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1.
Lipids and Atherogenic Indices Fluctuation in Rheumatoid Arthritis Patients on Long-Term Tocilizumab Treatment.
Cacciapaglia, F, Anelli, MG, Rinaldi, A, Fornaro, M, Lopalco, G, Scioscia, C, Lapadula, G, Iannone, F
Mediators of inflammation. 2018;:2453265
Abstract
Rheumatoid arthritis (RA) patients are at high risk of cardiovascular (CV) events, and the chronic inflammatory state may generate quantitative and qualitative changes in lipoprotein fractions. The anti-IL-6 receptor tocilizumab (TCZ), even if effective in inflammation and joint damage prevention, determined significant alterations to RA patients' lipid levels in randomized controlled trials, but real-world data are lacking. We evaluated the changes in lipid fraction levels and disease activity in a longitudinal cohort of RA patients on long-term treatment with tocilizumab (TCZ) in a community setting. We retrospectively selected 40 naïve-biologic RA patients on treatment with intravenous TCZ compared to 20 RA patients on methotrexate treatment as the control group. Total cholesterol (Tot-Chol), low-density lipoproteins (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured at the baseline and at 12, 24, and 52 weeks thereafter. At the same points, 28-joint disease activity score (DAS28), clinical disease activity index (CDAI), and EULAR clinical responses were also assessed. During the first 24 weeks, we observed in TCZ-treated patients a progressive statistically significant (p < 0.001) increase in Tot-Chol, LDL, HDL, and TG, which returned close to the baseline at 52 weeks. But no changes in the lipid-related CV risk indices Tot-Chol/HDL and LDL/HDL ratios and the atherogenic index (log10 TG/HDL) were detectable. Notably, we observed a statistically significant negative correlation between changes in lipid fractions and DAS28 or CDAI. The prolonged treatment with TCZ was associated to a transient increase in cholesterol's fractions during the first 6 months of treatment, with inverse correlation to disease activity, but with no impact on surrogate lipid indices of atherogenic risk. These findings may aid clinicians in interpreting the RA patient's lipid profile in daily clinical practice.
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2.
Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders.
Hirten, RP, Iacucci, M, Shah, S, Ghosh, S, Colombel, JF
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(9):1374-1384
Abstract
Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.
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3.
[Acupuncture combined with western medicine on rheumatoid arthritis and effects on blood stasis].
Zhu, Y, Yu, H, Pan, Y, Yang, J, Wu, B, Hu, X, Cao, Y
Zhongguo zhen jiu = Chinese acupuncture & moxibustion. 2018;(5):4793-82
Abstract
OBJECTIVE To observe the clinical efficacy of acupuncture combined with western medicine in the treatment of rheumatoid arthritis (RA) and its effect on blood stasis, and to explore ways to improve the clinical curative effect. METHODS A total of 56 patients of RA were randomly divided into an observation group and a control group, 28 cases in each one. ① ibuprofen sustained-release tablets, 2 times a day, each time 0.3 g; ② methotrexate tablets (MTX), once a week, each time 10 mg ③ folic acid tablets, once a week, each time 5 mg were given in the control group, 30 days as one course, a total of 3 courses were required. In the observation group, acupuncture was adopted on the basis of the treatment as the control group. The main acupoints were Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Hegu (LI 4), Quchi (LI 11), Zusanli (ST 36) combined with local ashi points. The treatment was given once every day for continuous 6 days a week, the treatment for 30 days as one course, a total of 3 courses were required. The serological indexs were evaluated before and after treatment, including the rheumatoid factor (RF), hypersensitive C-reactive protein (hs-CRP), erythrocyte sedirnentation rate (ESR), platelet (PLT), fibrinogen (FBG) and D-dimer (D-D), the changes of disease activity score (DAS-28), symptom grade quantitative score, blood stasis syndrome symptom (the joint tingling, lip color, tongue, pulse, subcutaneous ecchymosis, squamous and dry skin) score were observed. RESULTS ① The scores of RF, hs-CRP, ESR, PLT, D-D, FBG, DAS-28 and symptom grade quantitative were significantly improved in the two groups compared with those before treatment (all P<0.05), and the scores of hs-CRP, ESR, DAS-28 and symptom grading in the observation group were more better than those in the control group (all P<0.05). ② The total score of joint tingling, lip color, tongue, pulse, subcutaneous ecchymosis, squamous and dry skin and blood stasis syndrome in both groups were decreased after treatment (all P<0.05), the joint tingling, tongue, lip color and subcutaneous ecchymosis were improved obviously in the observation group than those in the control group (all P<0.05). ③ The total effective rate in the observation group was 85.7% (24/28), which was better than 75.0% (21/28) in the control group (P<0.05). CONCLUSION Acupuncture combined with western medicine can not only improve the clinical efficacy of RA patients but also improve the blood stasis.
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4.
[Irisin as a new marker for the early diagnosis of low-traumatic fractures in rheumatoid arthritis.].
Lavrova, DP, Zavodovsky, BV, Akhverdyan, YR, Polyakova, YV, Sivordova, LE, Zborovskaya, IA, Yakovlev, AT
Klinicheskaia laboratornaia diagnostika. 2018;(11):702-706
Abstract
The aim of this study was to study the relationship between serum irisin level and the presence of low-traumatic bone fractures in rheumatoid arthritis (RA) patients. We examined 170 people including 110 RA patients and 60 healthy individuals as comparison group. The serum irisin level was determined with solid-phase enzyme-linked immunosorbent assay using ELISA Irisin test system (BioVendor, cat. No. RAG018R). The average level of irisin in the group of healthy individuals was 20.49 ± 4.82 μg/ml (μ±σ). The level of normal values, defined as M ± 2σ, was 10.85-30.13 μg/ml. Decreased irisin level was detected in 41 of 110 patients with RA diagnosis (37% of cases). This group of patients had higher RA activity degree (DAS28), extra-articular manifestations, disease duration from 5 to 10 years, greater class of functional joint's failure, lower level of 25 (OH) -vitamin D. There was also a reliable relationship between serum irisin level and presence of low-fracture bone fractures in the anamnesis.
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5.
[Meta-analysis on efficacy and safety of combination therapy of Aconitum and Western medicine in treatment of rheumatoid arthritis].
Zhang, XM, Zhang, B, Li, F, Tian, ZP
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2018;(2):227-233
Abstract
To analyze the efficacy and safety of the combination therapy of Aconitum and Western medicine in the treatment of rheumatoid arthritis (RA) by Meta-analysis, and provide evidence for its clinic application for RA. The random clinical trials (RCTs) regarding the combination therapy for treating RA were retrieved in the database of China National Knowledge Infrastructure database, China Science and Technology Journal database, WanFang, Chinese Biomedical Medical Database, PubMed, and Cochrane Library up to July 2017. According to the given inclusion criteria, 8 RCTs involving 659 participants were included, and the included RCTs could be further divided into three subgroups according to the herb type, which were Aconiti Radix (Chuanwu) subgroup (6RCTs), Aconiti Kusnezoffii Radix (Caowu) subgroup (1RCT), and Chuanwu-Caowu subgroup (1RCT). The Meta-analysis results indicated that as compared with Western medicine, the combined use of Aconitum and Western medicine, no matter Chuanwu, Caowu or Chuanwu-Caowu subgroups, could improve the total effective rate of RA (6RCTs, RR=1.19, 95%CI [1.10, 1.28], P<0.000 01), (1 RCT, RR=1.43, 95%CI [1.18, 1.73], P=0.000 2), (1 RCT, RR=1.27, 95%CI [1.02, 1.58], P=0.03) respectively. The combined use of Aconitum and Western medicine was also effective on the number of joint swelling, duration of morning stiffness, patients' handgrip, and the erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor. However, its action was not significant on joint tenderness. And also, in the included RCTs, there were 34 cases of adverse drug reactions/events (ADR/ADE) in the Chuanwu subgroup, while 86 cases in the Western medicine control group. The ADR/ADE incidence was even more lower in Chuanwu-Caowu subgroup, but no difference between Caowu subgroup and Western medicine group. Based on the included RCTs, the combined use of Aconitum and Western medicine could achieve more satisfying efficacy and lower ADRs incidence for RA as compared with Western medicine alone. However, due to the limitation in the not-high quality of included RCTs and the lack of large-scale multi-center research, the results still need to be further validated in the clinic application.
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6.
Tackling Pain Associated with Rheumatoid Arthritis: Proton-Sensing Receptors.
Sun, WH, Dai, SP
Advances in experimental medicine and biology. 2018;:49-64
Abstract
Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. Chronic pain that comes with RA turns independent, essentially becoming its own disease. It could partly explain that a significant number (50%) of RA patients fail to respond to current RA therapies that focus mainly on suppression of joint inflammation. The acute phase of pain seems to associate with joint inflammation in early RA. In established RA, the chronic phase of pain could be linked to inflammatory components of neuron-immune interactions and noninflammatory components. Accumulating evidence suggests that the initial inflammation and autoimmunity in RA (preclinical RA) begin outside of the joint and may originate at mucosal sites and alterations in the composition of microbiota located at mucosal sites could be essential for mucosal inflammation, triggering joint inflammation. Fibroblast-like synoviocytes in the inflamed joint respond to cytokines to release acidic components, lowering pH in synovial fluid. Extracellular proton binds to proton-sensing ion channels, and G-protein-coupled receptors in joint nociceptive fibers may contribute to sensory transduction and release of neurotransmitters, leading to pain and hyperalgesia. Activation of peripheral sensory neurons or nociceptors further modulates inflammation, resulting in neuroinflammation or neurogenic inflammation. Peripheral and central nerves work with non-neuronal cells (such as immune cells, glial cells) in concert to contribute to the chronic phase of RA-associated pain. This review will discuss actions of proton-sensing receptors on neurons or non-neuronal cells that modulate RA pathology and associated chronic pain, and it will be beneficial for the development of future therapeutic treatments.
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7.
Efficacy and Safety of 22-Oxa-Calcitriol in Patients with Rheumatoid Arthritis: A Phase II Trial.
Li, C, Yin, S, Yin, H, Cao, L, Zhang, T, Wang, Y
Medical science monitor : international medical journal of experimental and clinical research. 2018;:9127-9135
Abstract
BACKGROUND Calcitriol (1 alpha, 25-dihydroxy vitamin D3) is a good vitamin D supplement but can cause hypercalcemia. Whereas, 22-oxa-1 alpha, 25-dihydroxy vitamin D3 (22-oxa-calcitriol) has less hypercalcemic activity than calcitriol and is reported to be effective for cell-proliferative diseases. The objective of the study was to compare renal function and blood tests of arthritis patients receiving calcitriol supplements with those receiving 22-oxa-calcitriol supplements. MATERIAL AND METHODS A total of 369 patients with clinically confirmed rheumatoid arthritis were included in this phase II trial. Patients received lactose powder (the placebo group, n=123), 50 000 IU/week of 22-oxa-calcitriol (the treatment group, n=123), or 50 000 IU/week of calcitriol (the control group, n=123) for 6 weeks. At the time of enrollment and after 6 weeks of supplementation, renal function tests, blood tests, and secondary outcome measures were evaluated. One-way ANOVA and the chi-squared test for independence were performed for continuous data and constant data at a 95% of confidence level. RESULTS Both 22-oxa-calcitriol and calcitriol successfully decreased swollen joints in patients with rheumatoid arthritis, and both improved Health Assessment Questionnaire Disease Activity Index scores and serum vitamin D levels. The intensity of improvement of serum vitamin D levels in both groups was the same (P<0.0001, q=0.24); however, calcitriol caused hypercalcemia (P<0.0001, q=12.59). CONCLUSIONS This study found that 22-oxa-calcitriol was a good option for vitamin D supplementation in rheumatoid arthritis patients.
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8.
Baricitinib: A Review in Rheumatoid Arthritis.
Al-Salama, ZT, Scott, LJ
Drugs. 2018;(7):761-772
Abstract
Baricitinib (Olumiant®) is an oral, targeted synthetic DMARD that inhibits JAK1 and JAK2, which are implicated in the pathogenesis of rheumatoid arthritis (RA). This novel, small molecule is approved for use as monotherapy, or in combination with methotrexate, for the treatment of adults with moderate to severe active RA who responded inadequately to or were intolerant of ≥ 1 DMARD. In pivotal multinational trials, once-daily baricitinib 4 mg, with/without methotrexate (± another csDMARD), improved the signs and symptoms of RA, disease activity and physical function in DMARD-naive patients and in patients with an inadequate response to methotrexate, csDMARDs or TNF inhibitors; baricitinib treatment also slowed structural joint damage in DMARD-naive patients and in those with an inadequate response to methotrexate and csDMARDs. Baricitinib plus methotrexate was more effective than adalimumab plus methotrexate in patients with an inadequate response to methotrexate. The onset of these benefits was generally rapid and sustained over time. Baricitinib was generally well tolerated during up to 5.5 years' treatment; the most commonly reported adverse drug reactions were upper respiratory tract infections, increased LDL cholesterol, nausea and thrombocytosis. Thus, once-daily baricitinib, as monotherapy or in combination with methotrexate, is an effective and generally well tolerated emerging treatment for patients with moderate to severe active RA who have responded inadequately to or are intolerant of ≥ 1 DMARD, and extends the options available for this population.
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9.
Seropositivity and Antibody Profiling of Patients Are Dramatically Impacted by the Features of Peptides Used as Immunosorbents: A Lesson from Anti-Citrullinated Protein/Peptide Antibody.
Cornillet, M, Babos, F, Magyar, A, Sebbag, M, Verrouil, E, Hudecz, F, Serre, G, Nogueira, L
Journal of immunology (Baltimore, Md. : 1950). 2018;(11):3211-3217
Abstract
Quantification of Abs toward a single epitope is critical to understanding immunobiological processes. In autoimmunity, the prognostic value of the serological profiles of patients draws much attention, but the detection of Abs toward a single epitope is not well controlled. Particularly, the rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide Abs (ACPA) are specific to a two-atom change on arginyl residues and are considered a heterogeneous family of Abs. As a model, we studied ACPA to decipher how peptide features used as immunosorbent impact Ab detection. We synthesized 30 peptides encompassing immunodominant epitopes of citrullinated fibrin differing by their length and biotin location and tested them using ELISA with 120 sera from RA and non-RA rheumatic disease controls, generating over 3000 experimental measurements. We showed that minor molecular changes in peptide chemical structure had dramatic consequences. Even when peptides exhibited the same epitope, measured Ab titers were extremely variable, and patients' seropositivity was discordant in up to 50% of cases. The distance between epitope and biotin was the most critical parameter for efficient Ab detection irrespective of biotin position or peptide length. Finally, we identified a 15-mer peptide bearing a single citrullinated epitope detecting almost all ACPA-positive sera, thus revealing a high degree of homogeneity in RA autoimmune response. This integrative analysis deciphers the dramatic impact of the molecular design of peptide-based technologies for epitope-specific Ab quantification. It provides a model for assay development and highlights that the studies using such technologies can give a wrong perception of biological processes and therefore that medical use of data must be cautious.
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10.
Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis.
López-Rodríguez, R, Ferreiro-Iglesias, A, Lima, A, Bernardes, M, Pawlik, A, Paradowska-Gorycka, A, Świerkot, J, Slezak, R, Dolžan, V, González-Álvaro, I, et al
Scientific reports. 2018;(1):7342
Abstract
About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.