Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes a considerable burden for the patient and society. It is not clear yet whether aiming for remission (REM) is worthwhile, especially when compared with low disease activity (LDA).

Methods

In 356 consecutive RA patients, we obtained data on physical function (health assessment questionnaire (HAQ)), health-related quality of life (HRQoL: Short Form 36 (SF36), Short Form 6 dimensions (SF-6D), Euro QoL 5D (EQ-5D)), work productivity (work productivity and activity impairment questionnaire (WPAI)), as well as estimation of direct and indirect costs. Cross-sectionally, data were compared in patients within different levels of disease activity according to the simplified disease activity index (SDAI; remission (REM ≤3.3); n = 87; low disease activity (LDA: 3.3 < SDAI ≤11); n = 103; moderate to high disease activity (MDA/HDA) >11 n = 119) by using analyses of variance (ANOVA). Longitudinal investigations assessed patients who changed from LDA to REM and vice versa.

Results

We found differences in patients achieving REM compared with LDA for HAQ (0.39 ± 0.58 versus 0.72 ± 68), WPAI (percentage impairment while working 11.8% ± 18.7% versus 26.8% ± 23.9%; percentage of overall activity impairment, 10.8% ± 14.1% versus 29.0% ± 23.6%)), EQ-5D (0.89 ± 0.12 versus 0.78 ± 0.6) and SF-36 (physical component score (PCS): 46.0 ± 8.6 versus 38.3 ± 10.5; mental component score (MCS): 49.9 ± 11.1 versus 47.9 ± 12.3) (P < 0.01 for all, except for SF36 MCS). Regarding costs, we found significant differences of direct and indirect costs (P < 0.05) within different levels of disease activity, with higher costs in patients with higher states of disease activity. Longitudinal evaluations confirmed the main analyses.

Conclusion

Patients with REM show better function, HRQoL, and productivity, even when compared with another good state, such as LDA. Also from a cost perspective, REM appears superior to all other states.     

Rheumatoid Arthritis Increases the Risk of Nontuberculosis Mycobacterial Disease and Active Pulmonary Tuberculosis

Background

Few studies have examined the association of rheumatoid arthritis (RA) with nontuberculosis mycobacterium (NTM) disease and pulmonary tuberculosis (PTB).

Methods

We identified 29 131 patients with RA from the catastrophic illness registry who were diagnosed from 1998–2008; 116 524 patients without RA from inpatient data files were randomly frequency matched according to sex, age, and index year and used as a comparison group. Both groups were followed-up until the end of 2010 to measure the incidence of NTM disease and active PTB. We analyzed the risk of NTM disease and active PTB using the Cox proportional hazards regression models, controlling for sex, age, and Charlson comorbidity index (CCI).

Results

The incidence of NTM disease was 4.22 times greater in the RA group than in the non-RA group (1.91 vs 0.45 per 10,000 person-years). The incidence of PTB was 2.99 times greater in the RA group than in the non-RA group (25.3 vs 8.46 per 10,000 person-years). After adjusting for age, sex, and CCI, the adjusted hazard ratios (HRs) of NTM disease and active PTB for the RA group were 4.17 (95% CI = 2.61–6.65) and 2.87 (95% CI = 2.55–3.23), respectively, compared with the non-RA group. In the first 2 years of follow-up, the RA group yielded corresponding adjusted HRs of 4.98 and 3.39 compared with the non-RA group. The follow-up time-specific RA group to the non-RA group HR of both the NTM disease and active PTB varied.

Conclusion

This study can serve as a reference for clinical physicians to increase awareness regarding the detection of NTM disease and active PTB in RA patients among the any stage of the clinical course even without CCI.     

Blood Monocyte Chemotactic Protein-1 (MCP-1) and Adapted Disease Activity Score28-MCP-1: Favorable Indicators for Rheumatoid Arthritis Activity

Objective

We assessed blood pentraxin 3 (PTX3) and macrophage chemotactic factor-1 (MCP-1) levels as indicators of disease activity in rheumatoid arthritis (RA) patients, because data on disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) and DAS28-C-reactive protein (CRP) are still imperfect.

Methods

In 111 patients with RA, we examined longitudinal and cross-sectional correlations of blood PTX3, MCP-1, CRP, and ESR levels with measures of clinical arthritic activity, namely, swollen joint count (SJC), tender joint count (TJC), visual analog scale for general health (GH), DAS28, and adapted DAS28-MCP-1.

Results

Blood MCP-1, but not PTX3, was significantly correlated with SJC, TJC, DAS28, and DAS28-CRP. DAS28-MCP-1 was strongly correlated with DAS28 (r  = 0.984, P<0.001) and DAS28-CRP (r  = 0.971, P<0.001), and modestly correlated with CRP (r  = 0.350, P<0.001), and ESR (r  = 0.386, P<0.001). Similarly, the duration of arthritic symptoms, but not sex, was significantly correlated with variables of arthritic activity. In particular, DAS28-MCP-1 significantly correlated with DAS28 during a 6-month period (r  = 0.944, P<0.001; r  = 0.951, P<0.001; r  = 0.862, P<0.001; and r  = 0.865, P<0.001 for month 0, 1, 3, and 6, respectively).

Conclusion

Blood MCP-1 and adapted DAS28-MCP-1, but not blood PTX3, may be useful in monitoring RA activity.     

Ultrasound composite scores for the assessment of inflammatory and structural pathologies in Psoriatic Arthritis (PsASon-Score)

Introduction

This study was performed to develop ultrasound composite scores for the assessment of inflammatory and structural lesions in Psoriatic Arthritis (PsA).

Methods

We performed a prospective study on 83 PsA patients undergoing two study visits scheduled 6 months apart. B-mode and Power Doppler (PD) findings were semi-quantitatively scored at 68 joints (evaluating synovia, perisynovial tissue, tendons and bone) and 14 entheses. We constructed bilateral and unilateral (focusing the dominant site) ultrasound composite scores selecting relevant sites by a hierarchical approach. We tested convergent construct validity, reliability and feasibility of inflammatory and structural elements of the scores as well as sensitivity to change for inflammatory items.

Results

The bilateral score (termed PsASon22) included 22 joints (6 metacarpophalangeal joints (MCPs), 4 proximal interphalangeal joints (PIPs) of hands (H-PIPs), 2 metatarsophalangeal joints (MTPs), 4 distal interphalangeal joints (DIPs) of hands (H-DIPs), 2 DIPs of feet (F-DIPs), 4 large joints) and 4 entheses (bilateral assessment of lateral epicondyle and distal patellar tendon). The unilateral score (PsASon13) compromised 13 joints (2 MCPs, 3 H-PIPs, 1 PIP of feet (F-PIP), 2 MTPs, 1 H-DIP and 2 F-DIPs and 2 large joints) and 2 entheses (unilateral lateral epicondyle and distal patellar tendon). Both composite scores revealed a moderate to high sensitivity (bilateral composite score 43% to 100%, unilateral 36% to 100%) to detect inflammatory and structural lesions compared to the 68-joint/14-entheses score. The inflammatory and structural components of the composite scores correlated weakly with clinical markers of disease activity (corr_coeffs 0 to 0.40) and the health assessment questionnaire (HAQ, corr_coeffs 0 to 0.39), respectively. Patients with active disease achieving remission at follow-up yielded greater reductions of ultrasound inflammatory scores than those with stable clinical activity (Cohen’s d effect size ranging from 0 to 0.79). Inter-rater reliability of bi- and unilateral composite scores was moderate to good with ICCs ranging from 0.42 to 0.96 and from 0.36 to 0.71, respectively for inflammatory and structural sub-scores. The PsASon22 and PsASon13 required 16 to 26 and 9 to 13 minutes, respectively to be completed.

Conclusion

Both new PsA ultrasound composite scores (PsASon22 and PsASon13) revealed sufficient convergent construct validity, sensitivity to change, reliability and feasibility.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0476-2) contains supplementary material, which is available to authorized users.     

The Belgian MIRA (MabThera In Rheumatoid Arthritis) registry: clues for the optimization of rituximab treatment strategies

Introduction  

This study describes the results of the Belgian 'MabThera In Rheumatoid Arthritis (MIRA)' registry: effectiveness, safety and evaluation of the current retreatment practice on the background of the Belgian reimbursement criteria for rituximab.     

Mining Disease Risk Patterns from Nationwide Clinical Databases for the Assessment of Early Rheumatoid Arthritis Risk

Rheumatoid arthritis (RA) is a chronic autoimmune rheumatic disease that can cause painful swelling in the joint lining, morning stiffness, and joint deformation/destruction. These symptoms decrease both quality of life and life expectancy. However, if RA can be diagnosed in the early stages, it can be controlled with pharmacotherapy. Although many studies have examined the possibility of early assessment and diagnosis, few have considered the relationship between significant risk factors and the early assessment of RA. In this paper, we present a novel framework for early RA assessment that utilizes data preprocessing, risk pattern mining, validation, and analysis. Under our proposed framework, two risk patterns can be discovered. Type I refers to well-known risk patterns that have been identified by existing studies, whereas Type II denotes unknown relationship risk patterns that have rarely or never been reported in the literature. These Type II patterns are very valuable in supporting novel hypotheses in clinical trials of RA, and constitute the main contribution of this work. To ensure the robustness of our experimental evaluation, we use a nationwide clinical database containing information on 1,314 RA-diagnosed patients over a 12-year follow-up period (1997–2008) and 965,279 non-RA patients. Our proposed framework is employed on this large-scale population-based dataset, and is shown to effectively discover rich RA risk patterns. These patterns may assist physicians in patient assessment, and enhance opportunities for early detection of RA. The proposed framework is broadly applicable to the mining of risk patterns for major disease assessments. This enables the identification of early risk patterns that are significantly associated with a target disease.     

A group-theoretical notation for disease states: an example using the psychiatric rating scale

ABSTRACT: BACKGROUND: While many branches of natural science have embraced group theory reaping enormous advantages for their respective fields, clinical medicine lacks to date such applications. Here we intend to explain a prototypal model based on the postulates of groups that could have potential in categorizing clinical states. METHOD: As an example, we begin by modifying the original 'Brief Psychiatric Rating Scale' (BPRS), the most frequently used standards for evaluating the psychopathology of patients with schizophrenia. We consider a presumptively idealized (virtually standardized) BPRS (denoted BPRS-I) with assessments ranging from '0' to '6' to simplify our discussion. Next, we introduce the modulo group Z7 containing elements {0,1,2,...,6} defined by composition rule, 'modulo 7 addition', denoted by *. Each element corresponds to a score resulting from grading a symptom under the BPRS-I assessment. By grading all symptoms associated with the illness, a Cartesian product, denoted Aj, constitutes a summary of a patient assessment. By considering operations denoted A(j->k) that change state Aj into state Ak, a group M (that itself contains Aj and Ak as elements) is also considered. Furthermore, composition of these operations obey modulo 7 arithmetic (i.e., addition, multiplication, and division). We demonstrate the application with a simple example in the form of a series of states (A4 = A1*A(1->2)*A(2->3)*A(3->4)) to illustrate this result. RESULTS: The psychiatric disease states are defined as 18-fold Cartesian products of Z7, i.e., Z7x18 = Z7x...xZ7 (18 times). We can construct set G {a(m)i| m = 1,2,3,...(the patient's history of the i-th symptom)} and M {Am | Am [element of] Z7x18 (the set of all possible assessments of a patient)} simplistically, at least, in terms of modulo 7 addition that satisfies the group postulates. CONCLUSIONS: Despite the large limitations of our methodology, there are grounds not only within psychiatry but also within other medical fields to consider more generalized notions based on groups (if not rings and fields). These might enable through some graduated expression a systematization of medical states and of medical procedures in a manner more aligned with other branches of natural science.     

类风湿性关节炎与系统性红斑狼疮重叠综合征一例报告及文献复习

目的:探讨类风湿关节炎(RA)与系统性红斑狼疮(SLE)重叠综合征(Rhupus综合征)的临床表现及治疗方法,以期提高对本病的认识。方法:对1例类风湿关节炎(RA)与系统性红斑狼疮(SLE)重叠的Rhupus综合征患者的病例资料进行分析。结果:本例患者为中年女性,以RA为首发表现,8年后出现SLE特征性表现。就诊时关节症状较严重,出现多关节变形。本例患者肾脏损害重,糖皮质激素联合甲氨喋呤治疗有效。结论:Rhupus综合征在临床上罕见,加强特异性抗体检查,可减少误诊漏诊,早期正确诊断,积极治疗,对于改善患者预后具有重要意义。     

The Cost-Effectiveness of Biologics for the Treatment of Rheumatoid Arthritis: A Systematic Review

Background and Objectives

Economic evaluations provide information to aid the optimal utilization of limited healthcare resources. Costs of biologics for Rheumatoid arthritis (RA) are remarkably high, which makes these agents an important target for economic evaluations. This systematic review aims to identify existing studies examining the cost-effectiveness of biologics for RA, assess their quality and report their results systematically.

Methods

A literature search covering Medline, Scopus, Cochrane library, ACP Journal club and Web of Science was performed in March 2013. The cost-utility analyses (CUAs) of one or more available biological drugs for the treatment of RA in adults were included. Two independent investigators systematically collected information and assessed the quality of the studies. To enable the comparison of the results, all costs were converted to 2013 euro.

Results

Of the 4890 references found in the literature search, 41 CUAs were included in the current systematic review. While considering only direct costs, the incremental cost-effectiveness ratio (ICER) of the tumor necrosis factor inhibitors (TNFi) ranged from 39,000 to 1 273,000 €/quality adjusted life year (QALY) gained in comparison to conventional disease-modifying antirheumatic drugs (cDMARDs) in cDMARD naïve patients. Among patients with an insufficient response to cDMARDs, biologics were associated with ICERs ranging from 12,000 to 708,000 €/QALY. Rituximab was found to be the most cost-effective alternative compared to other biologics among the patients with an insufficient response to TNFi.

Conclusions

When 35,000 €/QALY is considered as a threshold for the ICER, TNFis do not seem to be cost-effective among cDMARD naïve patients and patients with an insufficient response to cDMARDs. With thresholds of 50,000 to 100,000 €/QALY biologics might be cost-effective among patients with an inadequate response to cDMARDs. Standardization of multiattribute utility instruments and a validated standard conversion method for missing utility measures would enable better comparison between CUAs.     

Classifying Integrated Signature Molecules in Macrophages of Rheumatoid Arthritis,Osteoarthritis, and Periodontal Disease: An Omics-Based Study

Rheumatoid arthritis (RA), osteoarthritis (OA), and periodontal disease (PD) are chronic inflammatory diseases that are globally prevalent, and pose a public health concern. The search for a potential mechanism linking PD to RA and OA continues, as it could play a significant role in disease prevention and treatment. Recent studies have linked RA, OA, and PD to Porphyromonas gingivalis (PG), a periodontal bacterium, through a similar dysregulation in an inflammatory mechanism. This study aimed to identify potential gene signatures that could assist in early diagnosis as well as gain insight into the molecular mechanisms of these diseases. The expression data sets with the series IDs {"type":"entrez-geo","attrs":{"text":"GSE97779","term_id":"97779"}}GSE97779, {"type":"entrez-geo","attrs":{"text":"GSE123492","term_id":"123492"}}GSE123492, and {"type":"entrez-geo","attrs":{"text":"GSE24897","term_id":"24897"}}GSE24897 for macrophages of RA, OA synovium, and PG stimulated macrophages (PG-SM), respectively, were retrieved and screened for differentially expressed genes (DEGs). The 72 common DEGs among RA, OA, and PG-SM were further subjected to gene–gene correlation analysis. A GeneMANIA interaction network of the 47 highly correlated DEGs comprises 53 nodes and 271 edges. Network centrality analysis identified 15 hub genes, 6 of which are DEGs (API5, ATE1, CCNG1, EHD1, RIN2, and STK39). Additionally, two significantly up-regulated non-hub genes (IER3 and RGS16) showed interactions with hub genes. Functional enrichment analysis of the genes showed that “apoptotic regulation” and “inflammasomes” were among the major pathways. These eight genes can serve as important signatures/targets, and provide new insights into the molecular mechanism of PG-induced RA, OA, and PD.     

Comparison of the Belgian Rheumatoid Arthritis Disability Assessment and Health Assessment Questionnaires as Tools to Predict the Need for Support Measures in Patients with Rheumatoid Arthritis

Objective

Scores on the Health Assessment Questionnaire (HAQ) predict the need for support measures in patients with rheumatoid arthritis (RA). In this study we compare the performance of the HAQ in this context with that of the more disease-specific Belgian Rheumatoid Arthritis Disability Assessment (BRADA) questionnaire.

Methods

In this multicenter observational study, patients with RA and disease duration of at least one year who consulted their rheumatologist for a routine follow-up visit filled out the HAQ, and BRADA questionnaires. The performance of HAQ and BRADA to predict the need for support measures available to patients with RA was evaluated using Receiver Operator Characteristic (ROC) curves, with the expert opinion of the rheumatologist as a reference.

Results

The study analyzed data of 301 patients with RA (70.8% females) with mean age 59.8±12.8, disease duration 11.4±9.3 years, and DAS28 values of 2.84±1.18. HAQ scores averaged 0.97±0.73 and BRADA scores were 3.92±3.49 over the last week and 3.89±3.50 over the last 3 months. The area under the ROC curves for the BRADA scores for the support measures investigated ranged from 0.702 to 0.862 and did not differ significantly from those of the HAQ (range 0.725–0.860).

Conclusion

The disease-specific BRADA questionnaire is equivalent to the HAQ in predicting the need for support measures in patients with stable RA.     

Identification of Autoantibodies against Transthyretin for the Screening and Diagnosis of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic and inflammatory rheumatic disease that leads to inflammation of the joints and surrounding tissues. Identification of novel protein(s) associated with severity of RA is a prerequisite for better understanding of pathogenesis of this disease that may also have potential to serve as novel biomarkers in the diagnosis of RA. Present study was undertaken to compare the amount of autoantigens and autoantibodies in the plasma of RA patients in comparison to healthy controls. Plasma samples were collected from the patients suffering from RA, Osteoarthritis (OA), Systemic lupus erythematosus (SLE) and healthy volunteers. The screening of plasma proteins were carried out using 2-dimensional gel electrophoresis followed by identification of differentially expressed protein by MALDI-TOF MS/MS. Among several differentially expressed proteins, transthyretin (TTR) has been identified as one of the protein that showed significantly up regulated expression in the plasma of RA patients. The results were further validated by Western blot analysis and ELISA. In comparison to OA synovium, an exclusive significantly high expression of TTR in RA has been validated through IHC, Western blotting and IEM studies. Most importantly, the increase in expression of TTR with the progression of severity of RA condition has been observed. The autoantibodies against TTR present in the RA plasma were identified using immunoprecipitation-Western methods. The significant production of autoantibodies was validated by ELISA and Western blot analysis using recombinant pure protein of TTR. Hence, these novel observations on increase in TTR expression with the increase in severity of RA conditions and significant production of autoantibodies against TTR clearly suggest that a systematic studies on the role TTR in the pathogenesis of RA is immediately required and TTR may be used as a serum diagnostic marker together with other biochemical parameters and clinical symptoms for RA screening and diagnosis.     

Rheumatoid Arthritis and the Risk of Bipolar Disorder: A Nationwide Population-Based Study

Background

Studies have suggested that chronic inflammation plays an essential role in the pathophysiology of both rheumatoid arthritis (RA) and bipolar disorder. The most common clinical features associated with RA are anxiety and depression. The risk of bipolar disorder among patients with RA has not been characterized adequately.

Objective

To determine the association between RA and the subsequent development of bipolar disorder and examine the risk factors for bipolar disorder among patients with RA.

Methods

We identified patients who were diagnosed with RA in the Taiwan National Health Insurance Research Database. A comparison cohort was created by matching patients without RA with those with RA according to age, sex, and comorbidities. The occurrence of bipolar disorder was evaluated in both cohorts.

Results

The RA cohort consisted of 2,570 patients, and the comparison cohort consisted of 2,570 matched control patients without RA. The incidence of bipolar disorder (incidence rate ratio  = 2.13, 95% confidence interval [CI]  = 1.12–4.24, P =  .013) was higher among patients with RA than among control patients. Multivariate, matched regression models revealed that asthma (hazard ratio [HR]  = 2.76, 95% CI 1.27–5.96, P =  .010), liver cirrhosis (HR  = 3.81, 95% CI  = 1.04–14.02, P =  .044), and alcohol use disorders (HR  = 5.29, 95% CI  = 1.71–16.37, P =  .004) were independent risk factors for the development of bipolar disorder among patients with RA.

Conclusion

RA might increase the incidence of bipolar disorder development. Based on our data, we suggest that, following RA diagnosis, greater attention be focused on women with asthma, liver cirrhosis, and alcohol use disorder. Prospective clinical studies of the relationship between RA and bipolar disorder are warranted.     

类风湿性关节炎患者心血管并发症与脂蛋白a的相关性研究进展

类风湿性关节炎(RA)是成人常见的系统性炎症反应性疾病,其常见致命并发症为心血管病变,与脂代谢异常有关,其中脂蛋白a(Lp-a)近来发现是一种独立的心血管疾病危险因素,也有大量实验证实Lp-a水平在RA患者中异常升高。Lp-a不仅与心血管病变具有直接关系,也与RA患者的全身性炎症反应进程息息相关。Lp-a的基因编码具有丰富的多态性,影响着Lp-a的不同亚型的产生与表达,并进一步影响了Lp-a的生理功能。另一方面,尽管Lp-a的基因型特征与表现型特征差异明显,但其水平一般具有稳定性,不易受饮食、药物或代谢水平影响。但近几年发现,在系统性炎症疾病如RA发生时,Lp-a水平会异常增高,从而影响RA患者的炎症反应进程与心血管并发症的发生,对RA患者来说,Lp-a是一项值得长期关注的CVD并发症评估因素。     

The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab,Abatacept and Tociliziumab

Objectives

To assess whether treatment with one of three novel biological DMARDs; rituximab, abatacept or tocilizumab reduce cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA).

Methods

This is an open, observational and prospective study with visits at baseline, 3, 6, and 12 months. Patients were assigned to receive rituximab, abatacept or tocilizumab according to clinical indications assessed by an independent rheumatologist. Disease activity was quantified by the disease activity score (DAS28) and extensive ultrasonography. CVD risk was assessed by total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), blood pressure and arterial stiffness measurements [pulse wave velocity (PWV) and augmentation index (AIx)]. Within group change in disease activity and CVD risk over 3 months was explored using paired samples bivariate tests. Predictors of change in CVD risk at 3 months were identified in linear regression models. Changes in CVD risk markers over the 12- month follow-up in patients receiving rituximab were assessed by mixed models repeated analyses.

Results

24 patients on rituximab, 5 on abatacept and 7 on tocilizumab were included. At 3 months PWV was significantly reduced in the tocilizumab group only, but at 12 months rituximab patients showed a significant reduction in PWV. Reduced inflammation at 3 months was associated with increased TC and HDL-c in the entire cohort.

Conclusion

Treatment with tocilizumab and rituximab reduces PWV, a marker of CVD risk, in patients with RA.     

Orudis in Management of Rheumatoid Arthritis and Osteoarthrosis of the Hip: Comparison with Indomethacin

In double-blind cross-over studies in 46 patients with rheumatoid arthritis and in 42 patients with osteoarthrosis of the hip, Orudis—a new non-steroidal anti-inflammatory agent—has been shown to be well tolerated and to have comparable therapeutic efficacy with indomethacin when given in equal dosage. Side effects were less severe with Orudis. The results suggest that Orudis will prove valuable in the clinical management of rheumatic diseases.