Targeting tumor necrosis factor receptors in ankylosing spondylitis

Abstract

Over the past two decades, considerable advances in our understanding of inflammatory and immune pathways have allowed for the growing use of targeted biologic therapy. Most notably, the introduction of tumor necrosis factor (TNF) inhibitors has dramatically changed the management of autoimmune inflammatory disorders, including ankylosing spondylitis (AS). Despite the efficacy of TNF inhibitors documented in multiple clinical trials, anti-TNF therapy in AS is far from foolproof; it is associated with serious adverse effects and limited response to therapy in some patients. Moreover, specific questions regarding the role of TNF as a mediator of AS remain unanswered. Therefore, additional efforts are needed in order to better understand the role of TNF in the pathogenesis of AS and to develop safer and more effective treatment strategies. The purpose of this review is to better the understanding of the physiologic and pathogenic roles of TNF signaling in the course of AS. Relevant TNF biology and novel approaches to TNF blockade in AS are discussed.

Gene-regulatory network analysis of ankylosing spondylitis with a single-cell chromatin accessible assay

“…Concerning the TNF signaling pathway, TNF was able to recruit receptor-interacting serine/threonine-protein kinase 1 (RIPK1), adaptor protein TNFR1-associated death domain (TRADD), and TNRF-associated factor 2 (TRAF2) to form complex I after binding TNFR1, which could trigger related phosphorylation and ubiquitination processes. Finally, mitogen-activated kinase (MAPK) and nuclear factor kB (NF-kB) were activated to produce proinflammatory effects in AS patients 17 . As a result, 87 target genes were involved in this pathway, and they were regulated by the same 8 TFs with low accessibility that were found in the IL-17 signaling pathway.…”

Progranulin: A conductor of receptors orchestra, a chaperone of lysosomal enzymes and a therapeutic target for multiple diseases

“…Currently, various PGRN-targeted approaches are emerging as attractive therapeutic interventions in a broad spectrum of diseases including cancer [11], inflammatory diseases [19][20][21][22][23][24], neurological disorders [25], injury [26], tissue regeneration [27][28][29], and some rare diseases such as lysosomal diseases [30]. Multiple PGRN targeting strategies such as small molecule compounds that boost PGRN expression, viral vectors or mesenchymal stem cells (MSCs) delivering Grn genes, engineered full length proteins or domains, monoclonal neutralizing antibodies, and 3D-printed scaffold-incorporated recombinant proteins have been developed, and over 30 preclinical and clinical trials in this field have been undertaken (Table 1).…”

The Efficacy of Moxibustion and Acupuncture Therapy for Ankylosing Spondylitis: A Protocol for an Overview of Systematic Reviews and Meta-analyses

“…The incidence of AS in the United States has been reported from 0.2 to 0.55 in related epidemiological studies [3,8,9] .AS tends to occur in the second and third decade of life [2] ,as a result, the quality of life of patients is reduced, and the employment prospects of patients will also have a very negative impact [4] .In a series of economic evaluation studies on AS conducted in the United States, AS represents a substantial burden both on society and individuals with AS.In the total cost of AS, the indirect costs caused by AS ac,count for the majority [4,11−14] .In addition to the nancial burden, AS also brings other extra-articular disease burden, such as Acute anterior uveitis (AAU), Cardiac conduction system abnormalities, aortic regurgitation, neurological sequelae, and amyloidosis [2,15−17] .The etiology and pathogenesis of AS remain unclear, but the most convincing hypothesis is immune mediation mechanism, including several cytokines like tumor necrosis factor (TNF), genetic factors, interaction between T cell response and environmental factors. [18,19] Besides, some relevant genetic studies have con rmed that the incidence of AS has a strong correlation with HLA-B27 that is found in about 90% of patients with AS. [20][21][22][23] The basic principles of treat for patients with AS should be based on the presentation of the disease, severity of symptoms, and some other factors.…”