Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on ...evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.
ObjectivesTo evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid ...(GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients.MethodsThe incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices.ResultsIn the high-risk group, Classic (∆k€1.464, 95% CI −0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI −0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆−0.002, 95% CI −0.086 to 0.082) and Avant-Garde (∆−0.009, 95% CI −0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€−0.617, 95% CI −2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars.ConclusionsThe combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment.Trial registration number NCT01172639.
Abstract Rheumatoid arthritis (RA) is an autoimmune systemic inflammatory disease, characterized by chronic synovial inflammation and destruction of cartilage and bone, results in varying degrees of ...deformity and functional disability. Previous research has shown that there is a link between adipokines and RA, but also other systemic diseases such as cardiovascular disease and diabetes mellitus. Adipokines are biologically active substances, which are predominantly or exclusively secreted from adipocytes of adipose tissue, or other adipose tissue cells such as: preadipocytes, immune cells infiltrated in AT, or other cell types within this tissue. These molecules play a significant role in energy homeostasis and metabolism regulation, and are also involved in chronic inflammation and metabolic dysfunctions. Some of the adipokines act like hormones in glucose homeostasis and appetite regulation, while others, like cytokines, support the link between obesity and insulin resistance with the immune system and the inflammatory process. However, the clear role of adipokines in pathological conditions has not yet been established. This review will focus on current knowledge about the role of the two most prominent adipokines, leptin and adiponectin, in the pathogenesis of RA.
Biologic anti-rheumatic drugs are used with less frequency among older patients compared to young patients. This population is less represented in studies performed to evaluate the efficacy and ...safety of this drugs. We aimed to assess the efficacy and safety of biological agents between the older RA patients compared to young.
A comprehensive, systematic search was conducted in major indexing databases using key terms for RA and each biological agent. The review process was completed by 2 investigators. Both randomized controlled trials and observational studies of at least 6-month duration conducted in adult RA patients were included. Outcomes of interest were clinical efficacy and safety. Effect-estimates were pooled using random-effects modeling if 4 or more studies used the same scale and time-frame for measuring outcomes.
24 studies (16 focusing on anti-TNF agents) representing 63,705 patients (24% were older) were included. Older RA patients had worse baseline RA disease activity, longer disease duration at the time of enrollment in the trial (14.4 ± 3.6 vs. 10.9 ± 3.6 years; p < 0.001) and higher steroid use (73.2 vs. 64.7%, p < 0.001) than younger. 5 out of 6 studies assessing anti-TNF agents showed worse efficacy outcomes in older patients. The pooled OR of infection and ADRs with anti-TNF agents in older compared to young RA patients was OR 1.59 (95% CI: 1.45–1.76) and 1.40 (95% CI: 1.23–1.61) respectively.
Older patients had worse safety and efficacy with biological agents but also had worse baseline disease activity. There was significant heterogeneity in reporting outcomes and very limited studies in biological agents other than anti-TNF drugs.
An activatable probe able to detect RONS level underlying the development of rheumatoid arthritis (RA) would be far-reaching for the diagnosis and drug efficacy assessment of RA. Despite more and ...more evidence suggests that ONOO− is an important signaling molecule participating in the RA disease, only rare fluorescent probes can detect ONOO− in this disease with satisfying performance. To this end, we designed and synthesized a novel activatable AIE fluorescent probe (DPPO-PN) for the detection of ONOO− levels in RA. The probe linearly responds to 0–10 μM ONOO− with a significant far-red fluorescence enhancement at 632 nm in 30 s (F/F0 = 161-fold, LOD = 10 nM) upon the excitation of 490 nm, elucidating excellent sensing abilities for ONOO− in cuvettes. Moreover, the fluctuations of intracellular ONOO− levels caused by adscititious adding or stimulant provoking could be real-time captured and visualized with this probe by confocal imaging. Further, the intravital imaging of ONOO− in LPS-induced and CFA-induced RA mouse models also can be achieved with the aid of the probe, substantiating the burst of ONOO− in the RA process. Therefore, this work not only offers an auxiliary tool for the diagnosis of RA but also would benefit our understanding of the ONOO−‘s roles in RA.
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•An ONOO−-activatable fluorescent probe regulated by ESIPT and AIE is reported.•The probe revealed the ONOO− fluxes in LPS and CFA-induced RA mouse models.•The probe can advance the diagnoses and the evaluations of RA via in vivo imaging.
Matrix metalloproteinase-3 or MMP3 also known as stromelysin-1 is an enzyme that is actively involved in joint destruction in rheumatoid arthritis (RA) patients. Screening the last three decades, it ...appears that serum levels of MMP3 reflect positively RA disease activity, joint and bone injury, and radiological erosion and predict disease outcome and drug responsiveness as summarized in several publications reporting outcomes on more than 8000 patients with RA. MMP-3 monitoring should be embedded in the routine assessment and accompany therapeutic modalities, in personalized medical RA management.
Objective
To investigate the factors associated with cartilage proteoglycan content in patients with rheumatoid arthritis (RA).
Methods
A total of 32 RA patients received high‐field 3T delayed ...gadolinium‐enhanced magnetic resonance imaging of cartilage (dGEMRIC) to determine cartilage proteoglycan content. Measurements were performed in 3 individual cartilage regions (medial, central, and lateral) of metacarpophalangeal (MCP) joints 2 and 3. T1 dGEMRIC values were then related to disease duration, disease activity, anti–citrullinated protein antibody (ACPA) status, rheumatoid factor (RF) status, and C‐reactive protein (CRP) level.
Results
T1 dGEMRIC values did not differ significantly between MCP joints 2 and 3. Intraclass correlation coefficients were high (>0.92) for all 3 cartilage compartments (medial, central, and lateral). T1 dGEMRIC values were significantly lower in RA patients with longer disease duration (≥3 years) (P = 0.034 for the central compartment) and those with ACPA positivity (P = 0.0002 for the central compartment, P = 0.013 for the lateral compartment). In contrast, no associations were found between cartilage proteoglycan content and disease activity, CRP level, or RF status.
Conclusion
Decreased cartilage proteoglycan content in RA patients is associated with disease duration and ACPA positivity but not with actual disease activity, CRP level, or RF status. These data suggest that the cumulative burden of inflammation as well as ACPAs are the determinants of cartilage damage in RA.
The β common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. ...Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the β common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.
Dougan, Dranoff, and Dougan review the functions of the β common chain cytokines—GM-CSF, IL-3, and IL-5—in health and disease. They discuss current efforts targeting these pathways in the clinic and highlight important gaps in understanding of the basic biology of this cytokine family.
Objectives Porphyromonas gingivalis (P.g.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic ...peptidylarginine deiminase (PPAD) from P.g. CH2007 (RACH2007-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA.MethodsRecombinant RACH2007-PPAD was cloned and expressed in Escherichia coli. Purified RACH2007-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated.ResultsRACH2007-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RACH2007-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57–71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RACH2007-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RACH2007-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RACH2007-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018).ConclusionsRACH2007-PPAD induced internal citrullination of major RA autoantigens. Anti-RACH2007-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.
John B Nichols Hawke, Christopher
BMJ (Online),
10/2017, Letnik:
359
Journal Article
Recenzirano
John was a kind, conscientious, and extremely clever man, who became senior partner in the Fakenham group practice and developed it along modern lines. Eventually the complications of rheumatoid ...arthritis as well as increasing heart problems led to confinement to his own house, where he was cared for by his wife and son for the last few months of his life.
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