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The New England Journal of Medicine May 2023Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this pathway would be a novel approach to the treatment of patients with autoimmune or autoinflammatory diseases.
METHODS
In this phase 2a, double-blind, randomized, placebo-controlled trial, we assigned, in a 2:1:1 ratio, adult patients with moderate-to-severe rheumatoid arthritis who had had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). The DAS28-CRP ranges from 0 to 9.4, with higher scores indicating more severe disease. The primary comparison was between the 700-mg group and the placebo group. Secondary outcomes included the percentages of patients with American College of Rheumatology 20 (ACR20), ACR50, and ACR70 responses - defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains - at week 12.
RESULTS
At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [±SE], -2.09±0.18 vs. -0.99±0.26; difference in change, -1.09 [95% confidence interval, -1.73 to -0.46]; P<0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the ACR20 response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups.
CONCLUSIONS
Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.).
Topics: Adult; Humans; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Severity of Illness Index; Treatment Outcome; Immunoglobulin G; Administration, Intravenous; Programmed Cell Death 1 Receptor
PubMed: 37195941
DOI: 10.1056/NEJMoa2209856 -
ARP Rheumatology Oct 2022We aim to summarize the relevant evidence and provide guidance for perioperative management of disease-modifying antirheumatic drugs (DMARDs) and other immunomodulators... (Review)
Review
OBJECTIVES
We aim to summarize the relevant evidence and provide guidance for perioperative management of disease-modifying antirheumatic drugs (DMARDs) and other immunomodulators used in the treatment of the various inflammatory rheumatic diseases in patients submitted to elective surgery.
METHODS
This is a review article directed towards clinical practice, based on recent literature available in PubMed database, as well as guidelines published by Rheumatology Societies.
RESULTS
Treatment with conventional DMARDs (methotrexate, hydroxychloroquine, sulfasalazine and leflunomide) can be continued perioperatively; targeted synthetic DMARDs should be suspended at least 3 to 7 days before surgery, depending on the drug, and restarted 3-5 days after the procedure, while biologic DMARDs should be withheld a dosing cycle prior to surgery and resumed at least 14 days after the procedure, with evidence of complete wound healing. In the case of Systemic Lupus Erythematosus (SLE), one should consider the severity of the condition to make the decision about discontinuing immunomodulators (mycophenolate mofetil, azathioprine, cyclosporine, or tacrolimus) as these should be continued in severe SLE because of the increased risk of life-threatening flares. The usual dose of glucocorticoids should be continued perioperatively; however, elective procedures with high-risk surgical site infection should be postponed in patients under ≥20 mg/day prednisone or equivalent until the inflammatory process is controlled with the minimum effective dose.
CONCLUSIONS
The perioperative management of patients with rheumatic disease under DMARDs or other immunomodulators is challenging but vital for achieving the best outcome possible. A multidisciplinary approach agreed upon by the anesthesiologist, surgeon and rheumatologist is the best strategy for success.
Topics: Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Methotrexate; Lupus Erythematosus, Systemic; Immunologic Factors
PubMed: 36057090
DOI: No ID Found -
The New England Journal of Medicine Apr 2021The Janus kinase inhibitor upadacitinib is a potential treatment for psoriatic arthritis. The efficacy and safety of upadacitinib as compared with adalimumab, a tumor... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The Janus kinase inhibitor upadacitinib is a potential treatment for psoriatic arthritis. The efficacy and safety of upadacitinib as compared with adalimumab, a tumor necrosis factor α inhibitor, in patients who have an inadequate response to nonbiologic disease-modifying antirheumatic drugs are unclear.
METHODS
In a 24-week, phase 3 trial, we randomly assigned patients in a 1:1:1:1 ratio to receive oral upadacitinib at a dose of 15 mg or 30 mg once daily, placebo, or subcutaneous adalimumab (40 mg every other week). The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% decrease in the number of tender and swollen joints and ≥20% improvement in at least three of five other domains) at week 12 with upadacitinib as compared with placebo. Secondary end points included comparisons of upadacitinib with adalimumab.
RESULTS
A total of 1704 patients received an active drug or placebo. The percentage of patients who had an ACR20 response at week 12 was 70.6% with 15-mg upadacitinib, 78.5% with 30-mg upadacitinib, 36.2% with placebo (P<0.001 for both upadacitinib doses vs. placebo), and 65.0% with adalimumab. The difference between groups for 15-mg upadacitinib as compared with adalimumab was 5.6 percentage points (95% confidence interval [CI], -0.6 to 11.8) and for 30-mg upadacitinib as compared with adalimumab was 13.5 percentage points (95% CI, 7.5 to 19.4). Both upadacitinib doses were noninferior to adalimumab for the ACR20 response at week 12; the 30-mg dose but not the 15-mg dose was superior to adalimumab. The incidence of adverse events through week 24 was 66.9% with 15-mg upadacitinib, 72.3% with 30-mg upadacitinib, 59.6% with placebo, and 64.8% with adalimumab. There were serious infections in 1.2%, 2.6%, 0.9%, and 0.7% of the patients, respectively. Hepatic disorders occurred in 9.1% of patients in the 15-mg upadacitinib group and 12.3% in the 30-mg upadacitinib group, but grade 3 increases in aminotransferase levels occurred in 2% of patients or fewer in all groups.
CONCLUSIONS
The percentage of patients with psoriatic arthritis who had an ACR20 response at week 12 was significantly higher with 15-mg or 30-mg upadacitinib than with placebo. The 30-mg dose but not the 15-mg dose was superior to adalimumab. Adverse events were more frequent with upadacitinib than with placebo. (Funded by AbbVie; SELECT-PsA 1 ClinicalTrials.gov number, NCT03104400.).
Topics: Adalimumab; Adult; Antirheumatic Agents; Arthritis, Psoriatic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Least-Squares Analysis; Liver Diseases; Male; Middle Aged
PubMed: 33789011
DOI: 10.1056/NEJMoa2022516 -
Frontiers in Immunology 2021Adalimumab, as a TNF inhibitor biologic for the treatment of rheumatoid arthritis, is one of the top-selling drugs worldwide. As its various patents have gradually... (Review)
Review
Adalimumab, as a TNF inhibitor biologic for the treatment of rheumatoid arthritis, is one of the top-selling drugs worldwide. As its various patents have gradually expired, experiments on its biosimilars are constantly being implemented. In this review, we summarized clinical trials of seven biosimilars currently approved by the FDA and/or EMA for the treatment of rheumatoid arthritis, namely: ABP 501 (Amjevita/Amgevita/Solymbic), BI 695501 (Cyltezo), SB5 (Imraldi/Hadlima), GP2017 (Hyrimoz/Hefiya/Halimatoz), MSB11022 (Idacio), FKB327 (Hulio), and PF-06410293 (Abrilada). Overall, these biosimilars showed similar efficacy, safety, and immunogenicity to adalimumab. All biosimilar switching trials indicated that switching from adalimumab to a biosimilar does not have a significant impact on efficacy, safety, and immunogenicity.
Topics: Adalimumab; Antirheumatic Agents; Arthritis, Rheumatoid; Biosimilar Pharmaceuticals; Clinical Trials as Topic; Humans
PubMed: 33889152
DOI: 10.3389/fimmu.2021.638444 -
Medicina (Kaunas, Lithuania) Oct 2023Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA... (Review)
Review
Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA presents unique clinical features, including a more equitable distribution of sexes, a potential predilection for male involvement, a higher incidence of acute onset characterized by constitutional symptoms, a propensity for systemic manifestations, elevated sedimentation rates at disease onset, a reduced occurrence of rheumatoid factor positivity, increased titers of anti-citrullinated protein antibodies, a preference for involvement of large joints, elevated disease activity, the presence of bone erosions, and heightened patient disability. RA is recognized to consist of three partially overlapping subsets. One subset mirrors the classical RA clinical presentation, while the remaining subsets exhibit either a polymyalgia rheumatica-like phenotype or present with remitting seronegative symmetrical synovitis accompanied by pitting edema syndrome. In the initial stages of EORA management, non-steroidal anti-inflammatory drugs (NSAIDs) are not typically the first-line treatment choice, because seniors are much more prone to develop side effects due to NSAIDs, and the use of NSAIDs is in reality contraindicated to the majority of seniors due to comorbidities. Disease-modifying antirheumatic drugs (DMARDs), frequently methotrexate, are introduced immediately after the diagnosis is made. In cases where elderly patients demonstrate resistance to conventional DMARD therapy, the introduction of biological or targeted synthetic DMARDs becomes a viable treatment option. EORA presents a unique clinical profile, necessitating tailored treatment strategies. Our study emphasizes the challenges of NSAID use in seniors, highlighting the imperative shift toward DMARDs such as methotrexate. Future research should explore personalized DMARD approaches based on disease activity, comorbidities, and safety considerations, aiming to optimize treatment outcomes and minimize glucocorticoid reliance, thereby enhancing the quality of care for EORA patients.
Topics: Aged; Humans; Male; Middle Aged; Methotrexate; Arthritis, Rheumatoid; Antirheumatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Treatment Outcome
PubMed: 37893596
DOI: 10.3390/medicina59101878 -
Rheumatology (Oxford, England) Dec 2021Through treatment with biological DMARDs (bDMARDs) or targeted synthetic (tsDMARDs) such as Janus kinase (JAK) inhibitors in addition to MTX, clinical remission has... (Review)
Review
Through treatment with biological DMARDs (bDMARDs) or targeted synthetic (tsDMARDs) such as Janus kinase (JAK) inhibitors in addition to MTX, clinical remission has become a realistic therapeutic goal for the majority of patients with RA, and sustained remission facilitates prevention of joint damage and physical dysfunction. Long-term safety and sustained inhibition of structural changes and physical dysfunction by bDMARDs have been reported. The development of next-generation bDMARDs and expansion of their indications to various autoimmune diseases are expected. Five JAK inhibitors show comparable efficacy to bDMARDs, and the latest ones are effective for overcoming difficult-to-treat RA regardless of prior medications. Patients treated with JAK inhibitors should be adequately screened and monitored for infection, cardiovascular disorders, thrombosis, malignancies and so on. Advances in therapeutic strategies, including the differential use of therapeutic drugs and de-escalation of treatment after remission induction, are prioritized.
Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Therapy; Humans; Janus Kinase Inhibitors; Precision Medicine
PubMed: 34951925
DOI: 10.1093/rheumatology/keab609 -
Annals of Internal Medicine Mar 2020Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.
OBJECTIVE
To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.
DESIGN
Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333).
SETTING
North America.
PARTICIPANTS
Adults with known cardiovascular disease and diabetes or metabolic syndrome.
INTERVENTION
Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week.
MEASUREMENTS
Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication.
RESULTS
After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]).
LIMITATION
The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period.
CONCLUSION
Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased.
PRIMARY FUNDING SOURCE
National Institutes of Health.
Topics: Aged; Antirheumatic Agents; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Male; Methotrexate; Middle Aged; Placebos; Prospective Studies
PubMed: 32066146
DOI: 10.7326/M19-3369 -
Journal of Clinical Pharmacology May 2021We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy...
We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.
Topics: Antibodies, Monoclonal, Humanized; Antirheumatic Agents; C-Reactive Protein; Humans; Models, Biological; Protein Binding; Receptors, Interleukin-6
PubMed: 33314148
DOI: 10.1002/jcph.1795 -
Arthritis Research & Therapy Nov 2019
Topics: Antirheumatic Agents; Etanercept; Humans; Infliximab; Lupus Erythematosus, Systemic; Tumor Necrosis Factor-alpha
PubMed: 31718696
DOI: 10.1186/s13075-019-2028-2 -
Rheumatology (Oxford, England) Apr 2023
Topics: Pregnancy; Female; Humans; Rheumatology; Breast Feeding; Immunomodulating Agents; Antirheumatic Agents; Rheumatic Diseases; Adrenal Cortex Hormones
PubMed: 36318966
DOI: 10.1093/rheumatology/keac551