Dataset Information

Anti-TNF Therapy in Spondyloarthritis and Related Diseases, Impact on the Immune System and Prediction of Treatment Responses.

ABSTRACT: Immune-mediated inflammatory diseases (IMIDs), such as spondyloarthritis (SpA), psoriasis, Crohn's disease (CD), and rheumatoid arthritis (RA) remain challenging illnesses. They often strike at a young age and cause lifelong morbidity, representing a considerable burden for the affected individuals and society. Pioneering studies have revealed the presence of a TNF-dependent proinflammatory cytokine cascade in several IMIDs, and the introduction of anti-TNF therapy 20 years ago has proven effective to reduce inflammation and clinical symptoms in RA, SpA, and other IMID, providing unprecedented clinical benefits and a valid alternative in case of failure or intolerable adverse effects of conventional disease-modifying antirheumatic drugs (DMARDs, for RA) or non-steroidal anti-inflammatory drugs (NSAIDs, for SpA). However, our understanding of how TNF inhibitors (TNFi) affect the immune system in patients is limited. This question is relevant because anti-TNF therapy has been associated with infectious complications. Furthermore, clinical efficacy of TNFi is limited by a high rate of non-responsiveness (30-40%) in RA, SpA, and other IMID, exposing a substantial fraction of patients to side-effects without clinical benefit. Despite the extensive use of TNFi, it is still not possible to determine which patients will respond to TNFi before treatment initiation. The recent introduction of antibodies blocking IL-17 has expanded the therapeutic options for SpA, as well as psoriasis and psoriatic arthritis. It is therefore essential to develop tools to guide treatment decisions for patients affected by SpA and other IMID, both to optimize clinical care and contain health care costs. After a brief overview of the biology of TNF, its receptors and currently used TNFi in the clinics, we summarize the progress that has been made to increase our understanding of the action of TNFi on the immune system in patients. We then summarize efforts dedicated to identify biomarkers that can predict treatment responses to TNFi and we conclude with a section dedicated to the recently introduced inhibitors of IL-17A and IL-23 in SpA and related diseases. The focus of this review is on SpA, however, we also refer to RA on topics for which only limited information is available on SpA in the literature.

SUBMITTER: Menegatti S

PROVIDER: S-EPMC6434926 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-TNF Therapy in Spondyloarthritis and Related Diseases, Impact on the Immune System and Prediction of Treatment Responses.

Menegatti Silvia S Bianchi Elisabetta E Rogge Lars L

Frontiers in immunology 20190319

Immune-mediated inflammatory diseases (IMIDs), such as spondyloarthritis (SpA), psoriasis, Crohn's disease (CD), and rheumatoid arthritis (RA) remain challenging illnesses. They often strike at a young age and cause lifelong morbidity, representing a considerable burden for the affected individuals and society. Pioneering studies have revealed the presence of a TNF-dependent proinflammatory cytokine cascade in several IMIDs, and the introduction of anti-TNF therapy 20 years ago has proven effect ...[more]

PMID: 30941119

Similar Datasets

Project description:Concomitant tumor necrosis factor (TNF) neutralization in combination with immune checkpoint inhibitors (ICIs) reduces clinical immune-related adverse events (irAEs) and appears to improve antitumor efficacy in preclinical tumor models. Agonistic antibodies targeting costimulatory receptors such as CD40 represent an additional strategy to boost antitumor immune response and potentiate the activity of ICIs. However, the dose-limiting toxicities observed in anti-CD40-treated cancer patients have hindered its clinical development. We previously described a mouse model to assess both antitumor activity and irAEs induced by various effective combination immunotherapies. Using the BALB/c and C57BL/6 strains of FoxP3-GFP-DTR (FoxP3DTR) mice, transient depletion of T regulatory cells (Tregs) prior to immunotherapy with additional immunomodulatory antibodies, lowered immune self-tolerance, resulting in the development of a spectrum of physical and biochemical irAEs similar to that reported clinically. In MC38 and 4T1.2 tumor models, following transient Treg depletion, we evaluated the impact of anti-CD40 on antitumor efficacy and the development of irAEs and the impact of concomitant or delayed TNF blockade on both these parameters. Physical irAEs were scored and biochemical irAEs were measured in the serum (ALT and cytokine levels). Histopathological liver and colon tissue analysis were performed to assess immune cell infiltration and tissue damage. Similar to early clinical trials of CD40 agonists, in our tumor models we observed liver toxicities and rapid release of proinflammatory cytokines (TNF, interleukin 6, interferon-γ). In the BALB/c strain, anti-CD40 induced severe physical and biochemical irAEs. Concomitant anti-TNF treatment abrogated weight loss, liver damage and colitis, which consequently resulted in an improved clinical score. However, concomitant anti-TNF impaired antitumor response in a proportion of anti-CD40-treated C57BL/6 FoxP3DTR mice. Delaying TNF blockade in these mice reduced biochemical but not physical irAEs while preserving antitumor efficacy. Our results suggest concomitant rather than delayed anti-TNF is most effective in reducing biochemical and physical irAEs induced by anti-CD40, although it had the potential to negatively impact antitumor efficacy. Furthermore, our findings highlight the utility of our mouse model to assess the severity of irAEs induced by novel immunotherapeutic agents and evaluate whether their toxicity and antitumor efficacy can be uncoupled.

Project description:BACKGROUND:Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory form of arthritis in which tumor necrosis factor (TNF)-α, a potent inducer of inflammatory response and a key regulator of innate immunity and of Th1 immune responses, plays a central role. NETosis is a mechanism of innate immune defense that is involved in diverse rheumatology diseases. Nevertheless, spontaneous NETosis generation in r-axSpA, its association to disease pathogenesis, and the NETosis involvement on anti-TNF-α therapy's effects has never been explored. METHODS:Thirty r-axSpA patients and 32 healthy donors (HDs) were evaluated. Neutrophil extracellular trap (NET) formation, mediators of signal-transduction cascade required for NETosis induction and cell-free NETosis-derived products were quantified. An additional cohort of 15 r-axSpA patients treated with infliximab (IFX) for six months were further analyzed. In vitro studies were designed to assess the effects of IFX in NETosis generation and the inflammatory profile triggered. RESULTS:Compared to HDs, neutrophils from r-axSpA patients displayed augmented spontaneous NET formation, elevated expression of NET-associated signaling components, nuclear peptidylarginine deiminase 4 translocation and increased citrullinated histone H3. Furthermore, patients exhibited altered circulating levels of cell-free NETosis-derived products (DNA, nucleosomes and elastase). Additional studies revealed that cell-free NETosis-derived products could be suitable biomarkers for distinguish r-axSpA patients from HDs. Correlation studies showed association between cell-free NETosis-derived products and clinical inflammatory parameters. Besides, nucleosomes displayed potential as a biomarker for discriminate patients according to disease activity. IFX therapy promoted a reduction in both NETosis generation and disease activity in r-axSpA patients. Mechanistic in vitro studies further unveiled the relevance of IFX in reducing NET release and normalizing the augmented inflammatory activities promoted by NETs in mononuclear cells. CONCLUSIONS:This study reveals that NETosis is enhanced in r-axSpA patients and identifies the NETosis-derived products as potential disease activity biomarkers. In addition, the data suggests the potential role of NET generation analysis for assessment of therapeutic effectiveness in r-axSpA.

Project description:BackgroundAnti-tumor necrosis factor (anti-TNF) agents are an effective, but costly, treatment for spondyloarthritis (SpA). Worldwide, multiple sets of access criteria aim to restrict anti-TNF therapy to patients with specific clinical characteristics, yet the influence of access criteria on anti-TNF cost-effectiveness is unknown. Our objective was to use data from the DESIR cohort, a prospective study of early SpA patients in France, to determine whether the French anti-TNF access criteria are the most cost-effective in that setting relative to other potential restrictions.MethodsWe used data from the DESIR cohort to create five study populations of patients meeting anti-TNF access criteria from Canada, France, Germany, United Kingdom, and Hong Kong, respectively. For each study population, we calculated the costs and quality-adjusted life years (QALYs) over 1 year of patients treated and not treated with anti-TNF therapy. To control for differences between anti-TNF users and non-users, we used linear regression models to derive adjusted mean costs and QALYs. We calculated incremental cost-effectiveness ratios (ICERs) representing the incremental cost per additional QALY gained by treating with an anti-TNF within each of the five study populations, using bootstrapping to explore the range of uncertainty in costs and QALYs. A series of sensitivity analyses was conducted, including one to simulate the effect of a 24-week stopping rule for anti-TNF non-responders.ResultsAnti-TNF access criteria from France were satisfied by the largest proportion of DESIR patients (27.8%), followed by Germany (25.1%), Canada (23.8%), the UK (12.1%) and Hong Kong (8.6%). Confidence intervals around incremental costs and QALYs in the basecase analysis were overlapping, indicating that anti-TNF cost-effectiveness estimates derived from each subset were similar. In the sensitivity analysis that examined the effect of excluding costs accumulated past 24 weeks by anti-TNF non-responders, the incremental cost per QALY was reduced by approximately 25% relative to the basecase analysis (France: €857,992 vs. €1,105,859; Canada: € 626,459 vs. €818,186; Germany: € 422,568 vs. €545,808); UK €578,899 vs. €766,217; Hong Kong €335,418 vs. €456,850).ConclusionsAnti-TNF cost-effectiveness is strongly affected by treatment continuation among non-responders. Access criteria could improve anti-TNF cost-effectiveness by defining patients likely to respond.

Dataset Information

Anti-TNF Therapy in Spondyloarthritis and Related Diseases, Impact on the Immune System and Prediction of Treatment Responses.

Publications

Anti-TNF Therapy in Spondyloarthritis and Related Diseases, Impact on the Immune System and Prediction of Treatment Responses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets