Browse

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

ID PMID Title PublicationDate abstract
32560528 A Systematic Review Comparing Experimental Design of Animal and Human Methotrexate Efficac 2020 Jun 17 Increased awareness and understanding of current practices in translational research is required for informed decision making in drug development. This paper describes a systematic review of methotrexate for rheumatoid arthritis, comparing trial design between 147 animal and 512 human studies. Animal studies generally included fewer subjects than human studies, and less frequently reported randomisation and blinding. In relation to life span, study duration was comparable for animals and humans, but included animals were younger than included humans. Animal studies often comprised males only (61%), human studies always included females (98% included both sexes). Power calculations were poorly reported in both samples. Analyses of human studies more frequently comprised Chi-square tests, those of animal studies more frequently reported analyses of variance. Administration route was more variable, and more frequently reported in animal than human studies. Erythrocyte sedimentation rate and c-reactive protein were analysed more frequently in human than in animal studies. To conclude, experimental designs for animal and human studies are not optimally aligned. However, methotrexate is effective in treating rheumatoid arthritis in animal models and humans. Further evaluation of the available evidence in other research fields is needed to increase the understanding of translational success before we can optimise translational strategies.
32274443 Concomitant herpes simplex keratitis and autoimmune-associated ulcerative keratitis in rhe 2020 Jun PURPOSE: To describe four cases of concomitant herpes simplex keratitis (HSK) and autoimmune-associated ulcerative keratitis (UK) in patients with rheumatoid arthritis (RA). OBSERVATIONS: All patients developed HSK and UK while undergoing treatment for RA. The average age of onset for RA, UK and HSK was 49.3, 69.5 and 70.5 years, respectively. UK preceded HSK in three cases and followed HSK in one case. Two patients had bilateral UK and two had unilateral UK. HSK was unilateral in all cases. All the cases had been treated with immunosuppressive agents including steroid, methotrexate, calcineurin inhibitors, etanercept and tocilizumab at the onset of HSK. Every patient was treated for HSK with topical acyclovir ointment combined with oral valacyclovir. The final visual outcome was extremely poor despite intensive therapy. CONCLUSIONS AND IMPORTANCE: These cases raise the possibility that RA patients have an increased risk of HSK, and that HSK may tend to be severe in these patients because of their immunocompromised condition. Furthermore, the complication of HSK and UK in RA patients is difficult to treat because of the atypical clinical manifestation. Thus, the emergence of corneal ulcer, especially in patients with a long clinical history of RA, calls for careful follow-up.
33088326 Efficacy of synbiotic supplementation in improving rheumatoid arthritis. 2020 Jun BACKGROUND AND PURPOSE: Today, improving rheumatoid arthritis (RA) as a chronic inflammatory disease is attributed to the proper status of the gut microbiota. Although some supplements containing beneficial live microorganisms (probiotics) can reduce inflammation by altering the bacterial composition of the gut, there is limited information on the effect of synbiotic (probiotics mixed with prebiotics) supplements on RA. Therefore, this study aimed to evaluate the anti-inflammatory effects of a synbiotic supplement as an adjuvant therapy in rheumatic patients. Moreover, for the first time, it was attempted to investigate whether addition of a synbiotic (1000 mg/day) to the combination of methotrexate and prednisolone increases the effectiveness of these antirheumatic drugs. EXPERIMENTAL APPROACH: Eligible patients (186 subjects) were randomly divided into two groups. Both groups received their standard routine antirheumatic drugs, methotrexate and prednisolone. Moreover, the first group received a daily oral synbiotic supplement (1000 mg) for 3 months while the second group received a placebo. Various parameters indicating RA status were evaluated at baseline (time 0) and 3 months after the treatment. FINDINGS / RESULTS: The results showed the changes in the level of RA indicators, including tender joint count with a range of 0 to 28 joints, swollen joint count with a range of 0 to 28 joints, visual analog scale, erythrocyte sedimentation rate, CRP, and disease activity score based on 28 joints, after 3 months. CONCLUSION AND IMPLICATIONS: Overall, no significant differences in the measured parameters were observed between synbiotic and placebo groups probably due to the short duration of the treatment period, and it is suggested to extend the treatment period to six months.
31912462 Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis 2020 Mar INTRODUCTION: The Janus kinase (JAK) inhibitor therapeutic class has shown significant clinical benefit in the treatment of rheumatoid arthritis (RA). We sought to gain insight into the mode of action and immunological effects of filgotinib, a JAK1 selective inhibitor, in active RA by analyzing secreted and cell-based biomarkers key to RA pathophysiology in two phase 2b trials of filgotinib in active RA. METHODS: Immune cell subsets and 34 serum biomarkers were analyzed longitudinally over 12 weeks using blood samples collected from patients with active RA receiving filgotinib (100 or 200 mg once daily) or placebo (PBO) in the two phase 2b trials (DARWIN 1, on a background of methotrexate, and DARWIN 2, as monotherapy). RESULTS: Consistently across both studies, filgotinib treatment decreased multiple immune response biomarkers that have key roles in RA for immune response, and decreased markers that promote matrix degradation, angiogenesis, leukocyte adhesion, and recruitment. Filgotinib did not significantly modulate T and natural killer (NK) lymphoid subsets, but slightly increased B cell numbers after 12 weeks. Multiple correlations were observed for changes in biomarkers with disease activity score 28-CRP. MIP1β showed modest predictivity at baseline for ACR50 response at 12 weeks in the 100 mg filgotinib dose across both studies (AUROC, 0.65 and 0.67, p < 0.05). CONCLUSIONS: Filgotinib regulates biomarkers from multiple pathways, indicative of direct and indirect network effects on the immune system and the stromal response. These effects were not associated with reductions of major circulating lymphoid populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01888874, NCT01894516.
32571732 Systematic Review of the Impact of Drugs on Diffuse Interstitial Lung Disease Associated w 2020 Jun 19 OBJECTIVE: To review the available evidence on the impact of rheumatoid arthritis (RA) treatments in associated diffuse interstitial lung disease (ILD). METHODS: Systematic review of studies evaluating the impact of pharmacological treatment in patients with RA and ILD. A bibliographic search in MEDLINE, EMBASE and Cochrane, a selection of articles and the methodological quality assessment (FLC 3.0 OSTEBA) and grading of the level of evidence (SING) of the selected articles were performed. RESULTS: 1,720 references were identified in primary search and 7 in manual or indirect. Forty-three articles were included: 7 systematic reviews, 2 randomized clinical trials, 5 cohort studies, 8 case-control studies and 21 case series. Methotrexate (MTX) and leflunomide (LEF) do not increase incidence, complications or mortality due to ILD. Although the results are not uniform, anti-TNF have often had worse outcomes in incidence, progression and mortality due to ILD than MTX, LEF, abatacept (ABA) and rituximab (RTX). The evidence found is scarce for JAK kinase and antifibrotic inhibitors, and controversial for IL-6 inhibitors. CONCLUSIONS: There is no evidence that MTX or LEF worsens the prognosis of patients with AR-EPID. RTX and ABA seem to have better results than other biologicals, such as anti-TNF, often achieving stabilization and, in some cases, the improvement of ILD in patients with RA.
32982367 JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical 2020 Janus kinase (JAK) Inhibitors are the latest drug class of disease-modifying medication to emerge for the treatment of rheumatoid arthritis (RA). They are a small molecule-targeted treatment and are the first oral option to compare favourably to existing biologic disease-modifying anti-rheumatic drugs (DMARDs). Tofacitinib, baricitinib and upadacitinib are the first 3 JAK inhibitors to become commercially available in the field and are the core focus of this review. To date, they have demonstrated comparable efficacy to tumour necrosis factor (TNF) inhibitors in terms of American College of Rheumatology (ACR) response rates and disease activity (DAS28) scores with similar cost to the benchmark adalimumab. This narrative review article aims to synthesise and distil the key available trial data on JAK inhibitor efficacy and safety, along with their place in the ACR and European League Against Rheumatism (EULAR) guidelines for RA. The novel mechanism of action of the JAK/STAT pathway is highlighted along with the potential effects of modulating each pathway. The rapid onset of action, role in attenuation of central pain processing and effect on structural damage and radiographic progression are also all examined in detail. We also explore the latest meta-analyses and comparative performance of each of the 3 available JAKs in an effort to determine which is most efficacious and which has the most favourable safety profile. Post marketing concerns regarding thromboembolism risk and herpes zoster infection are also discussed. Additionally, we review the cost-benefit analyses of the available JAK inhibitors and address some of the pharmacoeconomic considerations for real-world practice in the UK and US by detailing the raw acquisition cost and the value they provide in comparison to the benchmark biologic adalimumab and the anchor DMARD methotrexate.
33268706 JTE-952 Suppresses Bone Destruction in Collagen-Induced Arthritis in Mice by Inhibiting Co 2020 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and structural destruction of the joints. Bone damage occurs in an early stage after onset and osteoclast activation plays a substantial role in its progression. Colony stimulating factor 1 receptor (CSF1R) is a receptor protein tyrosine kinase specifically expressed in monocytic-lineage cells such as macrophages and osteoclasts. Here, we investigated the effect of JTE-952, a novel CSF1R tyrosine kinase inhibitor, on osteoclast formation in vitro and on bone destruction in a mouse model of collagen-induced arthritis. JTE-952 completely inhibited osteoclast differentiation from human monocytes, with an IC(50) of 2.8 nmol/L, and reduced osteoclast formation from the synovial cells of RA patients. Detectable levels of colony stimulating factor 1 (CSF1), a ligand of CSF1R, were observed in the synovial tissues of the arthritis model, similar to those observed in the pathology of human RA. JTE-952 significantly suppressed increases in the bone destruction score, the number of tartrate-resistant-acid-phosphatase-positive cells, and the severity of arthritis in the model mice. We also examined the efficacy of JTE-952 combined with methotrexate. This combination therapy more effectively reduced the severity of bone destruction and arthritis than monotherapy with either agent alone. In summary, JTE-952 potently inhibited human osteoclast formation in vitro and suppressed bone destruction in an experimental arthritis model, especially when combined with methotrexate. These results indicate that JTE-952 should strongly inhibit bone destruction and joint inflammation in RA patients and effectively prevent the progression of the structural destruction of joints.
32775622 Low-dose Methotrexate Toxicity in the Setting of Vancomycin-induced Acute Kidney Injury. 2020 Methotrexate is a disease-modifying anti rheumatic drug (DMARD) that is often used in low dosages as the first line drug for rheumatoid arthritis patients. The chemotherapeutic agent works by inhibiting dihydrofolate reductase, and the primary route of clearance of the drug is via the kidneys. Kidney injury may delay this clearance and lead to toxic level accumulation of the drug- toxicity presenting as diarrhea, vomiting, mucositis, rash, transaminitis and myelosuppression. Antibiotics such as vancomycin may induce acute kidney injury (AKI) through various mechanisms include damage to the renal tubular epithelial cells. In this report, we describe a case in which an elderly female suffered AKI secondary to vancomycin induced nephrotoxicity. The AKI subsequently led to methotrexate accumulation and toxicity presenting as bleeding mouth ulcers, transaminitis and pancytopenia. The condition was managed with leucovorin rescue therapy and sodium bicarbonate to enhance methotrexate excretion. Renally dosing methotrexate in patients on other nephrotoxic drugs, and monitoring creatinine clearance are methods for preventing such a toxicity.
32232740 Methotrexate Discontinuation and Dose Decreases After Therapy With Tocilizumab: Results Fr 2020 Jun INTRODUCTION: Similar outcomes have been observed between patients with rheumatoid arthritis (RA) responding to tocilizumab (TCZ) with methotrexate (MTX) who discontinued vs. continued MTX and between patients receiving MTX who added TCZ vs. switched to TCZ monotherapy. This study examined MTX discontinuation and dose decreases in patients with RA initiating TCZ in a real-world setting. METHODS: TCZ-naïve patients enrolled in the Corrona RA registry who initiated TCZ in combination with MTX and had a 6-month follow-up visit without TCZ discontinuation were included. Patients were grouped by MTX dose at the time of TCZ initiation (≤ 10 mg, > 10 to ≤ 15 mg, > 15 to ≤ 20 mg, > 20 mg). The primary outcome was the proportion of patients with changes in MTX use at 6 months, with a secondary analysis at 12 months. Changes in disease activity [Clinical Disease Activity Index (CDAI)] and patient-reported outcomes (PROs) at 6 and 12 months were summarized descriptively. RESULTS: Of 444 included patients, 82.7% were female and 83.7% white, with mean (SD) disease duration of 11.6 (9.3) years, baseline CDAI score of 24.0 (15.4), and baseline MTX dose of 17.7 (5.8) mg. At 6 months, 139 patients (31.3%) discontinued or decreased their MTX dose. All MTX dose groups and patients who discontinued, decreased, maintained, or increased their MTX dose displayed improvements in CDAI scores and PROs at 6 months. Similar patterns and results were observed at 12 months. CONCLUSIONS: A considerable proportion of patients initiating TCZ discontinued or decreased their MTX dose after TCZ initiation. Improvements in disease activity and functionality were observed in patients who decreased or stopped MTX. This real-world study confirmed prior observations that discontinuing or decreasing MTX may be a treatment strategy for patients initiating TCZ combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01402661.
33052698 Optimization and Development of Methotrexate- and Resveratrol-Loaded Nanoemulsion Formulat 2020 Nov/Dec Methotrexate (MTX) is the first line of choice for the management of rheumatoid arthritis (RA) and has been reported for its low bioavailability and side effects. Combination therapy has been widely investigated to overcome bioavailability issues and to reduce adverse effects associated with monotherapy. Various phytoconstituents such as resveratrol (RSV) and curcumin have been found to possess potent anti-inflammatory activity via downregulating the signaling of cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor alpha) and nuclear factor kappa B signaling. The prime objective of this study was to develop transdermal gel containing MTX-RSV loaded nanoemulsions (NEs) to overcome bioavailability issues and adverse effects of RA monotherapy. The NEs optimized by using Box-Behnken Design were incorporated within gel, and an in vitro skin permeation study performed on rat skin by using vertical Franz diffusion cells exhibited controlled drug release up to 48 h. Subsequently, anti-inflammatory and potential anti-arthritic activities of the combination in nanocarrier were assessed in rats and showed 78.76 ± 4.16% inhibition in inflammation and better anti-arthritic effects. Consequently, integration of dual delivery with nanotechnology can hopefully produce successful therapeutic options for rheumatic diseases.
33138014 The Effectiveness and Retention Rate of Iguratimod in Japanese Rheumatoid Arthritis Patien 2020 Oct 29 (1) Background: We evaluated the clinical response of iguratimod (IGU) in patients with rheumatoid arthritis (RA) being treated with or without methotrexate (MTX) over 54 weeks. (2) Methods: 106 patients with RA undergoing IGU were retrospectively observed. RA patients were divided into those treated with MTX+IGU (n = 35) and those treated with IGU (n = 71). The primary endpoint was the clinical response of the Disease Activity Score assessing 28 joints with C-reactive protein (DAS28-CRP) differences in the changes from baseline to 54 weeks between MTX+IGU and IGU groups. Secondary endpoints, such as the clinical response, retention rate, and safety, were evaluated. (3) Results: The DAS28-CRP difference in the changes between the two groups were -0.2. DAS28-CRP were significantly reduced from the baseline in the MTX+IGU and IGU groups (-1.43 and -1.20 from baseline, respectively). The retention rates were 71.4% in the MTX+IGU groups and 59.2% in the IGU groups (p = 0.16). Adverse events were observed in a total of 6 (17.1%) MTX+IGU patients and 20 (28.2%) IGU patients (p = 0.21). (4) Conclusions: IGU therapy may be a useful treatment option for patients who cannot be treated with MTX.
32685594 A Network Meta-Analysis to Compare Effectiveness of Baricitinib and Other Treatments in Rh 2020 BACKGROUND/OBJECTIVES: This article compares the effectiveness of baricitinib (BARI) 4 mg (oral, Janus kinase [JAK] 1/2 inhibitor) versus other targeted synthetic/biologic disease-modifying antirheumatic drugs, in combination with methotrexate (MTX), in moderate-to-severe rheumatoid arthritis patients with inadequate response (IR) to MTX. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of the interventions of interest. Bayesian network meta-analyses (NMA) were used to compare American College of Rheumatology (ACR) responses at 24 weeks. A series of prespecified sensitivity analyses addressed the potential impact of, among others, baseline risk, treatment effect modifiers, and trial design on treatment response. RESULTS: Nineteen RCTs were included in the NMA (primary analysis). For ACR20, BARI 4 mg + MTX was found to be more effective than adalimumab (ADA) 40 mg + MTX (Odds Ratio [OR] 1.33), abatacept (ABA) 10 mg + MTX (IV/4 weeks) (OR 1.45), infliximab (IFX) 3 mg + MTX (IV/8 wks) (OR 1.63), and rituximab (RTX) 1000 mg + MTX (OR 1.63). No differences were found on ACR50. For ACR70, BARI 4 mg + MTX was more effective than ADA 40 mg + MTX (OR 1.37), ABA 10 mg + MTX (OR 1.86), and RTX 1000 mg + MTX (OR 2.26). Sensitivity analysis including 10 additional RCTs with up to 20% of patients with prior biologic use showed BARI 4 mg + MTX to be more effective than tocilizumab (TCZ) 8 mg + MTX on ACR20 (OR 1.44). Results for all sensitivity analyses were consistent with the direction and magnitude of the primary results. Key limitations include the time span in which trials were conducted (1999-2017), during which patient characteristics and treatment approaches might have changed. CONCLUSION: This NMA suggests that BARI 4 mg + MTX is an efficacious treatment option in the MTX-IR population as evidenced by the robustness of results.
32718263 Effects of betulinic acid on synovial inflammation in rats with collagen-induced arthritis 2020 Jan Betulinic acid (BA) inhibits the migration, invasion, and cytoskeletal reorganization of fibroblast-like synoviocytes (RA-FLS) in patients with rheumatoid arthritis. Here, to further explore the mechanism of action of BA in collagen-induced arthritis (CIA) rats, we investigated the pharmacodynamic effects of BA on synovial inflammation in a rat model of type II CIA. After inducing hind paw swelling, the rats were divided into four groups: healthy controls (normal), and rats that underwent CIA and received methotrexate treatment (MTX), BA treatment (BA), or no treatment (CIA). Body weight and hind paw swelling were determined regularly, and arthritis scores were calculated weekly. On day 35, rats were sacrificed and their hind ankle joints sectioned and stained with hematoxylin and eosin for histopathological evaluation. BA significantly reduced CIA-induced hind paw swelling, synovial tissue proliferation, cartilage destruction, and vasospasm. BA treatment also decreased serum interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) levels in rats with CIA. The CCK-8 assay was used to detect the proliferation of isolated vimentin(+)CD68(-) RA-FLS; RA-FLS were stimulated with TNF-α in vitro. BA significantly inhibited TNF-α-stimulated RA-FLS proliferation, as well as IL-1β and IL-6 secretion. BA also downregulated the transcription of vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β) and decreased the expression of the NF-кB pathway proteins (NF-kB-P65, IkBα, and IKKα/β) in the TNF-α-stimulated RA-FLS. These results indicate that BA alleviated the symptoms of CIA by inhibiting synoviocyte proliferation, modifying TNF-α- and NF-кB-related inflammatory pathways, and downregulating inflammatory mediators and growth factors including IL-1β, IL-6, VEGF, and TGF-β.
33343960 Complicated Rheumatoid Nodules in Lung. 2020 A 65-year-old nonsmoker lady carrying a diagnosis of seropositive erosive rheumatoid arthritis for nine years presented with acute shortness of breath, following a spontaneous pneumothorax while on combination therapy with methotrexate, leflunomide, and tocilizumab. Imaging studies revealed multiple cavitory lung nodules, and a transbronchial lung biopsy favoured a diagnosis of rheumatoid lung nodules. Her initial pathological samples were negative for any infectious cause. A follow-up computerized tomography scan (CT scan) confirmed enlargement of lung nodules with a positive antibody test for aspergillosis which needed antifungal therapy, and currently, her arthritis is managed well with rituximab therapy, sulfasalazine, and hydroxychloroquine.
32270926 Fenebrutinib versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Bl 2020 Apr 9 OBJECTIVE: To evaluate fenebrutinib, an oral and highly selective non-covalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). METHODS: Patients with RA and inadequate response to methotrexate (cohort 1, n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200 mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued methotrexate therapy. RESULTS: In cohort 1, American College of Rheumatology scores (ACR50) at week 12 were similar for fenebrutinib 50 mg once daily and placebo, and higher for fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo (15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most common adverse events for fenebrutinib included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. CONCLUSION: Fenebrutinib demonstrated efficacy comparable to adalimumab in patients with an inadequate response to methotrexate, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.
32346301 Cost-Effectiveness of a JAK1/JAK2 Inhibitor vs a Biologic Disease-Modifying Antirheumatic 2020 BACKGROUND: Baricitinib is a janus kinase (JAK1/JAK2) inhibitor developed for the treatment of patients suffering from rheumatoid arthritis (RA). Treating RA to the target of remission is current common practice. Cost-effectiveness of different treat-to-target (T2T) strategies, especially ones including new treatments is important for development and preference policy for treatment centers. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines are currently unclear about preference between a JAK1/JAK2 versus a biological disease-modifying antirheumatic drug (bDMARD). OBJECTIVE: The main goal of this paper was to evaluate the cost-effectiveness of baricitinib versus first biological for methotrexate inadequate responders in a T2T strategy using a Markov model that incorporates hospital costs as well as societal costs. Costs and utilities over five years were compared between the two strategies. METHODS: A Monte Carlo simulation model was developed to conduct cost-utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-erythrocyte sedimentation rate (ESR) categories. Effectiveness of baricitinib was retrieved from randomized controlled trials. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from the Dutch RhEumatoid Arthritis Monitoring (DREAM) cohorts. Annual discount rates of 1.5% for utility and 4% for costs were used. Probabilistic sensitivity analysis was employed to incorporate uncertainty and assess robustness of the results. RESULTS: Probabilistic sensitivity analysis results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe RA populations. CONCLUSION: Results suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.
33403019 Immunosuppressive agents for rheumatoid arthritis: a systematic review of clinical trials 2020 AIMS: With the arrival of conventional synthetic (csDMARDs), biological (bDMARDS) and then targeted synthetic (tsDMARDs) disease-modifying anti-rheumatic drugs, the therapeutic arsenal against rheumatoid arthritis (RA) has recently expanded. However, there are still some unmet needs for patients who do not achieve remission and continue to worsen despite treatments. Of note, most randomized controlled trials show that, for methotrexate-inadequate responders, only 20% of patients are ACR70 responders. With our better understanding of RA pathogenesis, finding new treatments is a necessary challenge. The objective of our study was to analyse the whole pipeline of immunosuppressive and immunomodulating drugs evaluated in RA and describe their mechanisms of action and stage of clinical development. METHODS: We conducted a systematic review of all drugs in clinical development in RA, in 17 online registries of clinical trials. RESULTS: The search yielded 4652 trials, from which we identified 243 molecules. Those molecules belong to csDMARDs (n = 22), bDMARDs (n = 118), tsDMARDs (n = 103). Twenty-four molecules are already marketed in RA in at least one country: eight csDMARDs, 10 bDMARDs and six tsDMARDs. Molecules under current development are mainly bDMARDs (n = 34) and tsDMARDs (n = 33). Seven of those have reached phase III. A large number of molecules (150/243, 61.7%) have been withdrawn. CONCLUSION: Despite the availability of 24 marketed molecules, the development of new targeted molecules is ongoing with a total of 243 molecules in RA. With seven molecules currently reaching phase III, we can expect an increase in the armamentarium in the years to come.
32844379 Dose Adjustment of Methotrexate Administered Concomitantly with Golimumab for Rheumatoid A 2020 Dec INTRODUCTION: The combination of methotrexate (MTX) with biological disease-modifying antirheumatic drugs (bDMARDs) is a recommended treatment option for rheumatoid arthritis (RA) patients showing an inadequate response to MTX monotherapy. However, the adequate dose of MTX, especially in long-term treatment with bDMARDs/MTX combination therapy, remains under-addressed. Since RA patients require long-term treatment, we examined the effects of using golimumab (GLM) in the long run as well as its persistency and associated factors. METHODS: We used the Japan Medical Data Center Inc. (JMDC) administrative claims data of 489 patients receiving GLM therapy for calculating the persistency in patients with constant, reduced, or escalated MTX dosing. The factors associated with GLM persistency were assessed using Cox proportional hazard modeling, controlling for the dose adjustment of concomitant MTX, age, sex, RA disease period, and the initial dose of GLM or concomitant MTX during GLM/MTX combination therapy. RESULTS: During GLM/MTX combination therapy, up to 52% of patients were reported to experience dose adjustments of concomitant MTX treatment (i.e., dose reduction and escalation in 34% and 18% of patients, respectively). Persistency was similar in the MTX dose-reduction patients and the MTX dose-constant patients. In the Cox proportional hazard model, no significant differences were observed in association with GLM persistency, including with respect to MTX dose adjustment. CONCLUSIONS: GLM prescription was continued in 80% or more (1 year) and 50% or more (3 years) of RA patients receiving reduced concomitant MTX dosing, suggesting that MTX dose adjustment (including MTX reduction) could be considered in GLM/MTX combination therapy.
33244703 A Matching-Adjusted Indirect Comparison of Upadacitinib Versus Tofacitinib in Adults with 2021 Mar INTRODUCTION: Upadacitinib and tofacitinib are Janus kinase inhibitors approved for moderate-to-severe rheumatoid arthritis (RA). In the absence of head-to-head trials comparing their effectiveness, this study assessed the efficacy of upadacitinib 15 mg once-daily monotherapy/combination therapy against tofacitinib 5 mg twice-daily combination therapy among patients with RA using matching-adjusted indirect comparisons (MAICs). METHODS: The first of two MAICs used individual patient data (IPD) from the 14-week SELECT-MONOTHERAPY trial (upadacitinib [n = 217] vs. methotrexate [n = 216]) and published data from the ORAL Standard trial (tofacitinib + methotrexate [n = 204] vs. methotrexate [n = 108]). The second MAIC used IPD from the 26-week SELECT-COMPARE trial (upadacitinib + methotrexate [n = 647] vs. adalimumab + methotrexate [n = 324]) and published data from ORAL Strategy (tofacitinib + methotrexate [n = 376] vs. adalimumab + methotrexate [n = 386]). Data from patients in the upadacitinib trials were re-weighted based on age, sex, race, swollen joint count 66/28, tender joint count 68/28, C-reactive protein (CRP), and patients' global assessments to match the patient characteristics in tofacitinib trials. After matching, ACR20/50/70 and clinical remission (SDAI[CRP] ≤ 3.3, CDAI ≤ 2.8, DAS28-ESR/CRP < 2.6) were compared for upadacitinib vs. tofacitinib + methotrexate at month 3 and upadacitinib + methotrexate vs. tofacitinib + methotrexate at months 3 and 6 using Wald tests. RESULTS: At month 3, upadacitinib monotherapy patients experienced significantly larger improvement in ACR70 compared to tofacitinib + methotrexate (mean difference in difference [DID]: 9.9%; p = 0.019), while upadacitinib + methotrexate was associated with higher ACR50 compared to tofacitinib + methotrexate (DID: 12.9%; p = 0.011). At month 6, upadacitinib + methotrexate patients experienced significantly larger improvement in SDAI/CDAI/DAS28-ESR clinical remission compared to tofacitinib + methotrexate, with DIDs of 9.1% (p = 0.011), 7.5% (p = 0.038), and 11.3% (p = 0.002), respectively. CONCLUSIONS: Compared to tofacitinib combination therapy, treatment with upadacitinib monotherapy and combination therapy were associated with improved outcomes at 3/6 months (monotherapy: ACR70; combination: ACR50, SDAI, CDAI, and DAS28-ESR remission).
32057667 Effectiveness of intravenous tocilizumab in routine clinical practice in a cohort of Costa 2021 Jun OBJECTIVE: To determine the effectiveness and the incidence of severe adverse events in a cohort of Costa Rican patients with Rheumatoid Arthritis (RA) treated with intravenous (IV) tocilizumab (TCZ). PATIENTS AND METHODS: A retrospective analysis was carried out in 45 patients that were unresponsive to disease-modifying antirheumatic drugs (DMARDs). The study included patients who received IV TCZ every 4 weeks (4mg/kg) along with methotrexate or leflunomide. Effectiveness was measured through the incidence of clinical remission according to a disease activity score - erythrocyte sedimentation rate (DAS28-ESR) less than 2.6. Safety was assessed by the incidence rate of serious adverse events. An univariate and multivariate logistic regression analysis was performed to assess the association of potential variables with the probability of achieving remission during the first 3 months of TCZ therapy. RESULTS: During the 3(rd) month of TCZ therapy, a total of 22 patients (48.9%; 95% Confidence Interval (CI) 34.3-63.5%) achieved remission. The cumulative incidence of patients with remission at month 12 was 75.0% (n=34) (95% CI: 62.3-87.6%). A total of 18 patients (40%; 95% CI: 25.7-54.3%) were switched to a 8mg/kg dose due to the absence of remission. The incidence rate of serious adverse events was .98 per 100 patients/year, all of them due to infectious diseases with no fatal events reported. Only basal DAS28-ESR was associated with the probability of achieving remission at month 3. CONCLUSIONS: IV TCZ (4mg/kg) is an effective and safe treatment for RA patients in a clinical setting in Costa Rica.