BACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen... Show moreBACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under "sub-immunogenic" conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273(CII) and NF-KB inhibitor 1,25-dihydroxycholecalciferol.METHODS. A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71-specific (Cit-Vim-specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate. RESULTS. DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim-specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181-treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim-specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSION. The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATION. Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING. Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287. Show less
Scally, S.W.; Law, S.C.; Ting, Y.T.; Heemst, J. van; Sokolove, J.; Deutsch, A.J.; ... ; Thomas, R. 2017
Background Anti-citrullinated protein antibodies (ACPA) are thought to be highly specific for RA. ACPA are associated with risk factors for RA and with joint destruction, and are therefore presumed... Show moreBackground Anti-citrullinated protein antibodies (ACPA) are thought to be highly specific for RA. ACPA are associated with risk factors for RA and with joint destruction, and are therefore presumed to be involved in RA pathogenesis. ACPA-positive RA patients also have increased cardiovascular mortality (1). In cardiovascular disease, inflammatory changes occur in vessel walls, raising the question whether ACPA (presumed to be pro-inflammatory) may contribute to this process.Objectives To investigate the prevalence and prognostic implications of ACPA in patients with cardiovascular disease without RA.Methods ACPA were determined by anti-CCP3 commercial assay in baseline sera from 290 patients with ST-elevation myocardial infarction participating in the MISSION intervention study (2). Patients with RA were excluded. The association between ACPA and long-term mortality was investigated.Results 30/290 (10.3%) of the non-RA patients with cardiovascular disease were ACPA-positive. ACPA-positive non-RA patients had a significantly increased long-term cardiac mortality compared to ACPA-negative non-RA patients (Figure). Corrected for age, ACPA positivity was independently associated with long-term mortality [HR 2.4 (CI 1.1–5.4) p-Value=0.026].Conclusions ACPA can be detected in a considerable proportion of non-RA patients with cardiovascular disease. This challenges the presumed specificity of ACPA for RA. In both RA and cardiovascular disease, ACPA are associated with a worse disease outcome possibly by an ACPA-specific enhancement of inflammation. Future studies into ACPA in patients with cardiovascular disease offer the opportunity to dissect which risk factors are associated with ACPA in RA versus non-RA patients. This may supply crucial insights into the development of this autoimmune reaction. Show less
Objective Current research in rheumatoid arthritis focuses on preclinical disease phases as it is hypothesised that early preclinical treatment might prevent progression to full-blown disease.... Show moreObjective Current research in rheumatoid arthritis focuses on preclinical disease phases as it is hypothesised that early preclinical treatment might prevent progression to full-blown disease. Since performance of studies in prearthritis phases in humans is challenging, animal models offer an opportunity to evaluate preventive treatments. We performed a systematic literature review and summarised treatment effects during different stages of arthritis development in animal models.Methods Eight medical literature databases were systematically searched. Studies were selected if they reported effects of synthetic or biological disease-modifying antirheumatic drugs in animal models of arthritis (collagen-induced arthritis and adjuvant-induced arthritis) on arthritis severity, as measured with arthritis severity scores, paw swelling or paw volume. Quality was assessed using an 11-item checklist. Study characteristics were extracted and effect sizes obtained in high-quality studies were summarised in meta-analyses. Studies were categorised into three groups: prophylactic (prior to generation of autoantibody response), prearthritis (after induction of autoantibody response) and therapeutic intervention (after arthritis development).Results Out of 1415 screened articles, 22 studies (including n=712 animals) were eligible of good quality and included in meta-analyses. Prophylactic (16 experiments, n=312 animals) and prearthritis treatment (9 experiments, n=156 animals) both were associated with a reduction of arthritis severity (p<0.001 and p=0.005, respectively). Stratified analyses for different antirheumatic drugs initiated in the prearthritis phase suggested higher efficacy of methotrexate than of anti-tumour necrosis factor.Conclusions Data of experimental studies in animal models of arthritis suggest that prophylactic and prearthritis treatment strategies are effective and hint at differences in efficacy between antirheumatic drugs. Show less
Suurmond, J.; Velden, D. van der; Kuiper, J.; Bot, I.; Toes, R.E. 2016
Rheumatoid Arthritis is a chronic autoimmune disease with a complex disease pathogenesis leading to inflammation and destruction of synovial tissue in the joint. Several molecules lead to... Show moreRheumatoid Arthritis is a chronic autoimmune disease with a complex disease pathogenesis leading to inflammation and destruction of synovial tissue in the joint. Several molecules lead to activation of immune pathways, including autoantibodies, Toll-Like Receptor ligands and cytokines. These pathways can cooperate to create the pro-inflammatory environment that results in tissue destruction. Each of these pathways can activate mast cells, inducing the release of a variety of inflammatory mediators, and in combination can markedly enhance mast cell responses. Mast cell-derived cytokines, chemokines, and proteases have the potential to induce recruitment of other leukocytes able to evoke tissue remodeling or destruction. Likewise, mast cells can secrete a plethora of factors that can contribute to tissue remodeling and fibroblast activation. Although the functional role of mast cells in arthritis pathogenesis in mice is not yet elucidated, the increased numbers of mast cells and mast cell-specific mediators in synovial tissue of rheumatoid arthritis patients suggest that mast cell activation in rheumatoid arthritis may contribute to its pathogenesis. Show less
Rheumatoid arthritis (RA) is a destructive autoimmune disease that mainly affects synovial joints. RA patients can be subdivided in two distinct disease subsets based on the presence of anti... Show moreRheumatoid arthritis (RA) is a destructive autoimmune disease that mainly affects synovial joints. RA patients can be subdivided in two distinct disease subsets based on the presence of anti-citrullinated protein antibodies (ACPA). These two disease phenotypes are associated with different environmental and genetic risk factors and clinical parameters. The HLA class II locus is the most important risk factor for ACPA-positive RA (ACPA+ RA). ACPA can be found up to 10 years before diagnosis and can be used as a predictive biomarker. During progression from breaking tolerance to a citrullinated protein to ACPA+ RA, the ACPA response matures. Recent work implicates the HLA class II locus as a risk factor in the progression from ACPA positivity to ACPA+ RA. We now propose that this locus directly influences the maturation of the ACPA response, most likely via antigen-specific T-cells providing help to ACPA-producing B-cells allowing for maturation of the citrullinated protein-specific autoantibody response. We present and discuss several models and underlying data, including antibody cross-reactivity, molecular mimicry, and neo-antigen formation, that could explain the HLA-RA connection. Show less
Jong, A. de; Kwekkeboom, J.C.; Andersen, S.N.; Kloppenburg, M.; Toes, R.E.; Ioan-Facsinay, A. 2014
