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ID PMID Title PublicationDate abstract
30589626 Assessing the Value of Sarilumab Monotherapy for Adults with Moderately to Severely Active 2019 Jan BACKGROUND: Rheumatoid arthritis is associated with a societal burden greater than $39 billion annually. Novel treatments, known as targeted immune modulators (TIMs), are expensive but effective, producing improvements in response rates compared with conventional disease-modifying antirheumatic drugs (cDMARDs). Sarilumab, a TIM approved in 2017, shows superior improvements compared with cDMARDs and produced significantly greater likelihood of achieving response and improvement in the Health Assessment Questionnaire Disability Index than adalimumab monotherapy. Although sarilumab monotherapy has shown improvements over cDMARDs and the TIM market leader adalimumab, treatment with sarilumab is costly, with an annual wholesale acquisition cost of $39,000. OBJECTIVE: To estimate the lifetime cost-effectiveness of starting treatment with sarilumab monotherapy for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to cDMARDs. METHODS: A sequential treatment cohort model followed a hypothetical cohort from initiation of sarilumab monotherapy until death. The model allowed patients to switch therapies up to 3 times due to effectiveness or adverse events. The first switch was to a TIM within the same treatment category; the second switch was to a TIM within a different treatment category; and the third switch was to a cDMARD. Sarilumab monotherapy was compared with a cDMARD (methotrexate) and the TIM market leader (adalimumab monotherapy). Key risk and benefit evidence came from clinical studies and network meta-analyses of data on radiographic progression and response. We used a lifetime time horizon and the U.S. health sector payer perspective assuming therapy net pricing. We also incorporated loss of productivity to reflect a restricted societal perspective. RESULTS: Over a lifetime time horizon, a treatment pathway starting with sarilumab resulted in 17.16 life-years and 13.66 quality-adjusted life-years (QALYs). Treatment pathways starting with the cDMARD resulted in 16.54 life-years and 11.77 QALYs; treatment pathways starting with adalimumab resulted in 17.05 life-years and 13.35 QALYs. Total costs for sarilumab ($492,000 for payer perspective, $634,000 for societal perspective) were less than total costs for adalimumab ($536,000 for payer perspective, $689,000 for societal perspective) but higher than total costs for the cDMARD ($63,000 for payer perspective, $272,000 for societal perspective). When compared with cDMARD therapy, sarilumab resulted in a cost-effectiveness estimate of $227,000 per QALY gained from the payer perspective and $191,000 per QALYs gained from the societal perspective. When compared with adalimumab, sarilumab was dominant from both perspectives. CONCLUSIONS: Sarilumab resulted in better health outcomes than conventional therapy alone. However, its additional cost with assumed class-level net prices led to cost-effectiveness estimates above commonly cited thresholds. When compared with the market leader, sarilumab achieved favorable value. This evaluation informs stakeholders of the value of sarilumab and its alternatives to promote high value practices in health care. DISCLOSURES: Funding for this research was contributed by the Institute for Clinical and Economic Review (ICER). Ollendorf, Chapman, Kumar, Synnott, and Agboola are employees of ICER, an independent organization that evaluates the evidence on the value of health care interventions, which is funded by grants from the Laura and John Arnold Foundation, Blue Shield of California Foundation, and the California HealthCare Foundation. The organization's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Omeda Rx, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, National Pharmaceutical Council, Takeda, Pfizer, Novartis, Lilly, and Humana. This work is an extension of an analysis presented at the New England Comparative Effectiveness Public Advisory Council on March 24, 2017, where the authors received public feedback on the analysis, results, and effect of a value assessment for targeted immune modulators. At the time of presentation, sarilumab was still an investigational product; therefore, a price was not known, so cost-effectiveness estimates were not generated. Since the presentation of that material, additional evidence for sarilumab has become available. The additional evidence has been incorporated into this analysis to present cost-effectiveness estimates for sarilumab.
30642376 The value of the simplified RAMRIS-5 in early RA patients under methotrexate therapy using 2019 Jan 14 BACKGROUND: The aim of the study was to evaluate a simplified version of the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) for five joints of the hand (RAMRIS-5) in patients with early rheumatoid arthritis (RA) before and after the initiation of methotrexate (MTX) therapy using high-resolution, 3-T magnetic resonance imaging (MRI). METHODS: Twenty-eight patients with a seropositive, early RA (disease duration of less than 6 months (range 2-23 weeks)) according to 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria (mean age 56.8 years, range 39-74) were prospectively assessed with a baseline investigation including clinical assessment (disease activity score of 28 joints (DAS-28) and C-reactive protein (CRP)) and 3-T MRI of the clinically dominant hand. Follow-up visits were performed 3 and 6 months after initiation of a MTX therapy at baseline. MRI scans were analyzed in accordance with RAMRIS and the simplified RAMRIS-5. RESULTS: DAS-28 and CRP decreased significantly after initiation of MTX therapy. Even though erosion scores increased over time, RAMRIS and RAMRIS-5 also decreased significantly after the start of therapy. There was a strong correlation between the total RAMRIS-5 and RAMRIS at baseline (r = 0.838; P <0.001) and follow-up (3 months: r = 0.876; P <0.001; 6 months: r = 0.897; P <0.001). In the short term (3-month follow-up), RAMRIS and RAMRIS-5 demonstrated similar ability to detect changes for all subgroups (bone edema, erosion, and synovitis). In the long-term comparison (6-month follow-up), RAMRIS-5 also showed similar effectiveness when detecting changes in bone edema and erosion compared with RAMRIS. Deviations occurred regarding only synovitis, where change was slightly higher in RAMRIS-5: SRM (RAMRIS) = 0.07 ± 0.14; SRM (RAMRIS-5) = 0.34 ± 0.06. CONCLUSIONS: Three-Tesla MRI-based RAMRIS-5 is a simplified and resource-saving RAMRIS score which compares favorably with the RAMRIS when detecting changes in early RA. Even though there is a slight abbreviation between RAMRIS-5 and the original score regarding the change of synovitis, it may be used for diagnosis and therapy monitoring in follow-up evaluations.
31617429 Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity i 2020 Feb OBJECTIVE: The objective was to explore the association of methylene tetrahydrofolate reductase (MTHFR) C667T and A1298C and reduced folate carrier 1 (RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China. METHODS: Two hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment. RESULTS: We detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity. CONCLUSIONS: In Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.
31820195 Influence of treatments on cell adhesion molecules in patients with systemic lupus erythem 2020 Apr BACKGROUND: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases characterized by changes in cell adhesion molecules (CAMs). OBJECTIVE: To review the influence of the main drugs used in the treatment of SLE and RA on CAM levels. METHODS: A bibliographic search was performed using electronic databases. The research included human studies, in vivo or in vitro, with an experimental or observational design, and with no limit of publication date or number of subjects. Animal studies and non-standard treatments were not considered. RESULTS: We included 21 studies, 3 on SLE and 18 on RA with monotherapy or combined trials. The most used drugs were cyclophosphamide (CY, in 2 studies) and methylprednisolone pulse (pMP, n = 2) in SLE; and methotrexate (MTX, n = 9) and infliximab (IFX, n = 4) in RA. In addition, the most frequently examined CAMs to predict response to treatment were vascular cell adhesion molecule-1 (VCAM-1, n = 2) in SLE, and intercellular adhesion molecule-1 (ICAM-1, n = 12), VCAM-1 (n = 12), and E-selectin (n = 14) in RA. After treatment, CAM levels were decreased in SLE and RA patients with active disease. CONCLUSIONS: It is concluded that the CAM biomarkers may reflect disease activity and the response to treatment in SLE and RA patients.
31791581 Theacrine alleviates chronic inflammation by enhancing TGF-β-mediated shifts via TGF-β/S 2020 Feb 12 Rheumatoid arthritis is a chronic and systemic autoimmune disease, which affects approximately 1% of the adult population worldwide. The present study investigated the therapeutic effect of theacrine (TC) on arthritis and its mechanisms in Freund's incomplete adjuvant (FIA)-induced SD rats. Rats were randomly divided into 5 groups: i) healthy control; ii) model; iii) positive control with methotrexate (MTX); iv) treatment with 12.5 mg/kg TC; and v) treatment with 25.0 mg/kg TC. The apparent scores, including changes in body weights, degree of paw swelling and arthritis indicators, were analyzed to evaluate the anti-chronic inflammatory effect of TC. The levels of interleukin (IL)-6 and transforming growth factor-β (TGF-β) in serum were measured by enzyme-linked immunosorbent assay. The protein and RNA expression levels of the critical factors in rats were measured to elucidate the mechanisms responsible for chronic inflammation and to verify molecular indexes of chronic inflammatory conditions. TC notably suppressed the severity of FIA-induced rat by attenuating the apparent scores, animal weight and inflammatory indexes in the 25 mg/kg TC group compared with the FIA rat model. Furthermore, TC significantly decreased the levels of IL-6 and increased the levels of TGF-β. Histopathological examinations indicated that TC rescued the synovial hyperplasia and inflammatory cell infiltration in joint tissues. In addition, TC enhanced TGF-β-mediated shifts in inflammatory marker expression in joint tissue. Overall, the present study demonstrated that TC exerted a superior anti-arthritic effect via the suppression of IL-6 and the activation of TGF-β by the TGF-β/SMAD pathway.
30767868 Conventional synthetic disease-modifying antirheumatic drugs and bone mineral density in r 2019 Sep OBJECTIVES: To investigate the effect of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) on bone mineral density (BMD) in rheumatoid arthritis (RA) patients with osteoporosis. METHODS: Patients with RA who were newly diagnosed with osteoporosis (T-score ≤ -2.5) between 2010 and 2017 were included. All patients received background bisphosphonate for treatment of osteoporosis. BMD was measured at baseline and after one year. To identify csDMARDs or other factors associated with significant increase in BMD (≥3%) at lumbar spine and femoral neck at one year, we performed logistic regression analysis. To exclude the possibility of confounding by methotrexate, which was commonly used as a combination therapy with other csDMARDs, we also performed logistic regression analysis in the methotrexate users (subgroup analysis). RESULTS: In total, 153 RA patients with newly diagnosed osteoporosis were included. Leflunomide was the only csDMARD associated with significant increase in lumbar spine BMD (adjusted odds ratio (OR) 3.000, 95% confidence interval (CI) 1.177-7.645, p=0.021). In regard to femoral neck BMD, no csDMARDs were associated with significant increase in BMD. In the subgroup analysis, use of leflunomide was still associated with significant increase in lumbar spine BMD (adjusted OR 2.653, 95% CI 1.030-6.836, p=0.043), whereas no csDMARDs were associated with significant increase in femoral neck BMD. CONCLUSIONS: Among the csDMARDs, leflunomide can be beneficial in lumbar spine BMD in RA patients with osteoporosis.
30761753 Real-world effectiveness and safety of rituximab in the treatment of rheumatoid arthritis: 2019 May AIM: To assess the real-world effectiveness and safety of rituximab (RTX) at 24 months in patients with established rheumatoid arthritis (RA) and to identify predictors of low disease activity/remission and a good European League Against Rheumatism (EULAR) response. METHODS: Seventy RTX-treated RA patients were enrolled. Predictors for low disease activity/remission and a good EULAR response at 24 months were identified by multivariate analyses. RESULTS: At 24 months, the mean Disease Activity Score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR) decreased from 6.88 ± 0.85 at baseline to 3.47 ± 0.85. Twenty-nine patients (41.4%) reached low disease activity/remission, while all patients had a moderate/good EULAR response. After adjustment by multivariate analyses, we found concomitant methotrexate at a dosage >10 mg/week (odds ratio [OR] 5.17; 95% CI 1.34-19.93; P = 0.017) predicted low disease activity/remission, and baseline DAS28 ≤6.5 (OR 4.97; 95% CI 1.22-20.30; P = 0.026) predicted good EULAR response at 24 months. The most common adverse events were infusion-related (5.7%), and there was no incidence of malignancy or mortality during the treatment. CONCLUSIONS: RTX was effective and safe in real-life management of RA patients with high disease activity. Patients taking concomitant methotrexate and with lower baseline DAS28-ESR were more likely to benefit from RTX.
31602895 [Effect of Tripterygium Glycosides Tablets in treating rheumatoid arthritis:a systematic r 2019 Aug To evaluate the effect of Tripterygium Glycosides Tablets extract in the treatment of rheumatoid arthritis( RA). Clinical trials of treating rheumatoid arthritis with Tripterygium Glycosides Tablets published by Meta-analysis were retrieved from EMbase,PubMed,Clinical Trials,Web of Science,Cochrane Library,CNKI,Wanfang,VIP,CBM and Chi CTR,and comprehensively analyzed. A total of 3 studies were enrolled,the modified Sharp score( m TSS),tender join joint erosions( JE) and joint space narrowing( JSN) of Tripterygium Glycosides Tablets group were significant superior to those of control group,including positive drugs methotrexate( MTX) and salazopyridine( SSZ)( P<0. 01). Tripterygium Glycosides Tablets had an effect in treating RA. Due to the small sample size,this study shall be verified with high-quality,large-sample-size double-blinded RCTs.
31327821 Gastric Perforation due to Iatrogenic Immunodeficiency-associated Lymphoproliferative Diso 2019 Nov 15 A 71-year-old woman being treated with methotrexate (MTX) and tacrolimus (TAC) for rheumatoid arthritis (RA) was admitted to our hospital and underwent surgery for gastric perforation and peritonitis. An endoscopic examination six days post-surgery showed an extensive ulcer in the stomach, and a biopsy revealed diffused large B-cell lymphoma. We diagnosed her with immunodeficiency-associated lymphoproliferative disorder (LPD) and discontinued the MTX and TAC. She underwent gastrectomy due to stenosis approximately two months after the first operation, but the histopathological findings of lymphoma had disappeared. LPD should be considered as a potential cause of gastric perforation during RA treatment.
31211506 Comparison of the efficacy and safety of tofacitinib and upadacitinib in patients with act 2019 Aug OBJECTIVES: The relative efficacy and safety of tofacitinib and upadacitinib were assessed in patients with rheumatoid arthritis (RA) with an inadequate response to conventional synthetic (cs) or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs). METHOD: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and upadacitinib in combination with methotrexate (MTX) in RA patients with an inadequate cs- or b-DMARD response. RESULTS: Nine RCTs including 5794 patients met the inclusion criteria. There were 15 pairwise comparisons including 10 direct comparisons of 6 interventions. Upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX were among the most effective treatments for active RA with an inadequate cs- or b-DMARD response, followed by tofacitinib 10 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX had the highest probability of being the best treatment in terms of the American College of Rheumatology 20 response rate (SUCRA = 0.820, 0.762), followed by tofacitinib 10 mg + MTX (SUCRA = 0.623), tofacitinib 5 mg + MTX (SUCRA = 0.424), adalimumab + MTX (SUCRA = 0.371), and placebo + MTX (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, upadacitinib + MTX, adalimumab + MTX, or placebo + MTX. CONCLUSIONS: In RA patients with an inadequate response to cs- or b-DMARDs, upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX were the most efficacious interventions and were not associated with significant risks of serious adverse events.
31338568 The impact of gender on time to rheumatoid arthritis classification: a retrospective analy 2019 Dec The objective is to compare the time to fulfillment of 1987 and 2010 ACR/EULAR classification criteria between female and male patients with rheumatoid arthritis (RA) and to assess the potential impact of gender on the time to DMARD therapy. Time from first provider-documented joint swelling to fulfillment of 1987 and 2010 ACR/EULAR criteria was measured in a population-based cohort of adults with incident RA, who were stratified by male or female gender. Disease characteristics, time to start of DMARD therapy, and choice of initial DMARD were compared between groups. The study included 214 patients with RA (148 females and 66 males). Median times from first joint swelling to fulfillment of 1987 (6.5 vs 2.5 days, p = 0.48) and 2010 (1 vs 0 days, p = 0.34) classification criteria were not different between female and male patients overall. There was no difference in time to first DMARD therapy in female vs male patients (15.5 vs 16 days, p = 0.90), and methotrexate was used most frequently as first DMARD in both genders (61% female vs 64% male, p = 0.76). Among the 49 female and 20 male RF/ACPA-negative patients, females experienced a higher median time from first joint swelling to fulfillment of the 1987 (65 vs 11 days, p = 0.063) and 2010 (65 vs 0 days, p = 0.035) classification criteria. Overall, there was no significant delay in meeting 1987 and 2010 ACR/EULAR classification criteria between female and male RA patients, though time to meeting both 1987 and 2010 criteria was slightly longer in males compared with females. Among seronegative patients, females experienced a significant delay to meeting 2010 criteria from first clinically detected synovitis.
31642025 Upadacitinib: First Approval. 2019 Nov Upadacitinib (Rinvoqâ„¢), an orally-administered Janus kinase 1 (JAK-1) inhibitor, is being developed by AbbVie for the treatment of rheumatoid arthritis. In August 2019, based on positive results from multinational phase III trials conducted in patients with rheumatoid arthritis, upadacitinib received marketing approval in the USA for the treatment of moderately to severely active rheumatoid arthritis and an inadequate response or intolerance to methotrexate. This article summarizes the milestones in the development of upadacitinib leading to this first approval for the treatment of rheumatoid arthritis.
30394138 Upadacitinib for the treatment of rheumatoid arthritis. 2019 Jan Introduction: Tofacitinib and baricitinib have recently been approved as second-line treatments for Rheumatoid arthritis (RA) though their maximum expected efficacy may be limited by dose-related toxicities. Upadacitinib selectively inhibits Janus Kinase 1 (JAK1) which could potentially reduce JAK2 and JAK3-related side effects. Areas covered: In this paper, we review a newly developed oral selective JAK inhibitor, upadacitinib for the treatment of RA. The doses of upadacitinib extended-release 15 and 30 mg daily selected in phase III RA studies have shown a near-maximum efficacy in phase II studies. Upadacitinib inhibited radiographic progression and displayed rapid and sustained clinical and functional efficacy in RA when in combination with methotrexate (MTX), upadacitinib was superior to placebo in MTX-Inadequate Responders (IRs) and biologic disease modifying antirheumatic drugs-IRs while as monotherapy, it was superior to MTX in MTX-IRs and MTX-naïve patients. Upadacitinib was superior to adalimumab using ACR70, reduction of pain-VAS and improvement of HAQ-DI. The comparison with abatacept is still ongoing. Expert commentary: Upadacitinib has displayed a rapid and favorable efficacy profile in RA but despite being a selective JAK1 inhibitor appears to have a similar safety profile to less-selective Jakinibs. Longer term safety data are awaited.
31136605 Reduced IgG titers against pertussis in rheumatoid arthritis: Evidence for a citrulline-bi 2019 BACKGROUND: The antibody response to pertussis vaccination in rheumatoid arthritis is unknown, a concerning omission given the relatively low efficacy of the pertussis vaccine, a rise in pertussis infections, and a general increased susceptibility to infection in rheumatoid arthritis. Additionally, the contributions from an intrinsically dysregulated immune system in rheumatoid arthritis and immune-suppressing medications to the response to pertussis vaccination is poorly defined. This study examines antibody titers against pertussis in vaccinated rheumatoid arthritis patients and controls as well as evaluates potential contributions from demographic factors, immune suppressing medications, and reactivity against citrullinated pertussis. METHODS: Serum IgG titers against native and citrullinated pertussis and tetanus were quantified by enzyme-linked immunosorbent assay in rheumatoid arthritis subjects and controls who were vaccinated within 10 years. Titers were compared by t-test and percent immunity by Fisher's exact test. Multivariable logistic regression was used to identify clinical factors that correlate with native pertussis titers. RESULTS: Compared to controls, rheumatoid arthritis subjects had lower titers against pertussis, but not tetanus, and reduced immunity to pertussis. These results were even more prominent at 5-10 years post-vaccination, when rheumatoid arthritis patients had 50% lower titers than controls and 2.5x more rheumatoid arthritis subjects were not considered immune to pertussis. Multiple logistic regression demonstrated that female sex and methotrexate use, but not TNF inhibiting medications, correlated with reduced immunity to pertussis. Finally, rheumatoid arthritis patients had higher IgG titers against citrullinated pertussis than native pertussis. CONCLUSIONS: Pertussis titers are lower in vaccinated rheumatoid arthritis patients with evidence for contributions from female sex, a citrulline-biased immune response, and methotrexate use.
31462329 Deletion at 2q14.3 is associated with worse response to TNF-α blockers in patients with r 2019 Aug 28 BACKGROUND: Structural variations such as copy number variations (CNVs) have a functional impact on various human traits. This study profiled genome-wide CNVs in Korean patients with rheumatoid arthritis (RA) to investigate the efficacy of treatment with TNF-α blockers. METHODS: A total of 357 Korean patients with RA were examined for the efficacy of TNF-α blocker treatment. Disease activity indexes were measured at baseline and 6 months after the treatment. The patients were classified as responders and non-responders based on the change in disease activity indexes according to the EULAR response criteria. CNVs in the same patients were profiled using fluorescence signal intensity data generated by a genome-wide SNP array. The association of CNVs with response to TNF-α blockers was analyzed by multivariate logistic regression accounting for genetic background and clinical factors including body mass index, gender, baseline disease activity, TNF-α blocker used, and methotrexate treatment. RESULTS: The study subjects varied in their responses to TNF-α blockers and had 286 common CNVs in autosomes. We identified that the 3.8-kb deletion at 2q14.3 in 5% of the subjects was associated with response to TNF-α blockers (1.37 × 10(- 5) ≤ P ≤ 4.07 × 10(- 4)) at a false discovery rate threshold of 5%. The deletion in the identified CNV was significantly more frequent in the non-responders than in the responders, indicating worse response to TNF-α blockers in the deletion carriers. The 3.8-kb deletion at 2q14.3 is located in an intergenic region with the binding sites of two transcription factors, MAFF and MAFK. CONCLUSIONS: This study obtained the CNV landscape of Korean patients with RA and identified the common regional deletion associated with poor response to treatment with TNF-α blockers.
30587928 Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient 2019 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular and systemic manifestations, such as anemia, fatigue, osteoporosis, and increased risk for cardiovascular diseases. The pathogenesis of RA is driven by a complex network of proinflammatory cytokines, with a pivotal role of IL-6 and tumor necrosis factor (TNF). The management of RA has been dramatically changed during the last years by the introduction of a treat-to-target approach aiming to achieve an acceptable disease control. Nowadays, TNF inhibitors (TNFis) are the most frequently prescribed class of biologic therapies, but the significant proportion of patients experiencing the failure of a TNFi led to the development of alternative therapeutic options targeted on different pathways. Considering the increasing number of targeted therapeutic options for RA, there is a growing interest in the identification of potential predictors of clinical response to each available mechanism of action, with the aim to drive the management of the disease toward a personalized approach according to the concept of precision medicine. Tocilizumab (TCZ) is the first humanized anti-IL-6 receptor subunit alpha (anti-IL-6R) monoclonal antibody approved for the treatment of RA refractory to methotrexate or TNFis. TCZ inhibits both the cis- and trans-signaling cascades involving the Janus kinase-signal transducer and the activator of transcription pathway, playing a crucial role in modulating not only joint inflammation but also the previously mentioned extra-articular manifestations and comorbidities of RA, such as fatigue, anemia, bone loss, depression, type 2 diabetes, and increased cardiovascular risk. In this review, moving from pathogenetic insights and evidence-based clinical data from randomized controlled trials and real-life observational studies, we will discuss the drivers for the selection of patient candidates to receive TCZ, in order to clarify the current positioning of this drug in the treatment algorithm of RA.
30830763 Synergistic Oxygen Generation and Reactive Oxygen Species Scavenging by Manganese Ferrite/ 2019 Mar 26 Poor O(2) supply to the infiltrated immune cells in the joint synovium of rheumatoid arthritis (RA) up-regulates hypoxia-inducible factor (HIF-1α) expression and induces reactive oxygen species (ROS) generation, both of which exacerbate synovial inflammation. Synovial inflammation in RA can be resolved by eliminating pro-inflammatory M1 macrophages and inducing anti-inflammatory M2 macrophages. Because hypoxia and ROS in the RA synovium play a crucial role in the induction of M1 macrophages and reduction of M2 macrophages, herein, we develop manganese ferrite and ceria nanoparticle-anchored mesoporous silica nanoparticles (MFC-MSNs) that can synergistically scavenge ROS and produce O(2) for reducing M1 macrophage levels and inducing M2 macrophages for RA treatment. MFC-MSNs exhibit a synergistic effect on O(2) generation and ROS scavenging that is attributed to the complementary reaction of ceria nanoparticles (NPs) that can scavenge intermediate hydroxyl radicals generated by manganese ferrite NPs in the process of O(2) generation during the Fenton reaction, leading to the efficient polarization of M1 to M2 macrophages both in vitro and in vivo. Intra-articular administration of MFC-MSNs to rat RA models alleviated hypoxia, inflammation, and pathological features in the joint. Furthermore, MSNs were used as a drug-delivery vehicle, releasing the anti-rheumatic drug methotrexate in a sustained manner to augment the therapeutic effect of MFC-MSNs. This study highlights the therapeutic potential of MFC-MSNs that simultaneously generate O(2) and scavenge ROS, subsequently driving inflammatory macrophages to the anti-inflammatory subtype for RA treatment.
31349410 Preparation and in vitro evaluation of radiolabeled HA-PLGA nanoparticles as novel MTX del 2019 Oct Radiosynovectomy is a technique used to decrease inflammation of the synovial tissue by intraarticular injection of a β-emitting radionuclide, such as (177)Lu, which is suitable for radiotherapy due to its decay characteristics. Drug-encapsulating nanoparticles based on poly lactic‑co‑glycolic acid (PLGA) polymer are a suitable option to treat several arthritic diseases, used as anti-inflammatory drugs transporters of such as methotrexate (MTX), which has been widely used in the arthritis treatment (RA), and hyaluronic acid (HA), which specifically binds the CD44 and hyaluronan receptors overexpressed on the inflamed synovial tissue cells. The 1,4,7,10‑Tetraazacyclododecane‑1,4,7,10‑tetraacetic acid (DOTA) was used as complexing agent of Lutetium-177 for radiotherapy porpoises. The aim of this research was to synthesize (177)Lu-DOTA-HA-PLGA(MTX) as a novel, smart drug delivery system with target-specific recognition, potentially useful in radiosynovectomy for local treatment of rheumatoid arthritis. The polymeric nanoparticle system was prepared and chemically characterized. The MTX encapsulation and radiolabelling were performed with suitable characteristics for its in vitro evaluation. The HA-PLGA(MTX) nanoparticle mean diameter was 167.6 nm ± 57.4 with a monomodal and narrow distribution. Spectroscopic techniques demonstrated the effective conjugation of HA and chelating agent DOTA to the polymeric nanosystem. The MTX encapsulation was 95.2% and the loading efficiency was 6%. The radiochemical purity was 96 ± 2%, determined by ITLC. Conclusion: (177)Lu-DOTA-HA-PLGA(MTX) was prepared as a biocompatible polymeric PLGA nanoparticle conjugated to HA for specific targeting. The therapeutic nanosystem is based on bi-modal mechanisms using MTX as a disease-modifying antirheumatic drug (DMARD) and (177)Lu as a radiotherapeutic component. The (177)Lu-DOTA-HA-PLGA(MTX) nanoparticles showed properties suitable for radiosynovectomy and further specific targeted anti-rheumatic therapy.
31240388 Cost per response for abatacept versus adalimumab in patients with seropositive, erosive e 2019 Sep BACKGROUND: Effective treatment of rheumatoid arthritis (RA) with biologic DMARDs poses a significant economic burden. The AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE RA subjects with background methotrexate) trial was a head-to-head, randomized study comparing abatacept with adalimumab. A post hoc analysis showed improved efficacy for abatacept in patients with versus without seropositive, erosive early RA. OBJECTIVE: The aim of the current study was to evaluate the cost per response (ACR20/50/70/90 and HAQ-DI) and patient in remission (DAS28-CRP, CDAI, and SDAI) for abatacept relative to adalimumab, in patients with seropositive, erosive early RA in the US, Germany, Spain, and Canada. METHODS: A previously published model was used to compare abatacept and adalimumab in a cohort of 1000 patients over 2 years. Clinical inputs were updated based on two subpopulations from the AMPLE trial. Cohort 1 included patients with early RA (disease duration ≤ 6 months), RF and/or ACPA seropositivity, and > 1 radiographic erosion. Cohort 2 included patients with RA in whom at least one of these criteria was absent. RESULTS: For cohort 1, all incremental costs per additional health gain (patient response or patient in remission) favoured abatacept in all countries, except for DAS28-CRP remission in Canada. Cost savings versus adalimumab were greater when more stringent response criteria were applied and also in cohort 1 patient (versus cohort 2 patients). CONCLUSION: The cost per responder and patient in remission favoured abatacept in patients with seropositive, erosive early RA across all the countries. In this patient population, the use of abatacept instead of adalimumab can lead to lower costs in the US, Germany, Spain, and Canada.
31061059 Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate tr 2019 May 5 OBJECTIVES: To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early rheumatoid arthritis (RA) inception cohorts with a focus on methotrexate (MTX) exposure. DESIGN: Multicentre prospective early RA inception cohort studies; the early RA study (ERAS) and the early RA network (ERAN). SETTING: Secondary care, ERAS nine centres, ERAN 23 centres in England, Wales and Ireland. PARTICIPANTS: Patients with new diagnosis of RA, n=2701. Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3-6 months, at 12 months and annually thereafter. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the association of MTX exposure on RA-ILD diagnosis. Secondary outcomes were the association of demographic, comorbid and RA-specific factors on RA-ILD diagnosis and the association of MTX exposure on time to RA-ILD diagnosis. RESULTS: Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of RA-ILD cases only developing after any conventional synthetic disease-modifying antirheumatic drug treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (OR 0.85, 95% CI 0.49 to 1.49, p=0.578) and a non-significant trend for delayed ILD diagnosis (OR 0.54, 95% CI 0.28 to 1.06, p=0.072). In an extended analysis including RA-ILD cases present at RA diagnosis (n=92), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (OR 0.48, 95% CI 0.3 to 0.79, p=0.004) and longer time to ILD diagnosis (OR 0.41, 95% CI 0.23 to 0.75, p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first outpatient visit. CONCLUSIONS: MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence suggested that MTX may delay the onset of ILD.