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Objective.Ankylosing spondylitis (AS) is characterized by chronic inflammation leading to ankylosis, but also to low bone mineral density (BMD) and vertebral fractures (VFx). Treatment with tumor necrosis factor-α blockers decreases inflammation and has shown to be effective in increasing BMD. We studied the effects of etanercept (ETN) on BMD and VFx in patients with AS after 2 years of treatment. Further, we studied changes in bone turnover markers and radiological damage.Methods.Patients with active AS, treated with ETN for 2 years, were included. BMD lumbar spine and hip were measured at baseline and after 2 years, as well as radiological damage (modified Stoke Ankylosing Spondylitis Spinal Score with the addition of the thoracic spine), VFx (Genant method), and change in bone turnover markers.Results.Forty-nine patients with AS were included. After 2 years of ETN, hip BMD increased by 2.2% (p = 0.014) and lumbar spine BMD by 7.0% (p < 0.001). The Bath Ankylosing Spondylitis Disease Activity Index decreased significantly (p < 0.001), as well as C-reactive protein and erythrocyte sedimentation rate (p < 0.001). Despite ETN therapy, the number of patients with VFx more than doubled (from 6 to 15 patients, p = 0.003). Also, the radiological damage increased significantly over time (from 12.1 to 18.5, p < 0.001); however, no significant change in bone turnover markers was found.Conclusion.This prospective longitudinal observational cohort study showed that after 2 years of ETN, BMD of the hip and spine increased significantly, but the number of patients with VFx and the severity of VFx increased as well. Besides that, radiological progression, including the thoracic spine, increased significantly. Thus, the favorable bone-preserving effect is accompanied by unfavorable outcomes on VFx and radiological damage.

BACKGROUND: Bone loss during glucocorticoid (GC) therapy is poorly quantified.OBJECTIVE: Quantification of bone loss in GC-treated patients with chronic inflammatory diseases (CID; low dose) and transplants (high dose).METHODS: Meta-analysis of cohorts: PubMed, Cochrane, EMBASE and bibliographic searches (1995-2012). Eligible studies prospectively included GC-treated patients with two dual X-ray absorptiometry measurements of spine or hip over a period of at least 12 months. Only supplementation with calcium or vitamin D3 was allowed. 5602 titles yielded 285 articles: 51 study arms in CID (N=1565), 18 study arms in transplantation (N=571). Prednisone-equivalent GC doses and inverse variance weighted mean bone changes were used in a random effects model.RESULTS: In CID, the mean GC dose was 8.7 mg/day (range 1.2-16.4). The mean 1-year bone loss in the lumbar spine was -1.7% (95% CI -2.2% to -1.2%); in the femoral neck: -1.3 (-1.8 to -0.7). In transplantation, the mean GC dose was 18.9 mg/day (range 6.0-52.7). Bone loss in the lumbar spine was -3.6% (-5.2% to -2.0%); in the femoral neck: -3.1% (-5.1% to -1.1%). Within the two groups, bone loss was not related to GC dose.CONCLUSION: In CID, GC-related bone loss appears limited and manageable if current anti-osteoporotic strategies are fully implemented. In transplantation, and probably also other high-dose settings, bone loss is considerable and represents unmet need. The heterogeneity probably reflects the important influence of other factors, most notably the underlying disease and the efficacy of GC treatment.

Objective To investigate the dose-related effects of glucocorticoid treatment on glucose tolerance, beta cell function, and insulin sensitivity in patients with early active rheumatoid arthritis (RA). Methods A randomized, controlled, single-blind trial was conducted in 41 patients with early active RA. At the beginning of the trial patients had not been treated for their RA, and were randomized to begin treatment with prednisolone at 60 mg/day or 30 mg/day. Before and at the end of 1 week of treatment, a frequently sampled oral glucose tolerance test was performed. The glucose area under the curve (AUCG) was calculated. In addition, beta cell function and insulin sensitivity parameters were computed. Results Patients (mean ± SD age 55.5 ± 14.8 years and 54.2 ± 12.6 years in the prednisone 60 mg/day and prednisone 30 mg/day groups, respectively; body mass index 24.5 ± 4.1 kg/m2 and 25.4 ± 4.2 kg/m2, respectively) had active disease at baseline (mean ± SD Disease Activity Score in 44 joints 4.1 ± 0.7 and 4.0 ± 0.8, respectively; median C-reactive protein [CRP] level 14 mg/liter [interquartile range 6–34] and 19 mg/liter [interquartile range 3–39], respectively). In addition, 56% of the patients had impaired glucose tolerance at baseline, and 7% were found to have previously unrecognized type 2 diabetes mellitus (DM). Associations of the AUCG with erythrocyte sedimentation rate (β = 2.430 [95% confidence interval 0.179–4.681], P = 0.04) and with CRP level (β = 2.358 [95% confidence interval 0.210–4.506], P = 0.03) were demonstrated. Treatment with prednisolone at both dosages reduced CRP levels significantly. The incidence of type 2 DM increased to 24% (P < 0.001) (evenly distributed across the groups). The mean AUCG did not change in either treatment arm. Beta cell function improved during prednisone treatment at 60 mg/day (P = 0.02) and at 30 mg/day (P = 0.04). Disease duration was associated with changes in the AUCG (β = 3.626 [95% confidence interval 1.077–6.174], P = 0.007) and with deterioration of the glucose state (odds ratio 1.068 [95% confidence interval 1.017–1.122], P = 0.009). Conclusion In this study, short-term treatment with prednisolone 60 mg or 30 mg per day improved disease activity without deterioration of glucose tolerance in patients with active RA. However, due to individual differences, monitoring is recommended.

Objective To conduct a prospective pilot study to determine whether macrophage targeting by 11C-(R)-PK11195 positron emission tomography (PET) can visualize subclinical synovitis in arthralgia patients who have anti–citrullinated protein antibodies (ACPAs). Methods Twenty-nine arthralgia patients who were positive for ACPAs but did not have clinical arthritis were studied. High (spatial)–resolution 11C-(R)-PK11195 PET scans of the hands and wrists were performed. For all metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient), tracer uptake was scored semiquantitatively (0–3 scale) by 2 observers who were blinded with regard to the clinical data. Patients were followed up prospectively for 24 months to investigate the development of clinical arthritis. Results Overall agreement and kappa values for the readings of the 2 observers were, respectively, 97% and 0.91 (95% confidence interval [95% CI] 0.74–1) at the patient level and 99% and 0.81 (95% CI 0.65–0.96) at the joint level. In 4 patients, at least 1 and as many as 5 PET-positive joints (score ≥1) were found at baseline. Within 2 years of followup, 9 patients had developed clinical arthritis. This included all 4 patients with positive findings on the 11C-(R)-PK11195 scan, who developed clinical arthritis in the hand/wrist region, as identified on PET scans. Of the 5 remaining arthritis patients with negative findings on PET scans, 2 developed arthritis in the hand joints and 3 developed arthritis at locations outside the field of view of the PET scanner. Conclusion Subclinical arthritis in ACPA-positive arthralgia patients could be visualized by 11C-(R)-PK11195 PET scanning and was associated with development of arthritis within 2 years of followup. This indicates that 11C-(R)-PK11195 PET may be useful in determining arthritis activity in the preclinical phase of RA.

ObjectiveTo compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up.Methods508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤2.4 during ≥6 months taper to maintenance dose; if DAS ResultsAfter 5 years, 48% of patients were in clinical remission (DAS ConclusionIrrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.

ObjectivesTo 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).MethodsASSERT 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.ResultsAge, 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.ConclusionAge, 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.

Objective To evaluate three disease activity score (DAS) alternatives without the Ritchie articular index (RAI). To compare the use of patient global assessment (PGA) of disease activity versus global assessment of health (GH) in DAS, DAS alternatives and DAS28. Methods Data from the BeSt study were used, a treatment strategy trial in early rheumatoid arthritis patients aiming at a DAS ≤2.4. DAS alternatives were DAS 0–1, with the RAI (0–3) reduced to a no–yes (0–1) score, DAS tender joint count 53 (DAS TJC53), with a 0–1 TJC in 53 separate joints and DAS TJC44 in 44 joints. Correlation patterns, mean difference from original DAS, classification differences in disease activity level and patient percentages with radiological damage progression per level were determined for all scores. Results In the majority of patients the scores were equal and correlation was high. Mean difference with the DAS at year 1 was −0.03 for DAS 0–1, 0.18 for DAS TJC53 and 0.11 for DAS TJC44. Classification agreement between scores was high (κ year 1 0.76–0.98). Patient percentages with joint damage progression were similar for all scores. DAS, DAS alternative and DAS28 perform similarly using either PGA or GH. Conclusion DAS without the RAI perform comparably to the original DAS and may be chosen as alternatives. PGA can replace GH in the DAS, the alternatives and DAS28.

OBJECTIVES: /st> To determine the fine specificity of anti-citrullinated protein antibodies (ACPA) in the early phase of arthritis development, the ACPA repertoire in arthralgia patients and the association with arthritis development were studied. METHODS: /st> A total of 244 patients with arthralgia positive for anti-cyclic citrullinated peptide antibodies (aCCPs) and/or IgM rheumatoid factor (IgM-RF), without arthritis were included. Development of arthritis was defined as presence of one or more swollen joints at clinical examination during follow-up. Sera were tested at baseline for reactivity to five citrullinated peptides derived from fibrinogen (three), vimentin (one) and α-enolase (one) and five corresponding arginine peptides in an ELISA. RESULTS: /st> In all, 69 patients (28%) developed arthritis in a median of 3 joints after a median follow-up of 11 (IQR 5-20) months. Reactivity to each peptide was significantly associated with arthritis development (p Arthritis development is not associated with recognition of a specific citrullinated peptide once joint complaints are present. The ACPA repertoire in some patients with arthralgia is expanded. High aCCP levels are associated with a qualitatively broad ACPA repertoire. Patients with an extended ACPA repertoire have a higher risk of developing arthritis

Objective We observed 3 patients who developed severe venous and arterial thromboembolic events during treatment with adalimumab, 2 of whom had rheumatoid arthritis (RA) and 1 of whom had psoriatic arthritis. Antiadalimumab antibodies were detected in all 3 patients. We undertook this study to determine whether the development of antiadalimumab antibodies was associated with thromboembolic events during adalimumab treatment. Methods A retrospective search (with blinding with regard to antiadalimumab antibody status) for thromboembolic events was performed in a prospective cohort of 272 consecutively included adalimumab-treated RA patients. Incidence rates were calculated and hazard ratios (HRs) were estimated using Cox regression. None of the index patients were part of the cohort. Results Antiadalimumab antibodies were detected in 76 of 272 patients (28%). Eight thromboembolic events were found, 4 of which had occurred in patients with antiadalimumab antibodies. The incidence rate was 26.9/1,000 person-years for patients with antiadalimumab antibodies and 8.4/1,000 person-years for patients without those antibodies (HR 3.8 [95% confidence interval 0.9–15.3], P = 0.064). After adjustment for duration of followup, age, body mass index, erythrocyte sedimentation rate, and prior thromboembolic events, the HR was 7.6 (95% confidence interval 1.3–45.1) (P = 0.025). Conclusion These findings suggest that the occurrence of venous and arterial thromboembolic events during adalimumab treatment is higher in patients with antiadalimumab antibodies than in those without antiadalimumab antibodies. Patient numbers were relatively small; therefore, validation in other cohorts is mandatory.

ObjectiveIncreased expression of insulin-like growth factor 2 (IGF2) by fibroblast-like synoviocytes (FLS) was associated with low inflammatory synovium of patients with rheumatoid arthritis (RA). The aim of this study was to analyse whether the differential expression of IGF2, whose expression is normally restricted to one allele, is due to activation of the normally suppressed allele.MethodsIGF2 gene expression of RA FLS was quantified by quantitative real-time PCR. FLS heterozygous for a 3′-untranslated region IGF2 polymorphism were selected to measure the relative contribution of the allelic transcripts by allele-specific transcript quantification assay. Proliferation was determined by [3H]thymidine incorporation.ResultsIGF2 was shown to contribute to RA FLS proliferation. FLS could be classified in IGF2 high and IGF2 low-expressing cell lines. Allelic IGF2 transcript quantification analysis revealed that in part of the RA FLS the normally suppressed allele was activated, resulting in biallelic expression of the IGF2 gene. Biallelic expression was associated with increased levels of IGF2 mRNA production.ConclusionThe findings indicate that the imprinting status of IGF2 might underlie the increased expression of IGF2, which may contribute to autonomous growth of RA FLS of low inflammatory synovial tissues.

Objective. To study the usefulness of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum amyloid A (SAA) for response prediction and monitoring of anti-tumor necrosis factor (anti-TNF) treatment in ankylosing spondylitis (AS) patients. Methods. Patients were included consecutively before starting etanercept or infliximab treatment. ASsessment in Ankylosing Spondylitis (ASAS) response, defined as a 50% improvement or an absolute improvement of 2 points of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; 0-10 scale), was assessed at 3 months. Inflammatory markers and the BASDAI were collected at baseline and 1 and 3 months. Longitudinal data analysis was performed to compare associations between inflammatory markers and the BASDAI over time by calculating standardized betas. Predictive values of baseline levels of inflammatory markers for ASAS response were calculated. Results. In total, 155 patients were included, of whom, after 3 months of treatment, 70% in the etanercept cohort and 71% in the infliximab cohort responded. All markers, notably SAA, decreased significantly (P

OBJECTIVE: To investigate how antibodies against anti-tumour necrosis factor (anti-TNF) agents influence response after switching from infliximab to adalimumab in rheumatoid arthritis (RA). METHODS: This cohort study consisted of 235 patients with RA, all treated with adalimumab. At baseline 52 patients (22%) had been previously treated with infliximab ('switchers'), and 183 (78%) were anti-TNF naive. Disease activity (using the 28-joint count Disease Activity Score (DAS28)) and presence of antibodies against infliximab and adalimumab were assessed. Clinical response to adalimumab was compared between switchers and anti-TNF naive patients and their anti-infliximab and anti-adalimumab antibody status. RESULTS: After 28 weeks of adalimumab treatment the decrease in DAS28 (Delta DAS28) for the 235 patients was 1.6+/-1.5 (mean+/-SD). Anti-adalimumab antibodies were detected in 46 patients (20%). Delta DAS28 was 1.8+/-1.4 in patients without anti-adalimumab and 0.6+/-1.3 in patients with anti-adalimumab (p

Background COBRA (for ‘COmbinatie therapie Bij Rheumatoide Artritis’) combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long-term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort. Methods In the COBRA trial, 155 patients with early RA were treated with sulfasalazine (SSZ) monotherapy (SSZ group) or a combination of step-down prednisolone, methotrexate (MTX) and SSZ (COBRA group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollised scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests. Results In all, 152 out of 155 patients yielded at least partial data. After a mean of 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, HR 0.57 (95% CI 0.21 to 1.52). Treatment for hypertension was significantly more prevalent in the COBRA group (p=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolaemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, that is, difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, that is, difference in yearly progression rates similar to that seen in the first 5 years of follow-up. Conclusions After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.

Objective To evaluate societal costs and quality-adjusted life years (QALYs) of treatment strategies for patients with recent-onset active rheumatoid arthritis (RA). Methods Patients (n = 508) were randomly allocated to 1 of 4 treatment strategy groups: sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination therapy with infliximab. For 2 years, patients reported cost and utility measures. Results Average QALYs (ideally 2.00) for groups 1–4 were 1.29, 1.31, 1.32, and 1.41, respectively, for the British EuroQol (P ≤ 0.05 for group 4 versus groups 1–3); 1.41, 1.43, 1.44, and 1.52, respectively, for the Dutch EuroQol (P ≤ 0.05 for group 4 versus groups 1–3); and 1.38, 1.38, 1.39, and 1.44, respectively, for the Short Form 6D (P ≤ 0.05 for group 4 versus groups 1–3). The Time Trade-Off showed no significant differences. In the primary analysis, using the friction cost method to value productivity, the cost-utility ratio for group 4 against the next best alternative was estimated at €130,000 (95% confidence interval €27,000, €3,000,000) per QALY. Using the human capital method, the value of sustained productivity in group 4 largely compensated for the extra medication costs. Conclusion Initial combination therapy with infliximab for patients with recent-onset active RA resulted in significantly better quality of life than other strategies. Using the friction cost method, costs to achieve this improvement are generally considered too high, and initial combination therapy with prednisone should be preferred. However, depending on the extent to which productivity is valued, infliximab costs could be largely compensated for by savings on productivity. Since patterns of infliximab use had not yet stabilized after 2 years, longer followup may change the economic conclusions.

Objective To determine whether multidrug-resistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF). Methods Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n = 17) or LEF (n = 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance–associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed. Results BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P = 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients. Conclusion These findings show that the drug resistance–related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

Objective To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis (RA) on 2-year patient-reported outcomes, including functioning and quality of life. Methods A total of 508 patients with recent-onset RA were randomly assigned to 1) sequential monotherapy, 2) step-up combination therapy, both starting with methotrexate, 3) initial combination therapy, including a tapered high-dose prednisone, or 4) initial combination therapy with methotrexate and infliximab. Treatment was adjusted every 3 months if the Disease Activity Score (DAS) remained >2.4. The McMaster Toronto Arthritis Patient Preference Disability Questionnaire, the Short Form 36 (SF-36), and scores for pain, global health, and disease activity measured on a 100-mm visual analog scale (VAS) were compared between groups at baseline and every 3 months thereafter for 2 years. Results After 2 years, all patient-reported outcomes had improved significantly from baseline, irrespective of the treatment strategy. SF-36 subscale scores approached population norms for 3 physical components, and achieved population norms (P > 0.05) for bodily pain and 4 mental components. Improvement in functioning, VAS scores, and physical items of the SF-36 occurred significantly earlier in patients treated with initial combination therapies (all comparisons after 3 months: overall P < 0.001; P < 0.05 for groups 1 and 2 versus groups 3 and 4). Conclusion All 4 DAS-driven treatment strategies resulted in substantial improvements in functional ability, quality of life, and self-assessed VAS scores after 2 years. Initial combination therapy led to significantly faster improvement in all patient-reported measures.

The proteasome inhibitor bortezomib is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug-resistance phenomena, the molecular basis of which remains elusive. Toward this end, we here developed high levels (45- to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib resistance in these cells revealed (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome β5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to β5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanism of bortezomib resistance associated with the selective overexpression of a mutant PSMB5 protein.

Background:Immunogenicity, specifically the onset of antibodies against tumour necrosis factor (TNF) blocking agents, seems to play an important role in non-response to treatment with these drugs.Objectives:To assess the relation of clinical response of ankylosing spondylitis (AS) to etanercept with etanercept levels, and the presence of antibodies to etanercept.Methods:Patients with AS were treated with etanercept 25 mg twice weekly, according to the international Assessment in Ankylosing Spondylitis (ASAS) working group consensus statement. Sera were collected at baseline and after 3 and 6 months of treatment. Clinical response was defined as a 50% improvement or as an absolute improvement of 2 points on a (0–10 scale) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Functional etanercept levels were measured by a newly developed ELISA, measuring the binding of etanercept to TNF. Antibodies against etanercept were measured with a two-site assay and antigen binding test. Clinical data were used to correlate disease activity with serum etanercept levels.Results:In all, 53 consecutive patients were included. After 3 months of treatment 40 patients (76%) fulfilled the response criteria. Mean etanercept levels were 2.7 mg/litre and 3.0 mg/litre after 3 and 6 months respectively. Characteristics and etanercept levels of responders and non-responders were similar. No antibodies to etanercept were detected with any of the assays.Conclusion:Etanercept levels of responders and non-responders were similar and no antibodies to etanercept were detected with any of the assays. This study indicates that etanercept is much less immunogenic compared with the other TNF-blocking agents.

Objectives:To evaluate changes in bone mineral density (BMD) in the hands, hip and spine after 1 and 2 years of follow-up, in relation to antirheumatic and antiresorptive therapies and disease and demographic variables in patients with recent-onset rheumatoid arthritis (RA).Methods:Changes in BMD measured in metacarpals 2–4 by digital x-ray radiogrammetry and in the hip and spine by dual energy x-ray absorptiometry were assessed at baseline and after 1 and 2 years of follow-up in 218 patients with recent-onset RA from the BeSt study, who received one of four treatment strategies: sequential monotherapy (group 1); step-up combination therapy (group 2); initial combination therapy with tapered high-dose prednisone (group 3); or initial combination therapy with infliximab (group 4).Results:After 1 and 2 years, there was significant BMD loss in all locations, with significantly greater BMD loss in the hands than generalised BMD loss in the hip and spine. Initial combination therapy with prednisone or infliximab were associated with less hand BMD loss compared with initial monotherapy after 1 and 2 years (−0.9 and −1.6%, −0.6 and −1.4%, −1.7 and −3.3%, and −2.6 and −3.6% for group 4–1 after 1 and 2 years, overall p = 0.001 and p = 0.014, respectively).Progression in erosions was independently associated with increased BMD loss both in the hands and hip after 1 year. The use of bisphosphonates protected only against generalised BMD loss in the hip and spine.Conclusions:The association between joint damage progression and both hand and generalised BMD loss in RA suggests common pathways between these processes, with hand BMD loss occurring earlier in the disease course than generalised BMD loss.

Objectives: We examined the effects of four different treatment strategies on bone mineral density (BMD) in patients with recently diagnosed, active rheumatoid arthritis (RA) and the influence of disease-related and demographic factors on BMD loss after 1 year of follow-up in the BeSt trial. Methods: BMD measurements of the lumbar spine and total hip were performed in 342 patients with recent onset RA at baseline and after 1 year. Multivariable regression analyses were performed to determine independent associations between disease and demographic parameters and BMD loss after 1 year. Results: Median BMD loss after 1 year was 0.8% and 1.0% of baseline in the spine and the hip, respectively. No significant differences between the treatment groups, including corticosteroids and the anti-tumour necrosis factor-α infliximab, were observed with regard to BMD loss after 1 year of treatment. Joint damage at baseline and joint damage progression according to the Sharp–van der Heijde score were independently associated with more BMD loss after 1 year. The use of bisphosphonates independently protected against BMD loss. Conclusions: After 1 year of follow-up in the BeSt study, we did not find differences in BMD loss between the four treatment strategies, including high doses of corticosteroids and anti-tumour necrosis factor-α. Joint damage and joint damage progression are associated with high BMD loss, which emphasises that BMD loss and erosive RA have common pathways in their pathogenesis.

Objective Noninvasive imaging by positron emission tomography (PET) of macrophages in inflamed joints of patients with rheumatoid arthritis (RA) may allow early detection of disease activity. We undertook this study to investigate whether rheumatoid synovitis can be visualized by PET using the tracer 11C-(R)-PK11195, which binds to peripheral benzodiazepine receptors (PBRs) on macrophages. Methods Knee joints of 11 RA patients with active arthritis of at least 1 knee joint were imaged with 11C-(R)-PK11195 PET. Tissue uptake of 11C-(R)-PK11195 was quantified. PET was followed by arthroscopy of the most inflamed knee joint of each RA patient. Synovial tissue samples were subjected to immunohistochemical staining. Results 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints than in joints with moderate or mild signs of inflammation. In addition, tracer uptake in contralateral uninflamed knee joints of RA patients was significantly higher than in uninflamed joints of control patients without inflammatory joint disease, suggesting the presence of subclinical disease activity. PET tracer uptake in joints correlated significantly with PBR staining in the sublining of synovial tissue. PBR staining correlated significantly with CD68 staining of macrophages. Conclusion 11C-(R)-PK11195 PET imaging allows noninvasive in vivo imaging of macrophages in rheumatoid synovitis and possibly even in subclinical synovitis. Noninvasive visualization of macrophages may be useful both for detecting early synovitis and for monitoring synovitis activity during treatment.

Rheumatoid arthritis (RA) is a heterogeneous disease with unknown etiology. Here we aimed to distinguish RA subtypes based on peripheral blood (PB) gene expression profiles in comparison with a pathogen-response transcriptional program. PB was obtained from 35 RA patients and 15 healthy individuals. For expression profiling we used DNA microarrays. A combined cluster analysis of RA and control samples together with samples from a viral infection model revealed that the gene expression profile of a subgroup of RA patients (RA(A)) was reminiscent to that of poxvirus-infected macaques. Statistical analysis, followed by Gene Ontology analysis of the RA(A) patients confirmed that these patients form a distinct group, with activation of several host defense mechanisms that resemble a common host-pathogen response. Analysis of the promoter region of genes that were overexpressed in the RA(A) patients, revealed an enrichment of transcription factor binding sites for NF kappaB and interferon-activated transcription factors. Moreover, this subgroup of RA patients expressed significantly increased titers of anti-cyclic citrullinated peptide antibodies. We conclude that activation of a host-pathogen response defines a subgroup of RA patients characterized by increased autoreactivity against citrullinated proteins.

Objective To determine the association of HLA–DRB1, rheumatoid factor (RF), and anti–citrullinated protein antibody (ACPA) status with progression of joint damage in early rheumatoid arthritis (RA) treated according to different treatment strategies. Methods The present study was conducted using data from the BeSt study (Behandelstrategieen voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]), a randomized trial comparing 4 targeted (toward achievement of a Disease Activity Score [DAS] of ≤2.4) treatment strategies: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with methotrexate, sulfasalazine, and prednisone (group 3), and initial combination therapy with methotrexate and infliximab (group 4), in 508 patients with early RA. Multivariate logistic regression analysis was used to predict progressive disease (increase of Sharp/van der Heijde score over 2 years beyond the smallest detectable change [4.6]) according to the presence or absence of the shared epitope (SE), DERAA, RF, and ACPA, with correction for other baseline characteristics. Results Progressive disease could not be predicted by presence of the SE: the odds ratio in groups 1, 2, 3, and 4, respectively, was 1.4, 2.6, 1.9, and 3.0. DERAA carriership did not protect against progressive disease (odds ratio 0.4, 1.4, 0.9, and 0.9 in groups 1, 2, 3, and 4, respectively). RF positivity and ACPA positivity predicted progressive disease in group 1 (odds ratio 4.7 [95% confidence interval 1.5–14.5] for RF and 12.6 [95% confidence interval 3.0–51.9] for ACPA), but not in groups 2–4 (for RF, odds ratio [95% confidence interval] 1.5 [0.5–4.9], 1.0 [0.3–3.3], and 1.4 [0.4–4.8] in group 2, group 3, and group 4, respectively; for ACPA, odds ratio [95% confidence interval] 3.4 [0.8–14.2], 1.7 [0.5–5.4], and 1.8 [0.5–6.8] in group 2, group 3, and group 4). Conclusion In patients with early RA treated with the goal of tight control of the DAS, no significant association between HLA–DRB1 status and radiographic progression was found. RF and ACPA were predictive of progressive disease only in patients treated with sequential monotherapy. These observations suggest that effective treatment can prevent radiographic progression, even in patients with risk factors for severe damage.

Objectives: A previous 24- week randomised trial demonstrated that sulfasalazine ( SSZ) treatment was superior to placebo ( PLAC) in suppressing disease activity in patients with oligo- and polyarticular onset juvenile idiopathic arthritis ( JIA). The current study determines the long- term outcome of the trial participants and evaluates whether the benefits of SSZ allocation are sustained over time.Methods: Between 2001 and 2003, 32 SSZ and 29 PLAC patients ( 90% of all patients) were prospectively examined clinically and by chart review, median 9 years ( range 7 to 10) after trial inclusion. In the follow- up assessment, variables of the American College of Rheumatology Pediatric 30 ( ACR Pedi 30) criteria were collected. The assessor was blinded to trial treatment allocation.Results: After the trial, patients had been routinely followed in rheumatology referral centres, and treated at the discretion of the attending physician. Almost all patients continued or started disease- modifying antirheumatic drugs ( DMARDs) ( SSZ 91%, PLAC 93%; SSZ treatment in about 80%). DMARD treatment appeared less intensive in the SSZ group as evidenced by a significantly shorter duration of SSZ use ( median 2.5 vs 5.2 years; p = 0.02) and a trend towards less use of methotrexate and other DMARDs. More than onethird of the patients reported long periods of non- compliance with DMARD treatment in both groups. At follow- up, 74% of the patients had active joints, and 30% showed active polyarthritis. Almost all outcome scores were better for SSZ compared with PLAC patients. Differences ( often exceeding 50%) were significant for the number of active joints, patients' overall well- being, number of patients with episodes of clinical remission off medication ( CROM) and duration of these episodes, patients in CROM and ACR Pedi 30 response at follow- up. Additional exploratory analyses performed to detect potential confounders related to patient characteristics or follow- up treatment showed that DMARD treatment compliance was positively correlated with an ACR Pedi 30 response ( odds ratio 3.8, 95% confidence interval ( CI) 1.1 to 13.4; p = 0.03). Adjusted for compliance, an SSZ patient was 4.2 times as likely as a PLAC patient to be an ACR Pedi 30 responder at follow- up ( 95% CI 1.3 to 14.3; p = 0.02).Conclusions: This follow- up study shows that effective suppression of disease activity by SSZ treatment early in active disease in JIA patients has beneficial effects that persist for many years. Given these results, compliance with DMARD treatment deserves serious attention.

BACKGROUND: Rheumatoid arthritis is characterised by inflammation and an increased cardiovascular risk. It was recently shown that active early rheumatoid arthritis is associated with dyslipidaemia, which may partially explain the enhanced cardiovascular risk. However, it is unknown when this dyslipidaemia starts.OBJECTIVE: To investigate the progression of the lipid profile over time and the influence of inflammatory parameters on this lipid profile, in people who later developed rheumatoid arthritis.METHODS: Levels of total cholesterol, high-density lipoprotein cholesterol (HDLc), triglycerides, apolipoprotein AI (apo AI), apolipoprotein B (apo B) and lipoprotein(a) (Lp(a)) were determined in 1078 stored, deep-frozen, serial blood bank samples, collected between 1984 and 1999, of 79 blood donors who later developed rheumatoid arthritis. These samples were compared with 1071 control samples of unselected blood donors, matched for age, sex and storage time.RESULTS: Samples of patients who later developed rheumatoid arthritis showed, on average, 4% higher total cholesterol, 9% lower HDLc, 17% higher triglyceride and 6% higher apo B levels than matched controls (p< or =0.05). The magnitude of the differences in lipid levels between groups, explained by C reactive protein (CRP), was limited. For example, only 3.6% of the difference in HDLc levels between the groups was explained by the CRP concentrations.CONCLUSION: Patients who later develop rheumatoid arthritis have a considerably more atherogenic lipid profile than matched blood donors at least 10 years before onset of symptoms. As inflammation only marginally explains the differences between the two groups, a modulating effect of lipids on inflammatory processes is hypothesised.

Objective To evaluate the efficacy of infliximab plus methotrexate (MTX) as induction therapy in patients with early rheumatoid arthritis (RA). Methods Disease-modifying antirheumatic drug (DMARD)–naive patients with active, early RA who were included as group 4 of the BeSt study were initially treated with infliximab (3 mg/kg) in combination with MTX (25 mg/week). The Disease Activity Score (DAS) was measured every 3 months. In patients with persistent low disease activity (DAS ≤2.4) for at least 6 months, the infliximab dosage was tapered and finally discontinued; the MTX dosage then was tapered to 10 mg/week. In patients with a DAS of >2.4, the infliximab dosage was increased (maximum 10 mg/kg), and they were subsequently switched to another DMARD. Except for intraarticular administration, corticosteroids were not permitted. Functional ability and the modified Sharp/van der Heijde score were determined after 2 years of therapy. Results Of the 120 patients, 67 responders (56%) had persistent low disease activity and discontinued infliximab after a median of 9.9 months, with a median MTX dosage of 10 mg/week after 2 years. Ten other patients experienced a disease flare after discontinuation and resumed infliximab after a median of 3.7 months. Thirteen patients did not achieve persistent low disease activity and received infliximab at various dosages. Treatment was unsuccessful in 30 patients. In the 67 responders, the progression of joint damage was lower than in the 30 patients in whom treatment failed. Conclusion Fifty-six percent of patients with active early RA, initially treated with infliximab plus MTX, could discontinue infliximab after achieving a DAS of ≤2.4. Low disease activity was maintained in these patients while the MTX dosage was tapered to 10 mg/week.

BACKGROUND: Cardiovascular mortality is increased in patients with ankylosing spondylitis. A possible explanation might be a more prevalent atherogenic lipid profile in patients with ankylosing spondylitis than in the general population. It has been postulated that inflammation deteriorates the lipid profile, thereby increasing cardiovascular risk.OBJECTIVE: To explore the association between disease activity and lipid profile in patients with ankylosing spondylitis.METHODS: Disease activity parameters for ankylosing spondylitis and lipid levels (total cholesterol, high-density lipoprotein cholesterol (HDLc) and triglycerides) were measured in 45 patients with ankylosing spondylitis for 6 months after starting treatment with leflunomide or placebo. Findings in this treatment group were compared with those in 10 patients with ankylosing spondylitis treated with etanercept. A specialised regression model, adjusting for repeated measurements, age and sex, was used to assess the influence of the disease activity variables on the lipid levels.RESULTS: Multilevel regression analyses showed significant associations between disease activity parameters and lipid levels-for instance, an increase of 30 mm at the end of the first hour in erythrocyte sedimentation rate was associated with a decrease of about 6% in total cholesterol level and a decrease of about 11% in HDLc levels. Similar significant associations were found between other disease activity parameters and lipid levels.CONCLUSION: Increase in disease activity was associated with decreases in lipid levels. The decrease in HDLc levels tended to be almost twice as large as the decrease in total cholesterol levels, resulting in a more atherogenic lipid profile. Hence, effective treatment of disease activity in patients with ankylosing spondylitis may lower the cardiovascular risk by improving the lipid profile.

Objective Treatment of patients with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, may result in the formation of infliximab-specific IgG antibodies. This study evaluated the clinical significance of these antibodies in patients with rheumatoid arthritis (RA). Methods Antiinfliximab antibodies were measured using a newly developed radioimmunoassay in a cohort of 51 consecutive patients with RA treated with infliximab, with a followup of 1 year. In addition, serum infliximab levels were determined by enzyme-linked immunosorbent assay. The results were analyzed in relation to the clinical response to treatment according to the European League Against Rheumatism criteria. Results Antibodies against infliximab were detected in 22 patients (43%). Patients without detectable antiinfliximab antibodies (n = 29 [57%]) were significantly more often classified as responders (20 of 29 [69%]) compared with patients with detectable antiinfliximab antibodies (8 of 22 [36%]; P = 0.04). Three patients had an infusion-related allergic reaction, all of whom had detectable antiinfliximab antibodies. Conclusion In this study, nearly half of the RA patients treated with infliximab developed antiinfliximab antibodies within the first year of treatment. This seems to be clinically relevant, since development of antiinfliximab antibodies is associated with a reduced response to treatment.

Objective To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS). Methods This was a multicenter, randomized (2:1 ratio), double-blind, placebo-controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission. Results At week 12, 58.2% of adalimumab-treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo-treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab-treated patients reported more adverse events (75.0% versus 59.8% of placebo-treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity. Conclusion Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

Objective To determine associations of methotrexate (MTX) efficacy and toxicity with single-nucleotide polymorphisms (SNPs) in genes coding for folate pathway enzymes in patients with early rheumatoid arthritis (RA). Methods Patients (n = 205) with active RA received MTX at an initial dosage of 7.5 mg/week, which was increased to 15 mg/week and combined with folic acid (1 mg/day) after 4 weeks. If the Disease Activity Score in 44 joints (DAS44) was >2.4 at 3 months, MTX was increased to 25 mg/week. MTX efficacy was evaluated at 3 and 6 months and compared for genotypes in 3 analyses: patients with and without good response (DAS44 ≤2.4), patients with and without good improvement (ΔDAS44 >1.2), and patients with and without moderate improvement (ΔDAS44 >0.6). The association between MTX-related adverse drug events (ADEs) and genotype was evaluated by comparing genotypes between patients with and without ADEs, specifically pneumonitis, gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme levels. The following SNPs were analyzed: methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, dihydrofolate reductase (DHFR) −473G>A, DHFR 35289G>A, and reduced folate carrier 80G>A. In case of significant differences, odds ratios (ORs) were calculated. Results At 6 months, MTHFR 1298AA was associated with good improvement relative to 1298C (OR 2.3, 95% confidence interval [95% CI] 1.18–4.41), which increased with increased copies of the MTHFR 677CC haplotype. In contrast, MTHFR 1298C allele carriers developed more ADEs (OR 2.5, 95% CI 1.32–4.72). Conclusion Patients with MTHFR 1298AA and MTHFR 677CC showed greater clinical improvement with MTX, whereas only the MTHFR 1298C allele was associated with toxicity. In the future, MTHFR genotypes may help determine which patients will benefit most from MTX treatment.

Contains fulltext : 48628.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To investigate whether a high-intensity exercise program accelerates the rate of radiologic damage of the large joints in predefined subgroups of patients with rheumatoid arthritis. METHODS: The data of 277 participants in a 2-year randomized controlled trial, comparing the effects of high-intensity exercises with usual care, were used. Linear regression analysis was used to test which predefined variables at baseline (age, disease duration, disease activity, physical capacity, functional ability, joint damage) modified the effect of high-intensity exercise on the progression of radiologic damage of the large joints over 24 months. RESULTS: Baseline radiologic joint damage was the only variable associated with the effect of high-intensity exercise on joint damage progression in large joints. In a subgroup of 218 patients with no or little joint damage (defined as Larsen score < or = 5; 80% of our study population) the proportions of patients with an increase in joint damage were similar for the exercise and usual-care group (35% versus 36%, risk ratio [RR] 1.0 [0.7-1.4]; P = not significant), whereas, in a subgroup of 59 patients who already had extensive damage of large joints (defined as Larsen score >5) the proportion was significantly higher in the exercise group (85% versus 48%, RR 1.8 [1.2-2.6]; P < 0.05). CONCLUSION: High-intensity weight-bearing exercises appear to accelerate joint damage progression in patients with preexisting extensive damage. Patients with extensive large joint damage should, therefore, be advised to refrain from activities excessively loading the damaged joints.

Objective: To determine the efficacy of weekly treatment with oral azithromycin for 13 weeks on the severity and resolution of reactive arthritis (ReA). Methods: 186 patients from 12 countries were enrolled in a randomised, double blind, placebo controlled trial. Inclusion criteria were inflammatory arthritis of ⩽6 swollen joints, and disease duration of ⩽2 months. All patients received a single azithromycin dose (1 g) as conventional treatment for possible Chlamydia infection, and were then randomly allocated to receive weekly azithromycin or placebo. Clinical assessments were made at 4 week intervals for 24 weeks. Results: 152 patients were analysable (34 failed entry criteria), with a mean (SD) age of 33.8 (9.4) and duration of symptoms 30.7 (17.5) days. Mean C reactive protein (CRP) was 48 mg/l, and ∼50% of those typed were HLA-B27+, suggesting that the inclusion criteria successfully recruited patients with acute ReA. Treatment and placebo groups were well matched for baseline characteristics. There were no statistical differences for changes in any end point (swollen and tender joint count, joint pain, back pain, heel pain, physician and patient global assessments, and CRP) between the active treatment and placebo groups, analysed on an intention to treat basis or according to protocol completion. The time to resolution of arthritis and other symptoms or signs by life table analyses was also not significantly different. Adverse events were generally mild, but were more commonly reported in the azithromycin group. Conclusions: This large trial has demonstrated that prolonged treatment with azithromycin is ineffective in ReA.

OBJECTIVE: We previously reported that approximately half of the patients with rheumatoid arthritis (RA) have specific serologic abnormalities (elevated serum concentrations of IgM rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) starting several years before the onset of symptoms. In this study, the presence of serologic signs of inflammation in patients with preclinical RA was investigated with serial measurements of C-reactive protein (CRP). METHODS: Seventy-nine patients (61% female; mean age at onset of symptoms 51 years) who had been blood donors before the onset of RA were identified. Frozen serum samples from each donor were retrieved, together with 1 sample from a control donor matched for age, sex, and date of donation. CRP was measured using a highly sensitive latex-enhanced assay. The dates of donation were categorized into 15 1-year periods preceding the onset of RA symptoms. For each period, the median CRP levels in the patient and control groups were compared using the Mann-Whitney U test. The course of CRP concentrations over time in the patient group was estimated with random coefficient analysis. RESULTS: A median of 13 samples (range 1-51) per patient were available; the earliest donation was made a median of 7.5 years (range 0.4-14.5 years) before the onset of symptoms. A total of 1,078 patient samples and 1,071 control samples were tested. For all 1-year periods, the median CRP concentration was increased in the patient group compared with the control group, but this difference was statistically significant only for the periods 0-1 year, 1-2 years, and 4-5 years before the onset of symptoms. The CRP concentration increased significantly over time in patients with preclinical RA; levels were slightly higher in the group of patients who had serologic abnormalities before the onset of symptoms than in those without such serologic abnormalities. CONCLUSION: After observing specific serologic abnormalities 5 years before the onset of RA symptoms, we now report increased levels of CRP in blood donors in whom RA later developed; these increases were most common within the 2 years before the onset of symptoms. The preclinical increase in CRP levels was observed both in donors with and in those without serologic abnormalities.

Since the first report in 1953 (1), several studies have confirmed the observation of excess mortality rates in various rheumatoid arthritis (RA) prevalence and incidence cohorts. On review, there appears to be little doubt that people with RA have a lower life expectancy (2–4). These reports, along with data from observational studies demonstrating that most patients eventually experience severe functional decline (5), work disability (6), and joint destruction (7), have led to considerable changes in treatment strategies. Rheumatologists have abandoned the traditional pyramid paradigm (“go low; go slow”) and are treating their patients earlier and more aggressively (8). Introduction of new diseasemodifying antirheumatic drugs (DMARDs), more aggressive use of “old” drugs both singly and in combination, as well as reintroduction of corticosteroids in the treatment of early disease have fundamentally changed the approach to treating patients with RA (9). Along with the therapeutic changes, there have been important advances in the standardization and adoption of outcome measures of disease activity, severity, and quality of life (10). Fortunately, these measures are now widely used in almost all trials and observational studies, and we know that therapeutic changes have been successful in improving the quality of life and functioning of RA patients. These changes in the approach to RA have led to improved morbidity rates, but evidence of improved mortality rates in RA remains relatively scant. For instance, recent cohort studies have documented similar mortality rates in patients with RA and the general population (11,12), and improved survival associated with response to methotrexate has been reported, but from only 2 treatment centers, albeit with important databases (13,14). Other studies, however, concluded that survival in RA has not improved in recent decades (15,16), and one study suggested increased mortality in methotrexate-treated RA patients who have cardiovascular disease (17). Several explanations have been offered for these conflicting signals. First, apparent improvement in survival in certain studies could be due to the more frequent use of population-based cohorts rather than clinic-based or referral cohorts in recent years (18,19). Second, since the excess mortality in RA does not become apparent until approximately 8–10 years after disease onset, inception cohorts followed too briefly will fail to capture this excess, and any improvement in mortality rates can only be identified after a long lag time (16,19). Furthermore, there may be hidden problems in retrospective cohort studies that could potentially bias the results (20). Finally, traditional measures of RA disease activity may not necessarily be the best predictors of mortality. This commentary suggests an additional explanation that rheumatologists should be able to address in the clinic: the undertreatment of—mostly cardiovascular— comorbidity. In very recent work, Navarro-Cano et al (21) confirmed the independent contributions of RA and comorbidity to mortality. Most of this contribution comes from the widespread cardiovascular comorbidity (22). Perhaps excess mortality in RA is primarily linked to etiologies such as the effects of systemic inflammation on vascular integrity (23), and the treatments, although Maarten Boers, MSc, MD, PhD, Ben Dijkmans, MD, PhD: VU University Medical Center, Amsterdam, The Netherlands; Sherine Gabriel, MD, MSc, Hilal Maradit-Kremers, MD, MSc: Mayo Clinic, Rochester, Minnesota; James O’Dell, MD: University of Nebraska Medical Center, Omaha; Theodore Pincus, MD: Vanderbilt University Medical Center, Nashville, Tennessee. Address correspondence and reprint requests to Maarten Boers, MSc, MD, PhD, Professor of Clinical Epidemiology, Department of Clinical Epidemiology and Biostatistics, 9B-116, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: keb.info@vumc.nl. Submitted for publication October 23, 2003; accepted in revised form February 28, 2004.

Drug resistance is generally accepted as an important cause of treatment failure for patients with neoplastic or infectious diseases. Molecular mechanisms underlying drug resistance include the action of drug efflux pumps belonging to the super-family of ATP binding cassette (ABC) proteins, which mediate the cellular extrusion of a large variety of therapeutic drugs, a phenotype that is referred to as multidrug resistance (MDR). Unlike neoplastic and infectious diseases, chronic inflammatory diseases have received little attention. The potential role of ABC transporters in determining the efficacy of anti-rheumatic drugs, notably disease modifying anti-rheumatic drugs (DMARDs), in patients with rheumatoid arthritis is unclear. Based on knowledge from the field of oncology and immunology, this review concentrates on the pharmacological role of MDR proteins in the (clinical) efficacy of several DMARDs, as well as the physiological role of MDR proteins in transporting signalling molecules important in inflammatory processes.

Management of ankylosing spondylitis (AS) is challenged by the progressive nature of the disease. To date, no intervention is available that alters the underlying mechanism of inflammation in AS. Currently available conventional treatments are palliative at best, and often fail to control symptoms in the long term. Current drug treatment may perhaps induce a spurious state of "disease remission," which is merely a low level of disease activity. Non-steroidal anti-inflammatory drugs are first line treatment, but over time, the disease often becomes refractory to these agents. Disease modifying antirheumatic drugs are second line treatment and may offer some clinical benefit. However, conclusive evidence of the efficacy of these drugs from large placebo controlled trials is lacking. Additionally, these drugs can cause treatment-limiting adverse effects. Intra-articular corticosteroid injection guided by arthrography, computed tomography, or magnetic resonance imaging is an effective means of reducing inflammatory back pain, but controlled studies are lacking. A controlled study has confirmed moderate but significant efficacy of intravenous bisphosphonate (pamidronate) treatment in patients with AS; further evaluation of bisphosphonate treatment is warranted. Physical therapy and exercise are necessary adjuncts to pharmacotherapy; however, the paucity of controlled data makes it difficult to identify the best way to administer these interventions. Surgical intervention may be required to support severe structural damage. Thus, for patients with AS, the future of successful treatment lies in the development of pharmacological agents capable of both altering the disease course through intervention at sites of disease pathogenesis, and controlling symptoms.

Objective The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial demonstrated that step-down combination therapy with prednisolone, methotrexate, and sulfasalazine (SSZ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis (RA). The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time, and to determine which baseline factors could predict outcome. Methods All patients had participated in the 56-week COBRA trial. During followup, they were seen by their own rheumatologists and were also assessed regularly by study nurses; no treatment protocol was specified. Disease activity, radiologic damage, and functional ability were the primary outcome domains. Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method. Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat, starting with data obtained at the last visit of the COBRA trial (56 weeks after baseline). Results At the beginning of followup, patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score (DAS28) and a significantly lower median radiologic damage (Sharp) score compared with those in the SSZ monotherapy group. The functional ability score (Health Assessment Questionnaire [HAQ]) was similar in both groups. During the 4–5 year followup period, the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group. The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group. After adjustment for differences in treatment and disease activity during followup, the between-group difference in the rate of radiologic progression was 3.7 points per year. The HAQ score did not change significantly over time. Independent baseline predictors of radiologic progression over time (apart from treatment allocation) were rheumatoid factor positivity, Sharp score, and DAS28. Conclusion An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA, independent of subsequent antirheumatic therapy.

Several new drugs have become available for the treatment of patients with osteoarthritis and rheumatoid arthritis (RA). These agents include selective cyclooxygenase (COX)-2 inhibitors, leflunomide and anti-tumour necrosis factor (TNF)-alpha antagonists. COX-2 inhibitors have a more favourable gastrointestinal adverse effect profile than conventional non-steroidal anti-inflammatory drugs (NSAIDs). However, the COX-2 inhibitors are also associated with hypertension, oedema and congestive heart failure, the well-known adverse effects of conventional NSAIDs. Patients with treated hypertension should be monitored regularly when conventional NSAIDs or COX-2 inhibitors are administered. At present, there is a considerable debate regarding the risk of cardiovascular events with the COX-2 inhibitors. The available literature gives no unequivocal answers. This matter can only be solved by an appropriate trial assessing the cardiovascular risk of these agents. Patients with RA appear to have an enhanced cardiovascular risk which might be related to an unfavourable lipid profile. Corticosteroids induce hypercholesterolaemia in patients other than those with RA. It was recently shown that total and high-density lipoprotein (HDL) cholesterol were low in patients with RA who had a high disease activity. Contrary to the expectation, combination therapy with prednisolone rapidly improved the atherogenic index (total/HDL cholesterol). Ongoing studies investigating this topic are underway. It is not known to what extent corticosteroids induce hypertension in patients with RA. Hence, we advocate blood pressure control for these patients. A small percentage of patients with RA develop hypertension when taking leflunomide, and no other serious cardiovascular adverse effects have been reported in the literature. Blood pressure monitoring is recommended especially in the first months of treatment. TNFalpha antagonists are contraindicated in patients with RA who have congestive heart failure. No specific cardiovascular adverse effects have been reported with the use of these agents in the non-cardiovascular compromised patient. TNFalpha antagonists are the most powerful anti-inflammatory drugs presently available. As inflammation plays an important role in RA as well as in cardiovascular disease and, in view of the increased cardiovascular risk in RA, it is tempting to expect that suppression of inflammation ultimately will lower the cardiovascular morbidity and mortality in patients with RA.

Although methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-α production.T cells in whole blood from 18 RA patients (including MTX-naïve, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with αCD3/αCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties. Drug concentrations exerting 50% inhibition (IC-50) of TNF-α production (by enzyme-linked immunosorbent assay, ELISA) were determined as an estimate for their anti-inflammatory capacity. In addition, induction of T-cell apoptosis was evaluated by flow cytometry.The new-generation antifolates PT523, PT644, raltitrexed, and GW1843 proved to be potent inhibitors of TNF-α production in activated T cells from all three groups of RA patients and from healthy volunteers. Based on IC-50 values, these antifolates were up to 10.3 times more potent than MTX. The anti-inflammatory effects were observed at drug concentrations that provoked suppression of T-cell activation and induction of apoptosis in 20-40% of activated T cells.In an ex-vivo setting, novel antifolates elicited marked inhibition of TNF-α production in activated T cells from RA patients. Further clinical evaluation is warranted to investigate whether a low dosage of these antifolates can elicit immunosuppressive effects equivalent to MTX, and whether they are superior to MTX in patients who fail to respond to MTX.

Objective Complement activation in patients with rheumatoid arthritis (RA) is considered to be triggered by immune complexes. Recently, it was shown that C-reactive protein (CRP) can activate the complement system in vivo. We therefore hypothesized that part of the complement activation in RA is due to CRP. The aim of this study was to investigate CRP-mediated complement activation in RA, and to assess its correlation with disease activity. Methods Complexes between CRP and the activated complement components C3d (C3d–CRP) and C4d (C4d–CRP), which reflect CRP-mediated complement activation, as well as the overall levels of activated C3 and C4 were measured in the plasma of 107 patients with active RA and 177 patients with inactive RA. Inactive RA was defined according to the American College of Rheumatology criteria for clinical remission. Disease activity was assessed by the modified Disease Activity Score (DAS28). Results Plasma levels of C3d–CRP and C4d–CRP were increased in the majority of the patients, and were significantly higher in patients with active disease versus those with inactive RA (P < 0.001). In patients with active RA, the plasma concentrations of C3d–CRP and C4d–CRP correlated significantly with the DAS28 (Spearman's rho 0.61 and 0.55, respectively; P < 0.001), whereas these correlations were less pronounced in patients with inactive RA (Spearman's rho 0.28 [P < 0.001] and 0.25 [P = 0.001], respectively). Levels of activated C3 and C4 were also increased in the majority of the patients, particularly in patients with active RA. Conclusion Part of the activation of complement in RA is mediated by CRP and is correlated with disease activity. We suggest that this activation is involved in the pathogenesis of RA.

Objective. Studies in mice have demonstrated an increased risk of ankylosing enthesopathy in earlier litters compared with later-born offspring. In humans, birth order and maternal age as risk factors for ankylosing spondylitis (AS) have not been investigated previously. This study was undertaken to investigate whether first-born children have a higher risk of AS than later-born children and whether maternal age at delivery is another risk factor. Methods. The birth order of 162 AS patients was compared with that of their healthy siblings, both for the total group and with stratification for maternal age at first delivery. Maternal age at the time of delivery of AS patients who were first-born children was compared with the mean maternal age at first delivery in the Dutch population. Results. The number of first-born children with AS was significantly higher than would be expected in case of an equal risk between first-born and later-born children (26 versus 20 for families with 2 children [P = 0.029] and 63 versus 47.6 for all families [P = 0.004] ). Also, the mean maternal age at first delivery was lower in mothers of AS patients (24.8 years) compared with mothers of healthy controls (26.1 years). Conclusion. Low birth order is a risk factor for AS in humans.

Cardiovascular morbidity and mortality are enhanced in rheumatoid arthritis (RA) and there is increasing evidence that this is due to the inflammatory process as well as to an increased prevalence of traditional cardiovascular risk factors, such as dyslipidaemia.1–3 Several investigators have indeed demonstrated dyslipidaemia, defined as higher total cholesterol and/or triglycerides and/or lower high-density lipoprotein (HDL) cholesterol levels in comparison to control subjects, in RA and this appears to be the consequence of systemic release of inflammatory cytokines such as tumour necrosis factor (TNF)α, interleukin (IL)1 and IL6, leading to a proatherogenic state with insulin resistance, endothelial cell activation and hypercoagulation as other consequences. The dyslipidaemia in RA is dependent on disease activity, ie, a higher disease activity is associated with lower total cholesterol levels and even more depressed HDL cholesterol levels, leading to a higher (ie, unfavourable) atherogenic index.4 Moreover, it appears that dyslipidaemia is already present in early RA and the question arises whether or not this phenomenon starts in the preclinical phase of RA. Hence, we investigated the lipid profile over time and its relationship with inflammation and serological markers, in subjects who later developed RA.5 The lipid profile was determined in 1078 serial blood bank samples, of 79 blood donors who later developed RA. These samples were compared with 1071 control samples of unselected blood donors, matched for age and sex. The samples of future patients with RA displayed, on average, 4% higher total cholesterol, 9% lower HDL cholesterol and 17% higher triglyceride levels compared to matched controls (p⩽0.05), at least 10 years before the onset of RA symptoms. Although the differences in the various lipid values were small they may have clinical relevance, in the light of results from other studies. For instance, in a placebo-controlled study with fibrates, the …

Background: The Combinatietherapie Bij Reumatoide Artritis (COBRA) trial has proved that combination therapy with prednisolone, methotrexate and sulphasalazine is superior to sulphasalazine monotherapy in suppressing disease activity and radiological progression of early rheumatoid arthritis (RA). In addition, 5 years of follow-up proved that COBRA therapy results in sustained reduction of the rate of radiological progression. Despite this evidence, Dutch rheumatologists seem reluctant to prescribe COBRA therapy. Objective: To explore the reasons for the reluctance in Dutch rheumatologists to prescribe COBRA therapy. Methods: A short structured questionnaire based on social–psychological theories of behaviour was sent to all Dutch rheumatologists (n = 230). Results: The response rate was 50%. COBRA therapy was perceived as both effective and safe, but complex to administer. Furthermore, rheumatologists expressed their concern about the large number of pills that had to be taken, the side effects of high-dose prednisolone and the low dose of methotrexate. Although the average attitude towards the COBRA therapy was slightly positive (above the neutral point), the majority of responding rheumatologists had a negative intention (below the neutral point) to prescribe COBRA therapy in the near future. Conclusion: The reluctance of Dutch rheumatologists to prescribe effective COBRA therapy may be due to perceptions of complexity of the treatment schedule and negative patient-related consequences of the therapy.

Background Early, intensive treatment of rheumatoid arthritis (RA) with the combination of (initially high dose) prednisolone, methotrexate and sulfasalazine (COBRA therapy) considerably lowers disease activity and suppresses radiological progression, but is infrequently prescribed in daily practice. Attenuating the COBRA regimen might lessen concerns about side effects, but the efficacy of such strategies is unknown. Objective To compare the ‘COBRA-light’ strategy with only two drugs, comprising a lower dose of prednisolone (starting at 30 mg/day, tapered to 7.5 mg/day in 9 weeks) and methotrexate (escalated to 25 mg/week in 9 weeks) to COBRA therapy (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks, methotrexate 7.5 mg/week and sulfasalazine 2 g/day). Method An open, randomised controlled, non-inferiority trial in 164 patients with early active RA, all treated according to a treat to target strategy. Results At baseline patients had moderately active disease: mean (SD) 44-joint disease activity score (DAS44) 4.13 (0.81) for COBRA and 3.95 (0.9) for COBRA-light. After 6 months, DAS44 significantly decreased in both groups (–2.50 (1.21) for COBRA and –2.18 (1.10) for COBRA-light). The adjusted difference in DAS44 improvement between the groups, 0.21 (95% CI –0.11 to 0.53), was smaller than the predefined clinically relevant difference of 0.5. Minimal disease activity (DAS44

An atherogenic lipid profile is an established risk factor for cardiovascular (CV) diseases. Interestingly, high inflammatory states as present in rheumatoid arthritis (RA) are associated with unfavourable lipid profile. Data about effects of novel immunomodulating agents as rituximab (RTX) on lipid profile are limited. Therefore, changes in lipids in RTX treated RA patients were evaluated. In 49 consecutive RTX treated RA patients, serum and EDTA plasma samples were collected at baseline, 1, 3 and 6 months. In these samples, lipid and levels were assessed to determine changes in time. Surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) MS analysis was performed in six good and six non-responding RA patients to study functional high density lipoprotein (HDL) protein composition changes in time. In the total group (n=49), the atherogenic index decreased from 4.3 to 3.9 (∼9%) after 6 months. Testing for effect modification revealed a difference in the effect on lipid levels between responders and non-responders upon RTX (p

Objective. Osteoporosis is a frequent complication of rheumatoid arthritis (RA). We therefore investigated the effect of oral pamidronate therapy as a specific bone-sparing agent in RA. Methods. The study design was a 3-year randomized, double-blind trial of 300 mg oral pamidronate/day compared with placebo in 105 RA patients. Bone mineral density (BMD) measured at 12-month intervals was the primary efficacy parameter. Results. In 3 years, lumbar spine and forearm BMD increased significantly in the pamidronate-treated group (by 8.4 ± 6.9% [mean ± SEM] [P < 0.0001] and 5.2 ± 6.5% [P < 0.005], respectively), compared with nonsignificant changes in the placebo-treated patients (increase of 0.6 ± 5.2% and decrease of 1.2 ± 5.8%, respectively). Femoral neck BMD increased in the pamidronate-treated group (by 2.6 ± 8.6%) and decreased significantly in the placebo-treated group (by 4.0 ± 1.3% [P < 0.005]). The changes in BMD with time at all 3 measurement sites were significantly different between the treatment groups (P < 0.0001). Changes in radiographic signs of joint damage and in disease activity were similar in the 2 groups. Conclusion. The present study provides the first evidence that long-term treatment with an orally administered bisphosphonate overcomes bone loss and increases bone mass when compared with placebo. This finding may have significance with regard to the treatment of patients with RA.

Objective. To assess the efficacy and tolerability of sulfasalazine (SSZ) in the treatment of spondyl-arthropathy. Methods. We conducted a 6-month randomized, placebo-controlled, double-blind, multicenter study of patients with spondylarthropathy whose disease had remained active despite treatment with nonsteroidal antiinflammatory drugs. Patients were treated with SSZ (3 gm/day) or placebo. The primary efficacy variables were the physician's and patient's overall assessments, pain, and morning stiffness. End points were analyzed in the intent-to-treat and completer patient populations; the time course of effect was analyzed in the completer patient population. Results. Of the 351 patients enrolled, 263 (75%) completed the 6-month treatment period. The withdrawal rates were 35 (20%) and 53 (30%) in the placebo and SSZ groups, respectively. In the intent-to-treat analysis of end point efficacy, the between-treatment difference reached statistical significance only for 1 of the 4 primary outcome variables, the patient's overall assessment of disease activity, for which 60% of the patients taking SSZ improved by at least 1 point on a 5-point scale, in contrast to 44% of the patients taking placebo. Laboratory markers of inflammation also showed statistically significant change in favor of SSZ. In subgroup analysis, the most impressive effects were seen in patients with psoriatic arthritis, both for the 4 primary efficacy variables and for secondary efficacy variables such as the number of inflamed joints. Adverse events were more frequent in the SSZ group than the placebo group, but all were transient or reversible after cessation of treatment. Conclusion. The results of this study show that SSZ had greater efficacy than placebo in the treatment of active spondylarthropathy, notably in patients with psoriatic arthritis.

Objective. Prednisone is frequently used in the treatment of elderly-onset rheumatoid arthritis (RA), but the balance between efficacy and toxicity, including the effect on bone mass, has not been investigated in long-term studies. This prospective, randomized study was undertaken to compare disease activity and bone mass during long-term treatment with prednisone versus chloroquine in this patient population. Methods. Patients with active RA diagnosed at age ≥ 60 were randomized to receive prednisone (15 mg/day for 1 month, with the dosage tapered as low as possible thereafter) (n = 28) or chloroquine (n = 28). Patients who did not show a response received other second-line drugs as an adjunct to prednisone or as a replacement for chloroquine. Bone mass was measured by dual-energy x-ray absorptiometry. The study duration was 2 years. Results. During the 2 years, treatment with other second-line drugs was needed for 12 patients in the prednisone group (43%) and 8 in the chloroquine group (29%). Functional capacity and disease activity improved significantly in both groups and did not differ significantly between the groups, except for a greater improvement in the prednisone group at 1 month. Radiographic scores for joint destruction progressed similarly in both groups. There was a nonsignificant excess bone loss of 1.8% in the spine and 1.5% in the hip in the prednisone group, compared with the chloroquine group. Conclusion. Neither treatment was entirely satisfactory since a significant number of patients needed an additional second-line drug over the 2-year period.