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RMD Open Jun 2024To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.
OBJECTIVES
To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.
METHODS
In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.
RESULTS
53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.
CONCLUSIONS
Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.
TRIAL REGISTRATION NUMBER
NCT04991753.
Topics: Humans; Arthritis, Rheumatoid; Male; Female; Middle Aged; Treatment Outcome; Antirheumatic Agents; Severity of Illness Index; Antibodies, Monoclonal, Humanized; Aged; Adult; Tumor Necrosis Factor-alpha; Double-Blind Method; Patient Reported Outcome Measures; Anti-Citrullinated Protein Antibodies
PubMed: 38942592
DOI: 10.1136/rmdopen-2024-004278 -
RMD Open Jun 2024The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and...
INTRODUCTION
The nature of the relationship between inflammation, cardiovascular (CV) risk factors and atherosclerosis in axial spondyloarthritis (axSpA) remains largely unknown and sex differences in this regard are yet to be assessed.
METHODS
Study including 611 men and 302 women from the Spanish multicentre AtheSpAin cohort to assess CV disease in axSpA. Data on CV disease risk factors were collected both at disease diagnosis and at enrolment, and data on disease activity, functional indices and carotid ultrasonography only at enrolment.
RESULTS
After a median disease duration of 9 years, patients of both sexes who at disease diagnosis had elevated acute phase reactants (APRs), more frequently had hypertension and obesity. The same occurred with dyslipidaemia in men and with diabetes mellitus in women. At enrolment, CV risk factors were independently associated with APR and with activity and functional indices, with various sex differences. C reactive protein (CRP) values were inversely associated with HDL-cholesterol in men (β coefficient: -1.2 (95% CI: -0.3 to -0.07) mg/dL, p=0.001), while erythrocyte sedimentation rate values were positively associated with triglycerides in women (β coefficient: 0.6 (95% CI: 0.04 to 1) mg/dL, p=0.035). Furthermore, only women showed an independent relationship between insulin resistance parameters and APR or disease activity. Both men and women with high-very high CV risk according to the Systematic Assessment of Coronary Risk Evaluation 2 and CRP levels higher than 3 mg/L at diagnosis of the disease presented carotid plaques significantly more frequently than those with normal CRP levels at disease diagnosis.
CONCLUSION
Inflammation is associated with atherosclerosis and CV disease in axSpA. A gender-driven effect is observed in this relationship.
Topics: Humans; Male; Female; Atherosclerosis; Middle Aged; Inflammation; Adult; Heart Disease Risk Factors; Sex Factors; Axial Spondyloarthritis; Risk Factors; Biomarkers; Cardiovascular Diseases; C-Reactive Protein
PubMed: 38942590
DOI: 10.1136/rmdopen-2024-004187 -
BMJ (Clinical Research Ed.) Jun 2024
Topics: Humans; Decision Making; Congresses as Topic; Patient Participation; Delivery of Health Care; Democracy
PubMed: 38942435
DOI: 10.1136/bmj.q1411 -
Journal of Affective Disorders Jun 2024This study aimed to analyze the associations between rheumatoid arthritis (RA) and all-cause mortality and cardiovascular disease (CVD)-related mortality using data from...
OBJECTIVE
This study aimed to analyze the associations between rheumatoid arthritis (RA) and all-cause mortality and cardiovascular disease (CVD)-related mortality using data from the National Health and Nutrition Examination Survey (NHANES) and examine the potential mediating role of depression in these correlations.
METHODS
19,165 participants across five NHANES cycles from 2007 to 2016 participated in this study. Multifactorial Cox regression models between RA, depression and two mortality outcomes and multifactorial regression models between RA and depression were constructed to examine their associations. The mediating role of depression has also been investigated.
RESULTS
The prevalence of RA in this study was 6.57 %, the all-cause mortality of RA patients was 20.57 %, and the CVD-related mortality was 6.12 %. In the fully adjusted model, RA was associated with all-cause mortality [hazard ratio (HR) = 1.28, 95 % confidence interval (CI) = 1.12 to 1.48] and CVD-related mortality (HR = 1.33, 95 % CI = 1.03 to 1.72), without detectable interaction among subgroups (P for interaction >0.05). RA also had a positive correlation with depression. Depression score demonstrated pronounced mediating effects in the connections between RA and two types of mortality, with mediation ratios of 18.2 % and 18.9 %.
LIMITATIONS
The diagnosis of RA is self-reported and may be subject to recall bias.
CONCLUSIONS
RA was positively correlated with the risk of all-cause mortality and CVD-related mortality. Depression partially mediates these associations. Close attention to and active improvement of mental health in RA patients will be critical to decrease all-cause mortality and CVD-related mortality.
PubMed: 38942208
DOI: 10.1016/j.jad.2024.06.108 -
Food and Chemical Toxicology : An... Jun 2024The human gut microbiome plays a crucial role in immune function. The synbiotic consortium or Defined Microbial Assemblage™ (DMA™) Medical Food product, SBD121,...
The human gut microbiome plays a crucial role in immune function. The synbiotic consortium or Defined Microbial Assemblage™ (DMA™) Medical Food product, SBD121, consisting of probiotic microbes and prebiotic fibers was designed for the clinical dietary management of rheumatoid arthritis. A 28-day repeated administration study was performed to evaluate the oral toxicity of SBD121 in male and female rats (age/weight at study start: 60 days/ 156-264 grams) administered levels of 0, 4.96 x 10, 2.48 x 10, or 4.96 x 10 colony forming units (CFU)/kg-bw. No treatment related changes in ophthalmological effects, mortality, morbidity, general health and clinical observations, urinalysis, hematology, serum chemistry, absolute or relative organ weights, gross necropsy, or histopathology. A significant decrease in body weight was reported in females in the low and high-concentration groups, which corresponded in part with a significant decrease in food consumption. Results of the functional observation battery indicated front grip strength was significantly greater in the high-concentration males compared to the controls; however, this effect was not considered adverse. Based on these findings, the administration of the Medical Food SBD121 to male and female rats has a no-observable adverse effect level (NOAEL) at the highest level tested of 4.96 x 10 CFU/kg-bw.
PubMed: 38942165
DOI: 10.1016/j.fct.2024.114839 -
Arthroscopy : the Journal of... Jun 2024The aim of this study was to present the short-term outcomes of arthroscopic in-situ biceps tenodesis combined with partial rotator cuff repair in patients with massive...
PURPOSE
The aim of this study was to present the short-term outcomes of arthroscopic in-situ biceps tenodesis combined with partial rotator cuff repair in patients with massive irreparable rotator cuff tears (MIRCT) and minimal arthritis.
METHODS
A retrospective review was conducted utilizing prospectively maintained institutional databases to identify patients who had undergone a partial rotator cuff repair with in-situ biceps tenodesis between March 2017 to December 2022. Patients were included if they (1) were diagnosed pre- or intra-operatively with MIRCT, and (2) had complete pre-operative and minimum 1-year post-operative patient-reported outcome measures.
RESULTS
Thirty-nine patients met the eligibility criteria and were included for analysis. The mean age of the study participants was 65 ± 7 years (range: 46 - 76) with 76.9% (n = 30) being male. The average follow-up was 21 ± 12 months (range: 12 - 58). Patients experienced significant improvement in visual analog scale for pain (VAS), American Shoulder and Elbow Surgeons (ASES) score, and subjective assessment numeric evaluation (SANE) score (p < 0.001 for all comparisons). The pre- to post-operative improvement was 3.1 ± 2.3 for VAS, 27.5 ± 20.6 for ASES, and 31.3 ± 24.8 for SANE. Postoperatively, the average scores for VAS, ASES, and SANE were 1.3 ± 1.5, 79.5 ± 17.0, and 69.6 ± 20.1, respectively. Twenty-six patients (66.7%) achieved the minimal clinically important difference (MCID) for VAS, thirty-three patients (84.6%) achieved the MCID for ASES, and thirty patients (76.9%) achieved the MCID for SANE..
CONCLUSIONS
Partial rotator cuff repair with in-situ biceps tenodesis is an effective treatment for MIRCT, leading to significant improvements in patient-reported outcome and range of motion measures compared to preoperative conditions.
PubMed: 38942098
DOI: 10.1016/j.arthro.2024.06.018 -
Drug Discovery Today Jun 2024Rheumatoid arthritis (RA) is an immune-mediated disease that necessitates a thorough understanding of its intricate pathophysiological mechanism for precise and... (Review)
Review
Rheumatoid arthritis (RA) is an immune-mediated disease that necessitates a thorough understanding of its intricate pathophysiological mechanism for precise and effective therapeutic targeting. The European League Against Rheumatism (EULAR) has established guidelines for RA treatment, endorsing monotherapy or combination therapy with corticosteroids and synthetic disease-modifying antirheumatic drugs (sDMARDs). This review delves into clinical trials and research outcomes related to combination drug delivery, with an emphasis on the role of natural products in combination with synthetic drugs. Given the significant adverse effects associated with systemic administration, topical delivery has emerged as an alternative avenue for effective management of RA.
PubMed: 38942070
DOI: 10.1016/j.drudis.2024.104071 -
The Lancet. Rheumatology Jun 2024
PubMed: 38942048
DOI: 10.1016/S2665-9913(24)00167-X -
The Lancet. Rheumatology Jun 2024Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial...
Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK (NAMASTE): a randomised, double-blind, placebo-controlled, phase 2 trial.
BACKGROUND
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis.
METHODS
This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658).
FINDINGS
From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five).
INTERPRETATION
Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated.
FUNDING
Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility.
PubMed: 38942047
DOI: 10.1016/S2665-9913(24)00099-7 -
Spectrochimica Acta. Part A, Molecular... Jun 2024Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory diseases in which innate and adaptive responses of the immune system are induced. RA and...
BACKGROUND
Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory diseases in which innate and adaptive responses of the immune system are induced. RA and PsA have complex signaling pathways. Despite the differences in their clinical presentation, there is a great demand for fast and accurate diagnosis of diseases to implement treatment and plan an individual therapeutic strategy quickly. In this report, we present the results of differential diagnosis of patients with RA and PsA and healthy subjects (C, control group), allowing for reliable differentiation of groups of rheumatoid patients based on biochemical parameters, attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectra, and combined data sets.
MATERIALS AND METHODS
Biochemical analyses, ELISA (enzyme-linked immunosorbent assays), and multiplex assays were conducted for blood sera from patients with RA (n = 32), patients with PsA (n = 28), and the control group (n = 18). ATR-FTIR spectra were collected for lyophilized sera.
RESULTS
The combination of six biochemical parameters (WBC, ESR, RF, CRP, HCC-4/CCL16, and HMGB1/HMGB) allowed the development of the partial least squares discriminant analysis (PLS-DA) model with an overall accuracy (OA) of 80% for test samples. The best separation between RA, PsA, and the control group was obtained utilizing spectral data. Using the interval PLS algorithm (iPLS) specific spectral ranges were selected and a classifier characterized by OA value for test set equal to 88% was obtained. This parameter, for the hybrid PLS-DA model constructed using selected biochemical parameters and a significantly reduced number of spectral variables, reached the level of 84%.
CONCLUSIONS
PLS-DA models developed on the basis of spectral data enable effective differentiation of patients with RA, patients with PsA, and healthy subjects. They appeared to be insensitive to existing inflammation processes which opens interesting perspectives for new diagnostic tests and algorithms for identification of patients with RA and PsA.
PubMed: 38941757
DOI: 10.1016/j.saa.2024.124654