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Arthritis Research & Therapy Mar 2024Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a... (Randomized Controlled Trial)
Randomized Controlled Trial
Urinary prostanoids are elevated by anti-TNF and anti-IL6 receptor disease-modifying antirheumatic drugs but are not predictive of response to treatment in early rheumatoid arthritis.
BACKGROUND
Disease-modifying antirheumatic drugs (DMARDs) are widely used for treating rheumatoid arthritis (RA). However, there are no established biomarkers to predict a patient's response to these therapies. Prostanoids, encompassing prostaglandins, prostacyclins, and thromboxanes, are potent lipid mediators implicated in RA progression. Nevertheless, the influence of DMARDs on prostanoid biosynthesis in RA patients remains poorly understood. This study aims to assess the impact of various DMARDs on urinary prostanoids levels and to explore whether urinary prostanoid profiles correlate with disease activity or response to therapy.
METHODS
This study included 152 Swedish female patients with early RA, all rheumatoid factor (RF) positive, enrolled in the NORD-STAR trial (registration number: NCT01491815). Participants were randomized into four therapeutic regimes: methotrexate (MTX) combined with (i) prednisolone (arm ACT), (ii) TNF-α blocker certolizumab pegol (arm CZP), (iii) CTLA-4Ig abatacept (arm ABA), or (iv) IL-6R blocker tocilizumab (arm TCZ). Urine samples, collected before start of treatment and at 24 weeks post-treatment, were analyzed for tetranor-prostaglandin E metabolite (tPGEM), tetranor-prostaglandin D metabolite (tPGDM), 2,3-dinor thromboxane B (TXBM), 2,3-dinor-6-keto prostaglandin F (PGIM), leukotriene E (LTE) and 12-hydroxyeicosatetraenoic acid (12-HETE) using liquid chromatography-mass spectrometry (LC-MS). Generalized estimating equation (GEE) models were used to analyze the change in urinary eicosanoids and their correlations to clinical outcomes.
RESULTS
Patients receiving MTX combined with CZP or TCZ exhibited significant elevations in urinary tPGEM and TXBM levels after 24 weeks of treatment. Other eicosanoids did not show significant alterations in response to any treatment. Baseline urinary eicosanoid levels did not correlate with baseline clinical disease activity index (CDAI) levels, nor with changes in CDAI from baseline to week 24. Their levels were also similar between patients who achieved CDAI remission and those with active disease at week 24.
CONCLUSIONS
Treatment with anti-TNF or anti-IL6R agents in early RA patients leads to an increased systemic production of proinflammatory and prothrombotic prostanoids. However, urinary eicosanoid levels do not appear to be predictive of the response to DMARDs therapy.
Topics: Humans; Female; Prostaglandins; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Arthritis, Rheumatoid; Methotrexate; Certolizumab Pegol; Dimaprit
PubMed: 38444034
DOI: 10.1186/s13075-024-03295-9 -
Current Opinion in Rheumatology May 2024This review discusses updates in the prediction and prevention of future rheumatoid arthritis (RA). (Review)
Review
PURPOSE OF REVIEW
This review discusses updates in the prediction and prevention of future rheumatoid arthritis (RA).
RECENT FINDINGS
In individuals with musculoskeletal symptoms and elevated antibodies to citrullinated proteins (ACPA) without clinical inflammatory arthritis (IA), a 'simple' score has a positive predictive value (PPV) of ∼28% for clinical IA/RA within 1 year, and a comprehensive score (including ultrasound) has a PPV of ∼71% for clinical RA within 5 years. Controlled clinical trials in individuals at-risk for future RA have been performed using corticosteroids, rituximab, atorvastatin, methotrexate, hydroxychloroquine and abatacept. Abatacept modestly reduced rates of incident clinical RA and imaging inflammation within the trials, rituximab delayed clinical IA, and methotrexate improved function, symptoms and imaging inflammation. Vitamin D with or without omega 3 fatty acids reduced incidence of autoimmune diseases, including RA. While not proven in controlled clinical trials, observational studies suggest exercise, weight loss and smoking cessation may reduce progression to clinical RA.
SUMMARY
Prediction and prevention of RA is advancing although there are no currently approved interventions for prevention. Future studies should include deeper evaluation of the pathophysiology of RA development to improve prediction and identify key pathways to target in future clinical trials, as well as develop infrastructure to support prevention-related research.
Topics: Humans; Methotrexate; Abatacept; Rituximab; Arthritis, Rheumatoid; Inflammation
PubMed: 38441488
DOI: 10.1097/BOR.0000000000001013 -
Microbiology Spectrum Apr 2024Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited....
The serological immunogenicity of the third and fourth doses of COVID-19 vaccine in patients with inflammatory rheumatic diseases on different biologic or targeted DMARDs: a Swedish nationwide study (COVID-19-REUMA).
UNLABELLED
Studies investigating the immunogenicity of additional COVID-19 vaccine doses in immunosuppressed patients with inflammatory rheumatic diseases (IRD) are still limited. The objective was to explore the antibody response including response to omicron virus subvariants (sBA.1 and sBS.2) after third and fourth COVID-19 vaccine doses in Swedish IRD patients treated with immunomodulating drugs compared to controls. Antibody levels to spike wild-type antigens (full-length protein and S1) and the omicron variants sBA.1 and sBA.2 (full-length proteins) were measured. A positive response was defined as having antibody levels over cut-off or ≥fourfold increase in post-vaccination levels for both antigens. Patients with arthritis, vasculitis, and other autoimmune diseases ( = 414), and controls ( = 61) receiving biologic/targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs) with or without conventional synthetic DMARDs participated. Of these, blood samples were available for 370 patients and 52 controls after three doses, and 65 patients and 15 controls after four doses. Treatment groups after three vaccine doses were rituximab ( = 133), abatacept ( = 22), IL6r inhibitors ( = 71), JAnus Kinase inhibitors (JAK-inhibitors) ( = 56), tumor necrosis factor inhibitor (TNF-inhibitors) ( = 61), IL12/23/17 inhibitors ( = 27), and controls ( = 52). The percentage of responders after three and four vaccine doses was lower in rituximab-treated patients (59% and 57%) compared to controls (100%) ( < 0.001). After three doses, the percentage of responders in all other groups was 100%, including response to omicron sBA.1 and sBA.2. In rituximab-treated patients, higher baseline immunoglobulin G (IgG) and longer time-period between rituximab and vaccination predicted better response. In this Swedish nationwide study including IRD patients three and four COVID-19 vaccine doses were immunogenic in patients treated with IL6r inhibitors, TNF-inhibitors, JAK-inhibitors, and IL12/23/17-inhibitors but not in rituximab. As >50% of rituximab patients responded to vaccines including omicron subvariants, these patients should be prioritized for additional vaccine doses.
IMPORTANCE
Results from this study provide further evidence that additional doses of COVID-19 vaccines are immunogenic and result in satisfactory antibody response in a majority of patients with inflammatory rheumatic diseases (IRD) receiving potent immunomodulating treatments such as biological or targeted disease-modifying anti-rheumatic drugs (DMARDs) given as monotherapy or combined with traditional DMARDs. We observed that rituximab treatment, both as monotherapy and combined with csDMARDs, impaired antibody response, and only roughly 50% of patients developed a satisfactory antibody response including response to omicron subvariants after the third vaccine. In addition, higher IgG levels at the last rituximab course before the third vaccine dose and a longer time after the last rituximab treatment increased the chance of a satisfactory antibody response. These results indicate that rituximab-treated patients should be prioritized for additional vaccine doses.
CLINICAL TRIALS
EudraCT (European Union Drug Regulating Authorities Clinical Trials Database) with number 2021-000880-63.
Topics: Humans; COVID-19 Vaccines; COVID-19; Rituximab; Sweden; SARS-CoV-2; Antirheumatic Agents; Rheumatic Fever; Immunoglobulin G; Interleukin-12; Antibodies, Viral; Immunogenicity, Vaccine
PubMed: 38441463
DOI: 10.1128/spectrum.02981-23 -
Clinical and Experimental Rheumatology Mar 2024While multiple studies have investigated treatment persistence rates with intravenous abatacept, limited information is available about real-world treatment continuation...
OBJECTIVES
While multiple studies have investigated treatment persistence rates with intravenous abatacept, limited information is available about real-world treatment continuation with the subcutaneous form. The international ASCORE study described the characteristics and treatment persistence of real-world patients with rheumatoid arthritis (RA) receiving subcutaneous abatacept. This article presents the findings of the French cohort.
METHODS
This was an observational study in French RA patients who initiated subcutaneous abatacept between August 2014 and January 2017. The primary endpoint was treatment maintenance at 2 years, analysed according to the number of previous biologic therapies.
RESULTS
Of 546 evaluable patients, 281 (51.5%) were biologic-naive, 265 (48.5%) had experienced failure with 1 (n=134; 24.5%) or ≥2 (n=131; 24.0%) biologic therapies. At enrolment, patients who had experienced failure with ≥1 biologic therapy had more erosions and a longer duration of RA compared with biologic-naive patients, but had comparable mean disease activity scores. Overall, 43.0% of patients (95% confidence interval 38.6-47.2) were still taking subcutaneous abatacept at 2 years, which was comparable with that in other countries participating in ASCORE. The abatacept persistence rate was higher in biologic-naive patients (48.8%) than in those with 1 (40.9%) or ≥2 (32.8%) biologic therapy failures. The main reason for discontinuing abatacept was lack of efficacy (46.6%).
CONCLUSIONS
In current practice in France, the rate of subcutaneous abatacept persistence at 2 years was comparable with that of the intravenous form. Treatment persistence was higher when abatacept was used as first-line versus later-line biologic therapy.
PubMed: 38436358
DOI: 10.55563/clinexprheumatol/ddx0fz -
Expert Opinion on Investigational Drugs Apr 2024Despite the improvements of insulin therapy, people with type 1 diabetes (T1D) still suffer from a decreased quality of life and life expectancy. The search toward a... (Review)
Review
INTRODUCTION
Despite the improvements of insulin therapy, people with type 1 diabetes (T1D) still suffer from a decreased quality of life and life expectancy. The search toward a cure for T1D is therefore still a scorching open field of research.
AREAS COVERED
Tackling the immune checkpoint signaling pathways has gained importance in the field of cancer immunotherapy. The same pathways can be targeted in autoimmunity with an opposite principle: to dampen the exaggerated immune response. In this review, we report a comprehensive excursus on the cellular and molecular mechanisms that lead to loss of immunological tolerance, and recent evidence on the role of immune checkpoint molecules in the development of T1D and their potential application for the mitigation of autoimmune diabetes.
EXPERT OPINION
Contrasting results about the efficacy of immune checkpoint modulators for T1D have been published, with very few molecules from preclinical studies eligible for use in humans. The heterogeneous and complex pathophysiology of T1D may explain the conflicting evidence. Designing clinical trials that acknowledge the pathophysiological and clinical complexity of T1D and that forecast the need of simultaneously tackling different disease pathways will be crucial to enhance the benefits which may be gained by such compounds.
Topics: Humans; Diabetes Mellitus, Type 1; Quality of Life; Immunotherapy; Autoimmunity; Insulin; Immunologic Factors
PubMed: 38427915
DOI: 10.1080/13543784.2024.2326036 -
Journal Der Deutschen Dermatologischen... Apr 2024The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending...
The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending on the subtype and localisation, structures such as adipose tissue, muscles, joints, and bones may also be affected. Involvement of internal organs or progression to systemic sclerosis does not occur. LoS can be classified into four main forms: limited, generalized, linear, and mixed forms, with some additional subtypes. For cases of limited skin involvement, the guideline primarily recommends therapy with topical corticosteroids. UV therapy can also be recommended. In subtypes with severe skin or musculoskeletal involvement, systemic therapy with methotrexate is recommended. During the active phase of the disease, systemic glucocorticosteroids can be used additionally. In cases of methotrexate and steroid refractory courses, contraindications, or intolerance, mycophenolate mofetil, mycophenolic acid, or abatacept can be considered as second-line systemic therapies. In the case of linear LoS, autologous adipose-derived stem cell transplantation can also be performed for correcting soft tissue defects.
Topics: Humans; Methotrexate; Scleroderma, Localized; Skin; Dermatologic Agents; Mycophenolic Acid
PubMed: 38426689
DOI: 10.1111/ddg.15328 -
Journal of Pharmaceutical and... May 2024T-cells play a significant role in the development of autoimmune diseases. The CD28-B7 costimulatory pathway is crucial for activating T-cells, and blocking this pathway...
T-cells play a significant role in the development of autoimmune diseases. The CD28-B7 costimulatory pathway is crucial for activating T-cells, and blocking this pathway is essential for treating autoimmune diseases. Therapeutic antibodies and fusion proteins that target costimulatory molecules like CD80, CD86, CTLA-4, and CD28 have been developed to explore the costimulation process and as targeted treatments. To advance our understanding of costimulation in autoimmunity and the inhibition of the costimulatory pathway, it is crucial to have an accurate, precise, and direct method for detecting and quantifying the soluble form of these molecules in body fluids and various biological systems. Herein, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying the four costimulatory proteins depending on the signature peptides derived from the soluble isoform of these proteins in multiple reaction monitoring (MRM) mode. The method was validated using the US FDA guidelines. The LOQ was determined as ∼0.5 nM for the four analytes, with quantification extended to 20 nM with a correlation coefficient of R>0.998. The developed MRM method was used to analyze on-bead digested protein mixtures to establish a competitive assay for the CD28-B7 costimulatory pathway using CTLA4-Ig (Abatacept ™) as an FDA-approved drug for rheumatoid arthritis. The IC was determined to be 2.99 and 159.8 nM for sCD80 and sCD86, respectively. A straightforward MRM-based competitive assay will advance the knowledge about the costimulatory role in autoimmunity and the autoimmune therapeutic drug discovery, with the need for broad application on different in vitro and in vivo models to discover new targeted inhibitors.
Topics: Humans; CD28 Antigens; Antigens, CD; B7-2 Antigen; Chromatography, Liquid; Liquid Chromatography-Mass Spectrometry; Tandem Mass Spectrometry; Immunoconjugates; B7-1 Antigen; Abatacept; Autoimmune Diseases
PubMed: 38422671
DOI: 10.1016/j.jpba.2024.116034 -
Circulation Research Mar 2024
Topics: Humans; Cardiotoxicity; Cardio-Oncology; Doxorubicin; Heart Diseases
PubMed: 38422182
DOI: 10.1161/CIRCRESAHA.124.324243 -
Frontiers in Medicine 2024The evaluation of microvascular alterations might provide clinically useful information for patients with an increased cardiovascular (CV) risk, such as those with...
Retinal microvascular alterations in patients with active rheumatoid arthritis without cardiovascular risk factors: the potential effects of T cell co-stimulation blockade.
BACKGROUND
The evaluation of microvascular alterations might provide clinically useful information for patients with an increased cardiovascular (CV) risk, such as those with rheumatoid arthritis (RA), being the small artery remodeling the earliest form of target organ damage in primary CV diseases, such as arterial hypertension. The evaluation of retinal arterioles is a non-invasive technique aimed to identify an early microvascular damage, represented by the increase of the wall-to-lumen ratio (WLR) index. Abatacept (ABA), a T-cell co-stimulator blocker, is used to treat RA. A CV protective action was hypothesized for its peculiar mechanism of action in the modulation of T-cells, potentially involved in the pathogenesis of CV comorbidity. The study aimed to non-invasively investigate morphological characteristics of retinal arterioles in a cohort of RA patients treated with ABA.
MATERIALS AND METHODS
Seventeen RA patients [median (25th-75thpercentile) age = 58 (48-64) years, baseline 28-joint Disease Activity Score DAS28-C-reactive protein (DAS28-CRP) = 4.4 (3.9-4.6), body mass index (BMI) = 24.2 (23.4-26) kg/m, rheumatoid factor positive:52.9%, anti-citrullinated peptide autoantibodies positive:76.5%] without known CV risk factors (arterial hypertension, diabetes, hypercholesterolemia, previous CV events, smoking) were evaluated by the adaptive optics imaging system of retinal arterioles before and every 6 months of therapy with ABA (T0, T6 and T12). Office blood pressure evaluation, 24-h ambulatory blood pressure monitoring and tissue-doppler echocardiography were also performed.
RESULTS
A progressive significant reduction of the WLR of retinal arterioles was observed [T0 = 0.28 (0.25-0.30), T6 = 0.27 (0.24-0.31), T12 = 0.23 (0.23-0.26); p T0 vs. T6 = 0.414; p T6 vs. T12 = 0.02; p T0 vs. T12 = 0.009], without significant variations in other parameters. The T0-T12 reduction of WLR was correlated with that of DAS28-CRP (r:0.789; = 0.005). Moreover, a significant reduction of diastolic office blood pressure and a trend for reduction of daily pressure measured by ambulatory monitoring were observed.
CONCLUSION
In a cohort of RA patients without known CV risk factors, a reduction of retinal microvascular alterations was demonstrated after treatment for 12 months with ABA, in parallel with the reduction of disease activity. These results might suggest the possibility of microvascular abnormalities regression induced by the immune system modulation.
PubMed: 38420362
DOI: 10.3389/fmed.2024.1247024 -
Transplantation and Cellular Therapy May 2024Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes...
Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.
Topics: Humans; Unrelated Donors; Female; Male; Middle Aged; Hematopoietic Stem Cell Transplantation; Adult; Histocompatibility Testing; Graft vs Host Disease; Minority Groups; Cohort Studies; HLA Antigens; Aged
PubMed: 38417677
DOI: 10.1016/j.jtct.2024.02.020