activity Score 28- erythrocyte sedimentation rate (DAS28-ESR). Cut-offs were defined by different techniques including empirical, measurement error and gold standard anchors. The external validity of these cut-offs was evaluated using the positive likelihood ratio (LR) based on the patient's perspective (for example, patient's global) and on low disease activity status (such as DAS28-ESR).
Ninety-seven (97) of the 108 recruited patients (age: 54 ± 13 years old, female gender: 75%, rheumatoid factor positive: 81%, disease duration: 8 ± 7 years, CRP: 18 ± 30 mg/l, DAS28-ESR: 5.4 ± 0.8) completed the 12 weeks of the study. The different techniques suggested thresholds ranging from 0.2 to 3 (absolute change) and from 6 to 50% (relative change) for defining MCII and thresholds from less than 1 to less than 4.2 for defining PASS. The evaluation of external validity (LR+) showed the highest LR+ was obtained with thresholds of 3 for absolute change; 50% for relative change and less than 2 for an acceptable status.
This study showed that thresholds defined for continuous variables are closely related to the methodological technique, justifying a systematic evaluation of their validity. Our results suggested that a change of at least 3 points (absolute) or 50% (relative) in the RAID score should be used to define a MCII and that a maximal value of 2 defines an acceptable status.
Trial Registration NCT004768053
PMCID: PMC3446510  PMID: 22647431
2.  Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: a comparative study 
Pulmonary involvement is a known manifestation in patients with ankylosing spondylitis (AS). However, previous studies have been based on small samples and the reported prevalence and associations with typical clinical features vary. The purpose of this study was to compare pulmonary function (PF) in patients with AS and population controls, and to study associations between PF and disease related variables, cardio-respiratory fitness and demographic variables in patients with AS.
In a cross-sectional controlled study, 147 AS patients and 121 controls underwent examinations, including demographic variables, laboratory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and clinical measures (disease activity (AS disease activity score, ASDAS), physical function (Bath ankylosing spondylitis functional index, BASFI), spinal mobility (Bath ankylosing spondylitis metrology index, BASMI), chest expansion, cardio-respiratory fitness (peak oxygen uptake, VO2peak) and pulmonary function test (PFT) (spirometry)). Cumulative probability plots were used to visualize associations between the ASDAS and BASMI scores and the corresponding forced vital capacity (FVC%, percentage of predicted value controlled for the influence of confounding factors) score for each patient. Univariate ANCOVAs were performed to explore group differences in PF adjusting for relevant variables, and a multiple regression model was used to estimate the explanatory power of independent variables (demographic, disease related, VO2peak) on restrictive ventilatory impairment (FVC%).
AS patients showed significantly lower PF values compared with controls, and significantly more patients were categorized with restrictive pattern (18% vs. 0%, P < 0.001). Cumulative probability plots showed significant associations between spinal mobility measures (BASMI) and FVC% for individual patients. BASMI, chest expansion and male gender contributed significantly and independently in a multiple regression model predicting the variation of FVC% in AS patients, whereas disease activity, physical function and VO2peak did not contribute significantly. The final model explained 45% of the variance in FVC% (P < 0.001).
This study showed significantly impaired pulmonary function in the AS patients compared to controls and reference data, and demonstrated a clear relationship between reduced spinal mobility and restrictive PF in AS patients. The results support the assumption of an association between musculoskeletal limitations and restrictive respiratory impairment in AS, emphasizing the importance of maintaining spinal flexibility in the management of the disease. Further, patients with severely reduced spinal mobility should be referred for pulmonary function examination and relevant follow-up treatment.
PMCID: PMC3392810  PMID: 22277377
3.  Generalized Bone Loss as a Predictor of 3-Year Radiographic Damage in African American Patients with Recent-Onset Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(8):2219-2226.
To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3-year disease duration in a longitudinal cohort of African Americans (AAs) with recent-onset RA.
Participants (n=141) included AAs with < 2 years of disease duration. All patients underwent baseline BMD measurement (femoral neck and/or lumbar spine) using DXA. T-scores were calculated using AAs normative data. Patients were categorized as having osteopenia/osteoporosis (T score ≤ −1) or healthy. Hand/wrist radiographs, obtained at baseline and at 3-year disease duration, were scored using modified Sharp/van der Heijde method. The association between baseline BMD and total radiographic score at 3-year disease duration was examined using multivariable negative binomial regression.
At baseline, the mean age and disease duration were 52.4 years and 14.8 months respectively (85.1% women). Average total radiographic scores at baseline and 3-year disease duration were 2.4 and 5.7. In the final reduced multivariable model adjusting for age, gender, anti-cyclic citrullinated peptide antibody positivity, and the presence of radiographic damage at baseline, the total radiographic score at 3-years of disease duration in patients with osteopenia/osteoporosis at the femoral neck was twice that in patients with healthy bone density and the difference was statistically significant (p=0.0084). No association between lumbar spine osteopenia/osteoporosis and radiographic score was found.
These findings suggest that reduced generalized BMD may be a predictor of future radiographic damage and support the hypothesis that radiographic damage and reduced generalized BMD in RA patients may share a common pathogenic mechanism.
PMCID: PMC2922001  PMID: 20506234
4.  Association of a Single-Nucleotide Polymorphism in CD40 With the Rate of Joint Destruction in Rheumatoid Arthritis 
Arthritis and rheumatism  2009;60(8):2242-2247.
The severity of joint destruction in rheumatoid arthritis (RA) is highly variable from patient to patient and is influenced by genetic factors. Genome-wide association studies have enormously boosted the field of the genetics of RA susceptibility, but risk loci for RA severity remain poorly defined. A recent meta-analysis of genome-wide association studies identified 6 genetic regions for susceptibility to autoantibody-positive RA: CD40, KIF5A/PIP4K2C, CDK6, CCL21, PRKCQ, and MMEL1/TNFRSF14. The purpose of this study was to investigate whether these newly described genetic regions are associated with the rate of joint destruction.
RA patients enrolled in the Leiden Early Arthritis Clinic were studied (n = 563). Yearly radiographs were scored using the Sharp/van der Heijde method (median followup 5 years; maximum followup 9 years). The rate of joint destruction between genotype groups was compared using a linear mixed model, correcting for age, sex, and treatment strategies. A total of 393 anti–citrullinated protein antibody (ACPA)–positive RA patients from the North American Rheumatoid Arthritis Consortium (NARAC) who had radiographic data available were used for the replication study.
The TT and CC/CG genotypes of 2 single-nucleotide polymorphisms, rs4810485 (CD40) and rs42041 (CDK6), respectively, were associated with a higher rate of joint destruction in ACPA-positive RA patients (P = 0.003 and P = 0.012, respectively), with rs4810485 being significant after Bonferroni correction for multiple testing. The association of the CD40 minor allele with the rate of radiographic progression was replicated in the NARAC cohort (P = 0.021).
A polymorphism in the CD40 locus is associated with the rate of joint destruction in patients with ACPA-positive RA. Our findings provide one of the first non–HLA-related genetic severity factors that has been replicated.
PMCID: PMC3121053  PMID: 19644859
5.  Predicting the outcome of ankylosing spondylitis therapy 
Annals of the Rheumatic Diseases  2011;70(6):973-981.
To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS).
ASSERT and GO–RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model.
Age, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population.
Age, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice.
PMCID: PMC3086037  PMID: 21402563
6.  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.
To investigate whether the PTPN22 1858T risk variant is associated with the rate of radiographic progression in rheumatoid arthritis (RA).
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.
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.
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.
PMCID: PMC2095332  PMID: 17472988
rheumatoid arthritis; PTPN22; longitudinal study; radiographic damage; genetic predisposition
7.  Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis 
Annals of internal medicine  2009;151(4):229-W51.
Extracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF) have been used in China for centuries to treat a spectrum of inflammatory diseases.
To compare the benefits and side effects of TwHF extract with those of sulfasalazine for the treatment of active rheumatoid arthritis.
Randomized, controlled trial. A computer-generated code with random, permuted blocks was used to assign treatment.
2 U.S. academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan).
121 patients with active rheumatoid arthritis and 6 or more painful and swollen joints.
TwHF extract, 60 mg 3 times daily, or sulfasalazine, 1 g twice daily. Patients could continue stable doses of oral prednisone or nonsteroidal anti-inflammatory drugs but had to stop taking disease-modifying antirheumatic drugs at least 28 days before randomization.
The primary outcome was the rate of achievement of 20% improvement in the American College of Rheumatology criteria (ACR 20) at 24 weeks. Secondary end points were safety; radiographic scores of joint damage; and serum levels of interleukin-6, cholesterol, cortisol, and adrenocorticotropic hormone.
Outcome data were available for only 62 patients at 24 weeks. In a mixed-model analysis that imputed data for patients who dropped out, 65.0% (95% CI, 51.6% to 76.9%) of the TwHF group and 32.8% (CI, 21.3% to 46.0%) of the sulfasalazine group met the ACR 20 response criteria (P = 0.001). Patients receiving TwHF also had significantly higher response rates for ACR 50 and ACR 70 in mixed-model analyses. Analyses of only completers showed similar significant differences between the treatment groups. Significant improvement was demonstrated in all individual components of the ACR response, including the Health Assessment Questionnaire disability score. Interleukin-6 levels rapidly and significantly decreased in the TwHF group. Although not statistically significant, radiographic progression was lower in the TwHF group. The frequency of adverse events was similar in both groups.
Only 62% and 41% of patients continued receiving TwHF extract and sulfasalazine, respectively, during the 24 weeks of the study. Long-term outcome data were not collected on participants who discontinued treatment.
In patients who continued treatment for 24 weeks and could also use stable oral prednisone and nonsteroidal anti-inflammatory drugs, attainment of the ACR 20 response criteria was significantly greater with TwHF extract than with sulfasalazine.
Primary Funding Source
National Institute of Arthritis and Musculoskeletal and Skin Diseases.
PMCID: PMC2938780  PMID: 19687490
8.  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.
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.
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.
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.
Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
PMCID: PMC1955155  PMID: 17485422
9.  Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(8):1093-1097.
Calprotectin is a major leucocyte protein, shown to correlate well with laboratory and clinical assessments in several inflammatory rheumatic diseases, and large concentrations of calprotectin have been found in synovial fluid from patients with rheumatoid arthritis (RA). The objective of the present study was to examine correlations between calprotectin and joint damage.
145 patients with RA were analysed cross sectionally with laboratory (calprotectin, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR)), clinical (28 joint counts (tender, swollen), physician global VAS, DAS28 and RA Articular Damage score (RAAD)), and radiographic (plain hand radiographs; modified Sharp's method) measurements, on the same day.
Calprotectin showed a highly significant correlation with measures of joint damage; modified Sharp score r = 0.43 (p<0.001) and RAAD r = 0.40 (p<0.001). The association with modified Sharp score and RAAD score was maintained after adjustment for CRP, ESR, rheumatoid factor, DAS28, sex, and age in a multiple regression analysis (p = 0.018 and p = 0.04, respectively), while neither CRP nor ESR showed any independent associations. Highly significant correlations (p<0.001) were also found between calprotectin and both laboratory and clinical markers of inflammation.
Calprotectin was found to significantly and independently explain the variation in the radiological and clinical assessments of joint damage. Longitudinal studies are required to examine whether calprotectin may predict the progression of joint damage in RA.
PMCID: PMC1954700  PMID: 17234650
calprotectin; rheumatoid arthritis; joint inflammation; joint damage; radiographs
10.  Humanized anti-interleukin-6-receptor antibody (tocilizumab) monotherapy is more effective in slowing radiographic progression in patients with rheumatoid arthritis at high baseline risk for structural damage evaluated with levels of biomarkers, radiography, and BMI: data from the SAMURAI study 
Modern Rheumatology  2010;21(1):10-15.
Our aim was to assess the ability of tocilizumab monotherapy to reduce progressive structural joint damage in rheumatoid arthritis patients at high risk of progression. This study was a subanalysis from a prospective 1-year, multicenter, X-ray-reader-blinded, randomized controlled trial of tocilizumab [Study of Active Controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 Inhibitor (SAMURAI) trial]. All patients were categorized into two or three groups according to four independent predictive markers for progressive joint damage [urinary C-terminal crosslinking telopeptide (uCTX-II), urinary pyridinoline/deoxypyridinoline (uPYD/DPD) ratio, body mass index (BMI), and joint-space narrowing (JSN) score at baseline]. One-year progression of joint destruction was assessed in high-risk versus low-risk groups receiving tocilizumab monotherapy and compared with patients receiving conventional disease-modifying antirheumatic drugs (DMARDs) (n = 157 and 145, respectively). In patients at high risk of progression of erosion as estimated by high uCTX-II, uPYD/DPD, or low BMI, and at high risk of progression of JSN as estimated by low BMI or high JSN score, the 52-week changes in radiological erosion and JSN, respectively, were significantly less in patients treated with tocilizumab monotherapy compared with those receiving DMARDs for each type of risk factor. In patients at low risk, those receiving tocilizumab also progressed less than those on DMARDs, although the difference did not reach statistical significance. Tocilizumab monotherapy is more effective in reducing radiological progression in patients presenting with risk factors for rapid progression than in low-risk patients. Patients at high risk for progression may benefit more from tocilizumab treatment.
PMCID: PMC3036807  PMID: 20574648
CTX-II; PYD/DPD; Rheumatoid arthritis; Interleukin-6; Tocilizumab; Joint destruction
11.  Tumour necrosis factor blockers and structural remodelling in ankylosing spondylitis: what is reality and what is fiction? 
Annals of the Rheumatic Diseases  2007;66(6):709-711.
A delineation of the differences in pathology between AS and RA
PMCID: PMC1954668  PMID: 17513569
12.  How do the EQ‐5D, SF‐6D and the well‐being rating scale compare in patients with ankylosing spondylitis? 
Annals of the Rheumatic Diseases  2007;66(6):771-777.
To compare aspects of validity of EuroQol—5 Dimensions (EQ‐5D) and Short‐Form—6 Dimensions (SF‐6D), two indirect utility instruments, and the well‐being rating scale (RS) in ankylosing spondylitis (AS).
EQ‐5D, SF‐6D and RS were available for 254 patients fulfilling modified New York criteria. 134 patients were part of an observational cohort and 120 were part of a randomised controlled trial (RCT). Aspects of validity assessed were truth (agreement and correlation with external health measures) and discrimination (differentiation between health states, repeatability and detection of treatment effect).
Median (range) values were 0.69 (−0.08–1.00) for the EQ‐5D, 0.65 (0.35–0.95) for the SF‐6D and 0.65 (0.14–1.00) for the RS. Agreement (intraclass correlation coefficient) was moderate (0.46–0.55). Instruments correlated equally with disease activity, functioning and quality of life. The SF‐6D showed smaller average differences in utility between patients with better and worse disease compared with the EQ‐5D and the RS. The smallest detectable difference (SDD) (in the control group of RCT) was 0.36, 0.17 and 0.33 for EQ‐5D, SF‐6D and RS, respectively. The ability to detect treatment effect (in the intervention trial) showed standardised effect sizes that were moderate for EQ‐5D and SF‐6D (0.63 and 0.64) and low for the RS (0.23).
In patients with AS, EQ‐5D, SF‐6D and the RS correlate equally well with external measures of health, but have different psychometric properties. The SDD is most favourable for the SF‐6D, but it discriminates less well between patients with different disease severities. The RS has a poorer ability to detect treatment effects. It is difficult to recommend one of the instruments.
PMCID: PMC1954676  PMID: 17213254
13.  The prognostic value of baseline erosions in undifferentiated arthritis 
Arthritis Research & Therapy  2009;11(5):R155.
Undifferentiated arthritis (UA) has a variable disease course; 40 to 50% of UA patients remit spontaneously, while 30% develop rheumatoid arthritis (RA). Identifying the UA patients who will develop RA is essential to initiate early disease-modifying anti-rheumatic drug (DMARD) therapy. Although the presence of bone erosions at baseline is predictive for a severe destructive disease course in RA, the prognostic importance of erosive joints for disease outcome in UA is unknown. This study evaluates the predictive value of erosive joints for the disease outcome in UA as measured by RA development and disease persistency.
Baseline hands and feet radiographs of 518 UA patients were evaluated for erosions using a clinical definition as well as the Sharp/van der Heijde method. After 1 year follow-up, patients were re-assessed for the fulfilment of the 1987 ACR classification criteria for RA. Disease persistency was defined as the absence of sustained remission during all available follow-up (mean 8 ± 3 years).
At baseline, 28.6% of UA patients had erosive joints. Presence of ≥2 erosive joints showed a positive predictive value for RA development of 53% and for persistent disease of 68%. Patients with erosions that did not develop RA were less often anticyclic citrullinated peptide antibody (ACPA)+ve, rheumatoid factor (RF)+ve and had lower C-reactive protein (CRP), erythrocytic sedimentation rate (ESR) and number of swollen joints compared to those who developed RA. Feet erosions are equally predictive compared to erosions at hands.
Presence of ≥2 erosive joints at baseline in UA patients gives a risk for RA development of 53% and for persistent disease of 68%, indicating that erosions in UA are not always predictive for unfavorable disease outcomes.
PMCID: PMC2787272  PMID: 19832979
14.  Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years 
Arthritis Research & Therapy  2009;11(4):R127.
Ankylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy.
Radiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method.
mSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744).
Two years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therapy.
Trial registration
Canadian study (M03-606) identifier: NCT00195819; ATLAS study (M03-607) identifier: NCT00085644.
PMCID: PMC2745811  PMID: 19703304
15.  Physical function, disease activity, and health-related quality-of-life outcomes after 3 years of adalimumab treatment in patients with ankylosing spondylitis 
Arthritis Research & Therapy  2009;11(4):R124.
We evaluated the three-year impact of adalimumab on patient-reported physical function and health-related quality-of-life (HRQOL) outcomes in patients with active ankylosing spondylitis (AS).
The Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS) is an ongoing five-year study that included an initial 24-week, randomized, placebo-controlled, double-blind period, followed by open-label extension treatment with adalimumab. Clinical and HRQOL data collected for up to three years from ATLAS were used for these analyses. Patients were randomized to receive adalimumab 40 mg or placebo by subcutaneous injection every other week. Physical function was assessed by the Bath AS Functional Index (BASFI), as well as by the Short Form 36 (SF-36) Health Survey Physical Component Summary (PCS) and Physical Function subscale scores. HRQOL was assessed using the AS Quality of Life (ASQOL) questionnaire. Disease activity was assessed by the Bath AS Disease Activity Index (BASDAI).
Of 315 patients enrolled in ATLAS, 288 (91%) participated in an open-label adalimumab treatment extension and 82% provided three-year outcome data. During the 24-week double-blind phase, adalimumab-treated patients experienced significant improvement compared with placebo-treated patients in the BASDAI (P < 0.001), BASFI (P < 0.001), ASQOL (P < 0.001), and both the SF-36 PCS (P < 0.001) and Physical Function subscale (P < 0.001) scores, but not the SF-36 Mental Component Summary score (P = 0.181) and Mental Health subscale scores (P = 0.551). Mean changes from baseline through three years of adalimumab treatment were statistically significant for the BASDAI (change score: -3.9, P < 0.001), BASFI (change score: -29.6, P < 0.001), SF-36 PCS (change score: 11.6, P < 0.001), and Physical Function (change score: 23.3, P < 0.001). Comparable results were observed for the other SF-36 scores and for the ASQOL (all P < 0.001).
Adalimumab significantly improved disease activity, patient-reported physical function, and HRQOL. These benefits were maintained over three years of treatment in patients with AS.
Trial registration NCT00085644.
PMCID: PMC2745808  PMID: 19686597
16.  The impact of infliximab treatment on quality of life in patients with inflammatory rheumatic diseases 
In this study, we compare the health-related quality of life (HRQoL) of patients with moderate-to-severe rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS), and study the effect of treatment with infliximab on the HRQoL of patients with these diseases. Short Form Health Survey-36 (SF-36) data from the placebo-controlled phases of 4 studies of infliximab in patients with inflammatory rheumatic diseases (n = 1990) were evaluated. Data came from the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) (n = 428), the Safety Trial for Rheumatoid Arthritis with REMICADE Therapy (START) (n = 1083), the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) (n = 279), and the Infliximab Multinational Psoriatic Arthritis Clinical Trial II (IMPACT II) (n = 200). SF-36 assessments were made at weeks 0, 10, 30, and 54 in ATTRACT, weeks 0, 6, and 22 in START, weeks 0, 12, and 24 in ASSERT, and weeks 0 and 14 in IMPACT II. All patient populations had significantly impaired physical aspects of HRQoL at baseline relative to the general population of the United States, and the magnitude of impairment was similar across the diseases. Mean baseline physical component summary scores were 29 in the RA cohort, 32 in the PsA cohort, and 29 in the AS cohort. In all 3 diseases, patients who received infliximab showed significant improvement in physical component summary scores compared with those who received placebo. The magnitude of the difference of improvement (effect size, 95%CI) between infliximab and placebo groups was similar in the AS (10.1, 9.2–11.0), PsA (8.6, 7.8–9.4), and RA (10.1, 9.2–11.0) cohorts. Patients with RA and those with PsA treated with infliximab also showed greater improvement in the mental component summary score than those in the placebo group with an effect size of 4.6 (4.2–5.1) in RA and 2.7 (2.4–3.1) in PsA. Patients in large randomized controlled studies of infliximab in RA, PsA, and AS had similar impairment in physical aspects of HRQoL at baseline and showed significantly greater improvement in HRQoL after treatment with infliximab.
PMCID: PMC2212571  PMID: 17922913
17.  Expert agreement confirms that negative changes in hand and foot radiographs are a surrogate for repair in patients with rheumatoid arthritis 
The objective of the present study was to test the hypothesis that experts recognize repair of erosions and, if so, to determine which, if any, morphologic features permitted them to recognize the repair. We also tested whether scoring by a standard method detected repair. Seven experienced readers of radiographs in rheumatoid arthritis were presented with 64 sets of single joints-of-interest at two time points, randomized and blinded for the correct sequence. The readers assessed which joint was better, and recorded whether any of six specific features were seen. Two independent readers, experienced in scoring by the van der Heijde-modified Sharp method who were not on the expert panel, then scored the complete films that included the joint-of-interest. The panel agreed very well on which of two joints was better, and, even though they did not know the true sequence, the panel accurately assigned a sequence slightly better than chance alone (58%) but worse than their agreement on which image was 'better or worse' (78%). The readers therefore indirectly assigned repair by choosing the second film as the best. Putative repair features were seen in cases of both repair and progression, and were not discriminatory. Similar results were obtained when the experts were presented with the entire hand or foot containing the joint-of-interest. In the third repair exercise, two independent readers who scored whole hands and feet using a standard method found a mean negative score in 22/60 joints-of-interest. All 22 joints were also scored as repair by the panel. Repair was detected reliably by a majority of the panel on viewing paired images based on a better/worse decision and assigning sequence in a set of images that were blinded for sequence by an independent project manager. In this test set of images, repair was manifested by a reduction in the size of erosion in many cases. Size was one feature that aided the experts to detect repair but cannot be the only one; the experts had to find other features to determine whether a smaller erosion was the first in a sequence of radiographs in a patient with progressive damage or was the second film in a patient exhibiting repair. The change in size of erosion was also picked up by independent readers applying the van der Heijde-modified Sharp scoring method and was reflected in their scores.
PMCID: PMC2206368  PMID: 17605816
18.  The validity of a rheumatoid arthritis medical records-based index of severity compared with the DAS28 
Outcome measures play an extremely important role in clinical trials and observational research. Outcome measures for rheumatoid arthritis cover a whole array of domains, ranging from measures describing the inflammatory process to measures describing the ultimate consequences of long-term disease, such as joint damage, physical function and quality of life. There is a scientific need to be able to quantify what is called the 'severity of rheumatoid arthritis', so that patients with rheumatoid arthritis can be clustered according to their propensity to develop an unfavourable outcome. It is a challenge to find an appropriate measure for severity. One attempt has been the development of the Rheumatoid Arthritis Medical Record-Based Index of Severity. This commentary elaborates on how such a measure of severity should be validated to determine whether it is appropriate for practical use.
PMCID: PMC1526622  PMID: 16677409
19.  Magnetic resonance imaging changes of sacroiliac joints in patients with recent-onset inflammatory back pain: inter-reader reliability and prevalence of abnormalities 
To study the inter-reader reliability of detecting abnormalities of sacroiliac (SI) joints in patients with recent-onset inflammatory back pain by magnetic resonance imaging (MRI), and to study the prevalence of inflammation and structural changes at various sites of the SI joints.
Sixty-eight patients with inflammatory back pain (at least four of the five following criteria: symptom onset before age 40, insidious onset, morning stiffness, duration >3 months, improvement with exercise — or three out of five of these plus night pain) were included (38% male; mean age, 34.9 years [standard deviation 10.3]; 46% HLA-B27-positive; mean symptom duration, 18 months), with symptom duration <2 years. A MRI scan of the SI joints was made in the coronal plane with the following sequences: T1-weighted spin echo, short-tau inversion recovery, T2-weighted fast-spin echo with fat saturation, and T1-spin echo with fat saturation after the administration of gadolinium. Both SI joints were scored for inflammation (separately for subchondral bone and bone marrow, joint space, joint capsule, ligaments) as well as for structural changes (erosions, sclerosis, ankylosis), by two observers independently. Agreement between the two readers was analysed by concordance and discordance rates and by kappa statistics.
Inflammation was present in 32 SI joints of 22 patients, most frequently located in bone marrow and/or subchondral bone (29 joints in 21 patients). Readers agreed on the presence of inflammation in 85% of the cases in the right SI joint and in 78% of the cases in the left SI joint. Structural changes on MRI were present in 11 patients. Ten of these 11 patients also showed signs of inflammation.
Agreement on the presence or absence of inflammation and structural changes of SI joints by MRI was acceptable, and was sufficiently high to be useful in ascertaining inflammatory and structural changes due to sacroiliitis. About one-third of patients with recent-onset inflammatory back pain show inflammation, and about one-sixth show structural changes in at least one SI joint.
PMCID: PMC1526558  PMID: 16356197
20.  Structural damage in rheumatoid arthritis as visualized through radiographs 
Arthritis Research  2002;4(Suppl 2):S29-S33.
Several agents show an effect on reducing radiographic progression in rheumatoid arthritis. It is tempting to retrospectively compare the effects of these agents on radiographic progression across clinical trials. However, there are several limitations in interpreting and comparing radiographic results across clinical trials. These limitations, including study designs, patient characteristics, durations of follow-up, scoring methodologies, reader reliability, radiograph sequence, handling of missing data, and data presentation, will be discussed. The consequences are illustrated with several examples of recent clinical trials that show an effect on radiographic progression. A guide in the interpretation and clinical relevance of radiographic results is presented, with the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy used as an example.
PMCID: PMC3238218  PMID: 12110155
radiography; infliximab; etanercept; leflunomide; methotrexate
21.  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.
Evaluate relationships between MRI and clinical/laboratory/radiographic findings in rheumatoid arthritis (RA).
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.
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.
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.
PMCID: PMC3212698  PMID: 21926186
22.  Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study 
Annals of the Rheumatic Diseases  2011;71(5):661-667.
To assess the efficacy and safety of golimumab over 104 weeks in patients with active ankylosing spondylitis.
At baseline, patients with active ankylosing spondylitis (n=356) were randomly assigned (1:1.8:1.8) to subcutaneous injections of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3) every 4 weeks. At week 16, patients in groups 1 and 2 with <20% improvement in total back pain and morning stiffness entered early escape to 50 or 100 mg, respectively. At week 24, patients still receiving placebo crossed over to golimumab 50 mg. Findings through week 24 were previously reported; those through week 104 are presented herein.
At week 104, 38.5%, 60.1% and 71.4% of patients in groups 1, 2 and 3, respectively, had at least 20% improvement in the Assessment in SpondyloArthritis international Society response criteria (ASAS20); 38.5%, 55.8% and 54.3% had an ASAS40 response and 21.8%, 31.9% and 30.7% were in ASAS partial remission. Mean Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores were <3 at week 104 for all the treatment regimens. Golimumab safety through week 104 was similar to that through week 24.
Clinical response that was achieved by patients receiving golimumab through 24 weeks was sustained through 52 and 104 weeks. The golimumab safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.
PMCID: PMC3329230  PMID: 22012970
23.  Serum markers associated with clinical improvement in patients with ankylosing spondylitis treated with golimumab 
Annals of the Rheumatic Diseases  2011;71(5):674-680.
Identify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis (AS).
Sera were collected at weeks 0, 4 and 14 from 100 patients with active AS in the GO–RAISE study. Patients were randomly assigned subcutaneous injections of placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks. Samples were tested for select inflammatory, bone and cartilage markers, and protein profiling was also performed.
Golimumab treatment resulted in significant decreases in several serum proteins at weeks 4 and 14 compared with placebo. Patients who achieved clinical response at week 14, as assessed by a ≥20% improvement in the Assessment in SpondyloArthitis international Society response criteria (ASAS 20), demonstrated a distinct biomarker profile with lower levels of acute phase reactants and inflammatory biomarkers compared with patients who did not. Notably, combinations of two or three biomarkers assessed at baseline were predictive of various clinical outcomes (ASAS 20, Bath ankylosing spondylitis disease activity index 50 or Bath ankylosing spondylitis functional index) using a logistic regression analysis, and the overall predictive values for these combined biomarkers were greater than observed for C-reactive protein (CRP) alone.
Golimumab modulated acute phase reactants and inflammatory markers in patients with active AS. Specific combinations of biomarkers at baseline demonstrated a stronger prediction for clinical efficacy than CRP alone. These data provide insights into the mechanism of golimumab on inflammatory processes driving AS pathology, and may have utility in managing the treatment of patients with AS.
PMCID: PMC3329231  PMID: 22039165
24.  Early response to adalimumab predicts long-term remission through 5 years of treatment in patients with ankylosing spondylitis 
Annals of the Rheumatic Diseases  2011;71(5):700-706.
To describe the efficacy and safety through 5 years of adalimumab treatment in patients with ankylosing spondylitis (AS), and to identify predictors of remission.
Patients with active AS were followed up to 5 years during a 24-week randomised, controlled period, followed by an open-label extension. Disease activity and clinical improvement were evaluated by Assessment in Spondyloarthritis International Society (ASAS) responses, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS). Kaplan–Meier was used to identify patients with sustained ASAS partial remission (PR) or ASDAS inactive disease (ID) for three or more consecutive visits spanning ≥6 months. Logistic regression was used to identify factors associated with remission. Explanatory variables included baseline demographic and disease characteristics and week 12 responses.
Of the 311 patients who received at least one dose of adalimumab, 202 (65%) completed the 5-year study. Among 125 patients who received 5 years of adalimumab, 70%, 77%, 51% and 61% achieved ASAS40, BASDAI 50, ASAS PR and ASDAS ID, respectively. Of 311 adalimumab-treated patients, 45% and 55% achieved sustained ASAS PR and ASDAS ID at any time during study participation. The strongest predictor of remission at years 1 and 5 and of sustained remission was achieving remission at 12 weeks of treatment; baseline characteristics showed weaker associations. Adverse events were comparable with previous reports on adalimumab safety.
In patients with active AS, the efficacy and safety of adalimumab were maintained through 5 years with about half of the patients experiencing sustained remission at any time during the study. Early achievement of remission was the best predictor of long-term and sustained remission.
PMCID: PMC3329233  PMID: 22128084
25.  Golimumab reduces spinal inflammation in ankylosing spondylitis: MRI results of the randomised, placebo- controlled GO-RAISE study 
Annals of the Rheumatic Diseases  2011;71(6):878-884.
To evaluate golimumab's effect on MRI-detected spinal inflammation in ankylosing spondylitis (AS).
Patients were randomly assigned to subcutaneous injections of placebo (n=78), golimumab 50 mg (n=138), or golimumab 100 mg (n=140) every 4 weeks. An MRI substudy comprising 98 patients (placebo n=23, 50 mg n=37, 100 mg n=38) at eligible MRI substudy sites had serial spine MRI scans (sagittal plane, 1.5T scanners, T1 and short tau inversion recovery sequences) at baseline and weeks 14 and 104. Two blinded (treatment, image order) readers independently evaluated MRI spinal inflammation using AS spine MRI-activity (ASspiMRI-a) scores; reader scores were averaged. Changes from baseline to weeks 14 and 104 were compared among treatment groups using analysis of variance on van der Waerden normal scores both with (post-hoc) and without (prespecified) adjustment for baseline ASspiMRI-a scores.
Median baseline ASspiMRI-a scores were lower in the 100 mg (3.5) than placebo (6.8) and 50 mg (7.8) groups. Median decreases in activity scores from baseline to week 14 were −0.5 for placebo, −3.5 for 50 mg (p=0.047 vs placebo), and −1.5 for 100 mg (p=0.14 vs placebo). After adjusting for baseline ASspiMRI-a score imbalance, significant improvements were observed with both 50 mg (p=0.011) and 100 mg (p=0.002) versus placebo. ASspiMRI-a scores improvement achieved with golimumab was maintained at week 104. Improvement in ASspiMRI-a scores correlated with improvement in the recently developed AS disease activity score (ASDAS) and C-reactive protein (CRP) levels but not with other key AS clinical outcomes.
Golimumab significantly reduced MRI-detected spinal inflammation of AS; improvements were sustained to week 104 and correlated with improvement in ASDAS and CRP.
PMCID: PMC3371220  PMID: 22128083

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