Sustained rheumatoid arthritis remission is uncommon in clinical practice

Introduction

Remission is an important goal of therapy in rheumatoid arthritis (RA), but data on duration of remission are lacking. Our objective was to describe the duration of remission in RA, assessed by different criteria.

Methods

We evaluated patients from the Brigham and Women''s Rheumatoid Arthritis Sequential Study (BRASS) not in remission at baseline with at least 2 years of follow-up. Remission was assessed according to the Disease Activity Score 28-C-reactive protein (DAS28-CRP4), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) scores, and the recently proposed American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for remission. Analyses were performed by using Kaplan-Meier survival curves.

Results

We identified 871 subjects with ≥2 years of follow-up. Of these subjects, 394 were in remission at one or more time-points and not in remission at baseline, according to at least one of the following criteria: DAS28-CRP < 2.6 (n = 309), DAS28-CRP < 2.3 (n = 275), SDAI (n = 168), CDAI (n = 170), and 2010 ACR/EULAR (n = 158). The median age for the 394 subjects at entrance to BRASS was 56 years; median disease duration was 8 years; 81% were female patients; and 72% were seropositive. Survival analysis performed separately for each remission criterion demonstrated that < 50% of subjects remained in remission 1 year later. Median remission survival time was 1 year. Kaplan-Meier curves of the various remission criteria did not significantly differ (P = 0.29 according to the log-rank test).

Conclusions

This study shows that in clinical practice, a minority of RA patients are in sustained remission.     

Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year

Introduction

Clinical trials of new treatments for rheumatoid arthritis (RA) typically require subjects to have an elevated acute phase reactant (APR), in addition to tender and swollen joints. However, despite the elevation of individual components of the Clinical Disease Activity Index (CDAI) (tender and swollen joint counts and patient and physician global assessment), some patients with active RA may have normal erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels and thus fail to meet entry criteria for clinical trials. We assessed the relationship between CDAI and APRs in the Consortium of Rheumatology Researchers of North America (CORRONA) registry by comparing baseline characteristics and one-year clinical outcomes of patients with active RA, grouped by baseline APR levels.

Methods

This was an observational study of 9,135 RA patients who had both ESR and CRP drawn and a visit at which CDAI was >2.8 (not in remission).

Results

Of 9,135 patients with active RA, 58% had neither elevated ESR nor CRP; only 16% had both elevated ESR and CRP and 26% had either ESR or CRP elevated. Among the 4,228 patients who had a one-year follow-up visit, both baseline and one-year follow-up modified Health Assessment Questionnaire (mHAQ) and CDAI scores were lowest for patients with active RA but with neither APR elevated; both mHAQ and CDAI scores increased sequentially with the increase in number of elevated APR levels at baseline. Each individual component of the CDAI followed the same trend, both at baseline and at one-year follow-up. The magnitude of improvement in both CDAI and mHAQ scores at one year was associated positively with the number of APRs elevated at baseline.

Conclusions

In a large United States registry of RA patients, APR levels often do not correlate with disease activity as measured by joint counts and global assessments. These data strongly suggest that it is appropriate to obtain both ESR and CRP from RA patients at the initial visit. Requiring an elevation in APR levels as a criterion for inclusion of RA patients in studies of experimental agents may exclude some patients with active disease.     

Levels of C-Reactive Protein Associated with High and Very High Cardiovascular Risk Are Prevalent in Patients with Rheumatoid Arthritis

Objective

C-reactive protein (CRP) levels>3 mg/L and>10 mg/L are associated with high and very high cardiovascular risk, respectively, in the general population. Because rheumatoid arthritis (RA) confers excess cardiovascular mortality, we determined the prevalence of these CRP levels among RA patients stratified on the basis of their RA disease activity.

Methods

We evaluated physician and patient global assessments of disease activity, tender and swollen 28 joint counts, erythrocyte sedimentation rate (ESR), and CRP measured in a single clinic visit for 151 RA patients. Disease activity was calculated using the Clinical Disease Activity Index (CDAI) and the Disease Activity Score 28 Joints (DAS28-ESR and DAS28-CRP).

Results

Median CRP level was 5.3 mg/L. 68% of patients had CRP>3 mg/L, and 25% had CRP>10 mg/L. Of those with 0–1 swollen joints (n = 56), or 0–1 tender joints (n = 81), 64% and 67%, respectively, had CRP>3 mg/L, and 23% and 20%, respectively, had CRP>10 mg/L. Of those with remission or mildly active disease by CDAI (n = 58), DAS28-ESR (n = 39), or DAS28-CRP (n = 70), 49–66% had CRP>3 mg/L, and 10–14% had CRP>10 mg/L. Of patients with moderate disease activity by CDAI (n = 51), DAS28-ESR (n = 78), or DAS28-CRP (n = 66), 67–73% had CRP>3 mg/L, and 25–33% had CRP>10 mg/L.

Conclusion

Even among RA patients whose disease is judged to be controlled by joint counts or standardized disease scores, a substantial proportion have CRP levels that are associated high or very high risk for future cardiovascular events in the general population.     

Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis

Background

Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment.

Objectives

To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis.

Methods

Candidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing.

Results

130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities.

Conclusion

We followed a stepwise approach to develop a quantitative serum-based measure of RA disease activity, based on 12-biomarkers, which was consistently associated with clinical disease activity levels.     

Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study

Introduction

Evidences of biologics-free disease control after discontinuing adalimumab (ADA) in rheumatoid arthritis (RA) patients in clinical practice have not been sufficiently investigated. Purpose of this study is to investigate whether disease activity score 28 (DAS28)- erythrocyte sedimentation rate (ESR) remission was preserved after discontinuation of ADA in patients with RA.

Methods

This is an observational but not a randomized controlled study. Among 197 RA patients who initiated with combination of ADA with concomitant MTX, 69 (35%) acquired DAS28 (ESR) < 2.6 for at least 24 weeks. Of those 69 patients, 51 went on ADA discontinuation with their consent, and finally 50 of those with follow-up of > 24 weeks were evaluated. The effect of discontinuing ADA on clinical disease activity, functional disability and radiographic progression were evaluated by DAS28 (ESR), the clinical disease activity index (CDAI) and the simplified disease activity index (SDAI), by a health assessment questionnaire-disability index (HAQ-DI) and by the modified total Sharp score (mTSS), respectively.

Results

The mean age of the participants was 59.5 years with the mean disease duration of 7.1 years. Out of the 50 patients, 29 (58%) were maintained in DAS28 (ESR) < 2.6 at 24 weeks after discontinuing ADA. A logistic regression analysis showed that DAS28 (ESR) at baseline significantly predicted a DAS28 (ESR) < 2.6 maintained after discontinuation of ADA, and a receiver-operating characteristic (ROC) analysis showed that the cut-off value of DAS28 (ESR) at discontinuation was 2.16. The mean HAQ-DI at six months after discontinuing ADA was 0.1 in patients who kept in DAS28 (ESR) < 2.6, and 94.9% (37/39) showed no evidence of radiographic progression (> 0.5 per year of a change in mTSS) at 1 year.

Conclusions

It was possible to maintain DAS28 (ESR) < 2.6 after discontinuation of ADA without functional and radiographic progression and very low DAS28 (ESR) at the discontinuation was associated with successful ADA-free DAS28 (ESR) < 2.6 in patients with RA.

Trial registration

University Hospital Medical Information Network Identifier: UMIN000006669.     

Is Ultrasound a Better Target than Clinical Disease Activity Scores in Rheumatoid Arthritis with Fibromyalgia? A Case-Control Study

Objectives

Our goal is to study the correlations among gray-scale seven-joint ultrasound score (GS-US7), power Doppler seven-joint ultrasound score (PD-US7), disease activity score-28 joints (DAS28), simplified disease activity index (SDAI) and clinical disease activity index (CDAI) in patients with and without fibromyalgia (FM).

Methods

A matched case-control study included all patients consecutively seen in the Rheumatoid Arthritis (RA) Clinic. Participants were allocated into one of two groups: RA with FM and RA without FM. Ultrasound (US) and clinical scoring were blinded for the presence of FM. Medians and proportions were compared by Mann-Whitney’s test and McNemar’s test, respectively. Spearman’s rank correlation coefficients (r_s) were calculated among clinical and US scores and differences were tested by r-to-z transformation test.

Results

Seventy-two women were included, out of 247 RA patients, mostly white, with median (IQR) age of 57.5 (49.3–66.8) years, with RA symptoms for 13.0 (6.0–19.0) years and FM symptoms for 6.0 (2.0–15.0) years. Disease-modifying antirheumatic drugs, non-steroidal anti-inflammatory drugs and prednisone use was comparable between groups. Objective activity parameters were not different between groups. RA patients with FM had greater DAS28, SDAI and CDAI but similar GS-US7 and PD-US7. GS-US7 correlated with DAS28, SDAI and CDAI in patients with and without FM (r_s = 0.36–0.57), while PD-US7 correlated with clinical scores only in patients without FM (r_s = 0.35–0.38).

Conclusion

To our knowledge, this is the first study to demonstrate that ultrasound synovitis scores are not affected by FM in RA patients. PD-US7 performed better than GS-US7 in long-standing RA patients with DAS28, SDAI or CDAI allegedly overestimated due to FM. Since sonographic synovitis predicts erosion better than swollen joint count, C-reactive protein and erythrocyte sedimentation rate, US should be considered a promising treatment target in RA patients with FM.     

A Comparison of Disease Burden in Rheumatoid Arthritis,Psoriatic Arthritis and Axial Spondyloarthritis

Objective

The main objective of this study was to compare disease burden in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (ax-SpA).

Methods

In this cross-sectional study, all the RA (1093), PsA (365) and ax-SpA (333) patients who visited the out-patient clinic of the Hospital of Southern Norway Trust during the year 2013 were included; the RA patients all had a RA diagnosis verified by the treating rheumatologist, the PsA patients all fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and the ax-SpA patients all fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for ax-SpA. Patient-reported health status, demographic variables, medications, and composite scores of disease activity were assessed. The main analyses were performed using General Linear Models adjusted for age, sex and multiple comparisons. Correlation analyses were performed using Spearman’s rho.

Results

The reported pain, joint pain, patient’s global assessment and fatigue were similar in PsA and ax-SpA, but significantly lower in RA. The 28-joint Disease Activity Score (DAS28) (0.3±0.1, p = 0.003), Clinical Disease Activity Index (CDAI) (1.0±0.4, p = 0.028) and Routine Assessment of Patient Index Data 3 (RAPID3) (0.4±0.1, p = 0.004) were all significantly higher in PsA vs. RA. RAPID3 showed moderate to high correlation with DAS28 (rho = 0.521, p<0.001) and CDAI (rho = 0.768, p<0.001) in RA and PsA, and with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (rho = 0.902, p<0.001) and Bath Ankylosing Spondylitis Functional Index (BASFI) (0.865, p<0.001) in ax-SpA and PsA.

Conclusion

In conclusion, patient- reported outcome measures were similar in our population of PsA and ax-SpA patients, but significantly lower for the RA patients. Composite disease activity measures were lower in RA than in PsA and ax-SpA, but the magnitude of these differences was small and probably not of clinical significance. Our study indicates that disease burden in RA, PsA and ax-SpA may be more similar than previously demonstrated.     

Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the DREAM remission induction cohort

Introduction

Clinical trials have demonstrated that treatment-to-target (T2T) is effective in achieving remission in early rheumatoid arthritis (RA). However, the concept of T2T has not been fully implemented yet and the question is whether a T2T strategy is feasible in daily clinical practice. The objective of the study was to evaluate the adherence to a T2T strategy aiming at remission (Disease Activity Score in 28 joints (DAS28) < 2.6) in early RA in daily practice. The recommendations regarding T2T included regular assessment of the DAS28 and advice regarding DAS28-driven treatment adjustments.

Methods

A medical chart review was performed among a random sample of 100 RA patients of the DREAM remission induction cohort. At all scheduled visits, it was determined whether the clinical decisions were compliant to the T2T recommendations.

Results

The 100 patients contributed to a total of 1,115 visits. The DAS28 was available in 97.9% (1,092/1,115) of the visits, of which the DAS28 was assessed at a frequency of at least every three months in 88.3% (964/1,092). Adherence to the treatment advice was observed in 69.3% (757/1,092) of the visits. In case of non-adherence when remission was present (19.5%, 108/553), most frequently medication was tapered off or discontinued when it should have been continued (7.2%, 40/553) or treatment was continued when it should have been tapered off or discontinued (6.2%, 34/553). In case of non-adherence when remission was absent (42.1%, 227/539), most frequently medication was not intensified when an intensification step should have been taken (34.9%, 188/539). The main reason for non-adherence was discordance between disease activity status according to the rheumatologist and DAS28.

Conclusions

The recommendations regarding T2T were successfully implemented and high adherence was observed. This demonstrates that a T2T strategy is feasible in RA in daily clinical practice.     

Decreased Circulating Visfatin Is Associated with Improved Disease Activity in Early Rheumatoid Arthritis: Data from the PERAC Cohort

Objective

To evaluate circulating visfatin and its relationship with disease activity and serum lipids in patients with early, treatment-naïve rheumatoid arthritis (RA).

Methods

Serum visfatin was measured in 40 patients with early RA before and after three months of treatment and in 30 age- and sex-matched healthy individuals. Disease activity was assessed using the Disease Activity Score for 28 joints (DAS28) at baseline and at three and 12 months. Multivariate linear regression analysis was performed to evaluate whether improved disease activity is related to serum visfatin or a change in visfatin level.

Results

Serum visfatin was significantly elevated in early RA patients compared to healthy controls (1.92±1.17 vs. 1.36±0.93 ng/ml; p = 0.034) and significantly decreased after three months of treatment (to 0.99±0.67 ng/ml; p<0.001). Circulating visfatin and a change in visfatin level correlated with disease activity and improved disease activity over time, respectively. A decrease in visfatin after three months predicted a DAS28 improvement after 12 months. In addition, decreased serum visfatin was not associated with an improved atherogenic index but was associated with an increase in total cholesterol level.

Conclusion

A short-term decrease in circulating visfatin may represent an independent predictor of long-term disease activity improvement in patients with early RA.     

Smoking in combination with antibodies to cyclic citrullinated peptides is associated with persistently high levels of survivin in early rheumatoid arthritis: a prospective cohort study

Introduction

High levels of the oncoprotein survivin may be detected in the majority of patients with early rheumatoid arthritis (RA). Survivin is a sensitive predictor of joint damage and persistent disease activity. Survivin-positive patients are often poor responders to antirheumatic and biological treatment. The aim of this study was to investigate the reproducibility of survivin status and its significance for clinical and immunological assessment of RA patients.

Methods

Survivin levels were measured in 339 patients from the Better Anti-Rheumatic FarmacOTherapy (BARFOT) cohort of early RA at baseline and after 24 months. The association of survivin status with joint damage (total Sharp-van der Heijde score), disease activity (Disease Activity Score based on evaluation of 28 joints (DAS28)), functional disability (Health Assessment Questionnaire (HAQ)), and pain perception (Visual Analogue Scale (VAS)) was calculated in the groups positive and negative for survivin on both occasions, and for the positive-negative and negative-positive groups.

Results

In 268 patients (79%) the levels of survivin were similar at baseline and after 24 months, 15% converted from survivin-positive to survivin-negative, and 5% from survivin-negative to survivin-positive. A combination of smoking and antibodies against cyclic citrullinated peptides (aCCP) predicted persistently (baseline and 24 months) high levels of survivin (odds ratio 4.36 (95% CI: 2.64 to 7.20), P < 0.001), positive predictive value 0.66 and specificity 0.83). The independent nature of survivin and aCCP was demonstrated by statistical and laboratory analysis. Survivin positivity on both test occasions was associated with the progression of joint damage, significantly higher DAS28 and lower rate of remission at 24 and 60 months compared to negative-negative patients. Survivin status was less associated with changes in HAQ and VAS.

Conclusions

Survivin is a relevant and reproducible marker of severe RA. Persistently high levels of survivin were associated with smoking and the presence of aCCP and/or RF antibodies and predicted persistent disease activity and joint damage.     

Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity

Introduction

It remains challenging to predict the outcomes of therapy in patients with rheumatoid arthritis (RA). The objective of this study was to identify immune response signatures that correlate with clinical treatment outcomes in patients with RA.

Methods

A cohort of 71 consecutive patients with early RA starting treatment with disease-modifying antirheumatic drugs (DMARDs) was recruited. Disease activity at baseline and after 21 to 24 weeks of follow-up was measured using the Disease Activity Score in 28 joints (DAS28). Immune response profiling was performed by analyzing multi-cytokine production from peripheral blood cells following incubation with a panel of stimuli, including a mixture of human cytomegalovirus (CMV) and Epstein-Barr virus (EBV) lysates. Profiles identified via principal components analysis (PCA) for each stimulus were then correlated with the ΔDAS28 from baseline to follow-up. A clinically meaningful improvement in the DAS28 was defined as a decrease of ≥1.2.

Results

A profile of T-cell cytokines (IL-13, IL-4, IL-5, IL-2, IL-12, and IFN-γ) produced in response to CMV/EBV was found to correlate with the ΔDAS28 from baseline to follow-up. At baseline, a higher magnitude of the CMV/EBV immune response profile predicted inadequate DAS28 improvement (mean PCA-1 scores: 65.6 versus 50.2; P = 0.029). The baseline CMV/EBV response was particularly driven by IFN-γ (P = 0.039) and IL-4 (P = 0.027). Among patients who attained clinically meaningful DAS28 improvement, the CMV/EBV PCA-1 score increased from baseline to follow-up (mean +11.6, SD 25.5), whereas among patients who responded inadequately to DMARD therapy, the CMV/EBV PCA-1 score decreased (mean -12.8, SD 25.4; P = 0.002). Irrespective of the ΔDAS28, methotrexate use was associated with up-regulation of the CMV/EBV response. The CMV/EBV profile was associated with positive CMV IgG (P <0.001), but not EBV IgG (P = 0.32), suggesting this response was related to CMV exposure.

Conclusions

A profile of T-cell immunity associated with CMV exposure influences the clinical response to DMARD therapy in patients with early RA. Because CMV latency is associated with greater joint destruction, our findings suggest that changes in T-cell immunity mediated by viral persistence may affect treatment response and possibly long-term outcomes of RA.     

Peroxisome proliferator-activated receptor γ agonist effect on rheumatoid arthritis: a randomized controlled trial

Introduction

Rheumatoid arthritis (RA), a chronic inflammatory disease, is associated with insulin resistance. Experimental evidence indicates that the relationship between insulin resistance and inflammation is bidirectional: Inflammation promotes insulin resistance, and insulin resistance promotes inflammation. Therefore, we examined the hypothesis that pioglitazone, a thiazolidinedione peroxisome proliferator-activated receptor γ agonist, would decrease inflammation and disease activity and improve insulin resistance in patients with RA.

Methods

In a single-center, randomized, double-blind, placebo-controlled crossover study patients with RA (N = 34) receiving stable therapy were randomized to also receive either pioglitazone 45 mg daily (n = 17) or matching placebo (n = 17) for eight weeks. This was followed by a four-week washout period and alternative treatment for eight weeks. Outcomes included change in Disease Activity Score in 28 joints (DAS28) score, individual components of the DAS28 score and homeostatic model assessment for insulin resistance (HOMA). Intention-to-treat analysis and linear mixed-effects models were used.

Results

Patients had a mean (±SD) age of 51 (±14.2) years, 82.4% were female and baseline DAS28 high-sensitivity C-reactive protein (DAS28-CRP) was 4.58 (±1.1) units. Addition of pioglitazone was associated with a 9.3% reduction (95% confidence interval (CI) = 0.17% to 17.6%) in DAS28-CRP (P = 0.046), but no significant change in DAS28 erythrocyte sedimentation rate (DAS28-ESR) (P = 0.92). There was a 10.7mm (95% CI = 0.4 to 20.9 mm) improvement in patient-reported global health (P = 0.042), a 48.6% decrease (95% CI = 27.6% to 63.5%) in CRP (P < 0.001) and a 26.4% decrease (95% CI = 3.7% to 43.8%) in insulin resistance as measured by HOMA (P = 0.025), but no significant reduction in swollen or tender joint count or in ESR (all P > 0.05). Lower-extremity edema was more common during pioglitazone treatment (16%) than placebo (0%).

Conclusion

Addition of pioglitazone to RA therapy improves insulin resistance and modestly reduces RA disease activity measured by DAS28-CRP and two of its components, including patient-reported global health and CRP, but not DAS28-ESR or ESR.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT00763139","term_id":"NCT00763139"}}NCT00763139     

CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients

Introduction

Single-nucleotide polymorphisms (SNPs) in the CRP gene are implicated in the regulation of the constitutional C-reactive protein (CRP) expression and its response to proinflammatory stimuli. Previous reports suggest that these effects may have an impact on clinical decision-making tools based on CRP, such as the Disease Activity Score in 28 joints (DAS28). We aimed to investigate the possible association between seven CRP SNPs, their haplotypes and the serum levels of CRP, as well as DAS28 scores, in two cohorts of untreated active early rheumatoid arthritis (RA) patients followed during their initial treatment.

Methods

Overall, 315 patients with RA from two randomized controlled trials (the CIMESTRA and OPERA trials) who were naïve to disease-modifying antirheumatic drugs and steroids with disease durations less than 6 months were included. Seven CRP SNPs were investigated: rs11265257, rs1130864, rs1205, rs1800947, rs2808632, rs3093077 and rs876538. The genotype and haplotype associations with CRP and DAS28 levels were evaluated using linear regression analysis adjusted for age, sex and treatment.

Results

The minor allele of rs1205 C > T was associated with decreased CRP levels at baseline (P = 0.03), with the TT genotype having a 50% reduction in CRP from 16.7 to 8.4 mg/L (P = 0.005) compared to homozygosity of the major allele, but no association was observed at year 1 (P = 0.38). The common H2 haplotype, characterized by the T allele of rs1205, was associated with a 26% reduction in CRP at baseline (P = 0.043), although no effect was observed at year 1 (P = 0.466). No other SNP or haplotype was associated with CRP at baseline or at year 1 (P ≥0.09). We observed no associations between SNPs or haplotypes and DAS28 scores at baseline or at year 1 (P ≥0.10).

Conclusion

CRP genotype and haplotype were only marginally associated with serum CRP levels and had no association with the DAS28 score. This study shows that DAS28, the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.

Trial registration

The OPERA study is registered at Clinicaltrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT00660647","term_id":"NCT00660647"}}NCT00660647). The CIMESTRA study is not listed in a clinical trials registry, because patients were included between October 1999 and October 2002.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0475-3) contains supplementary material, which is available to authorized users.     

In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis

Introduction

Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy. The aim of the study was to investigate the association between in vitro and in vivo GC sensitivity in RA.

Methods

Thirty-eight early and 37 established RA patients were prospectively studied. In vitro GC sensitivity was assessed with dexamethasone-induced effects on interleukin-2 (IL-2) and glucocorticoid-induced leucine zipper (GILZ) messenger RNA expression in peripheral blood mononuclear cells (PBMCs). A whole-cell dexamethasone-binding assay was used to measure number and affinity (1/K_D) of glucocorticoid receptors (GRs).In vivo GC sensitivity was determined by measuring the disease activity score (DAS) and health assessment questionnaire disability index (HAQ-DI) score before and after 2 weeks of standardized GC treatment.

Results

GR number was positively correlated with improvement in DAS. IL-2-EC₅₀ and GILZ-EC₅₀ values both had weak near-significant correlations with clinical improvement in DAS in intramuscularly treated patients only. HAQ responders had lower GILZ-EC₅₀ values and higher GR number and K_D.

Conclusions

Baseline cellular in vitro glucocorticoid sensitivity is modestly associated with in vivo improvement in DAS and HAQ-DI score after GC bridging therapy in RA. Further studies are needed to evaluate whether in vitro GC sensitivity may support the development of tailor-made GC therapy in RA.     

Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder

Introduction

Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.

Methods

Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.

Results

Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).

Conclusions

Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.     

Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: the ESPOIR cohort

Introduction

In development of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) remission definitions using clinical trials data, one criterion used to compare different remission definitions was whether, compared with those not in remission, those in remission had evidence of later disease stability defined by x-ray and functional status. Validation of the RA remission criteria using observational study data is necessary before recommending their use in practice.

Methods

Using data from those who met RA criteria in the ESPOIR cohort, we matched each person in remission with a person not in remission and then carried out analyses comparing later stability of x-ray and health assessment questionnaire (HAQ) between the two groups. We compared the predictive validity of the same candidate definitions of remission evaluated in the ACR/EULAR process. To minimize potential bias and produce more stable results, we used a bootstrap resampling approach to select those not in remission, repeating the sample matching analysis process 500 times.

Results

Results were similar to those of clinical trials analyzed for the ACR/EULAR remission criteria. Specifically, the ACR/EULAR remission definitions using either an simple disease activity index (SDAI) ≤ 3.3, clinical disease activity index (CDAI) ≤ 2.8 or a definition of remission requiring tender joint count, swollen joint count, patient global assessment all ≤ 1 performed as well or better than other candidate definitions of remission in terms of predicting later x-ray and function stability.

Conclusions

ACR/EULAR definitions of remission developed for trials are similarly valid in observational studies in RA and could be used in practice.     

Lack of validation of genetic variants associated with anti–tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis

Introduction

In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations.

Methods

The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients.

Results

None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis.

Conclusion

Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.     

The phenotype and genotype of rheumatoid arthritis in the Democratic Republic of Congo

Introduction

Little is known about rheumatoid arthritis in the black, particularly in Congolese, populations. Our objective was to describe the phenotype and genotype of rheumatoid arthritis (RA) in Congolese.

Methods

All consecutive rheumatoid arthritis (RA) patients attending Kinshasa University Hospital in a three-year time period were included. Demographics, clinical features and tobacco consumption were noted. Disease Activity Score (DAS)-28 based on the erythrocyte sedimentation rate (ESR), Health Assessment Questionnaire (HAQ), anti-citrullinated peptide antibodies (CCP) antibodies and rheumatoid factor (RF) were determined. Radiographs were scored according to Sharp-van der Heijde. On a subset of patients and controls HLA-DRB1 typing was performed.

Results

A total of 114 females and 14 males aged 51.2 ± 14.9 were included. Mean duration of symptoms was four years. Moderate tobacco consumption was reported in a minority of patients. DAS-28 at first visit was >5.1 and HAQ ≥0.5 in all patients. X-rays showed joint erosions and/or joint space narrowing, mostly of a moderate grade in 55.8% of patients. Anti-CCP and/or RF were present in 48.6% of patients with available data (n = 72) and in 3.0% of controls (n = 67). Radiographic changes and nodules were more frequent in RF or anti-CCP positive patients. One copy of the shared epitope was found in 13 patients (35.1%) and 3 controls (12.5%). Two copies were found in one patient (2.7%) and in one control (4.2%).

Conclusion

Congolese patients with RA consult long after disease onset. Despite this delay, the majority presents without major damage and is RF, anti-CCP and SE negative. We put forward the hypothesis that besides different environmental factors there is probably also a particular genetic risk profile in Congolese patients, different from the HLA-DRB1 shared epitope.     

Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized,two-center placebo-controlled study

Introduction

We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA).

Methods

A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15mg or 7.5mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP).

Results

All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures.

Conclusions

Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy.

Trial Registration

Clinicaltrials.gov identifier: NCT00746512     

Serum C-X-C motif chemokine 13 is elevated in early and established rheumatoid arthritis and correlates with rheumatoid factor levels

Introduction

We hypothesized that serum levels of C-X-C motif chemokine 13 (CXCL13), a B-cell chemokine, would delineate a subset of rheumatoid arthritis (RA) patients characterized by increased humoral immunity.

Methods

Serum from patients with established RA (the Dartmouth RA Cohort) was analyzed for CXCL13, rheumatoid factor (RF) levels, anticitrullinated peptide/protein antibody (ACPA) and total immunoglobulin G (IgG); other parameters were obtained by chart review. A confirmatory analysis was performed using samples from the Sherbrooke Early Undifferentiated PolyArthritis (EUPA) Cohort. The Wilcoxon rank-sum test, a t-test and Spearman’s correlation analysis were utilized to determine relationships between variables.

Results

In both the Dartmouth and Sherbrooke cohorts, CXCL13 levels were selectively increased in seropositive relative to seronegative RA patients (P = 0.0002 and P < 0.0001 for the respective cohorts), with a strong correlation to both immunoglobulin M (IgM) and IgA RF levels (P < 0.0001). There was a weaker relationship to ACPA titers (P = 0.03 and P = 0.006, respectively) and total IgG (P = 0.02 and P = 0.14, respectively). No relationship was seen with regard to age, sex, shared epitope status or inclusion high-sensitivity C-reactive protein (hsCRP) in either cohort or regarding the presence of baseline erosions in the Sherbrooke Cohort, whereas a modest relationship with Disease Activity Score in 28 joints CRP (DAS28-CRP) was seen in the Dartmouth cohort but not the Sherbrooke cohort.

Conclusion

Using both established and early RA cohorts, marked elevations of serum CXCL13 levels resided nearly completely within the seropositive population. CXCL13 levels exhibited a strong relationship with RF, whereas the association with clinical parameters (age, sex, DAS28-CRP and erosions) or other serologic markers (ACPA and IgG) was either much weaker or absent. Elevated serum CXCL13 levels may identify a subset of seropositive RA patients whose disease is shaped by or responsive to RF production.