Showing papers by "Désirée van der Heijde published in 2012"

A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: The Treatment of Early Aggressive Rheumatoid Arthritis trial

Abstract: Objective To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of ≥3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine. Methods The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was ≥3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102. Results At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047). Conclusion There were no differences in the mean DAS28-ESR during weeks 48–102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy.

A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis

Abstract: Objectives To review the available evidence for the efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and biological drug therapies for the different clinical manifestations of psoriatic arthritis (PsA) in order to provide data for the development of treatment recommendations by the European League Against Rheumatism (EULAR) taskforce. Methods A systematic literature review (SLR) of available treatments for PsA was performed using the largest electronic databases (MEDLINE, EMBASE and COCHRANE) by two working groups formed within the EULAR taskforce. This comprised a comprehensive sample of rheumatologists, dermatologists, epidemiologists and patients. The available evidence was reviewed for NSAIDs, synthetic disease modifying antirheumatic drugs (DMARDs), local and systemic corticosteroids and biologic drugs. All articles and abstracts published between 1962 and January 2010 were reviewed and considered and a meta-analysis of data on biological therapies was performed. Results While little data are available on NSAIDs, glucocorticoids and synthetic DMARDs, the available evidence suggests an acceptable efficacy and safety profile of both NSAIDs and synthetic DMARDs (methotrexate, cyclosporine A, sulfasalazine and leflunomide) in PsA. More evidence is available (level 1B) supporting the efficacy of anti-tumour necrosis factor (anti-TNF) agents (adalimumab, etanercept, golimumab and infliximab) in treating the signs and symptoms of PsA as well as reducing radiographic progression. Registry data show no new safety concerns, although the numbers studied to date are relatively small. Conclusions This SLR reveals some evidence to support the use of NSAIDs and synthetic DMARDs and good evidence for the efficacy of anti-TNF therapy in PsA.

Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis

Abstract: Objectives The aim was to compare continuous and on-demand NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels, ESR, ASDAS-levels or BASDAI-levels in comparison to patients with normal levels. Methods Post-hoc analyses were performed in a randomized trial comparing continuous and on-demand NSAID treatment. Relevant high/elevated subgroups were created based on time-averaged (ta) CRP (>5mg/L), ta-ESR (>12mm/hr), ta-BASDAI (>4), ta-ASDAS-CRP (>2.1) and ta-ASDAS-ESR (>2.1). Subgroups were further split according to NSAID-use (continuous vs. on-demand). Radiological progression was presented in probability plots. Statistical interactions were tested using multiple and logistic regression analysis. Differences in radiological progression were analysed using the Chi-square and Mann-Whitney U test. Results 150 participants randomized to either the continuous-treatment group (n=76), or the on-demand group (n=74) had complete radiographs and were included. The effect of slowing radiological progression with continuous NSAID therapy was more pronounced in patients with elevated ta-CRP-levels, elevated ta-ESR, high ta-ASDAS-CRP or high ta-ASDAS-ESR versus patients with low/normal values. No such effect was found for participants with high vs. low BASDAI. Also, in participants with elevated ta-ESR (irrespective of treatment), there appeared to be a higher rate of structural progression than in participants with normal ta-ESR. Regression analyses showed that continuous NSAID treatment neutralizes the negative effect of inflammation (high ta-ESR). Conclusions Patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs. Continuous NSAID-therapy in patients with elevated acute phase reactants may lead to an improved benefit-risk-ratio of these drugs.

Golimumab in psoriatic arthritis: One‐year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo‐controlled trial

Abstract: Objective Golimumab, administered subcutaneously every 4 weeks, has been shown to be effective in reducing the signs and symptoms of active psoriatic arthritis (PsA) through week 24 of the GO-REVEAL study. Herein we report 1-year clinical, radiographic, and safety findings. Methods Adult patients with active PsA (≥3 swollen and ≥3 tender joints) were randomly assigned to receive subcutaneous placebo, golimumab 50 mg, or golimumab 100 mg every 4 weeks through week 20. At week 16, patients with Results A total of 405 patients were randomized: 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups. Mean changes in PsA-modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group (-0.09) and the golimumab 50 mg group (-0.16) were significantly different versus placebo (0.27) (P = 0.015 and P = 0.011, respectively). Radiographic benefit was maintained through week 52 with golimumab. Clinical efficacy, including improvement in joint and skin responses and physical function, was maintained through 1 year. The frequency/types of adverse events were similar to those reported through week 24. Conclusion Treatment of PsA with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year.

Development of new syndesmophytes and bridges in ankylosing spondylitis and their predictors: a longitudinal study

Abstract: Background Structural damage of the spine in ankylosing spondylitis (AS) is associated with worse physical function and impaired spinal mobility. Knowledge about predictors of new syndesmophyte formation is limited. Objectives To assess the development of new syndesmophytes at the level of individual vertebral bodies and to assess predictors for this development. Methods Clinical and radiological data from 132 patients from the Outcome in Ankylosing Spondylitis International Study for whom complete sets of radiographs were available at baseline and at 2- and 4-year follow-up were used. Univariable and multivariable logistic regression analyses were performed to identify predictors associated with development of new syndesmophytes within 4 years. Results At baseline, 81 (61%) patients had syndesmophytes. New syndesmophytes developed in 44 (33%) patients within 2 years and in 63 (48%) patients within 4 years. The RR of developing new syndesmophytes was 5.0 (95% CI 2.5 to 10.2) at 4 years in patients with existing syndesmophytes as compared with patients without. In the univariable analysis, older age, worse functional status, male gender, erythrocyte sedimentation rate and existing syndesmophytes were associated with development of new syndesmophytes at 4 years. In the multivariable logistic regression analysis, only the presence of existing syndesmophytes was a significant predictor (OR 18.72, 95% CI 6.44 to 54.42). When existing syndesmophytes were taken out from the model, age (OR 1.07, 95% CI 1.03 to 1.11) and male gender (OR 3.98, 95% CI 1.47 to 10.77) were statistically significant contributors. Conclusion In AS, patients with existing syndesmophytes are prone to develop new syndesmophytes over time.

Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study

Abstract: Objective To assess the efficacy and safety of golimumab over 104 weeks in patients with active ankylosing spondylitis. Methods 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 Results 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 Conclusion 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.

Associations between MRI-defined synovitis, bone marrow lesions and structural features and measures of pain and physical function in hand osteoarthritis

Abstract: Objectives To explore associations between MRI features and measures of pain and physical function in hand osteoarthritis (OA). Methods Eighty-five patients (77 women) with mean (SD) age of 68.8 (5.6) years underwent contrast-enhanced MRI of the interphalangeal joints (dominant hand) and clinical joint assessment. One investigator read the MRIs for presence/severity of osteophytes, joint space narrowing, erosions, bone attrition, cysts, malalignment, synovitis, flexor tenosynovitis, bone marrow lesions (BMLs) and ligament discontinuity according to the proposed Oslo hand OA MRI score. Pain and physical function were assessed by joint palpation (tenderness yes/no), self-reported questionnaires (Australian/Canadian (AUSCAN) hand index, Functional Index of hand osteoarthritis (FIHOA), Arthritis Impact Measurement Scale-2 (AIMS-2) hand/finger) and grip strength. Logistic regression with generalised estimating equations was used to explore associations between the presence of MRI features and joint tenderness, and linear regression for associations between the burden of MRI abnormalities and patient-reported outcomes and grip strength (adjusted for age and sex). MRI features with p Results MRI-defined moderate/severe synovitis (OR=2.4; p Conclusion MRI-defined synovitis, BMLs, erosions and attrition were associated with joint tenderness. Synovitis and BMLs may be targets for therapeutic interventions in hand OA.

MRI inflammation and its relation with measures of clinical disease activity and different treatment responses in patients with ankylosing spondylitis treated with a tumour necrosis factor inhibitor

Abstract: Objectives To investigate the relationship between MRI inflammation and measures of clinical disease activity as well as treatment responses in patients with ankylosing spondylitis (AS) treated with a tumour necrosis factor inhibitor. Methods MRI at baseline (n=221), 24 (n=158) and 102 weeks (n=179) were scored for inflammation/activity (MRIa, Berlin scoring system). Treatment responses according to the AS disease activity score (ASDAS), Bath AS disease activity index (BASDAI) and assessment of spondyloarthritis 20 (ASAS20) criteria were calculated. For each treatment response criterion, subgroups of responders and non-responders changes in MRIa scores were compared. Results Higher baseline ASDAS and C-reactive protein (CRP) values were associated with higher baseline MRIa scores and with greater decreases in MRIa scores at follow-up. ASDAS and CRP improvements correlated with MRIa improvement. Stronger correlations were observed for CRP. Differences in MRIa change scores between responders and non-responders were greater when subgroups were defined according to ASDAS response than according to BASDAI or ASAS20 response. Conclusions MRIa correlates better with CRP than with other measures of disease activity. By including both CRP and patient-reported outcomes in its formula, ASDAS has the advantage of providing combined information on objective and subjective measures. As a status and response measure ASDAS better reflects the spinal inflammatory disease process in AS than other composite measures.

Early response to adalimumab predicts long-term remission through 5 years of treatment in patients with ankylosing spondylitis

Abstract: Objectives To describe the effi cacy and safety through 5 years of adalimumab treatment in patients with ankylosing spondylitis (AS), and to identify predictors of remission. Methods 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. Results 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. Conclusions In patients with active AS, the effi cacy 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.

Extended report: Golimumab administered subcutaneously every 4 weeks in ankylosing spondylitis: 104-week results of the GO-RAISE study

Abstract: Golimumab is a human monoclonal antibody to tumour necrosis factor (TNF) α that is administered subcutaneously every 4 weeks. We previously reported the 24-week results of the double-blind, randomised, placebo-controlled GO-RAISE (A Multicenter Randomized, Double-blind, Placebo-controlled Trial of Golimumab, a Fully Human Anti-TNFα Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Ankylosing Spondylitis) study, in which we evaluated the efficacy and safety of golimumab in patients with ankylosing spondylitis (AS).1 The primary end point of the GO-RAISE study was achieved; 59% of patients in the 50-mg group and 60% of patients in the 100-mg group achieved at least 20% improvement in the Assessment in SpondyloArthritis international Society response criteria (ASAS20) at week 14 compared with 22% in the placebo group (p<0.001 for comparisons of placebo with each golimumab group). No unexpected adverse events were observed through 24 weeks of golimumab treatment. Patients were followed up for up to 5 years, with the blind maintained through week 104 (for the type of treatment, placebo or golimumab, through week 24 and, following crossover, for the golimumab dose through week 104) to assess the long-term effects of golimumab therapy. Here we present the 104-week efficacy and safety findings from the GO-RAISE study.

Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative

Abstract: Objective. To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA).

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

Abstract: 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.

Golimumab reduces spinal inflammation in ankylosing spondylitis: MRI results of the randomised, placebo- controlled GO-RAISE study

Abstract: Objective To evaluate golimumab9s effect on MRI-detected spinal inflammation in ankylosing spondylitis (AS). Methods 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. Results 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. Conclusion Golimumab significantly reduced MRI-detected spinal inflammation of AS; improvements were sustained to week 104 and correlated with improvement in ASDAS and CRP.

Update of the literature review on treatment with biologics as a basis for the first update of the ASAS/EULAR management recommendations of ankylosing spondylitis

Abstract: Objective. To perform a literature review as basis for the update of the Assessment in SpondyloArthritis international Society/European League Against Rheumatism (ASAS/EULAR) treatment recommendations with biologics in AS. Methods. A literature search of all publications found in MedLine, Embase and Cochrane database between 2005 and 2009 and in the EULAR/ACR meetings between 2007 and 2009 was performed. The research evidence and strength of recommendation (SOR) for biologics were provided. Results. Out of 247 reports on AS treatment with biologics, 98 contained efficacy data and 25 had complete data for analysis. The treatment effect sizes (95% CI) for anti-TNF vs placebo varied between 0.34 (0.08, 0.6) and 1.5 (0.45, 2.5) for BASDAI and 0.33 (0.07, 0.59) and 2.5 (1.3, 3.7) for BASFI. The calculation of the numbers needed to treat all the different outcomes varied between 2.3 and 3.0 patients for all ASAS outcomes and between 2.7 and 6.5 patients for ASAS partial remission. Data on biologics other than anti-TNF and for TNF blockers on juvenile SpA were limited. The incidence rates of uveitis during anti-TNF treatment varied between 4.4/100 patient-years (pys) and 15.6/100 pys during placebo (P < 0.05). The incidence rates of IBD flares were significantly less during infliximab treatment (0.2/100 pys). The rate of infections was higher in patients treated with anti-TNF as compared with placebo, but there was no difference in the incidence of serious infections for treatment with anti-TNF vs placebo. Conclusions. The overall evidence was very high for anti-TNF treatment (1b, SOR: A) with respect to efficacy and safety, while it was low for biologic treatment other than anti-TNF (3, SOR: C).

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)

Abstract: Introduction 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).

Timing and magnitude of initial change in disease activity score 28 predicts the likelihood of achieving low disease activity at 1 year in rheumatoid arthritis patients treated with certolizumab pegol: a post-hoc analysis of the RAPID 1 trial.

Abstract: Objective. To determine the relationship between timing and magnitude of Disease Activity Score [DAS28(ESR)] nonresponse (DAS28 improvement thresholds not reached) during the first 12 weeks of treatment with certolizumab pegol (CZP) plus methotrexate, and the likelihood of achieving low disease activity (LDA) at 1 year in patients with rheumatoid arthritis. Methods. In a post-hoc analysis of the RAPID 1 study, patients achieving LDA [DAS28(ESR) ≤ 3.2] at Year 1 were assessed according to DAS28 nonresponse at various timepoints within the first 12 weeks. Results. Seven-hundred eighty-three patients were included (CZP 200 mg, n = 393; CZP 400 mg, n = 390). A total of 86.9% of patients in the CZP 200 mg group had a DAS28 improvement of ≥ 1.2 by Week 12. Of the 13.1% of patients with DAS28 improvement Conclusion. Failure to achieve improvement in DAS28 within the first 12 weeks of therapy was predictive of a low probability of achieving LDA at Year 1. Moreover, the accuracy of the prediction was found to be strongly dependent on the magnitude and timing of the lack of the response. (Clinical Trial Registration Nos. NCT00152386 and NCT00175877).

Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondyloarthritis) and gastrointestinal or liver comorbidity

Abstract: Background Even with optimal disease-modifying treatment and good control of disease activity, persistent pain due to structural damage is common in people with inflammatory arthritis and therefore additional treatment for pain might be required. Because comorbidity is highly prevalent in people with inflammatory arthritis, it is important to consider comorbidities such as gastrointestinal or liver diseases in deciding upon optimal pharmacologic pain therapy. Objectives To assess the efficacy and safety of pharmacological pain treatment in patients with inflammatory arthritis who have gastrointestinal or liver comorbidities, or both. Search methods We searched Cochrane CENTRAL, MEDLINE and EMBASE for studies, to June 2010. We also searched the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) conference abstracts (2007 to 2010) and performed a handsearch of reference lists of articles. Selection criteria All randomised or quasi-randomised controlled trials (RCTs or CCTs) were considered for inclusion, for the assessment of efficacy. For safety, we also considered single arm trials, controlled before-after studies, interrupted time series, cohort and case-control studies, and case series of 10 or more consecutive cases. Pain therapy comprised paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, opioid-like drugs (tramadol) and neuromodulators (antidepressants, anticonvulsants and muscle relaxants). The study population comprised adults (≥ 18 years) with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or other spondyloarthritis who had gastrointestinal or hepatic, or both, comorbid conditions. Outcomes of interest were pain, adverse effects, function and quality of life. Studies that included a mixed population of inflammatory arthritis and other conditions were included only if results for inflammatory arthritis were reported separately. Data collection and analysis Two review authors independently selected trials for inclusion, assessed risk of bias and extracted data. Main results From 2869 identified articles only one single arm open trial fulfilled our inclusion criteria. This trial assessed the safety and efficacy of naproxen (dosage not specified) in 58 patients with active rheumatoid arthritis and gastrointestinal comorbidities for up to 52 weeks. Thirteen participants (22%) remained on gold therapy, four participants (10%) remained on hydroxychloroquine, 27 (47%) remained on corticosteroids, 12 (21%) remained on salicylates and all participants continued on antacids and a bland diet. The presence of faecal occult blood was reported in 1/58 participants tested between weeks 1 to 26 and 2/32 participants tested between weeks 27 to 52. Over the course of the study, seven participants (12.1%) withdrew due to adverse events but, of these, only two participants withdrew due to gastrointestinal side effects (abdominal pain n = 1, nausea n = 1) and no serious adverse events were reported. It was noteable that out of 14 studies excluded due to inclusion of a mixed population (osteoarthritis or other rheumatic conditions) or an intervention that was already withdrawn, five trials reported a higher risk of developing gastrointestinal events in patients with prior gastrointestinal events when treated with NSAIDs. Authors' conclusions On the basis of the current review, there is scant evidence to guide clinicians about how gastrointestinal or liver comorbidities should influence the choice of pain treatment in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or other spondyloarthritis. Based upon additional studies that included a mixed population of participants with a range of rheumatic conditions, NSAIDs should be used cautiously in patients with inflammatory arthritis and a history of gastrointestinaI comorbidity as there is consistent evidence that they may be at increased risk.

Comparison of features by MRI and radiographs of the interphalangeal finger joints in patients with hand osteoarthritis

Abstract: Objectives To examine the construct validity of MRI in the detection of structural hand osteoarthritis features with conventional radiography (CR) as reference and explore the association between radiographic severity and MRI-defined pathology. Methods 106 hand osteoarthritis patients (97 women, mean age 68.9 years (SD 5.6)) had 1.0T contrast-enhanced MRI and CR of the dominant hand. The 2nd–5th interphalangeal joints were scored according to the preliminary Oslo hand osteoarthritis MRI score and Kellgren–Lawrence (KL) scale and Osteoarthritis Research Society International atlas for radiographs. The authors compared the number of joints with structural features by MRI and CR (Wilcoxon signed-rank test) and examined concordance at the individual joint level. The OR of MRI features in joints with doubtful (KL grade 1), mild (2) and moderate/severe (≥3) radiographic osteoarthritis was estimated by generalised estimating equations (KL grade 0 as reference). Results MRI detected approximately twice as many joints with erosions and osteophytes compared with CR (p Conclusion MRI detected more osteophytes and erosions than CR, suggesting that erosive osteoarthritis may be more common than indicated by CR. Synovitis was most common in mild osteoarthritis. Whether this is due to burn-out of inflammation in late disease must be investigated further.

Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden early arthritis cohort

Abstract: Objectives The performance of spondyloarthritis (SpA) classification criteria is not well-established in general early arthritis cohorts. Therefore, the authors tested their performance in the Leiden Early Arthritis Clinic (EAC) cohort and assessed whether these criteria can assist rheumatologists in diagnosing patients. Methods The authors identified all SpA and psoriatic arthritis (PsA) patients in the EAC cohort according to the diagnosis of the treating rheumatologist. A control group consisting of arthritis patients with other diagnoses was matched to the SpA and PsA patients on gender, age and symptom duration. The authors assessed the fulfilment of SpA criteria in all three groups. Results Of the patients in the EAC cohort (n=2011), 7.5% was diagnosed with PsA and 3.8% with SpA. In the PsA group, the ClASsification criteria for Psoratic ARthritis (CASPAR) criteria had the highest sensitivity (88.7%). In the SpA group, the Assessment of SpondyloArthritis international Society (ASAS) peripheral SpA and European Spondylarthropathy Study Group (ESSG) criteria had the highest sensitivity (both 48.7%). Specificity of all criteria sets was good: ranging from 88.5% (ESSG) to 100% (Amor). Conclusions In early arthritis, sensitivity of SpA classification criteria is modest except for the CASPAR criteria in PsA. However, specificity of classification criteria, including the new ASAS-peripheral SpA criteria, is high.

Measuring Pain and Efficacy of Pain Treatment in Inflammatory Arthritis: A Systematic Literature Review

Abstract: Objective. To systematically review the available literature on measuring pain and the efficacy of pain treatment in inflammatory arthritis (IA), as an evidence base for generating clinical practice recommendations. Methods. A systematic literature search was performed in Medline, Embase, Cochrane Library, and the American College of Rheumatology/European League Against Rheumatism 2008/2009 meeting abstracts, searching for studies evaluating clinimetric properties of pain measurement tools in IA (convergent validity, internal consistency, retest reliability, responsiveness, feasibility, and standardization). Studies that presented information on these properties were reviewed and their data were integrated into the pool of results available for pain measures in IA. Results. In total, 51 articles were included in the review. Validated information on pain was available for tools covering different facets such as overall pain, anatomically specific pain, or a mixture of both. Data from these studies showed that single pain-related items such as the visual analog scale (VAS), numeric rating scale (NRS), or verbal rating scale (VRS) provide sufficient clinimetric information. Similar results were obtained for the pain subscales of the Arthritis Impact Measurement Scales (AIMS/AIMS2) and the bodily pain subscale of the Medical Outcome Study Short-Form Survey 36. Most clinimetric coefficients showed acceptable results with respect to validity, reliability, and sensitivity to change, while the degree of standardization and feasibility mostly filled at least 2 of 3 predefined criteria. Conclusion. A variety of pain measures are available to cover different aspects of pain such as intensity, frequency, or location. Single-item tools such as VAS, NRS, or VRS can be recommended to measure overall pain in clinical practice. If more specific issues need to be addressed, more sophisticated tools should be taken into account.

What is the clinical relevance of erosions and joint space narrowing in RA

Abstract: The association between joint damage and disability in rheumatoid arthritis (RA), especially in the later stages of disease, is a main reason why radiographic joint damage is a common and valid outcome measure in RA clinical trials. Most studies have assessed the effect of global joint damage, which has limited our knowledge regarding the individual effects of erosions and cartilage damage on physical function. However, recent data have indicated that joint space narrowing is more closely related to functional status than erosions. Modern imaging techniques that provide improved assessment of the cartilage itself, instead of only joint space narrowing, might help disentangle the separate associations of erosive bone damage and cartilage damage with physical function in patients with RA. The aim of this article is to discuss the current knowledge within this field and the clinical consequences thereof.

Safety of Nonsteroidal Antiinflammatory Drugs and/or Paracetamol in People Receiving Methotrexate for Inflammatory Arthritis: A Cochrane Systematic Review

Abstract: Objective To systematically review the literature on the safety of using nonsteroidal antiinflammatory drugs (NSAID) and/or paracetamol in people receiving methotrexate (MTX) for inflammatory arthritis (IA), as an evidence base for generating clinical practice recommendations Methods A systematic literature review was performed using the Cochrane Library, Medline, Embase, and conference proceedings for the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) for 2008–2009 The search aimed to identify studies describing adverse events (AE) with the concurrent use of paracetamol and/or NSAID in people taking MTX for IA Articles fulfilling our predefined inclusion criteria were systematically reviewed and quality appraised Results Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis (RA) using various NSAID; there were no identified studies for other forms of IA or with paracetamol Of the studies examining concurrent use of MTX and NSAID, there were no reported adverse effects on lung, liver, or renal function, and no increase in MTX withdrawal or in major toxic reactions However, transient thrombocytopenia was demonstrated in 1 study Looking at specific NSAID, there were no clinically significant AE with concomitant piroxicam or etodolac, and only mild AE with celecoxib or etoricoxib Antiinflammatory dose aspirin was demonstrated to have an adverse effect on liver and renal function Conclusion In the management of RA, concurrent use of NSAID with MTX appears to be safe, provided appropriate monitoring is performed The use of antiinflammatory doses of aspirin should be avoided

Sustained efficacy of certolizumab pegol added to methotrexate in the treatment of rheumatoid arthritis: 2-year results from the RAPID 1 trial

Abstract: Objective. To evaluate the safety and efficacy of 2-year administration of certolizumab pegol (CZP) + MTX in patients with active RA. Methods. Patients completing 52 weeks in the Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 1 trial (52-week completers), or withdrawing at week 16 due to lack of ACR20 response were eligible for open-label treatment (CZP 400 mg every other week + MTX). After 2 years’ treatment, HAQ-Disability Index response, ACR20/50/70 responses, DAS-28 and radiographic progression were assessed in 52-week completers. ACR20/50/70 and DAS-28 were also calculated for the intent-to-treat (ITT) population. Adverse events were assessed in patients who received one or more CZP doses during the study. Results. At week 100, 88.9% (n = 216) of 52-week completers who originally received CZP 200 mg + MTX and open-label treatment remained in the study. In this group, ACR20/50/70 at week 100 were 68.2, 55.2 and 35.6%, respectively. HAQ-DI and DAS-28 improvements were sustained throughout the open-label extension (mean change � 0.79 and � 3.5 at week 100, respectively). A total of 46.7% (n = 113) of CZP 200 mg + MTX 52-week completers achieved low disease activity by week 100. Inhibition of radiographic progression was maintained. Similar findings were observed in 52-week completers who originally received CZP 400 mg + MTX and in the ITT population. Rates of serious infection or malignancies did not increase over time and no new safety signals were observed. Conclusion. CZP + MTX provided sustained, 2-year inhibition of radiographic progression and sustained improvements in RA clinical signs and symptoms, with no new safety signals observed in patients who completed 2 years of treatment. Trial registration: clinicaltrials.gov, http://www.clinicaltrials.gov, NCT00175877.

Sensitivity and discriminatory ability of the Ankylosing Spondylitis Disease Activity Score in patients treated with etanercept or sulphasalazine in the ASCEND trial

Abstract: Objectives. The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a new composite clinical tool combining subjective and objective measures. Using data from the randomized double-blind Ankylosing Spondylitis Study Comparing Enbrel with Sulfasalazine Dosed Weekly (ASCEND) trial, we tested ASDAS validity and assessed its capacity to discriminate between treatment effects and change-from-baseline improvements. Methods. These post hoc analyses were conducted in patients who received etanercept (50 mg/week) or SSZ (43 g/day) for 16 weeks. The ASDAS was tested for its capacity to discriminate between those who achieved and did not achieve Assessment of Spondyloarthritis International Society (ASAS) partial remission and ASAS20. Week 16 adjusted treatment differences and effect sizes of improvement from baseline of 42 outcomes were calculated. Results. Means for ASDAS were less than half in patients with ASAS partial remission compared with patients without partial remission across the entire study population (1.2 vs 2.6; P < 0.0001). Patients who achieved ASAS20 had greater mean changes from baseline in ASDAS than those who did not (� 1.8 vs � 0.3; P < 0.0001). ASDAS was consistently shown to have one of the highest discriminatory capacities compared with other measurements (including subjective measurements) regardless of normal vs high CRP, presence or absence of peripheral arthritis and high vs very high ASDAS at baseline. As a dichotomous variable using different thresholds for improvement and disease severity, ASDAS had slightly better discriminatory capacity than all corresponding ASAS measures. Conclusion. ASDAS is a validated and highly discriminatory tool for the detection of significant differences between treatments for AS as well as for detecting a significant improvement from baseline with etanercept and SSZ.

Remission by imaging in rheumatoid arthritis: should this be the ultimate goal?

Abstract: Remission is often selected as the 'treat to target'. There is a plea to include imaging. Imaging remission can apply to structural damage and/or inflammation. For structural damage, radiographs are mostly used. A definition is needed which could be either strict, with no progression occurring, or which takes measurement error into account and uses the smallest detectable change. Mostly imaging remission refers to inflammation as assessed by ultrasound or MRI. The reason for arguing that imaging remission should be included for inflammation is that inflammation may still be present in patients who are in clinical remission. The level of inflammation depends on the clinical remission definition that is used. Bone marrow oedema is the feature that is most predictive of radiographic progression. However, before imaging remission can be implemented as a recommendation, a definition of remission by imaging needs to be established. A choice has to be made about the level of inflammation that can be tolerated and how this needs to be assessed (which imaging method, which feature, which joints, which cut-off point). Moreover, imaging remission should only be selected as a target if it can be proved that it can be treated and that the outcome of the patients will be improved by trying to achieve imaging remission in addition to clinical remission. This proof is not yet available, and too many unanswered questions remain to recommend including imaging remission of inflammation in a definition of remission.

Serum markers associated with clinical improvement in patients with ankylosing spondylitis treated with golimumab

Abstract: Objective Identify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis (AS). Methods 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 infl ammatory, bone and cartilage markers, and protein profi ling was also performed. Results Golimumab treatment resulted in signifi cant 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 profi le with lower levels of acute phase reactants and infl ammatory 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. Conclusion Golimumab modulated acute phase reactants and infl ammatory markers in patients with active AS. Specifi c combinations of biomarkers at baseline demonstrated a stronger prediction for clinical effi cacy than CRP alone. These data provide insights into the mechanism of golimumab on infl ammatory processes driving AS pathology, and may have utility in managing the treatment of patients with AS.

The Efficacy and Safety of Antidepressants in Inflammatory Arthritis: A Cochrane Systematic Review

Abstract: Objectives. To determine the efficacy and safety of antidepressants in pain management in patients with inflammatory arthritis (IA). Methods. We searched the Cochrane Central Register of Controlled Trials, Medline, Embase, and PsychINFO for randomized controlled trials in adults with IA that compared any antidepressants (administered via any route) to another analgesic intervention or placebo. We also searched the 2008–2009 American College of Rheumatology and European League Against Rheumatism abstracts and performed a hand search of reference lists of relevant articles. Primary outcomes were patient-reported pain relief ≥ 30% and withdrawals due to adverse events. Two authors independently assessed methodological quality and extracted data. A risk of bias assessment was performed using methods recommended by the Cochrane Collaboration. Results. Eight trials (652 participants) in patients with rheumatoid arthritis (RA) and 1 trial in patients with ankylosing spondylitis (100 participants) were included in this review. The majority of studies were published in the late 1980s in patients with active disease receiving minimal disease-modifying antirheumatic drug therapy. All trials evaluated tricyclic antidepressants (TCA) and 2 studies included a selective serotonin uptake inhibitor. Seven of the 9 trials had high risk of bias, 2 were unclear, and metaanalysis was not performed due to trial heterogeneity. RA trials with short-term outcome ( 6 wks) benefits on pain. One trial in depressed patients with RA showed no significant difference between amitriptyline and paroxetine given for 8 weeks (65% vs 56% much or very much improved; RR 1.2, 95% CI 0.9 to 1.5). One trial found that amitriptyline was no better than placebo in reducing pain in patients with active AS over 2 weeks (MD −0.2, 95% CI −1.2 to 0.8). From 5 trials, withdrawals due to adverse events were not significantly different from placebo. However, there were significantly more minor adverse events in patients receiving TCA compared with those receiving a placebo (RR 2.3, 95% CI 1.2 to 4.4). These included somnolence, dizziness, dry mouth, and nausea. Conclusion. Based upon 9 trials of high or unclear risk of bias, it is not possible to draw firm conclusions about the efficacy of TCA as analgesics for patients with IA. The use of these agents may be associated with adverse events that are generally mild and do not lead to cessation of treatment. High-quality trials are needed in this area.

Therapeutic controversies in spondyloarthritis: nonsteroidal anti-inflammatory drugs.

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a first-line therapy in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis. NSAIDs reduce pain and stiffness effectively in most patients, are able to reduce systemic and local inflammation, and can inhibit progression of structural damage in the spine. However, effective control of symptoms and retardation of radiographic progression often require continuous and long-term treatment, which raises safety concerns. This article discusses controversies related to the current role of NSAIDs in axSpA treatment, risks and benefits of this treatment, and current trends for individualized treatment.

The efficacy and safety of opioids in inflammatory arthritis: a Cochrane systematic review.

Abstract: Objective. To determine the efficacy and safety of opioid analgesics in inflammatory arthritis (IA). Methods. We searched Medline, Embase, and Central to May 2010. Randomized controlled trials in adults with IA that compared opioids (administered via any route) to another intervention or placebo were included. Studies in the immediate postoperative setting were excluded. Two authors independently extracted data and assessed risk of bias. Primary endpoints were pain and adverse events (AE). Categorical data were pooled using RevMan5 and reported as relative risks (RR) or odds ratios (OR) with 95% confidence intervals (95% CI). Results. Eleven studies were included, all in patients with RA. The risk of bias of all studies was high. No study was longer than 6 weeks in duration and 4 studies used single doses of study drugs. Seven studies were between 1 and 6 weeks in duration and assessed 6 different oral opioids. Only 1 study investigated a strong opioid. Data could be pooled from 4 studies comparing weak opioids to placebo: there was no difference in withdrawals due to inadequate analgesia (RR 0.82, 95% CI 0.34, 2.01), but patient-reported global impression of change was superior with opioids (RR 1.44, 95% CI 1.03, 2.03). Opioids were more likely than placebo to cause AE (OR 3.90, 95% CI 2.31, 6.56). There was no difference between opioids and placebo in net efficacy after adjustment for AE. Conclusion. Based on 11 heterogeneous studies of short duration and high risk of bias, there is weak evidence that opioids are effective analgesics in RA. AE are common and may offset the benefits. The relative risks and benefits of opioids in IA beyond 6 weeks are unknown.

Safety of Pain Therapy During Pregnancy and Lactation in Patients with Inflammatory Arthritis: A Systematic Literature Review

Abstract: Objective. To systematically review the safety of various pain therapies used during pregnancy and lactation in patients with inflammatory arthritis. Methods. A systematic literature review was performed in Medline, Embase, the Cochrane Library, and the American College of Rheumatology/European League Against Rheumatism 2008–2009 meeting abstracts, as part of the multinational 3e (Evidence, Expertise, Exchange) Initiative for generating practical recommendations about Pain Management by Pharmacotherapy in Inflammatory Arthritis. Articles fulfilling predefined inclusion criteria were reviewed, and quality appraisal was performed. Results. The search yielded a total of 3974 articles and 7 abstracts. The only study that fulfilled the criteria for pain therapies in pregnancy was a systematic review published in 2008, evaluating the effects of nonsteroidal antiinflammatory drug (NSAID) use during pregnancy in patients with rheumatic conditions. Two of the 3 studies reviewed in the 2008 publication could be included in our current review. No studies were included in the review in relation to lactation. A total of 204 malformations were identified among infants exposed to NSAID, with an OR of 1.04. The number of identified cardiac defects was higher than expected, with an OR of 1.86. There seemed to be no specificity for the type of NSAID used. Among the 6 infants with orofacial clefts, 5 occurred with naproxen use and 1 with ibuprofen. Conclusion. Only 2 studies evaluating the risk of NSAID use in patients with inflammatory arthritis were identified, with results suggesting a higher rate of cardiac malformations in infants exposed to NSAID during the first trimester. No studies evaluating the effects of other treatments, such as paracetamol, corticosteroids, muscle relaxants, neuromodulators, antidepressants, opioids, or opioid-like therapy in the specific context of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or spondyloarthritis, and no studies with respect to lactation were identified. Research is needed to improve the risk-benefit ratio of the use of pain therapies for inflammatory arthritis during pregnancy.