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ID PMID Title PublicationDate abstract
30538709 DC32, a Dihydroartemisinin Derivative, Ameliorates Collagen-Induced Arthritis Through an N 2018 Artemisinins have been reported to have diverse functions, such as antimalaria, anticancer, anti-inflammation, and immunoregulation activities. DC32 [(9α,12α-dihydroartemisinyl) bis(2'-chlorocinnmate)], a dihydroartemisinin derivative possessing potent immunosuppressive properties, was synthesized in our previous study. Collagen-induced arthritis (CIA) in DBA/1 mice and inflammatory model in NIH-3T3 cells were established to evaluate the effect of DC32 on RA and discover the underlying mechanisms. The results showed that DC32 could markedly alleviate footpad inflammation, reduce cartilage degradation, activate the Nrf2/HO-1 signaling pathway, and increase the transcription of p62 in DBA/1 mice with CIA. Further mechanistic exploration with NIH-3T3 cells indicated that DC32 could increase the transcription, expression, and nuclear translocation of Nrf2. In addition, DC32 promoted degradation of Keap1 protein and upregulated HO-1 and p62 expression. Furthermore, the effect of DC32 on Keap1 degradation could be prevented by p62 knockdown using siRNA. Administration of DC32 could inhibit the activation of Akt/mTOR and ERK, and pretreatment of NIH-3T3 cells with the autophagy inhibitor 3-methyladenine (3-MA) attenuated the degradation of Keap1 induced by DC32. These results suggest that DC32 inhibits the degradation of Nrf2 by promoting p62-mediated selective autophagy and that p62 upregulation contributed to a positive feedback loop for persistent activation of Nrf2. In summary, our present study demonstrated that DC32 significantly suppressed rheumatoid arthritis (RA) via the Nrf2-p62-Keap1 feedback loop by increasing the mRNA and protein levels of Nrf2 and inducing p62 expression. These findings provide new mechanisms for artemisinins in RA treatment and a potential strategy for discovering antirheumatic drugs.
29548675 Effect on Risk of Stroke and Acute Myocardial Infarction of Nonselective Nonsteroidal Anti 2018 May 15 There are still debates on the association of increased cardiovascular risk with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA) because of inconsistent results. Therefore, our study aims to evaluate the transient effects of selective and nonselective NSAIDs on the risk of stroke and acute myocardial infarction (AMI) in patients with RA. We conducted a case-crossover study of 5,921 stroke or AMI patients with co-morbidity of RA. All cases were identified from the Taiwan National Health Insurance Database between January 1, 2006, and December 31, 2011, according to the International Classification of Diseases, 9th Revision and Clinical Modification diagnosis codes from inpatient claims. The index date was defined as the date of hospitalization for stroke or AMI. Exposure to NSAIDs was compared during a case period (1 to 30 days before the index date) with a control period (91 to 120 days before the index date). The adjusted odds ratios (ORs) of stroke and AMI were estimated using conditional logistic regression models. Our results showed that overall NSAIDs use increased the risk of stroke by 1.40-fold (95% confidence interval [CI] 1.25 to 1.56) and risk of AMI by 1.73-fold (95% CI 1.29 to 2.32). After classifying NSAIDs into selective and nonselective groups, only nonselective NSAIDs use significantly increased the risks of stroke (adjusted OR 1.39; 95% CI 1.25 to 1.55) and AMI (adjusted OR 1.82; 95% CI 1.37 to 2.41), respectively. In conclusion, nonselective NSAIDs were associated with an increased risk of both stroke and AMI in patients with RA.
29998842 Ultrasound detection of subclinical synovitis in rheumatoid arthritis patients in clinical 2018 Nov OBJECTIVES: The ability of ultrasound (US) to identify subclinical joint inflammation in rheumatoid arthritis (RA) patients in remission has been already reported. Nonetheless, current studies present a lack of homogeneity in patient's characteristics and number of joints assessed by US. The aim of this study was to identify a reduced set of target joints to be scanned in RA patients in clinical remission in order to detect subclinical synovitis. METHODS: Forty RA patients in clinical remission (DAS28 ≤2.6) for at least 3 months underwent an US examination of 18 joints: wrist, II-III-IV-V metacarpophalangeal (MCP) and II-III-IV-V metatarsophalangeal joints bilaterally. The presence of synovial hypertrophy (SH) and power-Doppler (PD) signal was registered following the OMERACT definitions and was graded according to a 4-point scale (0-3). Then, by applying a process of data reduction based on the frequency of joint involvement, a reduced assessment was obtained. RESULTS: Twenty (50%) subjects had at least one joint affected by active synovitis; 17.5% presented grade 1 PD and 32.5% grade 2 PD. The joints most frequently affected by active synovitis were the wrists (75%) and the II MCP joints (55%). After data reduction, the evaluation of 3 joints (both wrists and the II MCP of the dominant hand) obtained a sensitivity of 90% for the detection of subclinical synovitis. CONCLUSIONS: The US scan of 3 target joints showed a high sensitivity in detecting subclinical active synovitis in RA patients in clinical remission and can be feasible in the routine assessment of these patients.
29690734 [Effect of Dishevelled 2 on apoptosis in rheumatoid arthritis fibroblast-like synoviocytes 2018 Apr 17 Objective: To investigate if Dishevelled 2 (DVL2) regulates the apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) via the JAK-STAT pathway. Methods: DVL2 overexpressed lentivirus was transfected into RA-FLS and the apoptosis rate was detected by flow cytometry. The effect of DVL2 on RA-FLS signaling pathway was detected by RNA-seq, and then the key genes were verified by RT-PCR. Results: Compared with the control group, DVL2 significantly increased the apoptosis rate of MH7A (3.2%±2.2% vs 25.7%±4.5%). RNA-seq results showed that DVL2 down-regulated the JAK-STAT pathway.The results of RT-PCR showed that DVL2 inhibited the gene expression of JAK2, Stat1, and Stat2; DVL2 still inhibited the gene expression of JAK2 and Stat2 but not Stat1 after TNF-α stimulation.DVL2 inhibited the gene expression of Bcl-xL, and the gene expression of Bcl-2 and Bcl-xL after TNF-α stimulation. Conclusion: DVL2 can increase the apoptosis rate of RA-FLS through inhibiting the JAK-STAT pathway and its downstream anti-apoptotic gene.
30463656 [STAT4 rs7574865 polymorphism is associated with the susceptibility of rheumatoid arthriti 2018 Sep Objective To investigate the association of single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) rs7574865 and miRNA146a rs2910164 with rheumatoid arthritis (RA) in Wuling mountain area. Methods 287 RA patients and 305 age-matched healthy controls were included. The rs7574865 and rs2910164 SNPs of RA patients and control subjects were measured by multiplex PCR combined with high throughput sequencing(HI-SNP). The distributions of genotype and allele frequencies in the two groups were analyzed by the Chi-squared test, and also the relationship between these two SNPs and the risk of RA, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ACCP) antibody were investigated. Results Data showed that the genotype distribution of rs7574865 were significantly different between the cases and controls. The TT genotype and the T allele from rs7574865 were all associated with the risk of RA (OR=2.42, 95%CI: 1.37-4.28; OR=1.43, 95%CI: 1.12-1.82), and dominant and recessive models showed similar results. While, we found miRNA146a rs2910164 has no role in susceptibility to RA, and there was no statistically significant association between the SNPs of rs7574865 and rs2910164 and the level of RF or ACCP antibody. Conclusion STAT4 rs7574865 polymorphism is associated with RA, but not with RF or ACCP antibody levels in Wuling mountain area. In contrast, miRNA146a rs2910164 polymorphism is not correlated with RA.
30055006 Metallothionein-1 suppresses rheumatoid arthritis pathogenesis by shifting the Th17/Treg b 2018 Sep It is now well accepted that an imbalance between the Th17 and regulatory T-cell responses is closely associated with the development of rheumatoid arthritis (RA). However, the precise regulatory mechanism for the differentiation of Th17 and Treg in RA is not well characterized. The present study showed that metallothionein-1 (MT-1), which is a low molecular weight protein that is involved in the detoxification of heavy metals and scavenging of free radicals, was upregulated in RA. Furthermore, the synovial inflammation and pathologic symptoms in collagen-induced arthritis and collagen antibody-induced arthritis mice were significantly suppressed when MT-1 was expressed intraarticularly. Further investigation revealed that MT-1 inhibited the differentiation of Th17 cells but enhanced that of Treg cells. Furthermore, it markedly decreased both STAT3 and RAR-related orphan receptor gamma t (RORγt) expression in vitro and in vivo. Collectively, our studies demonstrated that MT-1 might manifest as a protein involved in immunosuppression of RA pathogenesis by shifting Th17/Treg balance and may prove to be a potential therapeutic target for RA autoimmune diseases.
29566767 Methotrexate upregulates circadian transcriptional factors PAR bZIP to induce apoptosis on 2018 Mar 22 BACKGROUND: Effects of methotrexate (MTX) on the proliferation of rheumatoid arthritis (RA) synovial fibroblasts are incompletely understood. We explored actions of MTX in view of circadian transcriptions of synovial fibroblasts. METHODS: Under treatment with MTX, expression of core circadian clock genes, circadian transcriptional factor proline and acidic amino acid-rich basic leucine zipper (PAR bZIP), and proapoptotic molecule Bcl-2 interacting killer (Bik) was examined by real-time polymerase chain reaction. Protein expression of circadian clock gene PERIOD2 (PER2) and CYTOCHROME C was also examined by western blotting and ELISA. Promoter activities of Per2 and Bik were measured by Luciferase assay. Expression of PER2, BIK, and CYTOCHROME C and morphological changes of the nucleus were observed by fluorescent immunostaining. Synovial fibroblasts were transfected with Per2/Bik small interfering RNA, and successively treated with MTX to determine cell viabilities. Finally, synovial fibroblasts were treated with MTX according to the oscillation of Per2/Bik expression. RESULTS: MTX (10 nM) significantly decreased cell viabilities, but increased messenger RNA expression of Per2, Bik, and PAR ZIP including D site of the albumin promoter binding protein (Dbp), hepatic leukemia factor (Hlf), and thyrotroph embryonic factor (Tef). MTX also increased protein expression of PER2 and CYTOCHROME C, and promoter activities of Per2 and Bik via D-box. Under fluorescent observations, expression of PER2, BIK, and CYTOCHROME C was increased in apoptotic cells. Cytotoxicity of MTX was attenuated by silencing of Per2 and/or Bik, and revealed that MTX was significantly effective in situations where Per2/Bik expression was high. CONCLUSIONS: We present here novel unique action of MTX on synovial fibroblasts that upregulates PAR bZIP to transcribe Per2 and Bik, resulting in apoptosis induction. MTX is important in modulating circadian environments to understand a new aspect of pathogenesis of RA.
30300358 Adherence to etanercept therapy in rheumatoid arthritis patients during 3 years of follow- 2018 OBJECTIVES: To determine the percentage non-adherence to etanercept in patients with rheumatoid arthritis during three years of follow-up. METHODS: During study visits in this prospective cohort study, blood samples were taken to determine serum etanercept concentrations using ELISA and patients were asked if they had missed an etanercept dose, at which date and for what reason. Non-adherence was defined as serum etanercept concentration <0.1 μg/mL and no valid reason to miss the prescribed etanercept dose. RESULTS: In total, 292 consecutive patients treated with etanercept were included. Most patients had a valid reason to miss their etanercept dose (25/37). In total 12 out of 292 patients (4.1%, 95% confidence interval 2.2-7.2) were non-adherent during the 3 year period. In a small percentage of patients (3.4%, 95% confidence interval 0.8-10.4) who failed to respond to etanercept therapy, according to their rheumatologist, this was associated with inadequate exposure to etanercept and thus non-adherence. CONCLUSION: In this study, adherence to etanercept therapy was measured using serum etanercept concentration. In most patients an absent etanercept concentration was due to a medical reason. Furthermore, the majority of patients were adherent to etanercept therapy and had adequate drug exposure. In total, only 12 out of 292 patients (4.1%) were non-adherent during 3 years of follow-up. These findings highlight that only a small minority of patients are non-adherent to etanercept treatment, especially compared to adherence rates of other drugs. However, physicians should be aware that in patients failing to respond to treatment, non-adherence is a possible cause.
29306209 Retinoid interferon-induced mortality19 (GRIM19) inhibits proliferation and invasion in rh 2018 Feb Rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) are reportedly involved in RA initiation, progression, and perpetuation. Previously a study showed that retinoid interferon-induced mortality 19 (GRIM19) improved the clinical and histological features of collagen-induced arthritis (CIA),and also inhibited osteoclast formation. However, the role of GRIM19 in RA-FLS remains unclear. In this study, we explored the biological function and underlying mechanism of GRIM19 in cultured RA-FLS. The expression of GRIM19 in synovial tissues and RA-FLS was detected by real-time quantitative RT-PCR(qRT-PCR).The effects of GRIM19 on proliferation, migration, invasion, apoptosis, and inflammatory cytokines levels in RA-FLS were determined using CCK8, wound healing, transwell invasion, and flow cytometry assays, and enzyme-linked immunosorbent assay (ELISA), respectively.GRIM19 and its related protein expression levels were determined by western blot. We found that GRIM19expression was significantly decreased in synovial tissues and FLS from RA patients.GRIM19significantly inhibited proliferation, migration, and invasion; promoted apoptosis; and suppressed inflammatory cytokine secretion by RA-FLS. Moreover, GRIM19 overexpression significantly decreasedthe expression levels of signal transducer and activator of transcription 3(STAT3)and its downstreamproteins,CyclinD1, Bcl-2, and MMP-9. These data indicate that promoting the expression of GRIM19 may yield therapeutic benefits in the treatment of RA.
29757670 Regulatory T-cell dynamics with abatacept treatment in rheumatoid arthritis. 2018 The progressive damage in rheumatoid arthritis (RA) has been linked to an increase in inflammatory Th1/Th17 cells and a decrease in number or function of immunomodulatory regulatory T cells (Tregs). Many therapies that are effective in RA are shown to affect Th1/Th17 cells and/or Tregs. One such therapy, abatacept, utilizes a physiologic immunomodulatory molecule called cytotoxic lymphocyte antigen-4 (CTLA-4) which causes contact-dependent inhibition of inflammatory T-cell activation. Recent advances in CTLA-4 research has uncovered the method by which this occurs physiologically but the actions of the CTLA-4Ig fusion protein are still not fully understood. The reported effects of the drug on Treg population number and suppressor function have been very mixed. In this review, we will discuss the current literature surrounding the effects of abatacept in rheumatoid arthritis and explore potential explanations for the differences in results. Future opportunities in this area include contributions to a unified definition for different immune cell populations, LAG3(+) Tregs which may pose an avenue for further study or the stratification of patients with regards to their specific disease characteristics, resulting in optimized treatment for disease remission.
30313057 Use of steroid and nonsteroidal anti-inflammatories in the treatment of rheumatoid arthrit 2018 Oct BACKGROUND: Rheumatoid arthritis affects 1% of the world's population and its current treatment options are costly. There are not enough studies that evaluated the efficacy and safety of anti-inflammatory drugs medications used to reduce rheumatoid arthritis's symptoms. This study will evaluate the effectiveness and the safety of steroid and nonsteroidal anti-inflammatory drugs for the treatment of patients with rheumatoid arthritis. METHODS: Randomized clinical trials eligible for our systematic review will enroll adults with rheumatoid arthritis treated with anti-inflammatory drugs compared with a control group (placebo or active control) at any dose, duration, and route of administration and double blind studies. In order to include all forms of rheumatoid arthritis and anti-inflammatory drugs, we will search the following electronic databases: Cochrane Central Register of Controlled Trials, MEDLINE (via Ovid); ExcerptaMedica Database (via Ovid); Cumulative Index to Nursing and Allied Health Literature (via Ovid); Web of Science; ClinicalTrial.gov; and WHO International Clinical Trials Registry Platform. We will not impose any language restrictions or publication status. Outcomes of interest include are pain, physical function, swelling, stiffness, grip force, radiological image of the joint, quality of life, adverse events, discontinuation due to adverse events, satisfaction with the treatment, and rescue medication for pain. A team of reviewers will independently screen search results, extract data from eligible trials, and assess risk of bias. We will use the Grading of Recommendations Assessment, Development and Evaluation approach to rate overall certainty of the evidence by outcome. Dichotomous data will be summarized as risk ratios; continuous data will be given as standard average differences with 95% confidence intervals. RESULTS: The evidence derived by this study will increase awareness of the effectiveness and safety of steroid and nonsteroidal anti-inflammatory drugs for the treatment of rheumatoid arthritis. CONCLUSION: The results could guide patients and healthcare practitioners and help facilitate evidence-based shared care decision making.
29419465 Safety, and Humoral and Cell-mediated Immune Responses to Herpes Zoster Vaccine in Patient 2018 Apr OBJECTIVE: To examine humoral and cellular immune responses induced by a live attenuated herpes zoster (HZ) vaccine in patients with rheumatoid arthritis (RA) compared with osteoarthritis (OA) patients. METHODS: This was an observational study of a live attenuated HZ vaccine in 41 patients with RA receiving conventional disease-modifying antirheumatic drugs (cDMARD) and/or low-dose glucocorticoids (GC) and in 28 patients with OA. Blood samples were obtained before and at 12 weeks after HZ vaccination. Immunogenicity was assessed using varicella zoster virus (VZV)-specific interferon gamma ELISA and an in-house ELISA. Clinical outcomes, including adverse events, HZ occurrence, and RA flares, were analyzed. RESULTS: No patients developed vaccination-induced HZ during the followup period (median = 1.6 yrs). The HZ vaccine induced a significant increase in the VZV-specific enzyme-linked immunospot spot-forming units and anti-VZV immunoglobulin G antibodies in patients with RA and OA. The number of spot-forming units was lower in patients with RA than in patients with OA both at baseline and at 12 weeks after vaccination. The disease activity index for patients with RA was similar at baseline and at 12 weeks after vaccination. However, 6 patients with RA (14.6%) experienced a flare during the 12 weeks. Overall, 17 (24.6%) participants reported a mild adverse event such as an injection site reaction (11.6%). CONCLUSION: The HZ vaccine induced VZV-specific cellular and humoral responses in patients with RA. Although patients with RA showed a weaker vaccine-induced VZV-specific cellular immune response than patients with OA, the vaccine may be considered in patients with RA receiving cDMARD and/or low dose GC.
30574751 Correlation between rheumatoid arthritis and immunological changes in a rheumatoid arthrit 2018 Nov Rheumatoid arthritis is an autoimmune disease characterized by the synovitis of joints and the modulation of chronic inflammation determined by increased levels of inflammatory cytokines. This study aimed to investigate the characteristics of the immunological profile of the cells of the synovial membrane and the expression of IL-10 and IL-17 in a rheumatoid arthritis rat model in order to provide a targetdirected treatment for immunological control. Eighty female Wistar rats were randomly divided into a rheumatic arthritis model group (model group) and a control group, 40 animals per group. After the successful rheumatoid arthritis rat model was obtained, 10 animals were sacrificed from each group every week starting from the third week till the sixth week and the expression levels of CD3, CD21, and CD68 in the synovial region along with the blood level of IL-10 and IL-17 were assessed. At the four stages after modeling, the expression of CD3 in the model group increased compared with the control group (P less than 0.05). The expression of CD21 was different between the model group and the control group, but the difference did not reach statistical significance (P>0.05). The expression of CD68 determined at weeks 4 and 5 after modeling was increased compared to the control group (P less than 0.05). At 6 week after modeling, IL-10 levels in the model group were higher than those in the control group (P less than 0.05). At weeks 4 and 5 after modeling, the level of IL-17 in the model group increased compared to the control group (P less than 0.05). The level of IL-17 increased with the increase of synovial inflammation in the rheumatoid arthritis-induced rats, and the level of IL-10 increased as the inflammation subsided, which shows that both cytokines are related to the occurrence and development of rheumatoid arthritis and its inflammation.
29404725 Comparison of the efficacy and tolerability of tocilizumab, sarilumab, and sirukumab in pa 2018 Jun The relative efficacy and tolerability of tocilizumab, sarilumab, and sirukumab were assessed in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or tumor necrosis factor (TNF) inhibitors. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tocilizumab, sarilumab, and sirukumab in RA patients and an inadequate MTX or TNF inhibitor response. Fourteen RCTs, comprising 9753 patients, met the inclusion criteria. Tocilizumab 8 mg combined with MTX or as monotherapy was the most effective treatment for active RA with an inadequate MTX or TNF antagonist response, followed by sarilumab and sirukumab, regardless of MTX combination. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg + MTX had the highest probability of being the best treatment to achieve the ACR50 response rate, followed by tocilizumab 8 mg, sarilumab 200 mg, sarilumab 200 mg + MTX, sirukumab 100 mg, tocilizumab 4 mg + MTX, sirukumab 100 mg + MTX, sirukumab 50 mg + MTX, sarilumab 150 mg + MTX, adalimumab 40 mg, and sirukumab 50 mg, and placebo + MTX. No significant differences were observed in withdrawals owing to adverse events after treatment with tocilizumab 8 mg + MTX, sirukumab 100 mg + MTX, or sarilumab 200 mg + MTX. In RA patients with an inadequate MTX or anti-TNF therapy response, tocilizumab 8 mg as monotherapy and combined with MTX showed acceptable tolerability and the highest performance based on the ACR50 response rate, followed by sarilumab and sirukumab.
29129009 IRAK2 is associated with susceptibility to rheumatoid arthritis. 2018 Apr This study was performed to investigate the association of the single nucleotide polymorphisms of interleukin-1 receptor-associated kinase 2 (IRAK2) rs3844283 and rs708035 with rheumatoid arthritis (RA). IRAK2 rs3844283 and rs708035genotyping was determined by mutagenically separated PCR with specifically designed primers in a cohort of 222 (30 men, 192 women, mean age 49 years) adult RA patients and 224 matched controls. IRAK2 rs3844283 C allele was detected in 66% of RA patients and 74% of controls. The CC genotype was the most frequent genotype in both RA patients (45.5%) and the controls (56.3%). The G allele was found to be associated with RA susceptibility (OR = 1.47, 95% CI = 1.10-1.96, p = 0.008). The GG genotype was found to be associated with RA in the co-dominant and the dominant models (OR = 2.03, 95% CI = 1.08-3.81, p = 0.042 and OR = 1.54, 95% CI = 1.06-2.23, p = 0.023, respectively). IRAK2 rs708035 was found not to be in the Hardy-Weinberg equilibrium. The hyperfunctional IRAK2 rs708035 A allele was more frequent in RA patients than in controls (69.9 versus 62.2%, respectively, p = 0.015). Moreover, IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium and the GA haplotype was significantly more frequent in RA patients than in controls (p = 0.034). This study for the first time ever reports the association of IRAK2 rs3844283, IRAK2 rs708035, and the corresponding haplotypes with RA. Functional studies are recommended to elucidate the risk posed by the GA haplotype for the development of RA.
30210123 An Analysis of the Biological Disease-modifying Antirheumatic Drug-free Condition of Adali 2019 Feb 15 Objectives The present study was performed with the aim of analyzing the biological disease-modifying antirheumatic drug (bDMARD)-free (Bio-free) condition of adalimumab (ADA)-treated rheumatoid arthritis (RA) patients in a real-world setting. Methods ADA was used in the treatment of 130 (male, n=21; female, n=109 females) RA patients. Among them, 26 patients (20.0%) discontinued ADA due to a good response. We analyzed 20 patients who were followed up for more than 6 months after the discontinuation of ADA. The Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and modified health assessment questionnaires (mHAQs) were evaluated. Results The mean age of the patients was 53.4±11.1 years. The mean disease duration was 4.5±4.3 years. Sixteen patients were bDMARD-naïve, while 4 switched from bDMARDs to ADA. At 6 months after the discontinuation ADA, 19 patients had achieved a clinical remission, and 1 had achieved a low disease activity. The Bio-free period was 26.4±15.5 months. The dose of prednisolone was significantly reduced from baseline (3.45±3.17 mg/day) at 6 months after the discontinuation of ADA (2.63±2.78 mg/day). The dose of methotrexate was unchanged. The number of conventional synthetic DMARDs (csDMARDs) was significantly increased (0.8±0.6 to 1.4±1.06). The mHAQ values were significantly ameliorated by ADA and remained good in patients with a Bio-free condition. A multivariate analysis showed that the dose of methotrexate (MTX) was an important factor for achieving a Bio-free condition. Conclusion A sustainable Bio-free condition in a real clinical setting can be achieved and may be a suitable way of reducing medical costs. The dose of MTX and the additional administration of csDMARDs is therefore thought to be important for ensuring a good outcome in these patients.
29297100 Effect of daily low dose prednisone, divided or single daily dose, in the treatment of Afr 2018 Feb Determine the effect of daily low divided or single daily dose of prednisone on the longitudinal change in the number of tender and swollen joints and HAQ scores in African Americans (AA) with early rheumatoid arthritis (RA) from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) 1 Registry. In a prospective, multicenter observational cohort study, AA with early RA were enrolled and followed longitudinally for up to 5 years. 345 were enrolled. The mean age at enrollment was 51 years and 82% were women. At baseline, the prevalence of low dose prednisone use was 77% and median prednisone dose was 10 mg. At enrollment 238 patients were on single daily and 107 on divided daily doses of prednisone. There was a significant reduction during follow-up in the number of tender and swollen joints and in the HAQ scores in all patients. Cohort retention was 54%. The adjusted mean number of tender joints was approximately 2-3 joints lower for patients on divided daily dose compared to a single daily dose in follow up. The rate of osteopenia and osteoporosis at 5 years remained similar to baseline prevalence and no difference in the treatment groups. At 5 years the percentage of patients with hypertension was lower in the divided daily prednisone group. During the 5 years of follow-up, clinical outcomes improved in all AA patients with early RA. Reduced number of tender joints was associated with divided daily low doses of prednisone. Hypertension was less in those treated with divided daily doses of prednisone.
30094742 Review of Biosimilar Trials and Data on Adalimumab in Rheumatoid Arthritis. 2018 Aug 9 PURPOSE OF REVIEW: Adalimumab is one of the top-selling drugs worldwide. Its imminent patent expiration has seen the emergence of numerous biosimilar agents. In this article, we recap the evidence from bio-originator trials in rheumatoid arthritis (RA) to provide context for a critical review of biosimilar trial data. RECENT FINDINGS: Currently, three adalimumab biosimilars are approved in Europe and/or the USA: Amgen's ABP 501 (AMJEVITA/Solymbic), Boehringer Ingelheim's BI 695501 (Cyltezo) and Samsung Bioepis's SB5 (Imraldi). All three agents met their pre-specified equivalence criteria. Subtle differences in adverse events and clinical responses between the reference and biosimilar products were noted. The introduction of adalimumab biosimilars will offer exciting opportunities in improving treatment access and increasing treatment options for RA and other licensed indications. Real-world data will further provide assurances on efficacy as well as safety.
29563337 TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflamma 2018 Mar 22 TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency. We report that the initiation of zymosan-induced inflammatory pain and zymosan-induced arthritic pain and disease are TNF dependent. Once arthritic pain and disease are established, blockade of GM-CSF or CCL17, but not of TNF, is still able to ameliorate them. TNF is required for GM-CSF-driven inflammatory pain and for initiation of GM-CSF-driven arthritic pain and disease, but not once they are established. TNF-driven inflammatory pain and TNF-driven arthritic pain and disease are dependent on GM-CSF and mechanistically require the same downstream pathway involving GM-CSF→CCL17 formation via JMJD3-regulated IRF4 production, indicating that GM-CSF and CCL17 can mediate some of the proinflammatory and algesic actions of TNF. Given we found that TNF appears important only early in arthritic pain and disease progression, targeting a downstream mediator, such as CCL17, which appears to act throughout the course of disease, could be effective at ameliorating chronic inflammatory conditions where TNF is implicated.
29470611 Osteoporosis in Rheumatic Diseases: Anti-rheumatic Drugs and the Skeleton. 2018 May Osteoporosis in rheumatic diseases is a very well-known complication. Systemic inflammation results in both generalized and localized bone loss and erosions. Recently, increased knowledge of inflammatory process in rheumatic diseases has resulted in the development of potent inhibitors of the cytokines, the biologic DMARDs. These treatments reduce systemic inflammation and have some effect on the generalized and localized bone loss. Progression of bone erosion was slowed by TNF, IL-6 and IL-1 inhibitors, a JAK inhibitor, a CTLA4 agonist, and rituximab. Effects on bone mineral density varied between the biological DMARDs. Medications that are approved for the treatment of osteoporosis have been evaluated to prevent bone loss in rheumatic disease patients, including denosumab, cathepsin K, bisphosphonates, anti-sclerostin antibodies and parathyroid hormone (hPTH 1-34), and have some efficacy in both the prevention of systemic bone loss and reducing localized bone erosions. This article reviews the effects of biologic DMARDs on bone mass and erosions in patients with rheumatic diseases and trials of anti-osteoporotic medications in animal models and patients with rheumatic diseases.