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RMD Open Jan 2022Patients with immune-mediated rheumatic diseases (IMRDs) are commonly treated with immunosuppressors and prone to infections. Recently introduced mRNA SARS-CoV-2...
BACKGROUND
Patients with immune-mediated rheumatic diseases (IMRDs) are commonly treated with immunosuppressors and prone to infections. Recently introduced mRNA SARS-CoV-2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-CoV-2 mRNA vaccines.
AIMS
To fully characterise B-cell and T-cell immune responses elicited by mRNA SARS-CoV-2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine's immunogenicity.
METHODS
Humoral, CD4 and CD8 immune responses were investigated in 100 naïve patients with SARS-CoV-2 with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-CoV-2 mRNA vaccine. Responses were compared with age, gender and disease-matched patients with IMRD not receiving immunosuppressors and with healthy controls.
RESULTS
Patients with IMRD showed decreased seroconversion rates (80% vs 100%, p=0.03) and cellular immune responses (75% vs 100%, p=0.02). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept decreased humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed impaired humoral responses, but cellular responses were often preserved. Antibody titres were reduced with mycophenolate and azathioprine but preserved with leflunomide and anticytokines.
CONCLUSIONS
Patients with IMRD exhibit impaired SARS-CoV-2 vaccine immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine's immunogenicity.
Topics: Antibodies, Neutralizing; Antibodies, Viral; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Humans; Immunity, Cellular; Immunogenicity, Vaccine; Rheumatic Diseases; SARS-CoV-2; Vaccines, Synthetic; mRNA Vaccines
PubMed: 34987093
DOI: 10.1136/rmdopen-2021-001898 -
Current Treatment Options in... Dec 2022This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently...
PURPOSE OF REVIEW
This review highlights current and emerging pharmacologic therapies for the treatment of dermatomyositis (DM). Current clinical evidence, in addition to recently published and ongoing clinical trials for various drugs in development, are summarized in this review.
RECENT FINDINGS
There has been significant progress in the research and development of potential treatments in DM. The FDA recently approved Octagam 10% Immune Globulin Intravenous (IVIg) for the treatment of DM. Several drug targets are being explored as viable therapeutic options in phase 2 and phase 3 clinical trials; at the forefront of these are JAK inhibitors (tofacitinib and baricitinib) and T-cell co-stimulation blockers (i.e. abatacept). In addition, clinical trials are currently under way for therapeutics targeting novel molecular pathways, including immunoproteasome inhibitors, anti-B cell therapy, anti-interferon drugs, complement inhibitors, and phosphodiesterase-4 inhibitors.
SUMMARY
With the large number of clinical trials, multiple novel therapeutics in development, and improved classification and outcome measures, the treatment landscape for DM will continue to rapidly evolve in the coming years as more options become available.
PubMed: 38650607
DOI: 10.1007/s40674-022-00193-6 -
Experimental Hematology & Oncology Jul 2023This review summarizes the significant advancements in prophylaxis against graft-versus-host disease (GvHD) presented at the 2022 ASH Annual Meeting. The use of...
This review summarizes the significant advancements in prophylaxis against graft-versus-host disease (GvHD) presented at the 2022 ASH Annual Meeting. The use of innovative agents and regimens, along with the conventional prophylactic approach of combining post-transplant cyclophosphamide and anti-thymocyte globulin, were discussed. The innovative agents and regimens highlighted in this review include abatacept, the first FDA-approved drug for acute GvHD prophylaxis; RGI-2001, which promotes the expansion of regulatory T cells; and cell therapies such as Orca-T and Orca-Q. These advancements provide promising strategies and options for GvHD prevention, offering hope for improved post-transplant patient outcomes in terms of survival rates.
PubMed: 37420283
DOI: 10.1186/s40164-023-00425-y -
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 -
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 -
Journal of Clinical Medicine Jun 2021Pediatric patients with early onset (before the age of 6 years), antinuclear antibody positive, oligoarticular or polyarticular juvenile idiopathic arthritis (JIA), and... (Review)
Review
Pediatric patients with early onset (before the age of 6 years), antinuclear antibody positive, oligoarticular or polyarticular juvenile idiopathic arthritis (JIA), and some children with no arthritis may develop chronic, anterior uveitis. Recent recommendations insist on the need to perform slit lamp examination every 3 months for at least 5 years in early onset JIA patients in order to diagnose uveitis before complications develop. Local steroid therapy is usually the first-line treatment. However, in patients requiring steroid eye drops for several months, systemic immunomodulatory therapy is indicated. Methotrexate (MTX) is then prescribed in most cases; however, some patients also need anti-tumor necrosis factor alpha monoclonal antibody therapy and, in some cases, other biologics to control uveitis and avoid long-term ocular damage. Expert ophthalmologists and pediatricians must be involved in taking care of such patients. Immunomodulatory treatment must not be too easily interrupted and may even be intensified in some cases, particularly if there is a need for optimal disease control before ophthalmologic surgery. In good responders to MTX and/or biologics, treatment must be maintained at least 1 year, possibly even 2 years after achieving remission before tapering treatment intensity.
PubMed: 34208973
DOI: 10.3390/jcm10132934 -
The Journal of Rheumatology Nov 2023To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or...
OBJECTIVE
To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or ABA monotherapy when prior MTX use was either ineffective or not tolerated.
METHODS
Posthoc analysis of 2 phase III trials of subcutaneous (SC) and intravenous (IV) ABA over 2 years in patients with pcJIA (aged 2-17 years). Patients were stratified by treatment with ABA + MTX or ABA monotherapy and further by prior biologic use. Efficacy outcomes included JIA-American College of Rheumatology (JIA-ACR) responses, Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP), and safety. Descriptive pharmacokinetic analyses were also performed.
RESULTS
Efficacy responses (JIA-ACR and JADAS27-CRP) were similar between patients receiving ABA + MTX (n = 310) or ABA monotherapy (n = 99) and persisted over 2 years. Clinical response rates were similar in biologic-naïve patients and prior biologic users; this was independent of MTX use. Across both studies, ABA + MTX and ABA monotherapy displayed similar safety profiles. Pharmacokinetic results revealed similar minimum steady-state trough ABA concentrations between studies. Further, baseline MTX did not influence ABA clearance and was not a significant predictor of JIA-ACR responses.
CONCLUSION
ABA monotherapy (SC and IV) was effective and well tolerated in children with pcJIA when prior MTX use was ineffective or not tolerated. Treatment effects of ABA appear to be independent of MTX coadministration. Consequently, ABA monotherapy can be considered for those with prior biologic therapy if MTX use is inappropriate. (ClinicalTrials.gov: NCT01844518 and NCT00095173).
Topics: Child; Humans; Methotrexate; Abatacept; Arthritis, Juvenile; Antirheumatic Agents; Drug Therapy, Combination; Biological Products; Treatment Outcome
PubMed: 37453737
DOI: 10.3899/jrheum.2022-1320 -
Frontiers in Immunology 2021
Topics: Animals; Cell-Derived Microparticles; Cytokines; Humans; Immune System; Immunity, Innate; Killer Cells, Natural; Myofibroblasts; Scleroderma, Systemic; Signal Transduction; T-Lymphocytes, Regulatory
PubMed: 34659272
DOI: 10.3389/fimmu.2021.770419 -
Cells Dec 2023Abatacept (CTLA4-Ig)-a monoclonal antibody which restricts T cell activation-is an effective treatment for rheumatoid arthritis (RA). Nevertheless, only 50% of RA...
A Peripheral Blood Signature of Increased Th1 and Myeloid Cells Combined with Serum Inflammatory Mediators Is Associated with Response to Abatacept in Rheumatoid Arthritis Patients.
Abatacept (CTLA4-Ig)-a monoclonal antibody which restricts T cell activation-is an effective treatment for rheumatoid arthritis (RA). Nevertheless, only 50% of RA patients attain clinical responses, while predictors of response are rather limited. Herein, we aimed to investigate for early biomarkers of response to abatacept, based on a detailed immunological profiling of peripheral blood (PB) cells and serum proteins. We applied flow cytometry and proteomics analysis on PB immune cells and serum respectively, of RA patients starting abatacept as the first biologic agent. After 6 months of treatment, 34.5% of patients attained response. At baseline, Th1 and FoxP3+ T cell populations were positively correlated with tender joint counts (-value = 0.047 and -value = 0.022, respectively). Upon treatment, CTLA4-Ig effectively reduced the percentages of Th1 and Th17 only in responders (-value = 0.0277 and -value = 0.0042, respectively). Notably, baseline levels of Th1 and myeloid cell populations were significantly increased in PB of responders compared to non-responders (-value = 0.009 and -value = 0.03, respectively). Proteomics analysis revealed that several inflammatory mediators were present in serum of responders before therapy initiation and strikingly 10 amongst 303 serum proteins were associated with clinical responses. Finally, a composite index based on selected baseline cellular and proteomics' analysis could predict response to abatacept with a high sensitivity (90%) and specificity (88.24%).
Topics: Humans; Abatacept; Antirheumatic Agents; Inflammation Mediators; Arthritis, Rheumatoid; Myeloid Cells
PubMed: 38132128
DOI: 10.3390/cells12242808 -
Science Translational Medicine Mar 2023Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe...
Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.
Topics: Humans; Abatacept; Immunotherapy; Ipilimumab; Immune Checkpoint Inhibitors; Nivolumab
PubMed: 36857433
DOI: 10.1126/scitranslmed.abm5663