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ID PMID Title PublicationDate abstract
26614458 Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synovi 2015 Nov Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 μmol·L(-1)) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF-κB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Rac1, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK.
27045991 Economic Burden and Treatment Patterns of Cycling between Conventional Synthetic Disease-m 2016 May PURPOSE: To assess the economic outcomes and treatment patterns among patients with rheumatoid arthritis (RA) who used 1, 2, or 3 or more conventional synthetic disease-modifying antirheumatic drugs (DMARDs) before receiving a biologic therapy. METHODS: Adult patients with ≥2 RA diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 714.xx) on different dates, ≥1 claim for a conventional synthetic DMARD, and ≥1 claim for a biologic DMARD were identified from a large commercial claims database. The initiation date of the first biologic DMARD was defined as the index date. Based on the number of distinct conventional synthetic DMARDs initiated between the first RA diagnosis and the index date, patients were classified into 3 cohorts: those who used 1, 2, or 3 or more conventional synthetic DMARDs. Baseline characteristics were measured 6 months preindex date and compared between the 3 cohorts. All-cause health care costs (in 2014 US$) were compared during the follow-up period (12 months postbiologic initiation) using multivariable gamma models adjusting for baseline characteristics. Time to discontinuation of the index biologic DMARD and time to switching to a new DMARD were compared using multivariable Cox proportional hazards models. FINDINGS: The 1, 2, and 3 or more conventional synthetic DMARD cohorts included 6215; 3227; and 976 patients, respectively. At baseline, patients in the 3 or more conventional synthetic DMARD cohort had the least severe RA, as indicated by the lowest claims-based index for RA severity score (1 vs 2 vs 3 or more = 6.1 vs 5.9 vs 5.8). During the study period, there was a significant association between number of conventional synthetic DMARDs and higher all-cause total health care costs (adjusted mean difference, 1 vs 2: $772; P < 0.001; 2 vs 3 or more: $2390; P < 0.001). The all-cause medical and pharmacy costs were also significantly higher with the increasing number of conventional synthetic DMARDs. Patients who cycled more conventional synthetic DMARDs were also more likely to switch treatment after biologic initiation (1 vs 2: adjusted hazard ratio = 0.89; P = 0.005; 2 vs 3 or more: adjusted hazard ratio = 0.89; P = 0.087). There were no differences in index biologic discontinuation between the 3 cohorts. IMPLICATIONS: Patients with RA who cycled more conventional synthetic DMARDs had increased economic burden in the 12 months following biologic initiation and were more likely to switch therapy. These results highlight the importance of timely switching to biologic DMARDs for the treatment of RA.
26137857 Brief report: enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis 2015 Oct OBJECTIVE: Innate lymphoid cells (ILCs) are a recently discovered group of cells that are essential to epithelial homeostasis and are implicated in psoriasis pathogenesis, yet they have never been reported in psoriatic arthritis (PsA). METHODS: ILC classes and subsets were characterized in the peripheral blood (PB) of healthy controls, patients with psoriasis, and patients with PsA and in the synovial fluid (SF) of patients with PsA and patients with rheumatoid arthritis (RA). Cell surface marker expression and intracellular cytokine production following stimulation were analyzed using flow cytometry. RESULTS: ILCs were identified in the SF and were 4-fold more abundant in PsA SF than in PsA PB. Fewer CCR6+ ILCs were found in PsA PB than in healthy control PB, while PsA SF was enriched for CCR6+ ILCs compared to PsA PB and RA SF. Natural cytotoxicity receptor NKp44+ group 3 ILCs were rare in PB and RA SF, but abundant in PsA SF. Increased numbers of interleukin-17A (IL-17A)-producing ILCs were present in PsA SF compared to RA SF. CCR6, NKp44, and melanoma cell adhesion molecule (MCAM) were expressed on the cell surface of SF ILCs that produced IL-17A. The number of circulating NKp44+, CCR6+, and MCAM+ ILCs in blood was inversely correlated with PsA disease activity. CONCLUSION: Our findings indicate that PsA SF is enriched for group 3 ILCs that express CCR6 and NKp44, which distinguishes the synovial compartment from RA. The increased IL-17A production by SF ILCs indicates a novel role for ILCs in PsA.
27445561 Early Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Cha 2016 When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT) lymphoma. We describe a patient with a history of Sjögren's syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP). However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH) polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.
27339406 Potential biomarkers of haemophilic arthropathy: correlations with compatible additive mag 2016 Sep INTRODUCTION: Although biomarkers are useful diagnostic tools to assess joint damage in osteoarthritis and rheumatoid arthritis, few data exist for biomarkers of haemophilic arthropathy. AIM: To evaluate the association between biomarkers and compatible additive magnetic resonance imaging (MRI) scores in patients with severe haemophilia A. METHODS: Patients aged 12-35 years with no history of factor VIII (FVIII) inhibitors were enrolled in a controlled, cross-sectional, multinational investigation. Patients received primary or secondary prophylaxis or on-demand treatment with FVIII and underwent MRI on four joints (two ankles, two knees). Soluble biomarkers of cartilage and bone degradation, inflammation, and angiogenesis were assessed (serum levels of C-terminal telopeptides of type I collagen [CTX-I], cartilage oligomeric matrix protein [COMP], chondroitin-sulphate aggrecan turnover 846 epitope [CS846], tissue inhibitor of metalloproteinase 1 [TIMP-1]; plasma levels of vascular endothelial growth factor [VEGF], matrix metalloproteinases 3 and 9 [MMP3, MMP9]). Relationships between biomarkers and MRI scores were evaluated using Spearman rank correlation. RESULTS: Biomarkers were assessed in 117 of 118 per-protocol patients. Mean and median CTX-I, COMP, TIMP-1, MMP3, MMP9, and VEGF values were within normal ranges (reference range not available for CS846 in healthy volunteers). No correlations between biomarkers and MRI scores were found, with the exception of CS846, which showed significant correlation in a subgroup of 22 on-demand patients (r = 0.436; P = 0.04). CONCLUSIONS: Compatible additive MRI scores showed no clear correlations with any of the potential biomarkers for haemophilic arthropathy in the overall population. CS846 levels were significantly correlated with MRI scores in patients treated on demand.
26815287 Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A 2016 Jul OBJECTIVE: Anticytokine autoantibodies occur across a range of hematologic, pulmonary, and infectious diseases. However, systematic investigation of their presence and significance in autoimmune diseases is lacking. This study was undertaken to examine the distinct functions of anticytokine autoantibodies in patients with systemic lupus erythematosus (SLE) compared to patients with other rheumatic diseases and healthy controls. METHODS: Serum samples from patients with SLE (n = 199), patients with primary Sjögren's syndrome (SS) (n = 150), patients with rheumatoid arthritis (RA) (n = 149), and healthy controls (n = 200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate the biologic activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in a subset of healthy controls and patients with SLE. RESULTS: Patients with SLE and those with SS had a striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible protein 10 (IP-10). Only autoantibodies against type I interferon, interleukin-12 (IL-12), and IL-22 exhibited neutralizing activity. In SLE, the presence of anti-interferon-γ autoantibodies was correlated with more severe disease activity, higher levels of anti-double-stranded DNA antibodies, and elevated expression of interferon-α/β-inducible genes. Conversely, in SLE patients with blocking anti-interferon-α autoantibodies, the type I interferon gene expression signature was normalized. Anti-type III interferon autoantibodies (λ2, λ3) and anti-IP-10 autoantibodies were newly recognized in SLE patient serum, and autoantibodies against macrophage-colony stimulating factor, IL-4, IL-7, IL-17, and IL-22, none of which have been previously identified in rheumatic conditions, were discovered. CONCLUSION: Anticytokine autoantibodies are associated with distinct patterns of disease in SLE, SS, and RA. Anti-interferon autoantibodies are overrepresented in patients with SLE and those with SS, and fall into distinct functional classes, with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-γ autoantibodies are correlated with increased disease activity and interferon-related gene expression, suggesting that such autoantibodies may contribute to the pathogenesis of SLE.
27105431 The Clinical Significance of Interleukin-1 Receptor Antagonist +2018 Polymorphism in Rheum 2016 OBJECTIVE: Interleukin-1 receptor antagonist (IL-1Ra) acts as an inhibitor of IL-1; which is one of the culprit cytokines in rheumatoid arthritis (RA). Although +2018 polymorphism of IL-1Ra has been implicated in the pathogenesis of RA, its importance remains poorly understood. Hence, the purpose of this study was to determine the clinical significance of interleukin-1 receptor antagonist (IL-1Ra) +2018 polymorphism in RA. METHODS: Polymerase chain reaction (PCR) and sequencing were used to determine the genotypes of the IL-1Ra +2018 for 77 RA patients and 18 healthy controls. All RA patients were assessed for the disease activity score that includes 28 joints (DAS28) and radiographic disease damage based on Modified Sharp Score (MSS). RESULTS: The frequency of the T/T and C/T genotypes did not differ significantly (p = 0.893) between the RA patients and the controls. The C/T genotype had significantly higher mean disease activity (DAS 28) and disease damage (MSS) scores with p values of 0.017 and 0.004, respectively. Additionally, the ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), the number of swollen and tender joints were higher for the C/T individuals. On multivariate analysis the CRP, swollen joint count and MSS remained significant with the following p values i.e. 0.045, 0.046 and less than 0.05. CONCLUSIONS: C/T genotype of IL-1Ra +2018 prognosticates more aggressive disease in RA.
27134261 Total Hip Arthroplasty in 6690 Patients with Inflammatory Arthritis: Effect of Medical Com 2016 Jul OBJECTIVE: We analyzed early mortality after total hip arthroplasty (THA) in patients with inflammatory arthritis (IA), adjusting for medical comorbidities and socioeconomic background. METHODS: Data on 6690 patients with IA who underwent THA during 1992-2012 were extracted from the Swedish Hip Arthroplasty Register. Data on comorbidity, measured using the Charlson Comorbidity Index (CCI), and socioeconomic data were gathered from the Swedish National Inpatient Register and Statistics Sweden. The CCI was divided into low (0), moderate (1-2), and high (> 2). Cox proportional hazards models were fitted to calculate adjusted HR of early mortality, with 95% CI. RESULTS: Twenty-five patients (0.4%) died within 0-90 days, giving a 90-day unadjusted survival rate of 99.6% (CI 99.5-99.8). Comorbidity was associated with an increased risk of death within 90 days postoperatively [high vs low CCI: adjusted HR 9.0 (CI 1.6-49.9)]. There was a trend toward lower risk of death during the period 1999-2005, although patients operated on during this period had more comorbidities than those operated on from 1992 to 1998. A large proportion of patients was re-admitted to hospital within 90 days after the index procedure (30.2%), but rarely for cardiovascular reasons. CONCLUSION: Medical comorbidity and an age above 75 years are associated with a substantial increase in the risk of early death after THA in patients with IA. Awareness of potential risk factors may alert clinicians and thus improve perioperative care.
25889583 Proteasome inhibitors as experimental therapeutics of autoimmune diseases. 2015 Jan 28 Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren's syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.
25995222 Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. 2015 May 20 Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients.
26920997 Methotrexate selectively targets human proinflammatory macrophages through a thymidylate s 2016 Dec OBJECTIVES: Methotrexate (MTX) functions as an antiproliferative agent in cancer and an anti-inflammatory drug in rheumatoid arthritis (RA). Although macrophages critically contribute to RA pathology, their response to MTX remains unknown. As a means to identify MTX response markers, we have explored its transcriptional effect on macrophages polarised by GM-CSF (GM-MØ) or M-CSF (M-MØ), which resemble proinflammatory and anti-inflammatory macrophages found in RA and normal joints, respectively. METHODS: The transcriptomic profile of both human macrophage subtypes exposed to 50 nM of MTX under long-term and short-term schedules were determined using gene expression microarrays, and validated through quantitative real time PCR and ELISA. The molecular pathway involved in macrophage MTX-responsiveness was determined through pharmacological, siRNA-mediated knockdown approaches, metabolomics for polyglutamylated-MTX detection, western blot, and immunofluorescence on RA and normal joints. RESULTS: MTX exclusively modulated gene expression in proinflammatory GM-MØ, where it influenced the expression of 757 genes and induced CCL20 and LIF at the mRNA and protein levels. Pharmacological and siRNA-mediated approaches indicated that macrophage subset-specific MTX responsiveness correlates with thymidylate synthase (TS) expression, as proinflammatory TS(+) GM-MØ are susceptible to MTX, whereas anti-inflammatory TS(low/-) M-MØ and monocytes are refractory to MTX. Furthermore, p53 activity was found to mediate the TS-dependent MTX-responsiveness of proinflammatory TS(+) GM-MØ. Importantly, TS and p53 were found to be expressed by CD163(+)/TNFα(+) GM-CSF-polarised macrophages from RA joints but not from normal synovium. CONCLUSIONS: Macrophage response to MTX is polarisation-dependent and determined by the TS-p53 axis. CCL20 and LIF constitute novel macrophage markers for MTX responsiveness in vitro.
27354689 Cost-effectiveness of biologic compared with conventional synthetic disease-modifying anti 2016 Oct OBJECTIVE: The aim of this study was to explore the cost-effectiveness of biological DMARDs (bDMARDs) compared with conventional synthetic DMARDs (csDMARDs) for RA using real-world data from Finnish registers. METHODS: RA patients starting their first bDMARD and comparator patients using csDMARDs during 2007-11 were obtained from the National register of biologic treatments in Finland and the Jyväskylä Central Hospital patient records. Propensity score matching was applied to adjust for differences between bDMARD and csDMARD users. Effectiveness was measured in quality-adjusted life years (QALY) and based on the register of biologic treatments in Finland and Jyväskylä Central Hospital patient records, whereas the direct costs were obtained from relevant Finnish national registers. Patients were followed up for 2 years, and both costs and effectiveness for the second year were discounted at 3%. The incremental cost-effectiveness ratio (ICER) with 95% CI was calculated based on bootstrapped mean costs and effectiveness. RESULTS: Of 1581 RA patients meeting study inclusion criteria, 552 bDMARD and 220 csDMARD users were included in analyses after matching. Mean costs for bDMARDs and csDMARDs were €55 371 and €24 879, while mean effectiveness was 1.23 and 1.20 QALYs, respectively. Consequent ICER was €902 210/QALY. Results were confirmed in sensitivity analyses. CONCLUSION: The high incremental cost and the small, non-significant difference in effectiveness resulted in high ICER, suggesting that bDMARDs are not cost-effective. Regardless of matching, latent confounders may introduce bias to the results.
27327927 Shoulder Arthroplasty: Disposition and Perioperative Outcomes in Patients With and Without 2016 May Shoulder arthroplasty (SA) is used to treat pain and disability associated with rheumatoid arthritis (RA). Although SA is an effective procedure in patients with RA, more investigation of perioperative outcomes is needed. We conducted a study to compare the perioperative complication rates and demographics of patients with and without RA. Given the potential for anemia of chronic disease and the systemic inflammatory nature of RA, we hypothesized that the perioperative complication profile of RA patients would be worse than that of non-RA patients. Data on SA patients were obtained from the Nationwide Inpatient Sample for the period 2006-2011. Of the 34,970 SA patients identified, 1674 had a primary diagnosis of RA and 33,296 did not. Demographics, hospital disposition factors, and complications were compared using regression analysis. Analyses of 14 different perioperative outcome measures demonstrated no significant difference in any category except blood transfusions; the blood transfusion rate was significantly higher (P < .001) for RA patients (9.00%) than for non-RA patients (6.16%). RA patients had longer hospital length of stay (2.196 vs 2.085 days; P < .001), higher inflation-adjusted charges ($54,284 vs $52,663; P = .018), and lower home discharge rates (63.0% vs 67.6%; P < .001). These results suggest that the complex nature of RA plays a role in perioperative SA outcomes. RA patients' longer hospital stays were not clinically significant. Research on postoperative care, billing practices, and hospital protocols is needed to determine the cause of these outcomes.
26909913 Association of IL-18 polymorphisms with rheumatoid arthritis: a meta-analysis. 2016 Jan 22 Interleukin-18 (IL-18), an important proinflammatory cytokine, has been reported to play a potential pathological role in rheumatoid arthritis (RA). Results from previous studies on the association between IL-18 polymorphisms and RA are conflicting. To clarify this, an updated meta-analysis of all available studies on IL-18 polymorphisms and RA was conducted. Eligible articles were identified by searching databases, including PubMed, Ovid, Cochrane Library, EMBASE, and China Knowledge Resource Integrated Database, for the period up to May 1, 2015. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were used to assess the strength of association in the homozygote, heterozygote, dominant, recessive, and additive models. The software STATA (Version 13.0) was used for statistical analysis. Finally, 14 articles were included in the present meta-analysis. The IL-18 -607C/A polymorphism showed pooled ORs and 95%CIs for the homozygote model (AA vs CC: OR = 0.598; 95%CI = 0.395-0.907), and the association between the IL-18 -137G/C polymorphism and RA showed pooled ORs and 95%CIs for the homozygote (CC vs GG: OR = 0.699; 95%CI = 0.364-1.342) and heterozygote (CG vs GG: OR = 0.924; 95%CI = 0.803-1.064) models. In summary, the current meta-analysis, which was based on the most current studies, showed that the -607A/C, -920C/T, and -105A/C polymorphisms in IL-18 were significantly associated with increased RA risk. However, the -137C/G polymorphism was not associated with RA risk under any genetic model. More evidence is needed to support or deny such a conclusion.
26314368 Treatment persistence among patients with rheumatoid disease (RA, AS, PsA) treated with su 2016 Jan Patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are frequently treated with subcutaneous biologic therapies when disease progresses or when response to synthetic disease-modifying antirheumatic drugs (DMARDs) is inadequate. This study analyzed treatment persistence and treatment patterns for RA, AS, and PsA patients in Germany initiating subcutaneous biologic therapies with and without prior DMARDs use. A retrospective cohort study was conducted using the Electronic Medical Record database of IMS Disease Analyzer, Germany. Patients who were ≥18 years old; had at least one ICD-10 diagnosis code of RA, AS, or PsA during the study period; and had exposure to a subcutaneous biologic agent between January 1, 2009 and June 30, 2012 were selected. Patients were required to have continuous observation ≥12 months prior to and after index medication date. Persistence was defined as consecutive days from treatment initiation until treatment discontinuation (≥60-day lapse in medication coverage). Patients were stratified by pre-index use of DMARDs. Kaplan-Meier analysis was conducted to assess time to discontinuation, and logistic regression was conducted to identify characteristics associated with persistence. A total of 576 RA, 108 AS, and 197 PsA patients without biologic experience during the pre-index period were selected. The percentages of RA, AS, and PsA patients persistent ≥12 months were 51.9, 48.1, and 57.9 %, respectively. Median persistent time over 12 months was 365.0 days for RA (mean 245.9 days), 281.0 for AS (mean 228.5), and 365.0 for PsA (mean 264.1). In the RA cohort, a significantly higher proportion of those with pre-index DMARD use were persistent compared to those without pre-index DMARD (56.1 vs. 33.3 %, p = 0.0001). No significant differences were observed for the AS and PsA cohorts. Multivariate analyses confirmed that DMARD-experienced patients were 2.45 times more likely to be persistent with subcutaneous biologic therapy in the RA cohort. Switching between subcutaneous biologics occurred in <10 % of patients in all three cohorts. In the subpopulations with at least two prescriptions for the index subcutaneous biologic and who remained persistent on the index subcutaneous biologic, dose escalation of ≥50 % occurred in 50, 60, and 49 % in the RA, AS, and PsA cohorts, respectively. Among RA, AS, and PsA patients newly initiating subcutaneous biologic agents in Germany, persistence at 12 months is relatively low (48-58 %). For the RA cohort, patients with pre-index DMARD use are more persistent than patients without. The majority of patients do not switch between subcutaneous biologics. A notable proportion of patients who remained persistent on their index subcutaneous biologic had a dose escalation. There are opportunities to improve outcomes of patient with rheumatoid disease through improved medication persistence.
25228430 The past versus the present, 1980-2004: reduction of mean initial low-dose, long-term gluc 2015 Quantitative observations are presented concerning treatment with glucocorticoids of 308 patients with rheumatoid arthritis (RA) at a weekly academic rheumatology setting over 25 years from 1980 to 2004. A database of all visits included medications and multidimensional health assessment questionnaire scores for physical function, pain and routine assessment of patient index data (RAPID3; and a surrogate RAPID3-EST), completed by each patient at each visit in routine care. Over the 5-year periods of 1980-1984, 1985-1989, 1990-1994, 1995-1999 and 2000-2004, the mean initial prednisone daily dose declined from 10.3 to 6.5, 5.1, 4.1 and 3.6 mg/day, as initial doses were >5 mg/day in 49, 16, 7, 7 and 3% of patients, 5 mg/day in 51, 80, 70, 26 and 10%, and <5 mg/day in 0, 4, 23, 67 and 86%. Reduction of prednisone doses in the respective five-year periods was accompanied by increased and earlier use of methotrexate as the first disease-modifying antirheumatic drug (DMARD) in 10, 26, 57, 71 and 78%, and methotrexate treatment in 10, 26, 74, 82 and 92% of patients within the first year of disease. Higher methotrexate doses in the respective five-year periods were used after 1990, along with lower prednisone doses. Most patients were treated indefinitely with both low-dose prednisone and methotrexate; 80% continued both medications for more than 5 years. The primary adverse events were skin-thinning and bruising. New hypertension, diabetes and cataracts were seen in fewer than 10% of patients. While efficacy and safety cannot be analyzed definitively from observational data, the data suggest that many patients with RA might be treated effectively with weekly low-dose methotrexate along with initial and long-term, low-dose prednisone of <5 mg/day.
26842890 Tapering and discontinuation of TNF-α blockers without disease relapse using ultrasonogra 2016 Feb 3 BACKGROUND: In this study, we assessed whether clinical and ultrasonography (US)-based remission could be used to select patients with rheumatoid arthritis (RA) eligible to taper and discontinue anti-TNF-α therapy after achievement of remission, looking at disease relapse. METHODS: Forty-two patients with RA in sustained remission who were receiving anti-TNF-α treatment (Disease Activity Score <1.6 at three visits 3 months apart) underwent US evaluation of synovial hypertrophy (SH) and power Doppler (PD) signal presence. Five SH+/PD- patients with RA underwent US-guided knee synovial tissue biopsy to assess histological features of residual synovitis (CD68, CD3 and CD20 immunostaining) after sustained clinical remission was achieved. All patients were enrolled to taper first then discontinue anti-TNF-α. They were followed every 3 months afterwards, and the relapse rate was recorded. RESULTS: Selected SH+/PD- patients showed low-grade synovitis as demonstrated by the presence of CD68+ cells in the lining layer and few infiltrating CD3+ and CD20+ cells at the time sustained clinical remission was achieved. After anti-TNF-α tapering, 13 patients (30.9 %) relapsed and 29 (69.1 %) SH+/PD- patients maintained disease remission after 3 months and discontinued anti-TNF-α treatment. Among them, 26 patients (89.7 %) maintained disease remission status after 6 months of follow-up. All patients who relapsed were retreated with the previous biologic, following the last effective therapeutic regimen, again reaching a good European League Against Rheumatism response within 3 months. CONCLUSIONS: US evaluation using PD signalling allows the identification of patients with RA in clinical and histological remission after tapering and discontinuing biologics.
24618262 IgM rheumatoid factor amplifies the inflammatory response of macrophages induced by the rh 2015 Jul OBJECTIVES: Anticitrullinated protein antibodies (ACPA) are specifically associated with rheumatoid arthritis (RA) and produced in inflamed synovial membranes where citrullinated fibrin, their antigenic target, is abundant. We showed that immune complexes containing IgG ACPA (ACPA-IC) induce FcγR-mediated tumour necrosis factor (TNF)-α secretion in macrophages. Since IgM rheumatoid factor (RF), an autoantibody directed to the Fc fragment of IgG, is also produced and concentrated in the rheumatoid synovial tissue, we evaluated its influence on macrophage stimulation by ACPA-IC. METHODS: With monocyte-derived macrophages from more than 40 healthy individuals and different human IgM cryoglobulins with RF activity, using a previously developed human in vitro model, we evaluated the effect of the incorporation of IgM RF into ACPA-IC. RESULTS: IgM RF induced an important amplification of the TNF-α secretion. This effect was not observed in monocytes and depended on an increase in the number of IgG-engaged FcγR. It extended to the secretion of interleukin (IL)-1β and IL-6, was paralleled by IL-8 secretion and was not associated with overwhelming secretion of IL-10 or IL-1Ra. Moreover, the RF-induced increased proinflammatory bioactivity of the cytokine response to ACPA-IC was confirmed by an enhanced, not entirely TNF-dependent, capacity of the secreted cytokine cocktail to prompt IL-6 secretion by RA synoviocytes. CONCLUSIONS: By showing that it can greatly enhance the proinflammatory cytokine response induced in macrophages by the RA-specific ACPA-IC, these results highlight a previously undescribed, FcγR-dependent strong proinflammatory potential of IgM RF. They clarify the pathophysiological link between the presence of ACPA and IgM RF, and RA severity.
26815734 Effectiveness of insole use in rheumatoid feet: a randomized controlled trial. 2016 Oct OBJECTIVES: To assess the effectiveness of foot orthoses with regard to pain, function, quality of life, and global perceived effect in patients with rheumatoid arthritis (RA). METHOD: A double-blind randomized controlled trial (RCT) was carried out. Eighty women with RA were randomly assigned to an experimental group (EG) or a control group (CG). The EG used an insole with metatarsal and medial arch supports and the CG used a flat insole for 6 months. Evaluations performed at baseline and after 45, 90, and 180 days by a blinded assessor were: foot pain while walking and at rest, function, quality of life, and global perceived effect with treatment. RESULTS: The groups were homogeneous for all parameters at baseline. A statistically significant improvement (p < 0.001) was found in the EG regarding pain while walking (mean difference: -2.2 for the right foot and -2.1 for the left foot) and at rest (mean difference: -0.3 for the right foot and -0.5 for the left foot) in comparison to CG. There were no differences in any other observed measures. The time of insole use correlated with foot pain and function in the EG. CONCLUSIONS: Foot orthoses with metatarsal and medial arch supports decreases pain during walking and at rest in both feet in patients with RA. Time of insole use correlated with improvements in pain and function.
26515757 Treatment of rheumatoid arthritis: Unraveling the conundrum. 2015 Dec Rheumatoid arthritis (RA) is a heterogeneous disease with a complex and yet not fully understood pathophysiology, where numerous different cell-types contribute to a destructive process of the joints. This complexity results into a considerable interpatient variability in clinical course and severity, which may additionally involve genetics and/or environmental factors. After three decades of focused efforts scientists have now achieved to apply in clinical practice, for patients with RA, the "treat to target" approach with initiation of aggressive therapy soon after diagnosis and escalation of the therapy in pursuit of clinical remission. In addition to the conventional synthetic disease modifying anti-rheumatic drugs, biologics have greatly improved the management of RA, demonstrating efficacy and safety in alleviating symptoms, inhibiting bone erosion, and preventing loss of function. Nonetheless, despite the plethora of therapeutic options and their combinations, unmet therapeutic needs in RA remain, as current therapies sometimes fail or produce only partial responses and/or develop unwanted side-effects. Unfortunately the mechanisms of 'nonresponse' remain unknown and most probable lie in the unrevealed heterogeneity of the RA pathophysiology. In this review, through the effort of unraveling the complex pathophysiological pathways, we will depict drugs used throughout the years for the treatment of RA, the current and future biological therapies and their molecular or cellular targets and finally will suggest therapeutic algorithms for RA management. With multiple biologic options, there is still a need for strong predictive biomarkers to determine which drug is most likely to be effective, safe, and durable in a given individual. The fact that available biologics are not effective in all patients attests to the heterogeneity of RA, yet over the long term, as research and treatment become more aggressive, efficacy, toxicity, and costs must be balanced within the therapeutic equation to enhance the quality of life in patients with RA.