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ID PMID Title PublicationDate abstract
35265215 Ultrasound imaging tracking of mesenchymal stem cells intracellularly labeled with biosynt 2022 Rationale: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and damage to articular tissues that can lead to irreversible joint damage and progressive disability. The multipotent mesenchymal stem cells (MSCs) play an important role in immune disorders and tissue regeneration. However, their immunosuppressive effects and the underlying mechanisms are largely unclear due to the lack of tools for real-time imaging of MSCs in vivo. Gas vesicles (GVs) are biosynthetic nanobubbles that are ejected from aquatic microbes, such as bacteria and archaea, and have an excellent ultrasound imaging capacity. Methods: We harvested MSCs from the bone marrow of Sprague Dawley (SD) rats. Then, GVs were synthesized and incubated with MSCs to obtain intracellularly labeled MSCs. We firstly tested the ultrasound imaging of GV@MSCs in vitro and in vivo and then explored the therapeutic effect of GV@MSCs combined with methotrexate (MTX) in RA rats. Results: These GV@MSCs showed significant contrast-enhanced ultrasound signals without a loss of viability and differentiation capacity. In addition, the GV@MSCs could be imaged in real-time for 5 days using ultrasound both in vitro and in vivo, making it possible to visually track their migration and homing to the joint cavity from the subcutaneous layer of lateral malleolus joints in the injected RA rats. Furthermore, GV@MSCs significantly enhanced the curative effect of methotrexate (MTX) against RA, resulting in decreased paw thickness, lower arthritis index score, reduced bone erosion and cartilage destruction, compared to the PBS, free MTX, and GV@MSCs groups. Conclusion: We developed a novel therapeutic strategy against RA using GVs-loaded MSCs that can be tracked in vivo in real-time.
35172859 Prediction of flare following remission and treatment withdrawal in early rheumatoid arthr 2022 Feb 16 BACKGROUND: Drug-free remission is a desirable goal in rheumatoid arthritis (RA) for both patients and clinicians. The aim of this post hoc analysis was to investigate whether clinical and magnetic resonance imaging (MRI) variables in patients with early RA who achieved remission with methotrexate and/or abatacept at 12 months could predict disease flare following treatment withdrawal. METHODS: In the AVERT study of abatacept in early RA, patients with low disease activity at month 12 entered a 12-month period with all treatment discontinued (withdrawal, WD). This post hoc analysis assessed predictors of disease flare at WD+6months (mo) and WD+12mo of patients with Disease Activity Score in 28 joints (DAS28)-defined remission (DAS28[C-reactive protein (CRP)] <2.6) at withdrawal using univariate and multivariable regression models. Predictors investigated included the Health Assessment Questionnaire-Disability Index (HAQ-DI), pain, Patient Global Assessment; MRI synovitis, erosion, bone edema, and combined (synovitis + bone edema) inflammation scores. RESULTS: Remission was achieved by 172 patients; 100 (58%) and 113 (66%) patients had experienced a flare at WD+6mo and WD+12mo, respectively. In univariate analyses, higher HAQ-DI and MRI synovitis, erosion, bone edema, and combined inflammation scores at WD were identified as potential predictors of flare (P ≤ 0.01). In multivariable analysis, high scores at WD for HAQ-DI and MRI erosion were confirmed as independent predictors of flare at WD+6mo and WD+12mo (P < 0.01). CONCLUSION: In patients with early RA achieving clinical remission, patient function (HAQ-DI), and MRI measures of bone damage (erosion) predicted disease flare 6 and 12 months after treatment withdrawal. These variables may help identify patients with early RA in clinical remission as candidates for successful treatment withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01142726 (date of registration: June 11, 2010).
34846624 Use of biologic agents and methotrexate improves renal manifestation and outcome in patien 2022 Apr BACKGROUND AND PURPOSE: We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). METHODS: We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990-1999 (n = 48); period 2, 2000-2009(n = 57); period 3, 2010-2019 (n = 51). RESULTS: Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010-2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1-3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. CONCLUSION: Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA.
33337811 Drug Survival of Biologic Therapy in Elderly Patients With Rheumatoid Arthritis Compared W 2022 Jan 1 OBJECTIVE: Although the proportion of elderly patients with rheumatoid arthritis (RA) is increasing, the persistency of biologic therapy in elderly patients requires additional investigation. This study evaluated the drug survival of biologic therapy and associated factors in elderly compared with nonelderly patients. METHODS: This longitudinal observational study included RA patients who were enrolled in the Korean College of Rheumatology Biologics Registry (NCT01965132, started from January 1, 2013) between 2013 and 2015. We compared the retention rate of biologic therapy between elderly (age ≥70 years) and nonelderly (age <70 years) patients, and investigated the causes and predictors of biologic withdrawal in both groups. RESULTS: Of 682 patients, 122 were aged 70 years or older. The retention rate of biologic therapy at 24 months was 57.8% and 46.5% in nonelderly and elderly patients, respectively (p = 0.027). Biologic withdrawal due to adverse events and inefficacy within 24 months was not significantly different between the 2 groups, although adverse events were more common in elderly patients (20.6% vs 12.8%, p = 0.360). Drug withdrawal due to patient refusal was more common in elderly patients (9.8% vs 1.8%, p < 0.001). In elderly patients, biologic withdrawal was associated with current smoking and older age at disease onset, whereas the use of tumor necrosis factor inhibitors, nonuse of methotrexate, and combination of corticosteroid were important in nonelderly patients. CONCLUSIONS: Elderly RA patients are more likely to discontinue biologic agents within 24 months. To increase the retention rate of biologic therapy, rheumatologists should consider patient characteristics before and during biologic therapy.
35266068 Repurposing monoamine oxidase inhibitors (MAOI) for the treatment of rheumatoid arthritis 2022 Apr Monoamine oxidase inhibitors (MAOI) are presently used to treat depression, parkinsonian, and other psychiatric disorders. The present study was aimed to repurpose the use of MOAI in Rheumatoid Arthritis (RA). The animal model of RA was developed using collagen type II (CII) in Freund's complete adjuvant (FCA) followed by lipopolysaccharide (LPS) and a booster dose of CII in FCA. The effect of MAOI, Selegiline was evaluated whereas the indicators like paw thickness, arthritic score, and the splenic index were measured and compared with the standard drug Methotrexate. Further to explore the molecular mechanism, the expression of serum inflammatory cytokines (IL-6 and TNF-α), radiographical and histopathological study of hind paw were also checked and analyzed. Treatment with MAOI, Selegiline not only reduced the paw thickness, arthritic score, and the splenic index, but also greatly improved the inflammatory biochemical and hematologic parameters and improved the arthritis score. The serum level of IL-6 and TNF-α are considerably decreased dose dependently, however, the notable significant effect (**p < 0.01) observed at concentration of 30 mg/kg b.w. when the RA animals treated by Selegiline. Collectively, Selegiline improved the progression of RA possibly via decreased catecholamine breakdown at synovial fluid resulting decrease hydrogen peroxide (H(2)O(2)) generation and inhibition of pro-inflammatory cytokines in situ. Thus, the finding support and indicate the repurposing of MAOI for the treatment of RA meriting further studies on synovial monoamine oxidase as a new therapeutic target to design a new drug for RA.
35338383 The beneficial effect of csDMARDs co-medication on drug persistence of first-line TNF inhi 2022 May The study aimed to compare treatment retention for first-line TNF inhibitor (TNFi) in the ATTRA registry patients receiving either combination with conventional synthetic DMARDs or TNFi as monotherapy. A retrospective multicenter study analyzed data of all adult patients with rheumatoid arthritis (n = 3032) starting TNF inhibitor as the first-line biological therapy in combination with csDMARDs or in monotherapy from January 1st 2012 to December 31st 2020. Kaplan-Meier method was employed to calculate drug retentions. Survival curves of treatment retentions were compared through Log-rank test between the studied subgroups. The hazard ratio for drug discontinuation was assessed through univariate cox regression models. In patients who started the first line TNFi therapy, the median treatment retention was 47.7 (42.2; 53.1) months for combination therapy and 22.7 (14.9; 30.6) months for TNFi monotherapy (p < 0.001). Estimated one-year survival was higher in patients on TNFi combined with csDMARDs as compared with TNFi monotherapy (75.3% vs 65.7%); two-year survival rate was 63.2% vs 49.2%, three-year survival rate was 55.4% vs 42.4% and five-year survival 44.9% vs 26.4% of patients. The estimated survival on the first TNFi was higher in patients taking combination therapy with methotrexate than with other csDMARDs (p = 0.003). Use of csDMARDs co-medication was associated with significantly better first TNFi drug survival compared to monotherapy. The combination of TNFi with MTX is more effective than the combination with leflunomide, which did not demonstrate a significant effect.
35637840 High Efficacy Combined Microneedles Array with Methotrexate Nanocrystals for Effective Ant 2022 INTRODUCTION: Methotrexate (MTX) is the first-line drug for the treatment of rheumatoid arthritis (RA) in several countries. However, MTX has an extremely low solubility in water, and the side effects caused by its delivery mode restrict its curative effect. In this study, we designed a dissolving microneedles array (DMNA) containing MTX nanocrystals (MTX-NCs) (MTX-NC@DMNA) to improve the treatment of RA. DMNA-based drug delivery combines the advantages of patient compliance with the use of transdermal drug delivery systems and high-efficiency injection administration; thus, it can mitigate the side effects that result from current administration routes. Carrier-free and surfactant-free MTX-NCs were prepared to overcome bioavailability limitations and poor drug loading problems. METHODS: The MTX-NCs prepared by reverse solvent precipitation method was encapsulated in the DMNA. The morphology, mechanical properties, safety, stability and in vivo dissolution were evaluated, and its pharmacodynamic characteristics were assessed in a rat model of RA. RESULTS: The particle size of the MTX-NCs was 148.1 ± 10.1 nm. The MTX-NC@DMNA were found to be rigid enough to penetrate the skin and deliver the drug successfully. The results indicated effective skin recovery after removal of the DMNA. It was found that the MTX-NC@DMNA significantly reduced foot swelling in the rats and regulated the balance in the levels of related cytokines. It also reduced pathological damage to the synovium, joint, and cartilage, and effectively alleviated organ injury in the rats. CONCLUSION: Transdermal administration of MTX-NC@DMNA may be an effective approach for treating RA.
34633502 [Visceral leishmaniasis mimicking Felty's syndrome in rheumatoid arthritis treated with me 2022 Apr Visceral leishmaniasis (VL) is a chronic parasitic disease caused by pathogens of the genus Leishmania, which can mimic numerous diseases. The leading symptoms of VL (splenomegaly, pancytopenia, fever) can be misinterpreted, especially if autoantibodies are detected, and lead to the misdiagnosis of an underlying rheumatic disease (e.g. systemic lupus erythematosus, Felty's syndrome). Proinflammatory cytokines such as tumour necrosis factor alpha (TNF-α) play an important role in infection control. In this context, there are increasing reports of VL as an opportunistic infection during treatment with anti-TNF‑α agents. A case of VL mimicking Felty's syndrome in a patient with rheumatoid arthritis treated with methotrexate and etanercept is presented.
34248117 Immune Reconstitution Inflammatory Syndrome Associated with Pneumocystis jirovecii Pneumon 2022 Jan 15 A 68-year-old woman presenting with rheumatoid arthritis was admitted due to pancytopenia caused by methotrexate. Pneumocystis jirovecii pneumonia was diagnosed based on the abnormal shadows observed on chest computed tomography, the presence of serum β-D-glucan, and positive P. jirovecii-DNA results in a sputum analysis. Subsequently, after treatment with leucovorin and trimethoprim-sulfamethoxazole, lung consolidation was found to be aggravated, along with a rapidly increasing leukocyte count. In addition, cytomegalovirus colitis was diagnosed. Both conditions were associated with immune reconstitution inflammatory syndrome caused by recovery from leukopenia. The patient was successfully treated with intravenous methylprednisolone pulse therapy and ganciclovir.
35234444 Development and Efficacy of an Orally Bioavailable Selective TAK1 Inhibitor for the Treatm 2022 Mar 18 Selective targeting of TNF in inflammatory diseases such as rheumatoid arthritis (RA) has provided great therapeutic benefit to many patients with chronic RA. Although these therapies show initially high response rates, their therapeutic benefit is limited over the lifetime of the patient due to the development of antidrug antibodies that preclude proper therapeutic benefits. As a result, patients often return to more problematic therapies such as methotrexate or hydroxychloroquine, which carry long-term side effects. Thus, there is an unmet medical need to develop alternative treatments enabling patients to regain the benefits of selectively targeting TNF functions in vivo. The protein kinase TAK1 is a critical signaling node in TNF-mediated intracellular signaling, regulating downstream NF-κβ activation, leading to the transcription of inflammatory cytokines. TAK1 inhibitors have been developed but have been limited in their clinical advancement due to the lack of selectivity within the human kinome and, most importantly, lack of oral bioavailability. Using a directed medicinal chemistry approach, driven by the cocrystal structure of the TAK1 inhibitor takinib, we developed HS-276, a potent (K(i) = 2.5 nM) and highly selective orally bioavailable TAK1 inhibitor. Following oral administration in normal mice, HS-276 is well tolerated (MTD >100 mg/Kg), displaying >95% bioavailability with μM plasma levels. The in vitro and in vivo efficacy of HS-276 showed significant inhibition of TNF-mediated cytokine profiles, correlating with significant attenuation of arthritic-like symptoms in the CIA mouse model of inflammatory RA. Our studies reinforce the hypothesis that TAK1 can be safely targeted pharmacologically to provide an effective alternative to frontline biologic-based RA therapeutics.
34236743 Patient's experiences of the barriers and facilitators to Methotrexate. 2022 Mar OBJECTIVE: To investigate the barriers and facilitators of adherence to methotrexate (MTX) in people with rheumatic diseases and to explore the experience of shared decision-making. METHODS: A qualitative study was carried out. People diagnosed with inflammatory arthritides or systemic autoimmune diseases and who were treated with MTX were invited to participate in focus groups. The discourse was coded and synthesised with a content analysis approach. RESULTS: The groups included 12 representative patients (rheumatoid arthritis, spondylarthritis, and systemic lupus erythematosus, taking either oral or subcutaneous MTX). Four main themes were identified: (1) drug-related aspects (package insert, adverse events, administration, and difficulties with treatment); (2) patient-physician relationship; (3) social environment (lack of visibility of rheumatic diseases and the support of patient associations); and (4) medication and medical care practicalities (information, reliable sources, and expanding knowledge in other health areas). CONCLUSIONS: Aspects identified might help improve adherence, including quality information, especially on adverse events, the role of the setting, and shared decision-making.
35133068 Long-term outcome of patients with palindromic rheumatism treated with methotrexate. 2022 Apr OBJECTIVE: Palindromic rheumatism (PR) is characterized by self-resolving and short duration attacks of arthritis/periarthritis. The present study was performed to report the results of PR treatment with methotrexate (MTX). METHODS: We reviewed the charts of 152 patients with diagnosis of PR. Inclusion criteria were diagnosis of PR according to the criteria of Weismann, age ≥16, active disease and treatment with MTX for at least 6 months. Disease outcome was assessed by reaching remission and prevention of disease evolution to chronic arthritis. Remission was defined as stopping the attacks for 12 weeks and prednisolone dose ≤5 mg/d. MTX treatment failure was defined as failure to achieve remission, the need to add other disease-modifying antirheumatic drugs and disease progression to chronic arthritis. RESULTS: Fifty-nine patients were included in the study. Median duration of follow-up was 43 months. Attacks were controlled in 89.8% of patients. In 80% of the patients remission occurred during 12 months after starting treatment with MTX. Treatment failed in 20.3% of patients. Wrist joint involvement and positive rheumatoid factor (RF) were significantly more common in the MTX treatment-failed group. In RF positive patients evolution to rheumatoid arthritis was more common than in RF negative patients. No significant differences were observed in remission rate and evolution to rheumatoid arthritis in anticitrullinated C peptide positive and negative patients. CONCLUSIONS: The present study, demonstrated the efficacy of MTX in controlling PR in seropositive and seronegative patients over a median of 43 months of treatment.
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.
34762577 Search of official nationwide database in Japan for adverse events associated with disease 2022 Apr BACKGROUND: Disease-modifying antirheumatic drugs (DMARDs) are essential for rheumatoid arthritis (RA) therapy. The adverse events (AEs) evaluation should focus on that methotrexate (MTX) is frequently prescribed in combination with others (combination MTX). METHODS: A search of the website of the official Japanese Agency for AEs, including lymphoproliferative disease (LPD), cytopenia, interstitial pneumonia, infectious pneumonia other than Pneumocystis jirovecii pneumonia (PCP) (i-Pn), and PCP, associated with MTX, tacrolimus, adalimumab, tocilizumab, and abatacept therapies reported from 2014 to 2016 was performed. Number of each AE cases and its ratio to total number of AEs cases were examined. Combination MTX was checked for RA cases. RESULTS: A total of 8874 cases were listed. In 3955 MTX cases, LPD was most frequent (36.4%). In any of the other four DMARDs cases, i-Pn was most frequent (4.2 ~ 15.3%); PCP cases showed most frequent combination MTX (94.4%). In total, including cases reported for MTX therapy, 98.2% of LPD and 97.6% of PCP cases had MTX, and less than 90% of the other AEs cases had MTX. CONCLUSION: LPD was by far the most frequent AE associated with MTX therapy. PCP was strongly associated with combination MTX. For any of the other four DMARDs, i-Pn was most frequent.
34739327 Neuropsychiatric adverse drug reactions associated with low dose methotrexate in rheumatoi 2022 Mar BACKGROUND: Neuropsychiatric adverse drug reactions (NPADRs) are not commonly associated with low dose methotrexate (LDMTX) in patients with rheumatoid arthritis (RA). RESEARCH DESIGN AND METHODS: In this case series assessment, we described the nature and frequency of NPADRs with LDMTX in the Dutch DREAM-RA registry, including causality of NPADRs, the impact on further LDMTX treatment and the impact on patient reported Health Related Quality of Life (HRQoL). RESULTS: A total of 71 NPADRs (frequency 6.8%) associated with LDMTX were captured in the DREAM-RA registry. NPADRs were registered for 62 (5.9%) out of 1048 patients with 10.9 NPADRs per 1000 patient years. Headache, dizziness and depression were most frequently reported. The causality was considered probable for 67 NPADRs (94.4%) and definite for 1 NPADR (1.4%). NPADRs led to LDMTX withdrawal in 34 cases (47.9%) and was not restarted in 16 cases (47.1%). Median mental HRQoL was significantly decreased around the occurrence of the NPADR and remained significantly lower after the event. Median physical HRQoL was not significantly affected. CONCLUSIONS: Knowledge on the nature, frequency and impact of the demonstrated NPADRs during LDMTX therapy will enhance attention toward these potential ADRs allowing better risk assessment and communication to patients.
34176840 Development of Intravascular Large B-cell Lymphoma during Methotrexate Treatment for Rheum 2022 Jan 1 A 56-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for six years visited our hospital with dyspnea and dizziness. Abdominal ultrasonography revealed mild splenomegaly. Laboratory examinations showed a marked elevation in soluble interleukin-2 receptor and lactate dehydrogenase levels. These abnormalities revealed a spontaneous regression after MTX discontinuation, however, they worsened again four months later. Skin biopsies revealed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and we diagnosed MTX-associated IVLBCL (MTX-IVLBCL) based on its characteristic course. Despite the recurrence of IVLBCL, it showed a good response to chemotherapy. MTX-IVLBCL should therefore be treated with consideration since it has different characteristics from that of de novo IVLBCL.
34347945 Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti- 2022 Feb OBJECTIVE: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. METHODS: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. RESULTS: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders. CONCLUSION: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.
34923285 Cost-Effectiveness Analysis of Etanercept 25 mg Maintenance Therapy After Treatment With E 2022 Mar OBJECTIVES: To use Markov modeling to estimate the cost-effectiveness of treatment with etanercept 25 mg once weekly plus methotrexate (MTX) in Japanese patients with rheumatoid arthritis who had achieved remission or low disease activity with etanercept 50 mg once weekly plus MTX. METHODS: Effectiveness data were estimated based on results from a clinical trial (PRESERVE) in patients with rheumatoid arthritis who had achieved remission or low disease activity and who were then randomized to receive etanercept 25 mg plus MTX or placebo plus MTX. A Markov model was established and included flare rates of 21% and 62% in the etanercept 25 mg and placebo groups, respectively. EQ-5D was calculated using an ordinary least-squares model that included the health assessment questionnaire disability index and pain visual analog scale. Worsening of the health assessment questionnaire score over 1 year was estimated to be 0.047 for patients with flare, and when associated with radiographic progression it was estimated to increase by 0.006 and 0.025 in the etanercept 25 mg and placebo groups, respectively. A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness for a 10-year time span. RESULTS: Compared with the placebo group, the quality-adjusted life-years for the etanercept 25 mg group was increased by 0.841. The incremental cost-effectiveness ratio was ¥6 173 772. CONCLUSION: These results suggest that maintenance treatment with etanercept 25 mg is cost-effective.
34344706 Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate 2022 Apr OBJECTIVE: To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study. RESULTS: A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies. CONCLUSIONS: Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368.
35287902 Targeted delivery of methotrexate by modified yeast β-glucan nanoparticles for rheumatoid 2022 May 15 The linear β-(1, 3)-glucans from yeast (BYGs) with good biocompatibility and targetability to macrophages were used for fabricating BYG-based nanoparticles to deliver methotrexate with systemic toxicity for treatment of rheumatoid arthritis. Methoxy poly (ethylene glycol) (mPEG) was successfully grafted onto BYGs chains, followed by chemical crosslinking to get the crosslinked copolymer (cBP) with amphiphilicity, which could self-assemble into spherical nanoparticles (ca.52.9 nm in diameter). The methotrexate-loaded cBP nanoparticles (cBPM) with the drug loading efficiency of 23.7% was proved to linearly release methotrexate due to reduction of disulfide bonds by glutathione. Cell experiments demonstrate that cBP nanoparticles were effectively internalized into macrophages due to the targetability. Animal experiments show that cBPM were highly targeted to the inflamed tissue, leading to macrophage transformation from M1 to M2 type and reduction of pro-inflammatory factors. This work provides an alternative safe strategy for the clinical treatment of rheumatoid arthritis with β-glucan nanoparticles as carrier.