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ID PMID Title PublicationDate abstract
30852105 Disseminated nocardiosis with Nocardia brasiliensis bacteremia in a patient with rheumatoi 2019 Jul Here, we present a case of disseminated nocardiosis, involving pneumonia, percutaneous abscess, and bacteremia, in a 67-year-old Japanese woman. She had also been treated for rheumatoid arthritis with prednisolone, methotrexate, and tocilizumab (interleukin-6 receptor inhibitor). Based on the 16S rRNA sequence analysis and a blast search, we identified the isolate as Nocardia brasiliensis. We discontinued methotrexate and tocilizumab on admission, and administered intravenous antimicrobial combination therapy for 6 weeks, followed by oral trimethoprim-sulfamethoxazole for 12 months, in total. Nocardia bacteremia is rare, often difficult to diagnose, and substantially fatal. However, due to our prompt diagnosis within one day of the onset of symptoms, and administration of appropriate treatment based on antimicrobial susceptibilities, this patient succeeded in surviving the infection. Not only microbiologists but also clinicians should be aware of the characteristic bacterial form of Gram/Kinyoun staining for early recognition of nocardiosis.
30418124 Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin se 2019 May OBJECTIVES: In patients with rheumatoid arthritis (RA), insulin resistance (IR), a component of the metabolic syndrome, is closely linked to the systemic inflammation induced by proinflammatory cytokines such as tumor necrosis factor-α and interleukin (IL)-6. In the present study, we aimed to assess if an intravenous administration of the anti-IL-6 receptor tocilizumab may yield a rapid improvement of IR in RA. METHODS: 50 consecutive non-diabetic patients with RA refractory to methotrexate, undergoing periodic treatment with tocilizumab, were studied. Besides disease activity, serum insulin, insulin/glucose ratio, insulin resistance (HOMA-IR) and insulin sensitivity (QUICKI) indexes were assessed immediately before and 1 hour after the end of an intravenous administration of tocilizumab (given in saline solution over 60 minutes). RESULTS: When comparing baseline data (immediately before) and 1 hour after finishing tocilizumab administration, we observed a dramatic decrease of the serum insulin levels and insulin/glucose ratio. Also, a statistically significant reduction of IR (HOMA-IR: mean± standard deviation immediately before: 2.62±2.03 vs. 1.65±1.15 1 hour after the end of the infusion (p<0.01) and a statistically significant increase of insulin sensitivity (QUICKI immediately before 0.34±0.03 vs. 0.37±0.04 1 hour after the end of tocilizumab infusion (p<0.01) was observed. CONCLUSIONS: The intravenous administration of tocilizumab yields a rapid beneficial effect on IR and insulin sensitivity in non-diabetic RA patients. These findings support the potential beneficial effect of the IL-6 blockade on the mechanisms associated with the development of metabolic syndrome and cardiovascular disease in patients with RA.
31089968 Deciphering the pharmacological mechanism of Guan-Jie-Kang in treating rat adjuvant-induce 2019 Oct Traditional Chinese medicine (TCM) formulas have attracted increasing attention worldwide in the past few years for treating complex disease including rheumatoid arthritis. However, their mechanisms are complex and remain unclear. Guan-Jie-Kang (GJK), a prescription modified from "Wu Tou Decoction," was found to significantly relieve arthritis symptoms in rats with adjuvant-induced arthritis after 30-day treatment, especially in the 24 g/kg/day group. By analyzing 1749 targets related to 358 compounds in the five herbs of GJK, we identified the possible anti-arthritis pathways of GJK, including the calcium signaling and metabolic pathways. Bone damage levels were assessed by micro-computed tomography, and greater bone protective effect was observed with GJK treatment than with methotrexate. Receptor activator of nuclear factor κB ligand (RANKL)-RANK signaling, which is related to calcium signaling, was significantly regulated by GJK. Moreover, a target metabolomics assay of serum was conducted; 17 metabolic biomarkers showed significant correlations with treatment. An integrated pathway analysis revealed that pyruvate metabolism, purine metabolism, and glycolysis metabolism were significantly associated with the effects of GJK in arthritis treatment. Thus, this study establishes a new omics analytical method integrated with bioinformatics analysis for elucidating the multi-pathway mechanisms of TCM.
29283072 Onset of Hypertension in Leflunamide Treated Low Socioeconomic Rheumatoid Arthritis Patien 2019 OBJECTIVE: To determine the frequency of new-onset hypertension in patients with Rheumatoid arthritis taking leflunomide, in comparison with methotrexate in Asian setting. MATERIAL AND METHODS: Perspective case-control study was conducted in 2014 in a tertiary care hospital located in Karachi, Pakistan. Adult patients, having rheumatoid arthritis were randomly prescribed leflunomide or methotrexate. Patients having chronic hypertension, proteinuria and chronic kidney disease were excluded. Patients were monthly followed for blood pressure and heart rate measurements. Hypertension was defined using JNC 7 criteria. RESULTS: Out of 144 patients enrolled, 80 patients received Leflunomide while 64 were started on methotrexate. Mean systolic blood pressure in leflunomide group at the start and at the end of study was 108.5 and 135.4mmHg, respectively while in methotrexate group, mean systolic BP was 109.8 and 110.5 mmhg, respectively. After one year follow up, 33 out of 80 (41%) patients were receiving leflunomide had pre-hypertension or hypertension, while only 3 out of 64 patients (4.7%) were receiving methotrexate had hypertension. CONCLUSION: Risk of developing hypertension in patient receiving Leflunomide is much higher in Asian population like Pakistan as compared to western population.
31167761 Development and validation of a methotrexate adherence assay. 2019 Sep BACKGROUND: The first-line therapy for rheumatoid arthritis (RA) is weekly oral methotrexate (MTX) at low dosages (7.5-25 mg/week). However, ~40% of patients are non-adherent which may explain why some do not respond and need to start more expensive biological therapies. To monitor adherence more accurately and develop strategies to improve it, a validated objective MTX adherence test is required. OBJECTIVE: To develop and validate the diagnostic accuracy of a novel MTX adherence assay using high-performance liquid chromatography-selected reaction monitoring- mass spectrometry (HPLC-SRM-MS) based biochemical analysis of drug levels. METHODS: 20 patients with RA underwent MTX pharmacokinetic assessment using HPLC-SRM-MS MTX plasma concentration analysis over a 6-day period. Directly observed therapy was the reference standard. Pharmacokinetic model validation was performed using independent plasma samples from real-world patients (n=50) with self-reported times of drug administration. Following assay optimisation, the sensitivity of the assay to detect adherence was established using samples from an observational cohort study (n=138). RESULTS: A two-compartment pharmacokinetic model was developed and validated. Simulations described the sensitivity required for MTX detection over 7 days; subsequent assay optimisation and retesting of samples confirmed that all patients were correctly identified as MTX adherers. Using real-world samples, the assays sensitivity was 95%. CONCLUSION: Non-adherence to MTX is common and can have a significant effect on disease activity. HPLC-SRM-MS plasma analysis accurately detects MTX adherence. The validated objective test could easily be used in clinic to identify patients requiring adherence support.
31099054 Membrane-Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcom 2019 Nov Methotrexate (MTX) is a first-line disease-modifying antirheumatic drug for rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. The differences in drug efficacy and adverse drug reactions may be caused by genetic variations. We investigated the effects of single-nucleotide polymorphisms (SNPs) in 2 genes encoding membrane-spanning proteins, namely, reduced folate carrier-1 RFC-1/SLC19A1 (G>A [rs7499], A>G [rs2838956] and 180G>A [rs1051266]) and adenosine triphosphate-binding cassette B1 (rs1045642). Tagged SNPs were genotyped in 162 patients with RA in China. Then, we analyzed the relationships between these SNPs and therapeutic outcomes related to MTX in Chinese RA patients. No significant associations were found between the RFC-1/SLC19A1 (G>A [rs7499] and A>G [rs2838956]) and adenosine triphosphate-binding cassette B1 (rs1045642) gene polymorphisms and the response to MTX in RA patients. However, MTX-related toxicity was associated with one SNP, RFC-1 rs1051266 AA vs GG (odds ratio, 6.523; 95% confidence interval, 1.596-26.565; P = .009). SLC19A1 A>G rs2838956 showed a trend toward a significant association (odds ratio, 0.377; 95% confidence interval, 0.124-1.143; P = .085) with toxicity. Our results suggest that the RFC-1 80G>A (rs1051266) SNP exerts a potentially protective effect against the risk of adverse drug reactions in Chinese RA patients treated with MTX. Further studies are required to validate these findings.
31353421 The longitudinal effect of biologic use on patient outcomes (disease activity, function, a 2019 Nov INTRODUCTION: Biologics effectively manage symptoms and disease activity in rheumatoid arthritis (RA), but their long-term effects remain unclear. METHOD: Longitudinal data were examined from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry. Linear regression modeled the effect of biologic exposure on changes in disease activity (Disease Activity Score-28 with C-reactive protein [DAS28-CRP]), functional status (modified Health Assessment Questionnaire [mHAQ]), and RA severity (Routine Assessment of Patient Index Data [RAPID3]). Biologic exposure was the ratio of time on a biologic relative to time participating in the BRASS cohort. RESULTS: The analysis included 1395 RA patients, 82.3% female, with 6783 unique study visits from 2003 to 2015. At the patient's first visit, mean (SD) age was 56.3 (14.2) years and mean (SD) duration of RA was 12.7 (11.9) years. Average follow-up duration was 5.59 years (range, 1-13). Over time, DAS28-CRP, mHAQ, and RAPID3 scores decreased as the biologic exposure ratio increased. In repeated measures regression models, increased biologic exposure was significantly associated with decreased DAS28-CRP score (β = - 0.647; P < 0.001), decreased mHAQ score (β = - 0.096; P < 0.001), and decreased RAPID3 score (β = - 0.724; P < 0.001) during follow-up. Methotrexate use at baseline predicted decreased DAS28-CRP, mHAQ, and RAPID3 scores during follow-up. Biologic use at baseline predicted increased DAS28-CRP or mHAQ during follow-up. CONCLUSIONS: Increased biologic exposure is associated with decreased disease activity, function impairment, and RA severity. Future studies should examine whether earlier initiation of biologics improves patient outcomes in RA. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01793103 Key Points • Biologics effectively manage symptoms and disease activity in rheumatoid arthritis (RA), but their long-term effects remain unclear. • In this analysis of longitudinal annual population samples of 1395 RA patients in the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) registry, disease activity, function, and severity scores improved as time on biologic therapy increased. • In repeated measures regression models, time on biologic therapy was a significant predictor of improved outcomes for disease activity, function, and RA severity. • Further studies should examine whether earlier initiation of biologics limits the long-term effect of inflammation on RA outcomes.
30649682 Contraception methods used by women with rheumatoid arthritis and psoriatic arthritis. 2019 Apr Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are common in women of childbearing age and are often treated with teratogenic medications. In this study, we assessed contraceptive methods in young women with RA or PsA and correlated contraceptive method efficacy with use of concomitant rheumatic medications. We combined the data from several cross-sectional surveys of women under the age of 40 with RA or PsA. Two surveys recruited participants from a clinic setting (RA and PsA Clinic Surveys), and the third survey recruited participants from CreakyJoints.org , an online forum for patients with inflammatory arthritis (CreakyJoints Survey). Of the 164 women included, 138 had RA (67 in RA Clinic Survey, 71 in CreakyJoints Survey) and 26 had PsA (19 in PsA Clinic Survey, 7 in CreakyJoints Survey). Use of specific contraceptive and rheumatic medications were similar between the clinic and online surveys. In the pooled analysis of the Clinic and CreakyJoints survey data, women with RA and PsA reported similar utilization of highly effective contraception methods (31.9% RA, 34.6% PsA) and effective methods (31.2% RA, 30.8% PsA), but different utilization of ineffective methods (35.5% RA, 11.5% PsA) and no methods (1.5% RA, 23.1% PsA), p = 0.0002. These proportions remained similar across subgroups taking methotrexate, anti-TNF biologics, and novel medications. Approximately two thirds of women with RA and PsA reported using effective or highly effective methods of contraception, though women with PsA were more likely to report no methods of contraception.
31522319 Clinico-genetic model to predict methotrexate intolerance in rheumatoid arthritis. 2020 Jan INTRODUCTION: Methotrexate is the gold-standard DMARD in rheumatoid arthritis but is often associated with "mild" adverse effects like intolerance or laboratory abnormalities. Although non-life threatening, they are responsible for drug discontinuation in 17-50%. There is limited data on clinical and genetic markers that predict their occurrence. METHODS: This prospective study enrolled patients with active rheumatoid arthritis. They were started on methotrexate at a weekly dose of 15 mg, escalated gradually to reach 25 mg which was continued till the end of the study. Intolerance (symptomatic adverse effects) was ascertained by a questionnaire at 4, 8, 16, and 24 weeks. Laboratory testing for occurrence of cytopenia and/or transaminitis was done at the same study visits. Seven SNPs in four genes involved in methotrexate handling were genotyped using real-time polymerase chain reaction. RESULTS: This study included 110 patients with rheumatoid arthritis who received methotrexate for 24 weeks; the final mean weekly methotrexate dose was 22.0 ± 4.0 mg. Methotrexate intolerance occurred in 40 (37%), common being nausea (and vomiting) in 29 and anxiety (and dizziness) in 9. It was associated with lower BMI at baseline (21.5 ± 3.7, 23.8 ± 4.6 kg/m(2), p = 0.01). FPGS rs10106 was significantly associated with intolerance with an allelic odds ratio (95% CI) of 2.02 (1.14-3.57) and the recessive genetic model (AA+AG versus GG) with an odds ratio of 3.8 (95% CI 1.5-9.6, p = 0.004). A model including both BMI and FPGS rs10106 could modestly predict methotrexate intolerance with an accuracy of 66.3%. CONCLUSIONS: A clinical-genetic model including BMI and SNP FPGS 10101 was found to have a modest prediction ability for methotrexate intolerance.Key Points• Methotrexate intolerance (symptomatic adverse effects) was common and occurred in 37% patients over 6 months.• SNP FPGS rs10106 and low body mass index were associated with methotrexate intolerance.• Clinico-genetic model had a modest ability of 66% for predicting intolerance.
31362993 Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with 2019 Nov BACKGROUND: In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks. Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response. METHODS: Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks. Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had <20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) >10 (week 26); remaining placebo patients were switched to upadacitinib at week 26. Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed). Treatment-emergent adverse events per 100 patient-years were summarised. RESULTS: Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation). Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab. Safety at week 48 was comparable to week 26. CONCLUSION: Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48. Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout.
31154348 Methotrexate and doxycycline interaction: a rare cause of pancytopenia. 2019 May 31 Methotrexate (MTX) was originally formulated as one of the first antitumour drugs due to its ability to alter folate metabolism, which renders it to be an antiproliferative agent. Classically, the higher dosage is administered via parenteral route, in a cyclical fashion, to achieve antitumour effects. Patients on high doses of MTX are prone to develop rare complications of myelosuppression and pancytopenia, in a dose-dependent fashion, secondary to altered folate metabolism. (1) Herein, we present a unique case of rheumatoid arthritis presented with pancytopenia due to low-dose MTX and doxycycline drug interaction. We also report the successful management of pancytopenia and oral ulcers with combination therapy of leucovorin and granulocyte colony-stimulating factor.
31067155 Multicenter, observational clinical study of abatacept in Japanese patients with rheumatoi 2019 Mar The aim of this study was to assess abatacept in rheumatoid arthritis (RA) patient. Patients (20 men, 89 women, aged 61.9 ± 10.4 y) who responded inadequately to conventional synthetic disease-modifying anti-rheumatic drug were treated with abatacept for 24-months. Disease activity score in 28 joints (DAS28-CRP) was evaluated. Of 109 patients, 82 (75.2%) were on methotrexate (MTX; mean dosage 9.0 ± 2.7 mg/week); 48 (44.0%) were naive to biologics and 61 (56.0%) had failed biologics. The 1- and 2-year retention rates were 77% and 53%, respectively. At 24-months, the DAS28-CRP remission rates were 54.5% in the biologic-naïve patients, and 28.2% in the biologic-failure patients (p < .01), while the structural remission rates were 83.9% and 73.1%, respectively (p = .461). Abatacept was equally effective in RA patients who were and were not on concomitant MTX. Biologic-naïve was associated with better clinical outcome. Abatacept was effective in patients who showed decreasing anti-CCP antibody titers or serum MMP-3 levels during treatment. Infection was the most frequent adverse effect of abatacept therapy. In conclusion, abatacept is more effective in biologic-naïve than in biologic-failure RA patients with or without concomitant use of MTX. Abatacept is more effective in RA patients with than without decreasing serum MMP-3 or anti-CCP antibody titers during treatment.
30658314 Highly aggressive plasmablastic neoplasms in patients with rheumatoid arthritis treated wi 2019 Mar Patients with rheumatoid arthritis occasionally develop lymphoproliferative disorders. Methotrexate-associated lymphoproliferative disorders is a lymphoproliferative disease or lymphoma in patients treated with methotrexate for autoimmune diseases, such as rheumatoid arthritis. Here we report two rare cases of highly aggressive plasmablastic lymphoproliferative disorders in rheumatoid arthritis treated with methotrexate. Case 1 is a 68-year-old female patient with leukemic transformation of malignant lymphoma. She received methotrexate therapy for rheumatoid arthritis for >6 years. The patient showed rapid progressive course and died on the 2nd hospital day. After the death, we diagnosed the patient as plasmablastic lymphoma. Case 2 is an 80-year-old female patient with plasmablastic plasma cell myeloma, with a history of methotrexate treatment for rheumatoid arthritis for >5 years. Although M-protein was decreased by chemotherapy, bone marrow examination revealed the further increase of plasmablastic cells and she died 2 months later. The present cases were difficult to diagnose because proliferation of malignant plasmablasts was hardly predicted because neither lymph node enlargement nor an evident M-protein was observed. Both cases showed aggressive features and extremely poor prognosis. Clinicians should be aware of the underlying malignant plasmablastic proliferation when inexplicable inflammatory findings are observed in inactive rheumatoid arthritis patients.
30730220 Abatacept for the treatment of rheumatoid arthritis. 2019 Apr Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the initiation and perpetuation of disease. Abatacept is a fusion protein composed of the Fc region of the immunoglobulin G1 (IgG1) fused to the extracellular domain of cytotoxic T lymphocyte-associated antigen (CTLA4). It has the ability to modulate T-cell activation by interfering with co-stimulation of these cells, a necessary step to become activated. This suggests that abatacept may play a role in the progression and/or even the initiation of RA. Areas covered: a review of the different studies carried out during clinical development of abatacept was performed. Both formulations, intravenous (IV) and subcutaneous (SC), showed a similar and consistent efficacy and safety profile. Abatacept was effective both in RA patients not responding to methotrexate (MTX) and to tumor necrosis factor (TNF) inhibitors. Expert commentary: abatacept, with its unique mechanism of action, proved to be a useful therapeutic alternative in RA, also having an acceptable safety profile. Evidence points out that abatacept may be able to alter the RA disease course. Ongoing studies will clarify this issue.
30295428 Risk for Herpes Zoster in Tofacitinib-Treated Rheumatoid Arthritis Patients With and Witho 2019 Sep OBJECTIVE: Increased incidence of herpes zoster (HZ) has been observed with JAK inhibitors such as tofacitinib. However, whether concomitant methotrexate (MTX) and/or glucocorticoids confer additional (additive or multiplicative) risk is unclear. We evaluated HZ risk in tofacitinib users with and without MTX and glucocorticoids. METHODS: Within MarketScan and Medicare data (2011-2016), we identified all patients with rheumatologist-diagnosed rheumatoid arthritis initiating treatment with tofacitinib (index date); demographics and baseline covariates were evaluated in the year prior to the index date. HZ was ascertained using International Classification of Diseases, Ninth Revision or Tenth Revision codes with antiviral drug use (±7 days). Multivariable Cox regression was used to evaluate hazard ratios (HRs) for HZ in tofacitinib users with and without current concomitant MTX and glucocorticoids, controlling for baseline covariates. RESULTS: We studied 8,030 new tofacitinib users (83.3% women). The mean ± SD age was 60.3 ± 12.6 years. HZ incidence in tofacitinib users was numerically lowest in the absence of glucocorticoids (3.4 per 100 patient-years with MTX; 3.7 per 100 patient-years without MTX). An approximately 2-fold increased incidence of HZ was observed for tofacitinib users receiving either glucocorticoids alone (6.0 per 100 patient-years) or both MTX plus glucocorticoids (6.5 per 100 patient-years). The adjusted HR for HZ in tofacitinib users was unchanged (HR 0.99 [95% confidence interval (95% CI) 0.64-1.54]) when given only with MTX, but was increased (HR 1.96 [95% CI 1.33-2.88]) for tofacitinib plus glucocorticoids. Older age and female sex were also risk factors, while prior vaccination was associated with a strong trend for lower risk. CONCLUSION: In tofacitinib users, HZ occurred at a rate of approximately 4% per year and was further doubled with glucocorticoid exposure. Concomitant MTX did not confer additional risk. Zoster vaccination may decrease risk.
30841475 Thymoquinone attenuates rheumatoid arthritis by downregulating TLR2, TLR4, TNF-α, IL-1, a 2019 Mar BACKGROUND: Thymoquinone (TQ), the most important active principle of Nigella sativa is known to have anti-inflammatory, analgesic, antimicrobial and antioxidant properties. AIM: The present study was designed to see the anti-arthritic effect of TQ in rat model of arthritis. METHODS: In the current research, anti-arthritic effect of TQ was determined in Freund's Complete Adjuvant (FCA)-induced arthritic rats by measuring TLRs expression levels. The mRNA expression levels of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), interleukin-1 (IL-1), nuclear factor-kappa B (NFκB) and tissue necrosis factor-α (TNF-α) were measured by reverse-transcription polymerase chain reaction. Arthritic signs were observed by macroscopic criteria. Hematoxylin and Eosin staining was used to perform ankle joint histopathology and agglutination method was used for measuring C-reactive protein (CRP) levels. Rheumatoid factor, alanine transaminase, aspartate aminotransferase, urea and creatinine were also determined in serum. RESULTS: TQ treatment reduced the macroscopic arthritic score, levels of CRP, synovial inflammation, pannus formation and bone erosion. It also reduced the mRNA levels of TLR2, TLR4, IL-1, NFκB and TNF-α. Methotrexate, used as a reference drug also significantly decreased their expression levels. TQ also normalized the hematological markers and did not depict any signs of hepatotoxicity and nephrotoxicity as determined by serum levels of alanine transaminase, aspartate aminotransferase, urea and creatinine. Our results showed that TQ possesses significant anti-arthritic activity which can be due to its anti-inflammatory and immunomodulatory effects. CONCLUSION: Results indicate that TQ has got the potential to ameliorate rheumatoid arthritis by downregulating TLR2, TLR4, TNF-α, IL-1, and NFκB expression levels.
31422723 Establishment of anti-C1q monoclonal antibodies to measure serum C1q levels discriminating 2020 Sep Objectives: To establish anti-C1q monoclonal antibodies which can measure serum C1q levels discriminating disease severity subsets of rheumatoid arthritis (RA) within 5 years of onset.Methods: In this multi-centre, longitudinal, observational study, 122 RA patients [102 females, baseline age 58.5 years, rheumatoid factor (RF) positivity 78.7%, serum C-reactive protein (CRP) 1.2 mg/dl, and concomitant methotrexate (MTX) 4.9 mg/week (29.5%)] within 5 years of onset (disease duration 21.0 months) were enrolled from 1985 to 2000. Patients were not treated by more than 8 mg/week of MTX or biologics which may strongly affect the course of joint destruction. Disease severity at 10-15 years of onset was classified according to the number of destructed joints of overall 68 joints on plain radiographs (36 patients were mild RA group involving only peripheral joints and 86 were severe RA group involving large axial joints). Baseline serum C1q levels were evaluated by ELISA with newly developed 4 monoclonal anti-C1q antibodies, and compared between two groups as well as conventional RA disease activity markers.Results: There were no significant differences between two groups in baseline conventional RA disease activity markers such as RF, erythrocyte sedimentation rate, CRP, and matrix metalloproteinase-3. However, compared to mild RA group, severe RA group showed higher baseline serum C1q levels (μg/ml) evaluated by anti-C1q monoclonal antibodies of no.33 (104.8 ± 22.3 vs. 118.3 ± 19.3; p = .0024), no. 40 (102.6 ± 21.9 vs 121.2 ± 22.3; p = .000069), no. 54 (102.1 ± 22.5 vs. 119.3 ± 26.9; p = .00052), and no. 76 (105.6 ± 21.8 vs. 122.6 ± 26.4; p = .00043). Receiver operating characteristic curve analysis revealed that in patients with serum C1q levels of ≥110.5 μg/ml (measured by antibody no. 40), 78.9% (75/95) belonged to severe RA group.Conclusion: Measuring serum C1q levels of RA within 5 years of onset by newly developed anti-C1q antibodies may be useful in predicting the prognosis of disease severity evaluated by the extent of joint destruction.
30971306 Drug tolerability and reasons for discontinuation of seven biologics in 4466 treatment cou 2019 Apr 11 BACKGROUND: The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). METHODS: This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve). Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling. RESULTS: A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission. Drug retention rates for each discontinuation reason were as follows: lack of effectiveness [from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P < 0.001)], toxic adverse events [from 81.8% (IFX) to 94.0% (ABT), Cox P < 0.001], and remission [from 92.4% (ADA and IFX) to 97.7% (ETN), Cox P < 0.001]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 53.4% (IFX) to 75.5% (ABT) (Cox P < 0.001). CONCLUSIONS: TCZ showed the lowest discontinuation rate by lack of effectiveness, ABT showed the lowest discontinuation rate by toxic adverse events, ADA and IFX showed the highest discontinuation rate by remission, and ABT showed the highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in the adjusted model.
31434637 Effect of disease duration and prior disease-modifying antirheumatic drug use on treatment 2019 Dec OBJECTIVES: To determine if disease duration and number of prior disease-modifying antirheumatic drugs (DMARDs) affect response to therapy in patients with established rheumatoid arthritis (RA). METHODS: Associations between disease duration or number of prior DMARDs and response to therapy were assessed using data from two randomised controlled trials in patients with established RA (mean duration, 11 years) receiving adalimumab+methotrexate. Response to therapy was assessed at week 24 using disease activity outcomes, including 28-joint Disease Activity Score based on C-reactive protein (DAS28(CRP)), Simplified Disease Activity Index (SDAI) and Health Assessment Questionnaire Disability Index (HAQ-DI), and proportions of patients with 20%/50%/70% improvement in American College of Rheumatology (ACR) responses. RESULTS: In the larger study (N=207), a greater number of prior DMARDs (>2 vs 0-1) was associated with smaller improvements in DAS28(CRP) (-1.8 vs -2.2), SDAI (-22.1 vs -26.9) and HAQ-DI (-0.43 vs -0.64) from baseline to week 24. RA duration of >10 years versus <1 year was associated with higher HAQ-DI scores (1.1 vs 0.7) at week 24, but results on DAS28(CRP) and SDAI were mixed. A greater number of prior DMARDs and longer RA duration were associated with lower ACR response rates at week 24. Data from the second trial (N=67) generally confirmed these findings. CONCLUSIONS: Number of prior DMARDs and disease duration affect responses to therapy in patients with established RA. Furthermore, number of prior DMARDs, regardless of disease duration, has a limiting effect on the potential response to adalimumab therapy.
30183607 Real-world experience with tofacitinib for the treatment of rheumatoid arthritis. 2019 May OBJECTIVES: Oral targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), including the Janus kinase inhibitors tofacitinib and baricitinib, are the latest addition to the therapeutic options for rheumatoid arthritis (RA). Tofacitinib 5 mg, twice daily, is approved for treatment, with or without methotrexate, of moderate to severe active RA in adults not adequately responding to, or not tolerating one or more DMARDs. In this narrative review we aimed to provide an overview of the real-world evidence for tofacitinib in RA. METHODS: The literature was reviewed up to March 2018 for studies regarding the efficacy and safety of tofacitinib for the treatment of RA. The focus was mainly on real-world studies with implications for every day clinical practice. RESULTS: The efficacy and safety of tofacitinib have been comprehensively assessed in a wide programme of randomised controlled trials. Extensive observational research on tofacitinib in RA is also ongoing worldwide and a substantial body of post-marketing real-world data from clinical practice is becoming available. There was a degree of consistency across the real-world studies reviewed. Tofacitinib tends to be used as monotherapy more frequently than bDMARDS and appears to be effective without background methotrexate. The data show a manageable safety profile, with no new safety signals and a discontinuation rate from safety issues <10%. Patients initiating tofacitinib usually have longer disease duration and have been exposed to longer bDMARDs than patients initiating a bDMARD. CONCLUSIONS: Real-world data are a key component of the evidence supporting the effectiveness of this novel drug and are of interest to all stakeholders. Treatment persistence and adherence to tofacitinib are good overall and similar to those seen for bDMARDs.