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ID PMID Title PublicationDate abstract
24443001 An extra dose of rituximab improves clinical response in rheumatoid arthritis patients wit 2015 Jun OBJECTIVES: Since clinical non-response to 2×1000 mg rituximab has previously been found to be associated with incomplete B cell depletion, we determined, in a randomised controlled proof of concept study, whether patients with initial incomplete B cell depletion would benefit from an additional infusion of rituximab at week 4. METHODS: Patients with active rheumatoid arthritis despite methotrexate received a first infusion of rituximab 1000 mg and were tested for persistent B cells using highly sensitive flow cytometry on day 15. All received a second infusion of 1 g (according to license), but patients with persistent B cells were subsequently randomised double-blind to receive, 2 weeks later, either a third infusion of 1000 mg rituximab or placebo. Clinical response was determined by European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) criteria. RESULTS: Baseline characteristics were balanced between groups. Treatment with 3×1000 mg rituximab resulted in significantly greater depletion (lower B cell and plasmablast numbers between 8 and 28 weeks) paralleled by significantly better EULAR and ACR20 response rates at 40 weeks (p=0.035 and p=0.027, respectively) and 52 weeks (p=0.021 and p=0.043, respectively) compared with 2×1000 mg. Immunoglobulin titres remained stable in both arms, and adverse event rates were balanced. CONCLUSIONS: In rituximab-treated patients with incomplete B cell depletion (predictive of poor response), an extra 1000 mg infusion of rituximab at 4 weeks produced both better depletion and clinical responses than placebo with no worsening of safety. Degree of depletion is an important, but modifiable, determinant of response.
26197156 Total Wrist Fusion Using an Intramedullary Rod Technique With Proximal Row Carpectomy. 2015 Sep Intramedullary pin fixation is a common total wrist fusion technique, particularly for patients with rheumatoid arthritis. However, appropriate alignment of the proximal carpal row on the carpus can be challenging. Inflammatory arthropathy may also degrade the proximal carpal bones to chondral shells, retention of which may promote failure of fusion. We describe an intramedullary rod technique for total wrist fusion that incorporates a proximal row carpectomy.
27911916 Incidence of Deep Vein Thrombosis and Venous Thromboembolism following TKA in Rheumatoid A 2016 This meta-analysis was designed to compare the incidence of deep vein thrombosis (DVT) and venous thromboembolism (VTE) following total knee arthroplasty (TKA) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). All studies directly comparing the post-TKA incidence of DVT and/or VTE in patients with RA and OA were included. For all comparisons, odds ratios and 95% confidence intervals (CI) were calculated for binary outcomes. Six studies were included in the meta-analysis. The pooled data showed that the combined rates of asymptomatic and symptomatic DVT did not differ significantly in the RA and OA groups (1065/222,714 [0.5%] vs. 35,983/6,959,157 [0.5%]; OR 0.77, 95% CI: 0.57 to 1.02; P = 0.07). The combined rates of asymptomatic and symptomatic DVT and pulmonary embolism (PE) after TKA were significantly lower in the RA than in the OA group (1831/225,406 [0.8%] vs. 63,953/7,018,721 [0.9%]; OR 0.76, 95% CI: 0.62 to 0.93; P = 0.008). Conclusiviely, the DVT rates after primary TKA were similar in RA and OA patients. In contrast, the incidence of VTE (DVT plus PE) after primary TKA was lower in RA than in OA patients, despite patients with RA being at theoretically higher risk of thrombi due to chronic inflammation.
27830964 Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab 2017 Sep OBJECTIVES: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis. METHODS: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients' charts. RESULTS: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p = 0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p = 0.01). CONCLUSIONS: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.
27823968 Therapeutic effect of erythroid differentiation regulator 1 (Erdr1) on collagen-induced ar 2016 Nov 22 Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and multiple inflammatory cytokines are involved in RA pathogenesis. Interleukin (IL)-18, in particular, has a significant positive correlation with RA. In this study, we investigated the effect of erythroid differentiation regulator 1 (Erdr1), which is negatively regulated by IL-18, in an animal model of inflammatory arthritis, collagen-induced arthritis (CIA) in DBA/1J mice. Treatment of mice with recombinant (r)Erdr1 significantly suppressed the severity of arthritis, histologic features of arthritic tissue, and serum levels of anti-collagen autoantibodies (IgG, IgG1, IgG2a and IgM) in CIA. In addition, IL-18 expression was reduced in the affected synovium of rErdr1-treated mice. Interestingly, Erdr1 treatment suppressed migration in contrast to the pro-migratory effect of IL-18, indicating the therapeutic effects of Erdr1 on CIA through inhibiting synovial fibroblast migration. In addition, Erdr1 inhibited activation of ERK1/2, a key signaling pathway in migration of various cell types. Taken together, these data show that rErdr1 exerts therapeutic effects on RA by inhibiting synovial fibroblast migration, suggesting that rErdr1 treatment might be an effective therapeutic approach for RA.
26818974 Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexat 2016 Jan 28 BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented. METHODS: Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate. Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID. Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted. Primary endpoints were adverse events, laboratory parameters and vital signs. Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Safety and efficacy data were assessed throughout the study. RESULTS: A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study. Median (range) duration of treatment in this extension study was 1185 (5-2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity. The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %). For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer). Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib. ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion. CONCLUSIONS: Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis. The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population. TRIAL REGISTRATION: Clinicaltrials.gov NCT00661661 . Registered 7 February 2008.
25298260 Posturography in patients with rheumatoid arthritis and osteoarthritis. 2015 The purpose of the paper was to investigate the usefulness of posturographic analysis in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). RA is a chronic inflammatory disorder responsible for destruction of active and passive components of joints. It is the most common autoimmune disease, and the second most common form of arthritis after OA. OA is a chronic disorder characterized by irreversible changes in the joint structure developing with advancing age. Both diseases lead to the destruction of many parts of the motor system, cause pain, weakness, and damage of ligaments, muscles, bones, and articular cartilage. The etiology of the diseases remains unknown. In the present study, evaluation of body balance in the standing position was performed by means of Pro-Med force plate system. Three posturographic tests were applied: with eyes open, closed, and with the biofeedback--under conscious visual control of body movements. The following posturographic parameters were measured: the radius of sways, the developed area, and the total length of posturograms, and also two directional components of sways: the length of left-right (in frontal plane) and forward-backward (in sagittal plane) motions. The results demonstrate that the biofeedback test is most useful in the evaluation of instability in rheumatic patients; it is more powerful than the other posturographic tests evaluated.
26698929 Discontinuation of etanercept after achievement of sustained remission in patients with rh 2016 Sep OBJECTIVES: To investigate the efficacy and safety of etanercept (ETN) in patients with rheumatoid arthritis (RA) with moderate disease activity and the possibility to discontinue ETN after achieving remission. METHODS: Multicenter, randomized, and open-label study was conducted in Japan and Korea. RA patients (disease duration <5 years) with moderate disease activity despite methotrexate (MTX) treatment were allocated to either MTX or ETN + MTX (Period 1) for 12 months. Patients who achieved sustained remission defined as DAS28 < 2.6 at both 6 and 12 months in the ETN + MTX group, were randomized to either continue or discontinue ETN for 12 months (Period 2). RESULTS: A total of 222 patients were enrolled in Period 1 and clinical remission was achieved in 106/157 (67.5%) and 5/28 (17.9%) patients in the ETN + MTX and MTX groups, respectively. In Period 2, sixty-seven patients were randomized and finally 28/32 (87.5%) and 15/28 (53.6%) patients who continued or discontinued ETN maintained clinical remission. Baseline disease activity and the presence of comorbid diseases influenced the maintenance of remission after ETN discontinuation. CONCLUSIONS: ETN + MTX was efficient for RA patients with moderate disease activity into remission. After achieving sustained remission, a half of the patients who discontinued ETN could maintain remission for 1 year.
25304308 Combined effect of individual and neighbourhood socioeconomic status on mortality of rheum 2015 Feb BACKGROUND: The National Health Insurance program in Taiwan is a public insurance system for the entire population of Taiwan initiated since March 1995. However, the association of socioeconomic status (SES) and prognosis of rheumatoid arthritis (RA) patients under this program has not been identified. OBJECTIVES: Using the National Health Insurance Research Database in Taiwan, we aimed to examine the combined effect of individual and neighbourhood SES on the mortality rates of RA patients under a universal health care coverage system. MEASURES: A study population included patients with RA from 2004 to 2008. The primary end point was the 5-year overall mortality rate. Individual SES was categorized into low, moderate and high levels based on the income-related insurance payment amount. Neighbourhood SES was defined by household income and neighbourhoods were grouped as an 'advantaged' area or a 'disadvantaged' area. The Cox proportional hazards regression model was used to compare outcomes between different SES categories. A two-sided P value < 0.05 was considered statistically significant. RESULTS: Medical data of 23900 RA patients from 2004 to 2008 were reviewed. Analysis of the combined effect of individual SES and neighbourhood SES revealed that 5-year mortality rates were worse among RA patients with a low individual SES compared to those with a high SES (P < 0.001). In the Cox proportional hazards regression model, RA patients with low individual SES in disadvantaged neighbourhoods incurred the highest risk of mortality (Hazard ratio = 1.64; 95% confidence interval, 1.26-2.13, P < 0.001). CONCLUSIONS: RA patients with a low SES have a higher overall mortality rate than those with a higher SES, even with a universal health care system. It is crucial that more public policy and health care efforts be put into alleviating the health disadvantages, besides providing treatment payment coverage.
24872377 Impact of a nurse-led programme on comorbidity management and impact of a patient self-ass 2015 Sep OBJECTIVES: Rheumatoid arthritis (RA) patients are at an increased risk of developing comorbid conditions. A close monitoring of the disease targeting a status of low disease activity is associated with a better outcome. The aim of this trial was to evaluate the impact of a nurse-led programme on comorbidities and the impact of patient self-assessment of disease activity on the management of RA. METHODS: We enrolled 970 patients (mean age 58 years, 79% women) in a prospective, randomised, controlled, open-label, 6-month trial. In the comorbidity group (n=482), the nurse checked comorbidities and sent the programme results to the attending physicians. In the self-assessment group (n=488), the nurse taught the patient how to calculate his/her Disease Activity Score which had to be reported on a booklet to be shared with the treating rheumatologist. The number of measures taken for comorbidities and the percentage of patients recording a change (initiation, switch or increased dose) in disease-modifying antirheumatic drugs (DMARDs) in the 6 months follow-up period of the study defined the outcomes of the trial. RESULTS: The number of measures taken per patient was statistically higher in the comorbidity group: 4.54±2.08 versus 2.65±1.57 (p<0.001); incidence rate ratio: 1.78 (1.61-1.96) and DMARD therapy was changed more frequently in the self-assessment group: 17.2% versus 10.9% (OR=1.70 (1.17; 2.49), p=0.006). CONCLUSIONS: This study demonstrates the short-term benefit of a nurse-led programme on RA comorbidity management and the impact of patient self-assessment of disease activity on RA treatment intensification. TRIAL REGISTRATION NUMBER: NCT #01315652.
26064888 Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells E 2015 Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-κB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-κB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells.
27414792 [Detecting shared pathways linked to rheumatoid arthritis with other autoimmune diseases i 2016 May Pathway-based analysis approach has exploded in use during the last several years. It is successful in recognizing additional biological insight of disease and finding groupings of risk genes that represent disease developing processes. Therefore, shared pathways, with pleiotropic effects, are important for understanding similar pathogenesis and indicating the common genetic origin of certain diseases. Here, we present a pathway analysis to reveal the potential disease associations between RA and three potential RA-related autoimmune diseases: psoriasis, diabetes mellitus, type 1 (T1D) and systemic lupus erythematosus (SLE). First, a comprehensive knowledge mining of public databases is performed to discover risk genes associated with RA, T1D, SLE and psoriasis; then by enrichment test of these genes, disease-related risk pathways are detected to recognize the pathways common for RA and three other diseases. Finally, the underlying disease associations are evaluated with the association rules mining method. In total, we identify multiple RA risk pathways with significant pleiotropic effects, the most unsurprising of which are the immunology related pathways. Meanwhile for the first time we highlight the involvement of the viral myocarditis pathway related to cardiovascular disease (CVD) in autoimmune diseases such as RA, psoriasis, T1D and SLE. Further Association rule mining results validate the strong association between RA and T1D and RA and SLE. It is clear that pleiotropy is a common property of pathways associated with disease traits. We provide novel pathway associations among RA and three autoimmune diseases. These results ascertain that there are shared genetic risk profiles that predispose individuals to autoimmune diseases.
27402873 Validation of disease activity indices using the 28 joint counts in systemic sclerosis. 2016 Oct OBJECTIVES: To validate the Disease Activity Score 28 using ESR (DAS28-ESR) and CRP (DAS28-CRP), the Simplified Disease Activity Index and the Clinical Disease Activity Index used in RA for SSc patients. METHODS: Seventy-seven SSc patients, 40 RA patients, 20 patients with primary RP (PRP) and 28 healthy volunteers were assessed. Besides the disease activity composite indices, the European Scleroderma Study Group Activity Index (EScSG-AI), the HAQ-DI, the Cochin Hand Function Scale and the Short Form Health Survey (SF36) were evaluated. The validation procedure included the assessment for truth, discrimination and feasibility. RESULTS: DAS28-ESR, DAS28-CRP, Simplified Disease Activity Index and Clinical Disease Activity Index showed significant correlation with EScSG-AI, HAQ-DI, Cochin Hand Function Scale and the physical component of SF36 (P < 0.001). All four indices discriminated patients with SSc from RA, PRS and healthy controls, respectively (P < 0.01). With the exception of DAS28-CRP, the other three indices also discriminated between subgroups of SSc based on value of EScSG-AI (⩽3 and >3) (P < 0.05). All four disease activity composite indices showed a good inter- and intraobserver reliability based on repeated measures of two independent investigators (P < 0.001). CONCLUSION: All four disease activity composite indices were found to be valid measures for assessing arthritis in SSc. DAS28-ESR showed the best performance regarding reliability and construct validity.
27539651 Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis. 2017 May OBJECTIVES: To clarify the use of musculoskeletal ultrasonography (US) of ankle joints in rheumatoid arthritis (RA). METHODS: Consecutive RA patients with or without ankle symptoms participated in the study. The US, clinical examination (CE), and patients' visual analog scale for pain (pVAS) for ankles were assessed. Prevalence of tibiotalar joint synovitis and tenosynovitis were assessed by grayscale (GS) and power Doppler (PD) US using a semi-quantitative grading (0-3). The positive US and CE findings were defined as GS score ≥2 and/or PD score ≥1, and joint swelling and/or tenderness, respectively. Multivariate analysis with the generalized linear mixed model was performed by assigning ankle pVAS as a dependent variable. RESULTS: Among a total of 120 ankles from 60 RA patients, positive ankle US findings were found in 21 (35.0%) patients. The concordance rate of CE and US was moderate (kappa 0.57). Of the 88 CE negative ankles, US detected positive findings in 9 (10.2%) joints. Multivariate analysis revealed that ankle US, clinical disease activity index, and foot Health Assessment Questionnaire, but not CE, was independently associated with ankle pVAS. CONCLUSION: US examination is useful to illustrate RA ankle involvement, especially for patients who complain ankle pain but lack CE findings.
27522715 [The Analysis of Efficacy of The Application of Interleukin-1 Inhibitor in the Complex The 2016 BACKGRAUND: Secondary osteoarthritis (OA) adversely affects the underlying disease and can enhance clinical manifestations of articular syndrome. Early detection of comorbid pathology and early treatment with the therapy of underlying condition is of primary importance to preserve adequate functional activity in patients. The Aim is to analyze the efficacy of the application of interleukin-1 inhibitor in the complex treatment of secondary OA in addition to rheumatoid arthritis (RA). MATERIALS AND METHODS: 248 patients with secondary OA and RA were divided in 4 groups: patients of group I (n = 62) took interleukin-1 inhibitor (50 mg x 2 times per day) in combination with laser therapy on the basis of methotrexate (10-20 mg per week), group II (n = 60) received interleukin-1 inhibitor in complex with methotrexate, in group III (n = 62)--laser therapy with methotrexate and in group 4--methotrexate. We estimated the treatment efficacy in 3 and 6 months according to the dynamics of pain on VAS, indexes HAQ and KOOS. RESULTS: according to VAS group 1 showed statistical significant reduction in pain on movement in 3 and 6 months of 28.53 mm (43.6%) and 31.3 mm (48%) respectively, to values of 36.87 ± 1.56* and 33.11 ± 1.11* (p < 0.05). The results showed the statistically significant advantage of HAQ dynamics in groups I and II in comparison with groups III, IV (p = 0.03). The most prominent statistically significant (p = 0.02) results according to the dynamics of index KOOS were noted in groups of patients who took diacerein (I and II) 6 months after the complex treatment. CONCLUSIONS: the inclusion of interleukin-1 inhibitor in the complex treatment of secondary OA in patients with RA contributes to clinical improvement according to VAS (p = 0.03), index KOOS that reflects functional condition of the knee and increases the quality of life by index HAQ (p = 0.03) after 6 months therapy.
26160473 Suppressed diversity of survivin splicing in active rheumatoid arthritis. 2015 Jul 10 INTRODUCTION: Alternative splicing distinguishes normal and pathologic cells. High levels of oncoprotein survivin recognise patients with severe rheumatoid arthritis (RA). Here, we assess clinical relevance of alternative splicing of survivin in leukocytes of peripheral blood (PBMC) and bone marrow (BM) in RA patients. METHOD: Transcription of survivin wild-type (survivin-WT), survivin-2B and survivin-ΔEx3 was measured in 67 randomly selected RA patients and in 23 patients before and after B cell depletion with rituximab. Analysis was done in relation to disease activity, anti-rheumatic treatment and serum levels of rheumatoid factor (RF) and survivin. RESULTS: Survivin-WT was the dominant splice variant equally expressed in T and B cells, while survivin-2B and survivin-ΔEx3 were higher in B cells. High disease activity (DAS28>5.1) was associated with an excess of survivin-WT and low ratios between survivin-2B/WT (p=0.035) and survivin-ΔEx3/WT in PBMC. Depletion of B cells by rituximab caused a decrease in survivin-WT (p=0.005) in PBMC, increasing the ratio between survivin-2B/WT (p=0.009) and survivin-ΔEx3/WT (p=0.001) in BM. This increase in survivin-2B/WT was associated with reduction in CD19+ BM cells (r=0.929, p=0.007), RF (IgM, r=0.857, p=0.024; IgA, r=0.739, p=0.021), and DAS28 (0.636, p=0.054). The increase in survivin-ΔEx3 in BM was associated with a reduction of CD19+ BM cells (r=0.714, p=0.058) and DAS28 (r=0.648, p=0.049), while survivin-ΔEx3/WT was associated with RF (IgG, r=0.882, p=0.016). CONCLUSION: This study demonstrates that the suppressed diversity of survivin splicing in leukocytes may attribute to adverse self-recognition in RA. Depletion of autoantibody producing B cells improves the balance of survivin splicing.
26031285 [Switching within the active ingredient group or changing the mechanism of action. Data si 2015 Jun Despite the use of biologics many patients do not achieve remission or reduced disease activity, which raises the question of the optimal therapy when these therapy targets are not achieved. Most data from clinical studies and registry data refer to the approach following the unsuccessful use of one or more tumor necrosis factor (TNF) inhibitors. Randomized controlled studies investigating the effectiveness of a further biologic or TNF inhibitor in patients who received abatacept, tocilizumab or rituximab in the first line therapy are currently lacking, with the exception of the German MIRAI study. The majority of registry data and observational studies suggest that when the use of a TNF inhibitor is unsuccessful it is advantageous to change to a non-TNF biologic. This does not exclude that a change within the group of TNF inhibitors can represent an appropriate option, e.g. by injection or infusion reactions or secondary therapy failure. Whether determination of serum levels and neutralizing antibodies aids decision-making for individual patients, must currently remain open. The option to change within an active ingredient group of biologics only currently applies to the group of TNF inhibitors; however, with the development of further antibodies inhibiting interleukin 6, this question will also apply to this group of substances. The question of the optimal strategy after failure of the first and second line biologics will be asked more frequently when the therapy targets of remission and low disease activity are more stringently strived for. Predictive markers for an optimal approach to the sequential administration of biologics are lacking. In order to answer this question clinical studies which investigate the therapeutic approach in a randomized and controlled manner will be necessary in the future.
25777156 Brief Report: Main Contribution of DRB1*04:05 Among the Shared Epitope Alleles and Involve 2015 Jul OBJECTIVE: The shared epitope is associated with increased joint destruction in rheumatoid arthritis (RA) as well as susceptibility to RA and the production of anti-citrullinated protein antibody (ACPA). However, previous studies addressing whether the association of the shared epitope with joint destruction is independent of ACPA have shown different results in different populations. Different allele distributions in the shared epitope may explain this ethnic heterogeneity. This study was undertaken to assess the associations of the shared epitope and HLA-DRB1*04:05, the most common shared epitope allele in the Japanese population, with joint destruction in patients with ACPA-positive RA. METHODS: A total of 861 patients with ACPA-positive RA who had not received any biologic agents were recruited from the institute of Rheumatology, Rheumatoid Arthritis cohort (sets 1 and 2) and the Kyoto University Rheumatoid Arthritis Management Alliance cohort (set 3). Joint destruction was assessed using the modified Sharp/van der Heijde score (SHS). The associations of the shared epitope alleles, HLA-DRB1*04:05, and other shared epitope allele groups with the SHS were analyzed in a linear regression analysis. Amino acid variations associated with the SHS were also analyzed. RESULTS: The shared epitope was significantly associated with an increased SHS (P = 0.0017). Although HLA-DRB1*04:05 was significantly associated with an increased SHS (P = 2.7 × 10(-5)), the group of other shared epitope alleles, including HLA-DRB1*01:01, did not show an association with the SHS in spite of sufficient power (P = 0.67). HLA-DRB1*04:05 was associated with joint destruction in a dose-dependent manner. Analyses of amino acid associations of HLA-DRB1 revealed that serine at position 57, recently shown to have a susceptibility effect for ACPA-positive RA in Asian populations, showed a significant association (P = 5.0 × 10(-6)). CONCLUSION: HLA-DRB1*04:05, characterized by serine at position 57, accounts for the detrimental association between the shared epitope and SHS in Japanese patients with ACPA-positive RA.
25420554 Combination therapy for early rheumatoid arthritis: a treatment holiday perspective. 2015 Jan To date, the significance of early intervention with methotrexate and biological disease-modifying anti-rheumatic drugs for rheumatoid arthritis (RA) has not been realized. Longitudinal safety and cost have arisen as new concerns. The concept of a treatment holiday, drug discontinuation after achieving remission, may solve these problems. The authors performed a systematic literature review and identified 13 reports from 10 studies (TNF20, BeSt, OPITMA, HIT-HARD, IMPROVED, PRIZE, IDEA, EMPIRE, tREACH and AVERT) for early RA (≤2 years). Eight out of 13 reports (61.5%) were published in 2013 or 2014, indicating emerging interest in recent years. Also, the authors performed a sub-analysis of the HONOR study (n = 51) to compare early (≤2 years) and established RA. The proportions of remission (REM) and low disease activity were higher in early RA (REM: 63.0 vs 33.3%, p = 0.0346; low disease activity: 77.8 vs 45.8%, p = 0.0185). In conclusion, early intervention is beneficial for successful treatment holiday, which may lead to risk and cost reduction. However, further investigation is required.
27586634 Lymphatic imaging to assess rheumatoid flare: mechanistic insights and biomarker potential 2016 Sep 1 Proliferation of draining lymphatic vessels coupled with dynamic changes in lymph node volume and flow are characteristic features in rheumatoid arthritis (RA). Furthermore, impaired lymph egress from inflamed synovium is associated with joint flare in murine models of inflammatory-erosive arthritis. Unfortunately, advances towards a greater understanding of lymphatic changes in RA pathogenesis have been slow due to the absence of outcome measures to quantify lymphatic function in vivo. While lymphoscintigraphy is the current standard to assess lymphedema and sentinel lymph nodes in cancer patients, its sensitivity and specificity are inadequate to study lymphatics in RA. The emergence of high-resolution MRI, power Doppler ultrasound, and near-infrared imaging that permits real-time quantification of lymphatic function in animal models has been a major advance, and these techniques have produced a new paradigm of altered lymphatic function that underlies both acute arthritic flare and chronic inflammation. In acute flare, lymphatic drainage increases several fold, whereas no lymphatic contractions are detected in lymph vessels draining chronic arthritic joints. Moreover, these outcomes are now being adapted to study lymphatics in RA towards the development of novel biomarkers of arthritic flare and the discovery of new therapeutic targets. In particular, interventions that directly increase lymphatic egress from diseased joints by opening collateral lymphatic vessels, and that restore lymphatic vessel contractions, provide novel therapeutic approaches with potential for minimal toxicity and immunosuppression. To summarize the origins of this field, recent advances, and future directions, we herein review: current knowledge of lymphatics in RA based on classic literature; new in-vivo imaging modalities that have elucidated how lymphatics modulate acute versus chronic joint inflammation in murine models; and how these preclinical outcome measures are being translated to study lymphatic function in RA inflammation and how effective RA therapies alter lymphatic flow and lymph nodes draining flaring joints. TRIAL REGISTRATION: ClinicalTrials.gov NCT02680067 . Registered 7 December 2015; ClinicalTrials.gov NCT01098201 . Registered 30 March 2010; and ClinicalTrials.gov NCT01083563 . Registered 8 March 2010.