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Genes Dec 2022(1) Background: Gut microbiota (GM) is the set of microorganisms inhabiting the gastroenteric tract that seems to have a role in the pathogenesis of rheumatic diseases.... (Review)
Review
(1) Background: Gut microbiota (GM) is the set of microorganisms inhabiting the gastroenteric tract that seems to have a role in the pathogenesis of rheumatic diseases. Recently, many authors proved that GM may influence pharmacodynamics and pharmacokinetics of several drugs with complex interactions that are studied by the growing field of pharmacomicrobiomics. The aim of this review is to highlight current evidence on pharmacomicrobiomics applied to the main treatments of Rheumatoid Arthritis and Spondyloarthritis in order to maximize therapeutic success, in the framework of Personalized Medicine. (2) Methods: We performed a narrative review concerning pharmacomicrobiomics in inflammatory arthritides. We evaluated the influence of gut microbiota on treatment response of conventional Disease Modifying Anti-Rheumatic drugs (cDMARDs) (Methotrexate and Leflunomide) and biological Disease Modifying Anti-Rheumatic drugs (bDMARDs) (Tumor necrosis factor inhibitors, Interleukin-17 inhibitors, Interleukin 12/23 inhibitors, Abatacept, Janus Kinase inhibitors and Rituximab). (3) Results: We found a great amount of studies concerning Methotrexate and Tumor Necrosis Inhibitors (TNFi). Conversely, fewer data were available about Interleukin-17 inhibitors (IL-17i) and Interleukin 12/23 inhibitors (IL-12/23i), while none was identified for Janus Kinase Inhibitors (JAKi), Tocilizumab, Abatacept and Rituximab. We observed that microbiota and drugs are influenced in a mutual and reciprocal way. Indeed, microbiota seems to influence therapeutic response and efficacy, whereas in the other hand, drugs may restore healthy microbiota. (4) Conclusions: Future improvement in pharmacomicrobiomics could help to detect an effective biomarker able to guide treatment choice and optimize management of inflammatory arthritides.
Topics: Humans; Methotrexate; Abatacept; Rituximab; Janus Kinase Inhibitors; Interleukin-17; Yin-Yang; Antirheumatic Agents; Arthritis, Rheumatoid; Interleukin-12
PubMed: 36672830
DOI: 10.3390/genes14010089 -
Frontiers in Immunology 2023Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role...
Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of keratinocytes and immune cell infiltration. The IL-17-producing T cells play a key role in psoriasis pathogenesis, while regulatory T (Treg) cells are diminished during psoriatic inflammation. Current psoriasis treatments largely focus on IL-17 and IL-23, however, few studies have explored therapeutic drugs targeting an increase of Treg cells to control immune homeostasis. In this study, we investigated the effects of a cytotoxic T lymphocyte antigen-4 (CTLA-4) signaling peptide (dNP2-ctCTLA-4) in Th17, Tc17, γδ T cells, Treg cells and a mouse model of psoriasis. Treatment with dNP2-ctCTLA-4 peptide showed a significant reduction of psoriatic skin inflammation with increased Treg cell proportion and reduced IL-17 production by T cells, indicating a potential role in modulating psoriatic skin disease. We compared dNP2-ctCTLA-4 with CTLA-4-Ig and found that only dNP2-ctCTLA-4 ameliorated the psoriasis progression, with increased Treg cells and inhibited IL-17 production from γδ T cells. experiments using a T cell-antigen presenting cell co-culture system demonstrated the distinct mechanisms of dNP2-ctCTLA-4 compared to CTLA-4-Ig in the induction of Treg cells. These findings highlight the therapeutic potential of dNP2-ctCTLA-4 peptide in psoriasis by augmenting Treg/Teff ratio, offering a new approach to modulating the disease.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Interleukin-17; CTLA-4 Antigen; Abatacept; Psoriasis; Dermatitis; Inflammation
PubMed: 37818377
DOI: 10.3389/fimmu.2023.1233514 -
Rheumatology International Feb 2018To assess the comparative effectiveness and safety of novel biologic therapies in psoriatic arthritis (PsA) and to establish the position of the non-anti-tumor necrosis... (Meta-Analysis)
Meta-Analysis Review
To assess the comparative effectiveness and safety of novel biologic therapies in psoriatic arthritis (PsA) and to establish the position of the non-anti-tumor necrosis factor α (TNF-α) biologic drugs in the treatment regimen of the disease. A systematic review and network meta-analysis (NMA) was conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) requirements. Two investigators identified the studies, abstracted data, and assessed the risk of bias independently. The NMA was conducted for efficacy [American College of Rheumatology (ACR) criteria, ACR20 and ACR50; psoriasis area and severity index (PASI), PASI75] and safety outcomes [any adverse events (AEs) and serious adverse events (SAEs)]; treatments were ranked using the P score for each outcome. The PROSPERO registration number was 42017072200. MEDLINE/PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched from the inception of each database to July 10, 2017. Randomized controlled trials (RCTs) for abatacept, apremilast, secukinumab or ustekinumab in adults with moderate and severe PsA were included. The overall PsA population and anti-TNF-α-naive, anti-TNF-α-failure, or anti-TNF-α-experienced subpopulations were considered. We identified eight eligible RCTs and included them in the systematic review and NMA. Significant differences in ACR20 response rate were revealed between secukinumab 150 mg and apremilast 20 mg [relative risk; RR = 2.55 (CI-confidence interval; 1.24, 5.23)] and between secukinumab 300 mg and apremilast 20 or 30 mg [RR = 3.57 CI (1.48, 8.64) and RR = 2.84 CI (1.18, 6.86), respectively]. Any AEs occurred more often in apremilast 20 and 30 mg compared with placebo [RR = 0.58 CI (0.45, 0.74) and RR = 0.58 CI (0.45, 0.75), respectively] but also compared with secukinumab 150 mg [RR = 0.54 CI (0.35, 0.81) and RR = 0.45 CI (0.35, 0.82), respectively]. No significant differences were revealed for SAEs among biologics and between biologics and placebo. In the overall population, as well as in the anti-TNF-α-naive subpopulation, secukinumab at a dose of 300 and 150 mg was ranked the highest for the ACR20 endpoint, while in the anti-TNF-α-experienced subpopulation, secukinumab 300 mg and apremilast 30 mg revealed the highest rank. Secukinumab 75 mg was the safest drug in terms of any AEs, but for SEAs the safest was ustekinumab 90 mg. Our study revealed no significant differences among non-anti-TNF-α biologics in the treatment of PsA in the comparisons performed with regards to the highest efficacy and safety. Both in the overall population and in the analyzed subpopulations, secukinumab 300 mg was ranked the highest for the ACR20 response rate. Secukinumab 300 mg was the safest drug in terms of any AEs, and ustekinumab 90 mg presented the lowest overall risk of SAEs. Head-to-head trials and evaluation of comparative efficacy and safety between non-TNF-α biologics are warranted to inform clinical decision making with a relevant treatment paradigm.
Topics: Abatacept; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Comparative Effectiveness Research; Humans; Remission Induction; Thalidomide; Time Factors; Treatment Outcome; Ustekinumab
PubMed: 29285605
DOI: 10.1007/s00296-017-3919-7 -
Transplant International : Official... Aug 2015Immunosuppressive therapy after kidney transplantation consists of a calcineurin inhibitor (CNI)-based therapy in combination with mycophenolic acid and steroids in most... (Review)
Review
Immunosuppressive therapy after kidney transplantation consists of a calcineurin inhibitor (CNI)-based therapy in combination with mycophenolic acid and steroids in most cases. In spite of low acute rejection rates and excellent graft survival, it is associated with major long-term complications, such as cardiovascular events, malignancy, and nephrotoxicity, and does not favor tolerogenic processes. Mammalian target of rapamycin (mTOR) inhibitors in combination with low-dose CNI offer good rejection rates and acceptable allograft function; however, de novo mTOR inhitibor-based treatment in combination with mycophenolate is not widely used due to higher acute rejection rates. Early conversion from a CNI to an mTOR inhibitor is a feasible option in selected patients with a slightly higher acute rejection rate, but equal or better GFR. Costimulation blockade has been proven to facilitate antirejection prophylaxis without CNI-associated side effects. So far, belatacept has been approved in combination with mycophenolate and steroids with better graft function, however, a slightly higher acute rejection rate. Recently, the combination of an mTOR inhibitor and belatacept with lymphocyte-depleting antibody induction and without maintenance steroids has been explored in two pilot studies with very low acute rejection rates, very good graft function, and an acceptable side effect profile.
Topics: Abatacept; Calcineurin Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 25959589
DOI: 10.1111/tri.12603 -
Common Transcriptomic Effects of Abatacept and Other DMARDs on Rheumatoid Arthritis Synovial Tissue.Frontiers in Immunology 2021Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other...
OBJECTIVES
Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.
METHODS
Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3, CD20, and CD68 cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.
RESULTS
Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.
CONCLUSION
We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.
Topics: Abatacept; Adalimumab; Adult; Aged; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Male; Methotrexate; Middle Aged; Rituximab; Signal Transduction; Synovial Membrane; Transcriptome
PubMed: 34526997
DOI: 10.3389/fimmu.2021.724895 -
RMD Open Oct 2023We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD).
METHODS
PubMed, EMBASE, the Cochrane Library and Web of Science were searched for relevant articles from inception to 1 June 2022. The results obtained from the analysis were expressed as mean difference (MD), effect size and 95% CI.
RESULTS
A total of 17 studies, including 1315 patients with RA-ILD, were eligible. The ncs-DMARDs included abatacept, rituximab, tocilizumab, tumour necrosis factor and Janus kinase inhibitors. Compared with the baseline, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in the first second (FEV) and diffusion lung capacity for carbon monoxide (DLCO) values in the pooled data after ncs-DMARD treatment (alone or combined with conventional therapy) (p=0.36 for FVC; p=0.96 for FEV and p=0.46 for DLCO). Of note, FVC was obviously increased in rituximab subgroup (MD=-4.62, 95% CI -8.90 to -0.33, p=0.03). Also, high-resolution CT non-progression rate and fatality rate due to ILD progression in patients with RA-ILD were 0.792 (95% CI 0.746 to 0.834, p=0.015) and 0.049 (95% CI 0.035 to 0.065, p=0.000), respectively.
CONCLUSION
ncs-DMARDs alone or combined with conventional therapy might be an optimal and promising treatment for stabilising or improving ILD in patients with RA-ILD.
PROSPERO REGISTRATION NUMBER
CRD42022356816.
Topics: Humans; Rituximab; Antirheumatic Agents; Arthritis, Rheumatoid; Lung Diseases, Interstitial; Abatacept
PubMed: 37899093
DOI: 10.1136/rmdopen-2023-003487 -
Scientific Reports Oct 2023Rheumatoid arthritis (RA) causes bone loss, only partly related to inflammation. The impact of RA treatments on bone metabolism and their ability to mitigate bone loss... (Observational Study)
Observational Study
Rheumatoid arthritis (RA) causes bone loss, only partly related to inflammation. The impact of RA treatments on bone metabolism and their ability to mitigate bone loss remains uncertain. The primary goal of our study was to examine the influence of abatacept on serum levels of markers and regulators involved in bone turnover. Secondary objectives included evaluating changes in bone mineral density (BMD), bone health parameters, erosions, and exploring potential correlations among these parameters. We conducted a prospective observational study on patients with active seropositive RA failure to biological disease modifying anti-rheumatic drugs initiating treatment with abatacept. We measured at baseline and after 1, 2, 3, 6, 9 and 12 months: serum bone turnover markers (CTX, P1nP, B-ALP), bone modulators (Dkk-1, sclerostin, vitamin D, PTH, OPG and RANKL), BMD and radiographic parameters (modified Sharp van der Heijde score [mSvdH], bone health index [BHI] and metacarpal index [MCI]). Disease activity and glucocorticoid intake was monitored. 33 patients were enrolled in the study. We found a significant increase in markers of bone formation (B-ALP and P1nP) from baseline to M6 and M12. PTH increased significantly at M6 but not at M12. All other bone markers and modulators did not change. We found a significant decrease in BHI and MCI from baseline to M12 (median difference - 0.17 95% CI - 0.42 to - 0.10, p 0.001 and - 0.09 95% CI - 0.23 to - 0.07, respectively). BMD at femoral neck transitorily decreased at M6 (mean difference - 0.019 g/cm 95% CI - 0.036 to - 0.001 p 0.04). BMD at total hip, lumbar spine and mSvdH score did not change significantly. P1nP delta at M12 correlated with delta mSvdH. Treatment with abatacept was associated with a significant increase in bone formation markers. The secondary and transient increase in PTH serum levels may be responsible of the transitory bone loss.
Topics: Humans; Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Prospective Studies
PubMed: 37821541
DOI: 10.1038/s41598-023-44374-2 -
Transplantation Oct 2018De novo donor-specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitization,... (Review)
Review
De novo donor-specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitization, limiting future transplant options. Forming high-affinity, long-lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. T follicular regulatory cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses.An imbalance between helper function and regulatory function can lead to excessive antibody production. High proportions of Tfh cells have been associated with DSA formation in transplantation; therefore, Tfr cells are likely to play an important role in limiting DSA production. Understanding the signals that govern Tfr cell development and the balance between helper and regulatory function within the GC is key to understanding how these cells might be manipulated to reduce the risk of DSA development.This review discusses the development and function of Tfr cells and their relevance to transplantation. In particular how current and future immunosuppressive strategies might allow us to skew the ratio between Tfr and Tfh cells to increase or decrease the risk of de novo DSA formation.
Topics: Abatacept; Antibody Formation; B-Lymphocytes; Biomarkers; Cell Differentiation; Germinal Center; Graft Rejection; Humans; Immunosuppressive Agents; Isoantibodies; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Transplantation
PubMed: 29757907
DOI: 10.1097/TP.0000000000002224 -
International Immunopharmacology Aug 2015Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage. The introduction of biologic agents... (Review)
Review
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and is characterized by synovitis that causes joint damage. The introduction of biologic agents has made it possible to induce remission in many patients and inhibit joint damage. Activated T cells in RA patients proliferate and stimulate the production of pro-inflammatory cytokines including tumor necrosis factor (TNF) and interleukin 6 that play important roles in RA pathogenesis. The most widely used biologic agents indicated for RA inhibit the activity of TNF. However, newly developed biologic drugs targeting different pathways are now currently part of the therapeutic options to induce remission in patients with RA. The present review focuses on biologic agents directed at molecular targets different from TNF and addresses the possible advantages of these drugs.
Topics: Abatacept; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Therapy; Humans; Rituximab
PubMed: 25840282
DOI: 10.1016/j.intimp.2015.03.019 -
Current Opinion in Organ Transplantation Aug 2019Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability... (Review)
Review
PURPOSE OF REVIEW
Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve.
RECENT FINDINGS
Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation.
SUMMARY
Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation.
Topics: Abatacept; Animals; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Organ Transplantation; Swine; Transplantation, Heterologous
PubMed: 31157670
DOI: 10.1097/MOT.0000000000000656