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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 -
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 -
Joint Bone Spine Jun 2024Denosumab (Dmab) is widely used for the treatment of post-menopausal osteoporosis. Its discontinuation is sometimes accompanied by multiple vertebral fractures....
INTRODUCTION
Denosumab (Dmab) is widely used for the treatment of post-menopausal osteoporosis. Its discontinuation is sometimes accompanied by multiple vertebral fractures. Romosozumab (Rmab) has not been tested for its ability to prevent the rebound phenomenon.
CASE PRESENTATION
We present the case of a 68-year-old female patient with post-menopausal osteoporosis under treatment with Rmab who presented with multiple vertebral fractures after denosumab discontinuation. The addition of Rmab did not prevent new-onset rebound-associated vertebral fractures. The patient discontinued Rmab and Dmab was re-initiated. After six months, no new vertebral fractures occurred, bone mineral density increased and bone turnover markers remained suppressed.
DISCUSSION
Our clinical case illustrates the effectiveness of Rmab to prevent the multiple vertebral fracture cascade attributable to discontinuation of Dmab. We believe that treatment with Rmab might not be enough to prevent this phenomenon. Treatment with Dmab or possibly combination treatment with Dmab and Rmab could be another treatment option.
PubMed: 38942353
DOI: 10.1016/j.jbspin.2024.105754 -
The Spine Journal : Official Journal of... Jun 2024Extreme Lateral Interbody Fusion (XLIF) has been established as an effective treatment for degenerative disorders of the lumbar spine. Nevertheless, there is a potential...
BACKGROUND CONTEXT
Extreme Lateral Interbody Fusion (XLIF) has been established as an effective treatment for degenerative disorders of the lumbar spine. Nevertheless, there is a potential risk of lumbar plexus damage associated with XLIF, especially during surgeries at the L4-5 segment. Diffusion Tensor Imaging (DTI) evaluates the directional diffusion of water molecules in tissue, providing a more intricate depiction of internal tissue microstructure compared to conventional MRI techniques. The capability of DTI sequences to elucidate the three-dimensional interplay between lumbar nerve pathways and adjacent musculoskeletal structures, potentially reducing the incidence of nerve injury complications related to XLIF, remains to be established.
PURPOSE
This study evaluates the effectiveness of preoperative Diffusion Tensor Imaging (DTI) in reducing neurological complications after Extreme Lateral Interbody Fusion (XLIF) surgeries at the L4-5 level, focusing on the interaction between lumbar nerves and the psoas major muscle.
STUDY DESIGN
Retrospective case-control study.
PATIENT SAMPLE
The study included 128 patients undergoing XLIF surgery for degenerative disorders at the L4-5 segment: 68 in the traditional group and 62 in the DTI group.
OUTCOME MEASURES
The study assessed Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) scores, along with complication rates. It also documented psoas major muscle morphology and its correlation with nerve pathways.
METHODS
A retrospective analysis of 128 patients undergoing XLIF surgery for degenerative disorders at the L4-5 segment between February 2020 and August 2022 was conducted. The cohort was divided into a traditional group (68 patients) receiving pre-surgery MRI scans to identify surgical entry points at the intervertebral space midpoint (Zones II-III junction) and a DTI group (62 patients) who additionally underwent preoperative DTI to customize entry points. The study evaluated VAS and ODI scores, complication rates, psoas major muscle morphology, and its interaction with nerve pathways.
RESULTS
The traditional group uniformly chose the Zone II-III junction for entry. In contrast, the DTI group's entry points varied. Postoperative follow-up revealed significant improvements in VAS and ODI scores in both groups. However, the DTI group experienced fewer immediate postoperative complications such as thigh pain, numbness, and motor disturbances. The study also noted a ventral shift in nerve positioning in patients with elevated psoas muscles.
CONCLUSIONS
Preoperative DTI effectively maps the relationship between the psoas major muscle and lumbar nerves. Tailoring surgical entry points based on DTI results significantly reduces the risk of nerve damage in XLIF surgeries. The study underscores the importance of recognizing variability in lumbar nerve pathways due to differing psoas muscle morphologies, highlighting a higher risk of nerve injury in patients with elevated psoas muscles during XLIF procedures.
PubMed: 38942298
DOI: 10.1016/j.spinee.2024.06.017 -
Journal of Clinical Epidemiology Jun 2024Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of...
OBJECTIVE
Frailty is a dynamic health state that changes over time. Our hypothesis was that there are identifiable subgroups of the older population that have specific patterns of deterioration. The objective of this study was to evaluate the application of joint latent class model (JLCM) in identifying trajectories of frailty progression over time and their group-specific risk of death in older people.
STUDY DESIGN AND SETTING
The primary care records of UK patients, aged over 65 as of January 1 2010, included in the CPRD: GOLD and AURUM databases, were analysed and linked to mortality data. Electronic frailty index (eFI) scores were calculated at baseline and annually in subsequent years (2010-2013). JLCM was used to divide the population into clusters with different trajectories and associated mortality hazard ratios (HR). The model was built in GOLD and validated in AURUM.
RESULTS
Five trajectory clusters were identified and characterised based on baseline and speed of progression: low-slow, low-moderate, low-rapid, high-slow and high-rapid. The high-rapid cluster had the highest average starting eFI score; 7.9, while low-rapid cluster had the steepest rate of eFI progression; 1.7. Taking the low-slow cluster as reference, low-rapid and high-rapid had the highest HRs: 3.73 (95%CI 3.71 to 3.76) and 3.63 (3.57 to 3.69), respectively. Good validation was found in the AURUM population.
CONCLUSION
Our research found that there are vulnerable subgroups of the older population who are currently frail or have rapid frailty progression. Such groups may be targeted for greater healthcare monitoring.
PubMed: 38942178
DOI: 10.1016/j.jclinepi.2024.111442 -
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 -
British Journal of Hospital Medicine... Jun 2024Systemic lupus erythematosus (SLE) is a complex autoimmune disease where the body loses tolerance to its own antigens, particularly nuclear antigens. Abnormal responses...
Systemic lupus erythematosus (SLE) is a complex autoimmune disease where the body loses tolerance to its own antigens, particularly nuclear antigens. Abnormal responses from T and B cells lead to the production of autoantibodies and the formation of immune complexes in tissues, triggering complement activation, inflammation, and irreversible organ damage. SLE can affect any part of the body, resulting in diverse clinical symptoms. One rare manifestation of SLE is lupus mesenteric vasculitis (LMV), which presents with vague symptoms, abnormal laboratory findings, and specific imaging features. LMV, although uncommon, can progress to severe complications such as bowel perforation, haemorrhage, and even mortality. Here, we report a case of LMV with the involvement of multiple organ systems (including mucocutaneous, musculoskeletal, serosal cavities, and haematological systems), presenting initially with life-threatening intractable gastrointestinal bleeding, and complicated by severe pulmonary infection. By sharing this case, we aim to enhance clinicians' confidence in managing critical SLE cases and raise awareness about disease surveillance.
Topics: Humans; Gastrointestinal Hemorrhage; Lupus Erythematosus, Systemic; Vasculitis; Female; Mesentery; Tomography, X-Ray Computed; Adult
PubMed: 38941968
DOI: 10.12968/hmed.2024.0108 -
Stem Cell Research Jun 2024Marfan Syndrome, a connective tissue disorder caused by Fibrillin-1 (FBN1) gene mutations, induces disease in the ocular, musculoskeletal, and cardiovascular systems and...
Marfan Syndrome, a connective tissue disorder caused by Fibrillin-1 (FBN1) gene mutations, induces disease in the ocular, musculoskeletal, and cardiovascular systems and increases aortic vulnerability to rupture associated with high mortality rates. We describe an induced pluripotent stem cell line (HFD1) generated from patient-derived human dermal fibroblasts harboring a heterozygous c.3338-2A>C intronic splice acceptor site variant preceding Exon 28 of FBN1. The clonal line, which produces abnormal FBN1 splice variants, has a normal karyotype, expresses appropriate stemness markers, and maintains trilineage differentiation potential. This line represents a valuable resource for studying how abnormal splicing variants contribute to Marfan Syndrome.
PubMed: 38941881
DOI: 10.1016/j.scr.2024.103475 -
Heart & Lung : the Journal of Critical... Jun 2024Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence... (Review)
Review
Respiratory, cardiovascular and musculoskeletal mechanisms involved in the pathophysiology of pulmonary hypertension: An updated systematic review of preclinical and clinical studies.
BACKGROUND
Progressive exercise intolerance is a hallmark of pulmonary hypertension (pH), severely impacting patients' independence and quality of life (QoL). Accumulating evidence over the last decade shows that combined abnormalities in peripheral reflexes and target organs contribute to disease progression and exercise intolerance.
OBJECTIVE
The aim of this study was to review the literature of the last decade on the contribution of the cardiovascular, respiratory, and musculoskeletal systems to pathophysiology and exercise intolerance in pH.
METHODS
A systematic literature search was conducted using specific terms in PubMed, SciELO, and the Cochrane Library databases for original pre-clinical or clinical studies published between 2013 and 2023. Studies followed randomized controlled/non-randomized controlled and pre-post designs.
RESULTS
The systematic review identified 25 articles reporting functional or structural changes in the respiratory, cardiovascular, and musculoskeletal systems in pH. Moreover, altered biomarkers in these systems, lower cardiac baroreflex, and heightened peripheral chemoreflex activity seemed to contribute to functional changes associated with poor prognosis and exercise intolerance in pH. Potential therapeutic strategies acutely explored involved manipulating the baroreflex and peripheral chemoreflex, improving cardiovascular autonomic control via cardiac vagal control, and targeting specific pathways such as GPER1, GDF-15, miR-126, and the JMJD1C gene.
CONCLUSION
Information published in the last 10 years advances the notion that pH pathophysiology involves functional and structural changes in the respiratory, cardiovascular, and musculoskeletal systems and their integration with peripheral reflexes. These findings suggest potential therapeutic targets, yet unexplored in clinical trials, that could assist in improving exercise tolerance and QoL in patients with pH.
PubMed: 38941771
DOI: 10.1016/j.hrtlng.2024.06.001 -
International Journal of Surgery Case... Jun 2024Adamantinomas are rare, low-grade, malignant skeletal tumors accounting for only 0.33-0.48 % of primary malignant bone tumors.
INTRODUCTION AND IMPORTANCE
Adamantinomas are rare, low-grade, malignant skeletal tumors accounting for only 0.33-0.48 % of primary malignant bone tumors.
CASE PRESENTATION
An 11-year-old boy with adamantinoma of the ulna was treated with en bloc resection, kryptonite bone cement, and plate fixation. The surgery resulted in marked pain relief and good functional recovery. No evidence of recurrence was observed for 5 years postoperatively, and the Musculoskeletal Tumor Society score was 93.
CLINICAL DISCUSSION
This case of an 11-year-old previously treated for an aneurysmal bone cyst (ABC) illustrates the complexity of diagnosing adamantinoma, especially in atypical locations like the ulna. The successful use of en bloc resection and synthetic bone graft highlights the importance of accurate diagnosis and advanced surgical methods in achieving favorable outcomes in pediatric orthopedic oncology.
CONCLUSION
Ulnar adamantinomas are rare and can be difficult to diagnose. The successful treatment of this tumor, as described in this case report, can help guide the management of similar cases in the future.
PubMed: 38941733
DOI: 10.1016/j.ijscr.2024.109935