Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
32384515 Does concomitant methotrexate confer clinical benefits in patients treated with prior biol 2020 May Most studies of methotrexate (MTX) in combination with tumor necrosis factor (TNF) inhibitors have focused on treatment-naive patients with early disease. The goal of this study was to evaluate whether previous biologic therapy influenced the impact of concomitant MTX in patients initiating treatment with adalimumab.We retrospectively analyzed data from 2 large noninterventional studies of German patients with active rheumatoid arthritis (RA) who initiated adalimumab therapy during routine clinical practice. Patients were seen between April 2004 and February 2013 for study 1 and between April 2003 and March 2013 for study 2. Key outcomes were Disease Activity Score-28 joints (DAS28), patient global assessment of health (PGA), and pain. Subgroup analyses by prior biologic treatment were performed on patients treated with continuous adalimumab monotherapy or adalimumab plus MTX for 12 months and 2-sample t tests were used to evaluate differences. We also assessed outcomes in subgroups in which MTX had been added or removed at 6 months and compared outcomes with 1-sample t tests.Of 2654 patients, 1911 (72%) were biologic naive and 743 (28%) had received prior biologic therapy, usually with a TNF inhibitor. All subgroups showed improvements following initiation of adalimumab therapy. In patients with no previous biologic treatment, continuous adalimumab plus MTX was associated with greater improvements in DAS28, PGA, and pain at month 12 compared with continuous adalimumab monotherapy (P = .0006, .0031, and .0032, respectively). In patients with previous biologic treatment, concomitant MTX was associated with statistically significant benefits in pain only. Adding MTX at month 6 resulted in additional benefits in patients with no prior biologic therapy, but not those with previous biologics.We conclude that concomitant MTX resulted in additional improvements in DAS28 and PGA vs adalimumab monotherapy in patients with no previous biologic therapy, but changes were not statistically significant in patients treated with prior biologics. These findings may help inform the patient/provider treatment decision during routine clinical care.
32061742 Andrographolide ameliorates oxidative stress, inflammation and histological outcome in com 2020 Mar 1 OBJECTIVES: As one of the main active ingredients of Chinese herbal medicine Andrographis paniculate, andrographolide is used in domestic clinical treatment for respiratory infections and inflammation. This study was designed to investigate the effects of andrographolide as an antioxidant on the level of oxidative stress, neutrophil accumulation and infiltration in joints and synovial tissue of arthritis rats induced by complete freund's adjuvant. METHODS: A rat model of rheumatoid arthritis was induced by subcutaneous injection of complete Freund's adjuvant in the footpad. The model was established 14 days after induction. The treatment was performed from 14th day to 35th day with different doses of andrographolide (25, 50, 100 mg/kg) and positive control methotrexate (3 mg/kg). The effects of andrographolide on oxidative stress, neutrophil accumulation and infiltration were measured by the paw swelling, arthritis score, the hot plate test, biochemical analysis, and histology. RESULTS: The medium and high-dose andrographolide (50, 100 mg/kg) group declined the levels of tumor necrosis factor-α, interleukin-6 and CXC chemokine ligand2, articular elastase and myeloperoxidase, and increased the levels of antioxidant enzymes superoxide dismutase, catalase, and glutathione. The activity of malondialdehyde and nitrite/nitrate in andrographolide (50, 100 mg/kg) group was weakened than the model group. The degree of swelling and arthritis score of andrographolide group was lower than the model group. The results of hot plate test showed that high dose of andrographolide significantly improved the anti-injury ability of rats; Radiological and histological results showed that the joint osteoporosis, inflammatory cell infiltration, synovial hyperplasia and other phenomena in the andrographolide group were significantly improved. CONCLUSIONS: Andrographolide acts as a protective agent for the treatment of complete freund's adjuvant induced rheumatoid arthritis by inhibiting lipid peroxidation and nitrite/nitrate levels in a dose-dependent manner, enhancing antioxidant enzyme activity, reducing levels of chemokines and inflammatory factors, preventing neutrophil accumulation and infiltration.
32311948 Favorable retention rates and safety of conventional anti-rheumatic drugs in older patient 2020 Apr Physicians are challenged by the recognition and treatment of older patients with rheumatoid arthritis (RA). The aim of this case-control study was to evaluate the retention and safety of conventional disease-modifying anti-rheumatic drugs in older patients with RA.In this observational case-control study, we assessed older patients with RA (≥65 years) who were diagnosed in 3 different rheumatology centers from Turkey. Patients were divided as to those aged ≥65 years (elderly rheumatoid arthritis [ERA]) and those aged <65 years (young rheumatoid arthritis [YRA]) at the time of conventional DMARD treatment initiation. The Mann-Whitney U test was used for the comparison of 2 non-normally distributed groups. The Chi-square (χ) test was used for categorical variables. Survival analysis were performed using the Kaplan-Meier method.Four hundred eighteen patients with RA (296 females [71%]) were included from January 2010 to January 2018. The age of treatment onset of 190 (47%) patients was in the elderly period and they were included in the ERA group. In the analysis of drug retention rates, there was no significant difference between the ERA and YRA groups for each conventional DMARD (methotrexate 71.2% in ERA, 62.7% in YRA, P = .817; hydroxychloroquine 82.9% in ERA, 78.8% in YRA, P = .899; leflunomide 81.4% in ERA, 84.4% in YRA, P = .205; sulfasalazine 37.5% in ERA, 40.9% in YRA, P = .380). The adverse event data were also similar in both groups.The drug retention and adverse effect rates in older patients with RA using conventional DMARDS are similar to the rates in young patients with RA.
31154414 Magnetic Resonance Imaging (MRI) Results Following Discontinuation of Methotrexate in Rheu 2020 Mar OBJECTIVE: To assess differences in joint damage and inflammation using magnetic resonance imaging (MRI) between patients with rheumatoid arthritis (RA) who achieved low disease activity with tocilizumab (TCZ) + methotrexate (MTX) and subsequently continued or discontinued MTX. METHODS: In the COMP-ACT trial, US patients with RA received subcutaneous TCZ 162 mg + MTX. Those who achieved 28-joint count Disease Activity Score calculated with erythrocyte sedimentation rate (DAS28-ESR) ≤ 3.2 at Week 24 were randomized 1:1 (double-blind) to discontinue MTX (TCZ monotherapy; mono) or continue TCZ + MTX until Week 52. In a subset of patients, 1.5-Tesla MRI was used to obtain images of bilateral hands and wrists at weeks 24 and 40. Outcomes included changes in MRI-assessed synovitis, osteitis, erosion, and cartilage loss from Week 24 to Week 40, and in the proportion of patients with progression of each score. RESULTS: Of 296 patients who achieved DAS28-ESR ≤ 3.2 at Week 24, 79 were enrolled in the pilot MRI substudy and randomized to TCZ mono (n = 38) or TCZ + MTX (n = 41). Treatment with either TCZ mono or TCZ + MTX suppressed erosion progression, synovitis, osteitis, and cartilage loss. The proportion of patients with no progression in each outcome measure was similar between groups (range, TCZ mono: 84.8-97.0%; TCZ + MTX: 92.3-100%). CONCLUSION: In a subset of patients who achieved low disease activity with TCZ + MTX, MRI changes were minimal in intraarticular inflammation and damage measures in patients who discontinued MTX versus those who continued TCZ + MTX.
32805045 Nonvitamin, Nonmineral Dietary Supplement Use in Individuals with Rheumatoid Arthritis. 2020 Sep 1 BACKGROUND: Over-the-counter, natural product-based (nonvitamin, nonmineral) dietary supplement (NVNM DS) use is common in adults with rheumatoid arthritis (RA), a group at risk for drug-DS interactions, due to polypharmacy, but this use is underreported to health care providers. Recent dramatic changes in US sales of specific NVNM DS suggest that the prevalence and types of NVNM DS used in RA populations may also have shifted. OBJECTIVES: A study was undertaken to identify current and past use of specific NVNM DS for RA disease treatment and to examine associations between use of NVNM DS, RA pharmaceuticals, and/or vitamin or mineral (VM) DS. METHODS: We developed a survey instrument to capture current and ever use of specific NVNM DS, VM DS, and RA pharmaceuticals, with 696 subjects self-reporting an RA diagnosis recruited online or in clinic for survey participation. Analyses were limited to 611 subjects reporting RA diagnosis after age 18 y and treatment with specific RA pharmaceuticals. RESULTS: Most participants reported DS use, with current usage prevalence 49.6% (n = 303), 83.5% (n = 510), or 87.6% (n = 535) for NVNM, VM, or any DS, respectively. While not having appeared in previous RA surveys, turmeric and ginger were among the top 3 NVNM DS in current use, along with fish oil/ω-3 (n-3) PUFA. Concurrent NVNM DS use was reported by 48.2% (n = 243) of participants currently using RA pharmaceuticals (n = 504) and was more common in those using disease-modifying antirheumatic drugs only (no biologics). Most methotrexate users (83%) reported concurrent folate supplementation, with one-third also using turmeric, which is notable because methotrexate and turmeric have been associated with hepatotoxicity. CONCLUSION: Individuals with RA commonly use NVNM DS in combination with RA pharmaceuticals, including a previously undocumented but popular use of turmeric or ginger supplements with an unclear risk/benefit ratio.
31244428 Methotrexate Hepatotoxicity in Rheumatoid Arthritis: An Analysis of the Physicians' Policy 2020 BACKGROUND: Methotrexate hepatotoxicity could be a reason for the discontinuation or dose reduction in patients with Rheumatoid Arthritis (RA); however, the consequence of different policies in this situation is unclear and the physicians need to know what would happen after their decision. OBJECTIVE: To demonstrate the consequence of multiple approaches towards transaminitis management in patients with RA receiving Methotrexate (MTX). METHODS: Data were obtained from the previous work (2006) on 295 patients with RA undergoing MTX treatment. Those who developed transaminitis at least one time were selected for this study. Then, the physicians' decisions regarding discontinuing, decreasing, or prescribing a fixed dose of MTX along with the effect of each decision on the next liver enzyme were evaluated. RESULTS: Strategies of decreasing dose or discontinuing MTX were adopted in 31.4% of patients and prescribing fixed dose was done in 53.9% of patients, leading to 93% and 65% next enzyme normalization, respectively. Thirty-four patients had definite MTX induced transaminitis and 55.9% of the physicians decided to decrease MTX dose for them, causing normalization of the next enzyme in 83% of these patients. In contrast, continuing MTX, even with the same dose, in definite MTX induced transaminitis cases led to consecutive enzyme elevations in 88.9% of these patients (p=0.001). CONCLUSION: Normalization of liver enzymes was observed after decreasing dose or discontinuing MTX, suggesting this policy as the best practice for the management of MTX induced transaminitis. However, the trend to improvement, despite the type of physicians' decision, was observed. This trend was not found in definite MTX induced transaminitis, revealing the prominence of the physician's policy in this situation.
31498447 Real-world evidence for increased deep neck infection risk in patients with rheumatoid art 2020 Jun OBJECTIVE: To investigate the association between rheumatoid arthritis (RA) and deep neck infection (DNI). STUDY DESIGN: Retrospective cohort study. METHODS: Patients newly diagnosed with RA between 2000 and 2011 were identified from the National Health Insurance Research Database in Taiwan. Moreover, patients without RA were randomly selected and matched at a 1:4 ratio by age, sex, urbanization level, income, and diabetes mellitus. The patients were followed up until death or the end of the study period (December 31, 2013). The primary outcome was the occurrence of DNI. RESULTS: In total, 30,207 patients with RA and 120,828 matched patients without RA were enrolled. Patients with RA had a significantly higher cumulative incidence of DNI than those without RA (P < 0.001). The adjusted Cox proportional hazard model demonstrated that RA was significantly associated with a higher incidence of DNI (hazard ratio: 2.80, 95% confidence interval: 2.26-3.46, P < 0.001). Therapeutic methods (surgical or nonsurgical) did not differ significantly between the patients with RA-DNI and with non-RA-DNI. Patients with RA-DNI had higher rates of tracheostomy, mediastinitis, mediastinitis-related mortality, and mortality than patients with non-RA-DNI, although these differences were without statistical significance. RA patients receiving no therapy experienced higher rates of DNI compared with those receiving methotrexate alone, disease-modifying antirheumatic drugs, or biologic therapies. CONCLUSION: This study is the first to investigate the association between RA and DNI. We conclude RA is an independent predisposing factor for DNI. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:1402-1407, 2020.
32590796 Deep surgical site infection after posterior instrumented fusion for rheumatoid upper cerv 2020 Jun 26 INTRODUCTION: Patients with rheumatoid arthritis (RA) tend to be immunosuppressed due to RA itself and the therapeutic drugs administered. The management of surgical site infection (SSI) following upper cervical spinal instrumented fusion in RA patients is challenging; however, literature on the treatment for such conditions is scarce. We report 3 consecutive patients with RA, who developed deep SSI following upper cervical posterior fusion and were treated using antibiotic-loaded bone cement (ALBC). PATIENT CONCERNS: All 3 patients reported in the current study experienced compression myelopathy with upper cervical spinal deformity and received prednisolone and methotrexate for controlling RA preoperatively. The patient in Case 1 underwent C1-2 posterior fusion and developed deep SSI due to methicillin-sensitive Staphylococcus aureus at 3 months postoperatively; the patient in Case 2 underwent occipito-C2 posterior fusion and developed deep SSI due to methicillin-sensitive Staphylococcus aureus at 2 weeks postoperatively; and the patient in Case 3 underwent occipito-C2 posterior instrumented fusion and laminoplasty at C3-7, and developed deep SSI due to methicillin-resistant coagulase negative staphylococci at 3 weeks postoperatively. DIAGNOSIS: All patients developed deep staphylococcal SSI in the postoperative period. INTERVENTIONS: All 3 patients were treated using ALBC placed on and around the instrumentation to cover them and occupy the dead space after radical open debridement. OUTCOMES: The deep infection was resolved uneventfully after the single surgical intervention retaining spinal instrumentation. Good clinical outcomes of the initial surgery were maintained until the final follow-up without recurrence of SSI in all 3 cases. CONCLUSION: ALBC embedding spinal instrumentation procedure can be a viable treatment for curing SSI in complex cases, such as patients with RA who undergo high cervical fusion surgeries without implant removal.
32636183 Comparative effectiveness of biological medicines in rheumatoid arthritis: systematic revi 2020 Jul 7 OBJECTIVE: To assess the comparative effectiveness of biological medicines in rheumatoid arthritis in sufficiently similar patient populations, based on the current definitions of key outcomes. DESIGN: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. DATA SOURCES: Clinical study reports and aggregate results from reanalyses of individual patient data on key outcomes for rheumatoid arthritis provided by study sponsors for studies conducted up to 2017, and several databases and registries from inception up to February 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials investigating patient relevant outcomes in adults with rheumatoid arthritis treated with biological medicines in combination with methotrexate after methotrexate failure for at least 24 weeks. RESULTS: 45 eligible trials were identified. Combining data from clinical study reports and aggregate results from reanalyses of individual patient data allowed extensive analyses yielding sufficiently similar populations and homogeneous study results for network meta-analyses, including up to 35 studies on eight biological medicines combined with methotrexate. These analyses showed few statistically significant differences between the combination treatments. For example, anakinra showed less benefit than almost all the other seven biological medicines regarding clinical remission or low disease activity (clinical disease activity index ≤2.8 or ≤10, respectively) and certolizumab pegol showed more harm than the other seven biological medicines regarding serious adverse events or infections. Some outcomes had very wide 95% confidence intervals, potentially implying unidentified differences between the eight biological medicines, but wide 95% confidence intervals were less prominent for low disease activity, serious adverse events, and infections. Owing to a lack of head-to-head trials, results were mainly based on indirect comparisons with a limited number of studies, and recently approved Janus kinase inhibitors could not be included. CONCLUSIONS: For patients with rheumatoid arthritis after methotrexate failure, only minor differences in benefits and harms were seen between biological medicines in combination with methotrexate. However, the analysis was hampered by a lack of long term direct comparisons. The substantial information gain achieved by the reanalysis of individual patient data calls for the routine availability of individual patient data.
32801134 The Risk of Cardiovascular Events Associated With Disease-modifying Antirheumatic Drugs in 2021 May OBJECTIVE: To examine the comparative effects of biologic disease-modifying antirheumatic drugs (bDMARD) and tofacitinib against conventional synthetic DMARD (csDMARD) on incident cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). METHODS: RA patients with ≥ 1 year of participation in the FORWARD study, from 1998 through 2017, were assessed for incident composite CVD events (myocardial infarction, stroke, heart failure, and CVD-related death validated from hospital/death records). DMARD were categorized into 7 mutually exclusive groups: (1) csDMARD-referent; (2) tumor necrosis factor-α inhibitor (TNFi); (3) abatacept (ABA); (4) rituximab; (5) tocilizumab; (6) anakinra; and (7) tofacitinib. Glucocorticoids (GC) were assessed using a weighted cumulative exposure model, which combines information about duration, intensity, and timing of exposure into a summary measure by using the weighted sum of past oral doses (prednisolone equivalent). Cox proportional hazard models were used to adjust for confounders. RESULTS: During median (IQR) 4.0 (1.7-8.0) years of follow-up, 1801 CVD events were identified in 18,754 RA patients. The adjusted model showed CVD risk reduction with TNFi (HR 0.81, 95% CI 0.71-0.93) and ABA (HR 0.50, 95% CI 0.30-0.83) compared to csDMARD. While higher GC exposure as weighted cumulative exposure was associated with increased CVD risk (HR 1.15, 95% CI 1.11-1.19), methotrexate (MTX) use was associated with CVD risk reduction [use vs nonuse HR 0.82, 95% CI 0.74-0.90, and high dose (> 15 mg/week) vs low dose (≤ 15 mg/week) HR 0.83, 95% CI 0.70-0.99]. CONCLUSION: ABA and TNFi were associated with decreased risk of CVD compared to csDMARD. Minimizing GC use and optimizing MTX dose may improve cardiovascular outcomes in patients with RA.
32506311 Clinical effectiveness of iguratimod based on real-world data of patients with rheumatoid 2021 Jan OBJECTIVES: Iguratimod (IGU) is a conventional synthetic disease-modifying drug that has been approved based on its additive effects with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). The objective of the study is to establish the effectiveness of IGU with versus IGU without MTX irrespective of whether MTX is well tolerated or not by the patients. METHODS: Disease activity scores in 177 RA patients treated using IGU were retrospectively evaluated at baseline and after 4, 12, and 24 weeks, and adverse events (AEs) were noted. RESULTS: IGU reduced the disease activity parameters, disease activity score (DAS)-ESR, DAS-CRP, the simplified disease activity index (SDAI), and clinical disease activity index (CDAI) in the concomitant MTX and non-MTX, female and male, and young and elderly patient groups after 24 weeks. Multivariate analysis demonstrated that IGU was more effective with concomitant MTX and in elderly and male patients. Severe AEs were observed only in the elderly group: two cases of pneumonia, 1 of pneumocystis pneumonia, 1 of heart failure, and 1 of salivary gland adenoma. CONCLUSIONS: IGU is effective for RA, especially with concomitant MTX, and in elderly and male patients. Key Points • Iguratimod is effective for RA, especially with concomitant MTX, and in elderly and male patients. • Since all serious adverse events were in the elderly group in this study, sufficient monitoring for adverse events, especially for elderly RA patients, is needed during iguratimod therapy.
30725185 Comparative efficacy and safety of 15 and 30 mg upadacitinib administered to patients wi 2020 Feb OBJECTIVES: We assessed the relative efficacy and safety of once-daily administration of 15 and 30 mg upadacitinib (a JAK1-selective inhibitor) in patients with active rheumatoid arthritis (RA). METHODS: We conducted a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of upadacitinib in patients with active RA. RESULTS: Five RCTs involving 4381 patients met the inclusion criteria. There were 15 pairwise comparisons, including eight direct comparisons and six interventions. The ACR20 response rate was significantly higher in the upadacitinib 15 and 30 mg + MTX (methotrexate) groups than in the MTX group (OR: 4.98, 95% CrI: 2.66-10.10; OR: 4.73, 95% CrI: 2.25-10.98). Adalimumab 40 mg + MTX, upadacitinib 30 mg, and upadacitinib 15 mg groups showed a significantly higher ACR20 response rate than did the MTX group. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg + MTX was likely to achieve the best ACR20 response rate (SUCRA = 0.838), followed by upadacitinib 30 mg + MTX, adalimumab 40 mg + MTX, upadacitinib 30 mg, upadacitinib 15 mg, and MTX (SUCRA = 0.784, 0.495, 0.471, 0.404, and 0.008, respectively). The safety based on the number of serious adverse events (SAEs) did not differ significantly among the six interventions. CONCLUSIONS: Upadacitinib 15 and 30 mg administration once daily in combination with MTX was the most efficacious intervention for active RA, with no significant risk for SAEs.
33087003 Tuberculosis osteomyelitis in an old fused hip; activated by prednisolone, salazosulfapyri 2020 Jul Osteoarticular tuberculosis can occur in patients with rheumatoid arthritis (RA) receiving immunosuppressive therapy. Here, we describe a case of tubercular osteomyelitis in an old fused hip of a patient with RA who received prednisolone, salazosulfapyridine (SASP), and low-dose methotrexate (MTX). A 77-year-old man with a 4-year history of RA was admitted with a complaint of general fatigue. His symptoms of RA had been well controlled with a combination of prednisolone, SASP, and low-dose MTX. Because the laboratory data showed an increase in serum C-reactive protein levels, we suspected pneumonia. There was expansion of a pre-existing consolidation in the right lower lobe of his lung on chest computed tomography, and the sputum culture was positive for Klebsiella oxytoca. His family physician prescribed empiric antibiotics for pneumonia. Although the QuantiFERON(®) test result was positive, the acid-fast bacillus staining result was negative in the sputum. He started complaining of pain in his left hip, where arthrodesis was performed for an unknown reason at the age of 20 years. Sonographic examination of his left thigh revealed fluid collection. The aspiration culture of the fluid was positive for Mycobacterium tuberculosis. He was initiated on rifampicin, isoniazid, pyrazinamide, and ethambutol. Surgical debridement of the fused left hip was performed twice along with a removal of previously implanted materials. Although infrequent, osteoarticular tuberculosis can occur during immunosuppressive therapy, especially in elderly patients. Physicians should be aware of a history of possible tuberculosis infection, such as hip arthrodesis, when prescribing MTX along with SASP and corticosteroid in the elderly.
33089506 Screening of dental and sinus infections in rheumatoid arthritis. 2021 Apr BACKGROUND: Rheumatoid arthritis (RA) is associated with increased risk of infections. Screening for oral (dental and/or sinus) infection could be proposed before biologic disease-modifying antirheumatic drugs (bDMARDs) initiation but is not systematically recommended. The aim of our study was to assess the prevalence of oral infection in RA patients requiring bDMARDs. MATERIALS AND METHODS: This was a monocentric retrospective study. We included patients with RA and active disease requiring bDMARDs. Dental infection and sinusitis were assessed by a stomatologist and otorhinolaryngologist after clinical, panoramic dental X-ray and sinus CT evaluation. Factors associated with oral infections were analysed in uni- and multivariate models, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included 223 RA patients (79.4% women, mean disease duration 8.9 ± 8.6 years). The mean age was 54.4 ± 10.9 years and mean Disease Activity Score in 28 joints 5.5 ± 2.6. Systematic dental screening revealed infection requiring treatment before bDMARDs initiation in 46 (20.9%) patients. Sinusitis was diagnosed by the otorhinolaryngologist in 33 (14.8%) patients. Among the 223 patients, 69 (30.9%) had dental and/or sinus infection. On univariate analysis, active smoking was associated with increased probability of oral infection (OR = 2.16 [95% CI 1.02-4.57], P = .038) and methotrexate with reduced probability (OR = 0.43 [95% CI 0.23-0.81], P = .006). On multivariate analysis, no RA variables were associated with oral infection. CONCLUSION: In our study, asymptomatic oral infection was confirmed in one third of RA patients.
32739893 Effect on Costs and Quality-adjusted Life-years of Treat-to-target Treatment Strategies In 2021 Apr OBJECTIVE: Our study aimed to evaluate the cost effectiveness of initiating tocilizumab (TCZ) ± methotrexate (MTX) versus initiating MTX as treat-to-target treatment strategies over 5 years in early disease-modifying antirheumatic drug (DMARD)-naïve rheumatoid arthritis (RA). METHODS: Data on resource use were collected with questionnaires at baseline, 3, 6, 12, and 24 months, and yearly thereafter, and were converted to costs using Dutch reference prices. Quality-adjusted life-years (QALY) were calculated using the EQ5D5L, with utility based on Dutch tariff or estimated by the Health Assessment Questionnaire. To account for missing cost data and QALY data and for sample uncertainty, first bootstraps (10,000 samples) were obtained. Second, single imputation using chained equations nested within these bootstrap samples was performed. An economic evaluation was performed for TCZ + MTX and TCZ, compared to MTX, as initial treatment in a treat-to-target strategy from a healthcare and societal perspective over 5 years. Several sensitivity analyses were performed. RESULTS: Mean differences in QALY were small and not significant (TCZ + MTX vs MTX: 0.06, 95% CI -0.02 to 0.13; TCZ vs. MTX: -0.03, 95% CI -0.05 to 0.11). Limited savings in indirect nonhealthcare costs and productivity loss costs (for TCZ only) were observed, but these did not compensate for the higher medication costs. Sensitivity analyses did not materially change these findings, although lower-priced TCZ, or reserving TCZ as initial therapy for prognostically unfavorable RA patients, improved cost effectiveness considerably but did not individually lead to a strategy being cost effective. CONCLUSION: Based on our analyses, early initiation of TCZ + MTX is not cost effective compared to MTX initiation in a step-up treat-to-target treatment strategy over 5 years in early RA patients.
31867699 Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthr 2020 May Upadacitinib is a Janus kinase 1 inhibitor developed for treatment of moderate to severe rheumatoid arthritis (RA) and was recently approved by the US Food and Drug Administration for this indication in adults who have had an inadequate response or intolerance to methotrexate. Upadacitinib is currently under regulatory review by other agencies around the world. Ongoing trials are investigating the use of upadacitinib in other inflammatory autoimmune diseases. In this article, we review the clinical pharmacokinetic data available to date for upadacitinib that supported the clinical development program in RA and ultimately regulatory applications for upadacitinib in treatment of patients with moderate to severe RA.
32174196 The safety of baricitinib in patients with rheumatoid arthritis. 2020 May Introduction: Despite improvement in disease outcomes and prognosis, a substantial number of patients with rheumatoid arthritis (RA) still require a novel agent for effective treatment. Baricitinib is a targeted synthetic disease-modifying antirheumatic drug (tsDMARDs) that selectively inhibits Janus kinase (JAK1/JAK2), an important enzyme in the pathogenesis of RA.Areas covered: This paper aimed to evaluate the pharmacodynamics and pharmacokinetics of baricitinib while reviewing its safety and efficacy in the treatment of RA.Expert opinion: Randomized controlled trials of baricitinib showed its efficacy and safety in patients with active RA who were methotrexate (MTX)-naïve or were not adequately responsive to MTX, conventional synthetic DMARDs, or tumor necrosis factor inhibitors. Baricitinib may be suitable in patients who prefer oral therapy and do not have a history of severe renal impairment, recent history of malignancy, or risk factors for adverse events (AEs) such as venous thromboembolism, opportunistic infection, and diverticulitis. Dose adjustment of baricitinib, based on the assessment of patient conditions including their renal function and disease activity, is an important strategy for successful and safe treatment. However, long-term post-marketing surveillance studies with a larger sample size are required to evaluate the overall safety and AEs with low incidence rates in clinical settings.
32173513 Personalized medicine in rheumatoid arthritis: How immunogenicity impacts use of TNF inhib 2020 May Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay - RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.
32381123 Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depen 2020 May 7 BACKGROUND: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.
31969172 Abatacept in rheumatoid arthritis: survival on drug, clinical outcomes, and their predicto 2020 Jan 22 BACKGROUND: There are limited data regarding efficacy of abatacept treatment for rheumatoid arthritis (RA) outside clinical trials. Quality registers have been useful for observational studies on tumor necrosis factor inhibition in clinical practice. The aim of this study was to investigate clinical efficacy and tolerability of abatacept in RA, using a national register. METHODS: RA patients that started abatacept between 2006 and 2017 and were included in the Swedish Rheumatology Quality register (N = 2716) were investigated. Survival on drug was estimated using Kaplan-Meier analysis. The European League Against Rheumatism (EULAR) good response and Health Assessment Questionnaire (HAQ) response (improvement of ≥ 0.3) rates (LUNDEX corrected for drug survival) at 6 and at 12 months were assessed. Predictors of discontinuation were investigated by Cox regression analyses, and predictors of clinical response by logistic regression. Significance-based backward stepwise selection of variables was used for the final multivariate models. RESULTS: There was a significant difference in drug survival by previous biologic disease-modifying antirheumatic drug (bDMARD) exposure (p < 0.001), with longer survival in bionaïve patients. Men (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.74-0.98) and methotrexate users (HR 0.85, 95% CI 0.76-0.95) were less likely to discontinue abatacept, whereas a high pain score predicted discontinuation (HR 1.14 per standard deviation, 95% CI 1.07-1.20). The absence of previous bDMARD exposure, male sex, and a low HAQ score were independently associated with LUNDEX-corrected EULAR good response. The absence of previous bDMARD exposure also predicted LUNDEX-corrected HAQ response. CONCLUSIONS: In this population-based study of RA, bDMARD naïve patients and male patients were more likely to remain on abatacept with a major clinical response.