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30285533 Safety and effectiveness of high-dose methotrexate (over 8 mg/week) in 2838 Japanese pat 2020 Jan Objectives: To confirm the safety and effectiveness of high-dose (>8 mg/week) methotrexate (MTX) for the treatment of rheumatoid arthritis in Japan.Methods: A postmarketing surveillance program enrolled Japanese patients with rheumatoid arthritis starting on high-dose MTX followed up for 24 or 52 weeks. Analyses for safety, risk factors affecting safety, and effectiveness were conducted.Results: The safety/effectiveness analysis sets included 2838/2779 and 335/326 patients in the 24 and 52-week follow-up groups, respectively. Incidence of adverse drug reactions (ADRs) and serious ADRs was 21.42 and 1.66% in the 24-week and 35.52 and 2.69% in the 52-week groups, respectively. The Disease Activity Score in 28 Joints (DAS28) was significantly decreased as early as four weeks from the start of high-dose MTX; after 24-week (4.09-3.21) and 52-week treatment (3.91-2.80; both p < .001). In a majority of patients at baseline who had high-to-moderate disease activity, the remission rate (defined as DAS28-4ESR <2.6) increased three-fold from 10.6% (baseline) to 33.0% (24-week) compared to patients with low disease activity whose remission rate increased two-fold from 24.0% (baseline) to 53.6% (24 weeks).Conclusion: High-dose MTX was well tolerated in Japanese patients, resulted in improved disease control, and can be considered a step forward in achieving treat-to-target goals.
32686533 Presence of anti-citrullinated protein antibodies and costs and disease activity in early 2020 Sep Objective: To analyse healthcare utilization, loss of productivity, and disease activity in relation to presence of anti-citrullinated protein antibodies (ACPAs). Method: In total, 447 ACPA-positive and 224 ACPA-negative patients from two early rheumatoid arthritis cohorts, recruited 1996-1998 (cohort 1) and 2006-2009 (cohort 2), were followed during 3 years. Data on disease activity were collected, and patients reported healthcare utilization and days lost from work. Disease activity, healthcare costs, and loss of productivity were compared between ACPA groups. Linear regression was performed, controlling for confounders. Results: Healthcare costs did not differ significantly by ACPA status (EUR 3214 for vs EUR 2174 for ACPA-positive vs ACPA-negative patients in cohort 1, ns; EUR 4150 vs EUR 3820 in cohort 2, ns). Corresponding values for loss of productivity were EUR 9148 vs EUR 7916 (ns) and EUR 5857 vs EUR 5995 (ns). Total prescription of traditional disease-modifying anti-rheumatic drugs was higher in cohort 2 than in cohort 1. Methotrexate prescription was higher in ACPA-positive patients, but biologics did not differ significantly between ACPA groups. Disease activity was significantly more improved in cohort 2, but there was no difference in achieving remission in relation to ACPA status. In cohort 1, 25% of ACPA-positive patients were in remission vs 31% of ACPA-negative (ns) and in cohort 2, 55% vs 60% (ns). Conclusions: With increasing drug treatment for both ACPA-positive and ACPA-negative patients, outcome in ACPA-positive was no more severe than in ACPA-negative patients. Healthcare costs and loss of productivity were similar in the two groups.
33021334 Six-month flare risk after discontinuing long-term methotrexate treatment in patients havi 2020 Aug OBJECTIVES: We investigated the disease flare rate in patients with rheumatoid arthritis (RA) who achieved low disease activity following long-term methotrexate (MTX) treatment and the factors related to flare. METHODS: This retrospective longitudinal cohort study included patients with RA and low disease activity who were exposed to MTX for >10 years. Disease flare was defined as an increase in Disease Activity Score of 28 joints (DAS28) of >1.2 within 6 months of discontinuation of MTX. Logistic regression analysis was performed to identify the factors associated with flare. RESULTS: In total, 97 patients with RA were included in the study. The mean baseline DAS28 was 1.96 ± 0.56. The median cumulative MTX dose was 11.7 g; the median duration of exposure to MTX was 19 years. Following MTX discontinuation, flare occurred in 43 (44.3%) patients; the median time to flare was 99 (28-168) days. According to univariate logistic regression analysis, C-reactive protein, erythrocyte sedimentation rate (ESR) at discontinuation, the average ESR in the 6 months before discontinuation of MTX, a weekly dose of MTX before discontinuation, and use of other conventional synthetic disease-modifying antirheumatic drugs were associated with a higher risk of disease flare. In multivariable analysis, a weekly dose of MTX before discontinuation (odds ratio 1.014; 95% CI 1.014-1.342; P = .031) was significantly associated with flare risk. CONCLUSION: Among patients with RA who achieved low disease activity with long-term treatment with MTX, more than half remained flare free after MTX discontinuation. A higher MTX dose before discontinuation was associated with a high flare risk.
32472302 Autoantibodies against a novel citrullinated fibrinogen peptide related to smoking status, 2020 Nov Treatment recommendations of early rheumatoid arthritis (RA) suggest differential management of patients on the basis of prognostic factors. In this study we aimed to investigate the relationship between autoantibodies against a novel citrullinated fibrinogen peptide (anti-CFP), smoking status, clinical activity and therapeutic response in Cuban patients with early RA, receiving treatment with methotrexate in comparison to rheumatoid factor (RF), anti-cyclic citrullinated peptide of second generation (anti-CCP2) and anti-mutated citrullinated vimentin (anti-MCV). A 6-month prospective observational study was performed in 60 early RA patients at baseline and 6 months after receiving methotrexate. Baseline and outcome measures included disease activity score of 28 joints (DAS 28), simplified disease activity index (SDAI), anti-CFP antibodies, RF, anti-CCP2 and anti-MCV. Therapeutic response was determined using 20/50/70 American College of Rheumatology (ACR) response rates. DAS28 (p < 0.0001), SDAI (p < 0.0001) as well as titres of anti-CFP (p = 0.0481), anti-CCP2 (p = 0.0082), RF IgM (p = 0.0187) and RF IgA (p = 0.0252) decreased under therapy. Multivariate analyses showed association of final anti-CFP values with sex and smoking status (p = 0.0296). It is of note that anti-CFP antibodies were one of predictors for DAS 28 (p = 0.0072) SDAI (p < 0.0001) and ACR response (p = 0.0003) in multivariate models. Anti-CFP antibodies decrease in correspondence with clinical improvement after 6-month therapy and are associated with sex and smoking status. Moreover, baseline anti-CFP antibodies, using in combination with sex, smoking status and autoantibodies (anti-CCP2, anti-MCV or RF) seems to have clinical relevance for predicting clinical activity and therapeutic response.
32118795 Association between biologic disease modifying anti-rheumatic drugs and incident hypertens 2020 Feb There has been some debate between biologic disease modifying anti-rheumatic drugs (bDMARDs) treatment and hypertension (HTN) in rheumatoid arthritis (RA). The aim of this study was to determine the effect of bDMARDs on the development of HTN in patients with RA.A total of 996 patients eligible for analysis were recruited from the Korean College of Rheumatology Biologics & Targeted Therapy (KOBIO) registry from 2012 to 2018. The bDMARDs were tumor necrosis factor (TNF) inhibitors, abatacept, and tocilizumab. The cDMARDs included methotrexate, hydroxychloroquine, and leflunomide. The incidence rate and 95% confidence interval of HTN were estimated using the Kaplan-Meier method. Hazard ratio (HR) of risk factors associated with hypertension was assessed by cox proportional hazard model analysis.Among the 996 patients, 62 patients (6.2%) were newly diagnosed with HTN. There were differences in incidence rate of HTN among conventional DMARDs (cDMARDs), TNF inhibitors, tocilizumab, and abatacept during the follow-up period (P = .015). Kaplan-Meier analysis showed that there was a significant difference in incident HTN only between cDMARDs and tocilizumab (P = .001). Systolic blood pressure and positive rheumatoid factor were associated with development of HTN (HR = 1.049, P = .016 and HR = 1.386, P = .010, respectively). Cox proportional hazard model analysis showed no difference in the development of HTN between bDMARDs and cDMARDs in RA.This study showed that bDMARDs treatment might not increase risk of incident HTN in patients with RA, compared to cDMARDs.
32321893 Effective Treatment with Tocilizumab in a Rheumatoid Arthritis Patient Complicated with Hu 2020 Aug 1 A 61-year-old woman with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and interstitial pneumonia (IP) was admitted to our hospital. She complained of sicca symptoms, polyarthralgia, and swollen joints. She was diagnosed with rheumatoid arthritis (RA) and Sjögren's syndrome. Methotrexate and anti-tumor necrosis factor therapy were not utilized because of the inclusion of severe respiratory disorders among the complications and the neurological symptoms of HAM/TSP. Tocilizumab monotherapy improved the RA disease activity without exacerbating HAM/TSP. The present case suggests that tocilizumab might be a suitable treatment option in patients with RA and HAM/TSP.
33162488 Familial Mediterranean fever phenotype progression into anti-cyclic citrullinated peptide 2020 Dec 10 Familial Mediterranean fever (FMF) is caused by dysfunction of the MEFV gene product, pyrin. Here we report a case of FMF phenotype which developed into rheumatoid arthritis (RA), based on a positive result for anti-cyclic citrullinated peptide (CCP) antibody (Ab). A 42-year-old woman presented to our clinic with more than 6 months of intermittent arthralgia in the wrists, feet, and fingers associated with menstruation. No fever was reported and there was no family history of FMF or other autoimmune diseases. Laboratory tests revealed elevated C-reactive protein (CRP) and rheumatoid factor (RF). Tests for autoantibodies including anti-CCP Ab, antinuclear Ab, and anti-DNA Ab were all negative. Genetic analysis identified an R304R homozygous mutation in MEFV; however, the pathological significance is unclear because this mutation does not cause amino acid substitution. We diagnosed incomplete FMF phenotype despite the lack of fever due to periodic arthritis, lack of autoantibodies, and complete resolution of arthritis following colchicine treatment within a day. Several months later, increased stiffness and arthralgia persistently occurred in finger joints on both sides. Ultrasonography revealed synovitis at the metacarpophalangeal and metatarsophalangeal joints. Laboratory analysis revealed the patient to be positive for anti-CCP Ab. Therefore, we finally diagnosed RA. Her arthritis diminished following administration of methotrexate and salazosulfapyridine. We consider the possibility that pyrin dysfunction may have affected the acquired immunity, contributing to the onset of RA as an autoimmune disease. This is an interesting case of equivalent FMF progressing into RA and will be valuable to raise awareness of a continuum from autoinflammatory to autoimmune disease.
33087004 A case of acute diffuse large B cell lymphoma in an anti-human T-cell leukaemia virus type 2020 Jul A 70-year-old woman was hospitalised due to jaundice and fever. She was diagnosed with rheumatoid arthritis (RA) at 54 years of age. Treatment with methotrexate (MTX) was successful, and her RA was in remission. Five weeks before the hospitalisation, she was diagnosed with optic neuritis due to a decline in the visual acuity of the right eye. She was treated with methylprednisolone pulse therapy, followed by prednisolone (PSL), before the hospitalisation, which were not effective. Blood tests showed increased C-reactive protein (CRP) levels, liver injury, and thrombocytopenia. Abdominal echo revealed numerous enlarged lymph nodes in the hepatic portal region. Malignant lymphoma was suspected due to high serum levels of soluble interleukin-2 receptor. None of the treatments were effective, and she died on the fifth hospital day. Diffuse large B cell lymphoma was diagnosed during the autopsy, which showed infiltration of CD20-positive atypical lymphocytes in almost all organs. Since she was taking MTX, she was diagnosed with immunosuppressive drug-associated lymphoproliferative disease (LPD). Anti-human T-cell leukaemia virus type 1 (HTLV-1) antibody was detected in her serum after her death; however, adult T cell leukaemia/lymphoma was not observed. LPD develops during the treatment of RA with disease modifying anti-rheumatic drugs; however, a rapid clinical course leading to death is rarely observed. Previous reports suggest that T cell dysregulation observed in HTLV-1 may contribute towards the development of B cell lymphoma. We have discussed the possible roles of HTLV-1 in LPD development in this case.
32377996 Serum homocysteine levels and their association with clinical characteristics of inflammat 2020 Nov OBJECTIVE: The aim of our study was to explore the serum levels of homocysteine (Hcy) and its association with clinical characteristics in patients with different types of inflammatory arthritis. METHODS: A total of 242 patients diagnosed with inflammatory arthritis (which included rheumatoid arthritis (RA), ankylosing spondylitis (AS), and gout), 49 with osteoarthritis (OA), and 36 with hyperuricaemia (HUA) and 81 healthy controls (HCs) were enrolled for comparisons. RESULTS: The serum Hcy levels of patients with RA, AS, and OA were comparable with those of the HC group (P > 0.05). However, the serum level of Hcy was significantly higher in patients with gout than in HCs (18.75 ± 9.98 vs. 14.20 ± 6.22 μmol/L, P = 0.007). In addition, we found that the serum Hcy level was much higher in RA patients who received methotrexate (MTX) therapy without folic acid supplementation than in those who received MTX with folic acid supplementation (13.39 ± 4.80 vs. 9.41 ± 2.04 μmol/L, P = 0.001). Furthermore, there was a positive correlation between uric acid and Hcy in patients without uric acid-lowering treatment (r = 0.537, P = 0.002), but the correlation was eliminated after adjusting uric acid-lowering treatment (r = 0.139, P = 0.393). Finally, consistent with the above findings, hyperhomocysteinaemia (HHcy) was more common in gout patients (P < 0.05). CONCLUSION: Screening for HHcy in patients with gout and RA, especially RA patients treated with MTX, might be necessary, and patients with HHcy might benefit from earlier supplementation with folic acid. Key Points • Serum homocysteine (Hcy) was elevated and the rate of hyperhomocysteinaemia (HHcy) was significantly higher in gout. • Rheumatoid arthritis (RA) patients who received methotrexate (MTX) treatment without folic acid supplementation showed higher serum Hcy than those who received MTX treatment with folic acid supplementation. • The serum Hcy level was positively correlated with age in only RA patients. • Serum Hcy was correlated with uric acid in gout patients, but the correlation was eliminated after adjusting uric acid-lowering treatment.
31566134 Cardiovascular Risk of Synthetic, Non-Biologic Disease-Modifying Anti- Rheumatic Drugs (DM 2020 Patients with rheumatoid diseases have an increased risk of cardiovascular disease (CVD) and CVD-related death compared with the general population. Both the traditional cardiovascular risk factors and systemic inflammation are contributors to this phenomenon. This review examines the available evidence about the effects of synthetic, non-biologic disease-modifying antirheumatic drugs (DMARDs) on CVD risk. This is an important issue for clinicians when deciding on individual treatment plans in patients with rheumatic diseases. Evidence suggests that synthetic, non-biologic DMARDs such as methotrexate, sulfasalazine, hydroxychloroquine, leflunomide and tofacitinib show decreased CVD morbidity and mortality. However, the strongest data in favour of a reduction in CVD events in rheumatoid patients are shown with methotrexate, which has been the focus of most studies. Adequate proof for a favourable effect also exists for hydroxychloroquine. Larger, prospective studies and randomized clinical trials are needed to better characterize the effect of synthetic, non-biologic DMARDs on CVD outcomes in these patients. Design of future studies should include areas with lack of evidence, such as the risk for heart failure, arrhythmias and valvular heart disease. The clinically relevant question whether synthetic, non-biologic DMARDs are inferior to biologic DMARDs in terms of CVD outcomes remains not adequately addressed.
33320289 Comparison of therapeutic efficacy and mechanism of paclitaxel alone or in combination wit 2022 Mar OBJECTIVE: To compare the therapeutic efficacy of paclitaxel (PTX) alone to its combination with methotrexate (MTX) on rheumatoid arthritis. METHODS: A collagen-induced arthritis (CIA) rat model was established by induction of type II collagen. Rats were divided into blank control group, CIA model group, MTX group 1 mg/kg, PTX 1.5 mg/kg, PTX 2.5 mg/kg, PTX 3.5 mg/kg, and MTX 1 mg/kg + PTX 3.5 mg/kg, with 10 rats per group. The inflammation of the ankle joint was analyzed by H&E staining and interleukin (IL)-1β and IL‑6 expression was detected by immunohistochemistry. TUNEL assay was performed to detect synovial tissue cell apoptosis after administration of PTX and MTX either alone or in combination. TLR4 and p‑NF-κBp65 protein expression in synovial tissue and the changes of serum IL‑1β, IL‑6, IL‑12, MMP‑3, and TNFα protein factors were detected by western blot and ELISA, respectively. RESULTS: PTX and MTX improved histopathological changes in CIA rats. Besides, the apoptosis rate of synovial tissue cells in the PTX 3.5 mg/kg group was more than that of the PTX + MTX group. Immunohistochemistry and western blot results indicated that PTX and MTX reduce the expression rate of IL‑6 and IL‑1β and downregulate TLR4 and p‑NF-κBp65 protein expression. Furthermore, TLR4 and p‑NF-κBp65 reduced the concentration of MMP‑3, IL‑12, IL‑6, IL1‑β, and TNFα. CONCLUSION: Both PTX and MTX exert significant suppression on rheumatoid arthritis, and the combined effect of the two drugs is weaker than that of PTX alone. Moreover, intraperitoneal injection of PTX 3.5 mg/kg every other day was the optimal dose observed in this study.
31651077 Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexat 2020 Jan Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2-deoxycytidine, and corresponding reductions in 2-deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis.
32242853 ASSOCIATIONS BETWEEN EFFICACY OF THE THERAPY AND CIRCADIAN FLUCTUATIONS OF ENDOTHELIAL NIT 2020 Feb Despite significant progress in treatment of rheumatoid arthritis (RA), a considerable part of patients remains resistant to the current therapy, apparently for the reasons of undefined mechanisms of its pathogenesis. Recently, the disturbances of circadian regulation of inflammatory processes in RA have been highlighted as important ones. Endothelial nitric oxide synthase (NOS3) and soluble toll-like receptors 2 (sTLR2) take part in the regulation of angiogenesis, osteoclastogenesis, immune responses but their circadian rhythms and predictive significance in RA patients are still unknown. Aim - to estimate the associations between efficacy of treatment and the circadian rhythms of NOS3 and sTLR2, and NOS3 polymorphism in females with rheumatoid arthritis, Ukraine. 97 RA patients (100% female) aged 46.3±8.89 years with disease duration 8.44±6.52 years were examined. All patients as a disease-modifying therapy received methotrexate (MTX) orally in a dose ≤15 mg/week, folic acid 5 mg/week, NSAIDs and corticosteroids (CS) ≤10 mg/day by prednisone. Doses of MTX, NSAIDs and CS were stable 4 weeks prior to the enrolment and during the whole period of study. The efficacy end points included DAS28, RAID and American College of Rheumatology response criteria (ACR20/50/70). Serum levels of NOS3 and sTLR2 were determined at 08:00 and 20:00 using Cloud-Clone Corp kits (USA). NOS3 T-786С polymorphism was determined by Real-Time PCR. The SPSS22 software package was used for statistical processing of the results. The study was performed in accordance to the bioethical standards. After 12-week treatment among RA patients were revealed 52.6% ACR 20 responders and 47.4% non-responders. Opposite diurnal variation of NOS3 and sTLR2 serum levels were found in RA patients. There were significant differences in NOS3/sTLR2 ratio at 08:00 accordingly to NOS3 T786C genotype. The disturbances in daily variability of NOS3 or sTLR2 serum levels were more significant in non-responders compare to responders. Decrease of NOS3/sTLR2 ratio was a predictor of non-response to treatment in RA patients (β=0.366, р=0.000). In RA patients the disturbances of circadian rhythms of endothelial nitric oxide synthase or toll-like receptors 2 expression are associated with an increase of resistance to disease-modifying therapy with methotrexate.
30557057 Fibrosis-4 index at diagnosis can predict all-cause mortality in patients with rheumatoid 2020 Jan Objectives: Comorbidities and conventional risk factors influence the prognosis of patients with rheumatoid arthritis (RA). We investigated whether liver fibrosis burden is associated with all-cause mortality in patients with RA.Methods: A total of 2812 patients with RA were retrospectively selected and reviewed. Liver fibrosis was assessed using the fibrosis-4 index (FIB-4) [age (years)× aspartate aminotransferase level (IU/L)/platelet count (10(9)/L)/√alanine aminotransferase (IU/L)].Results: The mean patient age was 51.5 years (482 men and 2330 women). The mean erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and FIB-4 were 43.5 mm/h, 9.0 mg/L, and 1.0, respectively. Methotrexate was used in 2524 (89.9%) patients, and biological or targeted synthetic disease-modifying antirheumatic drugs were used in 310 (11.0%) patients. During the follow-up period (mean 93.7 months), 89 (3.2%) patients died. Deceased patients had a significantly higher age (mean 64.4 vs. 51.1 years); frequency of male sex (31.5% vs. 16.7%), hypertension (HTN; 40.4 vs. 18.5%), and diabetes mellitus (DM; 25.8% vs. 7.7%); ESR (mean 57.1 vs. 43.0 mm/h); CRP (mean 16.9 vs. 8.7 mg/L); and FIB-4 (mean 1.5 vs. 1.0) (all p < .05) than the survivors. On multivariate analysis, higher FIB-4 was found to be independently associated with a higher rate of all-cause mortality (hazard ratio =1.130, p = .004), together with male sex, HTN, DM, ESR, and intensity of glucocorticoid exposure, whereas the use of methotrexate was independently protective (all p < .05).Conclusion: Besides conventional risk factors, fibrotic burden, assessed using FIB-4, might be useful for risk stratification of patients newly diagnosed as having RA.
32911284 Predictive ability, validity, and responsiveness of the multi-biomarker disease activity s 2020 Oct BACKGROUND/OBJECTIVE: We assessed the predictive value, validity, and responsiveness of the multi-biomarker disease activity (MBDA) score in rheumatoid arthritis (RA) patients initiating methotrexate. METHODS: We examined data from a 16-week, open-label study of methotrexate in RA. Disease activity was assessed and the MBDA score was calculated using serum that was collected and banked from baseline and week 16. Multivariable logistic regression models assessed whether MBDA scores predicted treatment response. Pearson correlations assessed the convergent validity and external responsiveness of the MBDA score with other measures of RA disease activity. Internal responsiveness was assessed by calculating standardized response means (SRMs). RESULTS: A total of 130 patients initiated the study, with follow-up MBDA scores available on 95 patients. Baseline MBDA scores did not predict ACR response or achieving low disease activity. Higher baseline DAS28-ESR scores were significantly associated with an ACR20 response (odds ratio 1.89 per unit, 95% CI 1.20-2.96) but not ACR50, ACR70, or low disease activity. The MBDA score moderate-to-weakly correlated with the DAS28-ESR and ESR at baseline and week 16, with weak-to-very weak correlations with patient global and function. Change in MBDA scores moderately correlated with changes in DAS28-ESR and ESR, while weakly correlating with changes in patient global and function. The DAS28-ESR (SRM 1.31) demonstrated greater responsiveness following methotrexate treatment than the MBDA score (SRM 0.71). CONCLUSIONS: MBDA scores did not predict treatment response to methotrexate. The MBDA score weak-to-moderately correlated with baseline and post-treatment disease activity measures and was less responsive to methotrexate-related improvement than the DAS28-ESR.
32662413 ICHIBAN, a non-interventional study evaluating tocilizumab long-term effectiveness and saf 2021 Mar OBJECTIVES: We aimed to measure long-term effectiveness and safety of tocilizumab in patients with rheumatoid arthritis in daily German practice. METHODS: ICHIBAN was a prospective, multi-centre, non-interventional study (ML22928) that enrolled adult patients with active moderate to severe rheumatoid arthritis. Patients were to be treated according to tocilizumab label and observed for up to two years. Effectiveness outcomes included DAS28-ESR remission, EULAR response, CDAI and HAQ. RESULTS: Overall, 3164 patients received at least one dose of tocilizumab. Patient mean age was 55.5±13.1 years (74.8% female). At baseline, 72.1% of patients had at least one comorbidity. Approximately 50.9% of patients received concomitant csDMARDs, mostly methotrexate, and 80.7% received concomitant glucocorticoids (GCs). In patients receiving GCs at baseline, the mean dose decreased from 9.32±16.36 mg/d to 4.60±4.48 mg/d at week 104. In the effectiveness population with no prior TCZ (n=2902), 61.4% of patients achieved the primary outcome, DAS28-ESR remission. Improvements were seen as early as week 4. At week 104, 77.9% of patients had DAS28-ESR low disease activity, 89.6% achieved good or moderate EULAR response, and 29.5% achieved a CDAI-based remission. Effectiveness outcomes were similar in all previous therapy subgroups. The incidence of serious infections was similar to the rates in former studies involving tocilizumab. Patients receiving GC at baseline experienced slightly higher rates of treatment-related serious adverse events, mainly infections. No new safety signals were observed. CONCLUSIONS: Long-term effectiveness and safety in ICHIBAN were in line with previously reported tocilizumab efficacy and safety studies.
30836801 Radiographic and clinical outcomes following etanercept monotherapy in Japanese methotrexa 2020 Mar Objectives: Compare outcomes with methotrexate (MTX) or etanercept (ETN) monotherapy in Japanese patients with active rheumatoid arthritis (RA) who were MTX-naïve or with intolerance or inadequate response to prior MTX (MTX-IR).Methods: Post hoc analysis of a phase 3 study comparing MTX, ETN 10 mg twice weekly, and ETN 25 mg twice weekly in Japanese patients with RA. Disease activity was evaluated using American College of Rheumatology (ACR) scores and 28-joint Disease Activity Score (DAS28), radiographic progression evaluated using van der Heijde's modified Total Sharp Score (mTSS), and functional status evaluated using Health Assessment Questionnaire Disability Index (HAQ-DI).Results: Among MTX-naïve and MTX-IR patients, greater proportions of those randomized to either ETN group achieved ACR20, ACR50, ACR70, DAS28 ≤3.2 or <2.6, clinically relevant inhibition of mTSS changes, and reductions in HAQ-DI compared with MTX at the majority of time points. There were very few clinically meaningful differences between ETN groups for any of the variables evaluated.Conclusion: ETN monotherapy was more effective than MTX in both MTX-naïve and MTX-IR patients, with very few clinically meaningful differences between ETN 10 mg and ETN 25 mg when given twice weekly. The relative benefits of ETN were greater in MTX-naïve patients than MTX-IR patients.ClinicalTrials.gov identifierNCT00445770.
33269836 [Involvement of NF-κB signal pathway in acupuncture treatment of patients with rheumatoid 2020 Nov 25 OBJECTIVE: To observe the effect of acupuncture on nuclear factor kappa-B(NF-κB)signaling pathway in patients with rheumatoid arthritis (RA), so as to explore the mechanism of acupuncture in the treatment of RA. METHODS: A total of 120 RA patients admitted to the Xinyu Hospital of Traditional Chinese Medicine in Jiangxi Province from June 2018 to June 2019 were selected and randomly divided into a control group and a treatment group, with 60 cases in each group. The patients in the control group received oral administration of Methotrexate, (10-15) mg/time, once a week, for a total of 10 weeks. On the basis of oral administration of Methotrexate, patients in the treatment group were treated with acupuncture at Quchi(LI11), Zusanli(ST36), Taichong(LR3), Hegu(LI4), Shenshu(BL23), Geshu(BL17) and Dazhui(GV14) once daily. The treatment was conducted 6 consecutive times as a course for 10 courses. The serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), pain visual analog scale (VAS) score, number of swollen joints, and morning stiffness time before and after treatment were compared between the two groups. The expression levels of inflammatory related factors and NF-κB p65 protein in the synovial fluid were detected by enzyme-linked immunosorbent assay and Western blot separately. RESULTS: After treatment, both groups had significant decrease in CRP, ESR, VAS score, number of swollen joints and morning stiffness time, levels of NF-κB p65 protein, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 (P<0.05) in the joint fluid, and increase in transforming growth factor-β (TGF-β) and IL-10 (P<0.05). After treatment, compared with the control group, CRP, ESR, VAS score and morning stiffness time, and the levels of NF-κB p65, TNF-α, IL-1β and IL-6 in the treatment group were down-regulated (P<0.05), while the level of TGF-β was up-regulated (P<0.05). The treatment group had a higher total effective rate than the control group［85.0%(51/60) vs 75.0%(45/60), P<0.05］. CONCLUSION: Acupuncture can inhibit the expression of NF-κB signaling pathway in RA patients, regulate the levels of related inflammatory factors, and thus improve the symptoms of RA patients.
32500745 Using pharmacogenetics to predict methotrexate response in rheumatoid arthritis patients. 2020 Jul INTRODUCTION: Methotrexate (MTX) is a folate antagonist and a first-line drug for the treatment of rheumatoid arthritis (RA). However, in up to 30% of cases, MTX monotherapy is insufficient, while a further 30% of patients suffer with severe adverse effects. Despite extensive clinical evidence, it is not currently possible to predict therapy outcomes and drug toxicity for MTX. Therefore, to establish biomarkers of toxicity and successful disease remission, pharmacogenomic approaches are rapidly becoming more popular. AREAS: This review summarizes recent pharmacogenomic studies evaluating MTX efficacy and toxicity. In recent years, multiple genetic alterations associated with MTX therapy outcomes and toxicity have been identified in genes associated with MTX metabolism and effector pathways. However, the data are inconsistent and require further validation. EXPERT OPINION: To date, several single nucleotide polymorphisms (SNPs) have been linked with MTX efficacy. However, thanks to equivocal data, pharmacogenomic testing in routine clinical practice remains a distant prospect. Genome-wide association studies (GWAS) could facilitate the evaluation of current SNPs, and support searches for new genetic variations Once achieved, only then will it be possible to introduce more personalized and individualized therapies for RA patients.
31722413 An updated matrix to predict rapid radiographic progression of early rheumatoid arthritis 2020 Aug 1 OBJECTIVE: In early RA, some patients exhibit rapid radiographic progression (RRP) after one year, associated with poor functional prognosis. Matrices predicting this risk have been proposed, lacking precision or inadequately calibrated. We developed a matrix to predict RRP with high precision and adequate calibration. METHODS: Post-hoc analysis by pooling individual data from cohorts (ESPOIR and Leuven cohorts) and clinical trials (ASPIRE, BeSt and SWEFOT trials). Adult DMARD-naïve patients with active early RA for which the first therapeutic strategy after inclusion was to prescribe methotrexate or leflunomide were included. A logistic regression model to predict RRP was built. The best model was selected by 10-fold stratified cross-validation by maximizing the Area Under the Curve. Calibration and discriminatory power of the model were checked. The probabilities of RRP for each combination of levels of baseline characteristics were estimated. RESULTS: 1306 patients were pooled. 20.6% exhibited RRP. Four predictors were retained: rheumatoid factor positivity, presence of at least one RA erosion on X-rays, CRP > 30mg/l, number of swollen joints. The matrix estimates RRP probability for 36 combinations of level of baseline characteristics with a greatly enhanced precision compared with previously published matrices (95% CI: from ± 0.02 minimum to ± 0.08 maximum) and model calibration is excellent (P = 0.79). CONCLUSION: A matrix proposing RRP probability with high precision and excellent calibration in early RA was built. Although the matrix has moderate sensitivity and specificity, it is easily usable and may help physicians and patients to make treatment decisions in daily clinical practice.