Anti-IL-17 Agents in the Treatment of Axial Spondyloarthritis.
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ABSTRACT:
SUBMITTER: Atzeni F
PROVIDER: S-EPMC8104974 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The term spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory musculoskeletal diseases with several common genetic background and clinical features, including the possible involvement of the axial skeleton with peripheral mono- or oligo- arthritis and frequently coexisting skin, eye and intestinal manifestations. When the sacroiliac joints or other parts of the spine or thoracic wall are predominantly affected at magnetic resonance or X-ray imaging with inflammatory back pain, the disease is classified as axial SpA and the therapeutic choices are significantly different compared to cases of peripheral arthritis. Moving from the narrow effectiveness and safety profiles of non-steroidal anti-inflammatory drugs, there has been a significant research effort aimed at identifying new treatments based on our better understanding of the pathogenesis of SpA. Indeed, in parallel with the solid data demonstrating that IL-17 and IL-23 are key cytokines in the development of enthesitis and spondylitis, monoclonal antibodies interfering with this pathway have been developed for the treatment of axial SpA. Furthermore, the IL-17/IL-23 axis is key to extra-articular manifestations such as inflammatory bowel disease, uveitis, and psoriasis which are frequent comorbidities of SpA. Currently available drugs act through these mechanisms recognizing IL-23 and targeting IL-17, such as secukinumab and ixekizumab. These therapeutic approaches are now envisioned in the international treatment recommendations for psoriatic arthritis with an axial phenotype as well as for ankylosing spondylitis (AS). We will provide herein a concise comprehensive overview of the clinical evidence supporting the use of these and other drugs acting on IL-23 and IL-17 in axial SpA.
| S-EPMC8206811 | biostudies-literature
Project description:Axial spondyloarthritis (axSpA) is a chronic inflammatory condition that predominantly affects the axial skeleton. All patients receive conservative management measures which include physiotherapy, patient education and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Those with significant active disease will require escalation of their treatment with the use of biologics. Currently, there are five approved TNF inhibitors and two approved IL-17 inhibitors for use in axSpA. However, despite this up to 40% of patients do not respond or are intolerant to current available treatment. This leaves a significant number of patients with uncontrolled disease and unmet need for additional therapies. Though many drug classes have been trialed for axSpA they show poor efficacy; however, over the last few years there are three which demonstrate much greater promise as novel therapies for axSpA, these include dual neutralization of IL-17A and IL-17F, Janus kinase (JAK) inhibitors, and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors. This article reviews the evidence for these novel emerging therapeutic options for axSpA.
| S-EPMC8269276 | biostudies-literature
Project description:This article highlights and emphasizes how new knowledge of mechanisms linked to the interleukin-23 (IL-23)/IL-17 pathway is relevant to the pathophysiology of axial spondyloarthritis (axSpA) and demonstrates how molecules in IL-23/IL-17 pathway provide novel therapeutic targets for axSpA patients.Similarly to ankylosing spondylitis (AS), the increased frequency of Th17 cells in nr-axSpA patients underscores the concept that these disorders can be viewed on a spectrum. Recent findings suggest that the contribution of IL-23/IL-17 signaling pathways possibly differs in male and female AS patients. The finding that IL-17 and IL-22 secreting-type 3 innate lymphoid cells are increased in AS patients point to their potential role in the pathogenesis of axSpA. Reports of dysbiosis in the gut microbiome of AS patients support previous work indicating a possible causal relationship between altered gut flora, ileocolonic inflammation and axSpA. Of important clinical relevance are results from clinical trials supporting the efficacy and safety of agents that block IL-12/23 (ustekinumab) and IL-17 (secukinumab and ixekizumab) in AS patients.Recent studies further establish the central position of the IL-23/IL-17 pathway in the pathogenesis of axSpA. Targeting the IL-23/IL-17 pathway appears to be a safe and effective strategy for treatment of axSpA patients.
| S-EPMC5777167 | biostudies-literature
Project description:The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.
| S-EPMC8446672 | biostudies-literature
Project description:Knowledge regarding the mechanisms of the IL17-IL23 pathway and its role in spondyloarthritis (SpA) has been pivotal to the development of IL-17 blockade in patients with axial SpA. Previously, only anti-TNF has proven to be clinically efficacious in patients with active disease, despite non-steroidal anti-inflammatory drugs and physiotherapy. However, up to 50% fail to achieve a clinically significant response. Secukinumab, a fully humanized monoclonal antibody targeting IL-17A, has recently been approved for use in patients with active ankylosing spondylitis. Clinical studies and current issues surrounding the use of secukinumab will be discussed.
| S-EPMC5241317 | biostudies-literature
Project description:Two main treatment targets in axial spondyloarthritis (axSpA) could be currently defined: (1) reduction of inflammation resulting in control of signs and symptoms such as pain and stiffness and (2) prevention or retardation of structural damage progression in the spine resulting in preservation of functional status and improvement in the long-term outcome. A good control of signs and symptoms could be successfully achieved nowadays in the majority of patients treated with non-steroidal anti-inflammatory drugs (NSAIDs-the first-line therapy in axSpA) and with tumour necrosis factor (TNF) ? blockers (the second-line therapy, if NSAIDs fail). Several pipeline drugs including interleukin (IL) 17 and IL-23 antagonists might be helpful in the immediate future in achievement of this treatment target in case of inefficacy of NSAIDs and TNF? blockers. Retardation of radiographical spinal progression in axSpA-disease modification-is currently a much more challenging task than a good symptom control. In this review, we discuss symptomatic and possible disease-modifying properties of current and forthcoming treatment options for axSpA.
| S-EPMC4632151 | biostudies-literature
Project description:Axial spondyloarthritis (axSpA) is a chronic disease characterized by inflammation and new bone formation that causes pain and results in functional impairment and long-term disability. Biologic agents targeting TNFα or IL-17 have been the mainstay of treatment for patients with axSpA and an inadequate response to nonsteroidal anti-inflammatory drugs. However, a proportion of axSpA patients do not respond adequately to those drugs either, creating the need to target alternative disease pathways. Janus kinase (JAK) inhibitors (JAKis) are a group of targeted synthetic disease-modifying anti-rheumatic drugs that block the intracellular signalling pathway of several proinflammatory cytokines. Given their efficacy in the management of rheumatoid arthritis and that JAKs mediate the signalling of cytokines involved in the pathogenesis of axSpA as well, JAKis have been successfully tested in a number of clinical trials in axSpA, which has led to the approval of two compounds, tofacitinib and upadacitinib for the treatment of the disease. Data from new clinical trials, long-term extensions of completed trials, and real-life observational studies that continuously emerge will shape the efficacy and safety profile and ultimately the place of JAKis in the treatment of AxSpA.
| S-EPMC10466367 | biostudies-literature
Project description:We aimed to develop evidence-based recommendations for treating axial spondylarthritis (axSpA) in Korea. The development committee was constructed, key clinical questions were determined, and the evidence was searched through online databases including MEDLINE, Embase, Cochrane, KoreaMed, and Kmbase. Systematic literature reviews were conducted, quality of evidence was determined, and draft recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluations methodology. Recommendations that reached 80% consensus among a voting panel were finalized. Three principles and 21 recommendations were determined. Recommendations 1 and 2 pertain to treatment strategies, regular disease status assessment, and rheumatologist-steered multidisciplinary management. Recommendations 3 and 4 strongly recommend patient education, exercise, and smoking cessation. Recommendations 5-12 address pharmacological treatment of active disease using nonsteroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, biologics, and Janus kinase inhibitors. Recommendations 13-16 address treatment in stable disease. We suggest against spa and acupuncture as therapies (Recommendation 17). Recommendations 18 and 19 pertain to total hip arthroplasty and spinal surgery. Monitoring of comorbidities and drug toxicities are recommended (Recommendations 20 and 21). Recommendations for axSpA treatment in a Korean context were developed based on comprehensive clinical questions and evidence. These are intended to guide best practice in the treatment of axSpA.
| S-EPMC10493447 | biostudies-literature
Project description:We aimed to develop evidence-based recommendations for treating axial spondylarthritis (axSpA) in Korea. The development committee was constructed, key clinical questions were determined, and the evidence was searched through online databases including MEDLINE, Embase, Cochrane, KoreaMed, and KMbase. Systematic literature reviews were conducted, quality of evidence was determined, and draft recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluations methodology. Recommendations that reached 80% consensus among a voting panel were finalized. Three principles and 21 recommendations were determined. Recommendations 1 and 2 pertain to treatment strategies, regular disease status assessment, and rheumatologist-steered multidisciplinary management. Recommendations 3 and 4 strongly recommend patient education, exercise, and smoking cessation. Recommendations 5~12 address pharmacological treatment of active disease using nonsteroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, biologics, and Janus kinase inhibitors. Recommendations 13~16 address treatment in stable disease. We suggest against spa and acupuncture as therapies (Recommendation 17). Recommendations 18 and 19 pertain to total hip arthroplasty and spinal surgery. Monitoring of comorbidities and drug toxicities are recommended (Recommendations 20 and 21). Recommendations for axSpA treatment in a Korean context were developed based on comprehensive clinical questions and evidence. These are intended to guide best practice in the treatment of axSpA.
| S-EPMC10351367 | biostudies-literature
Project description:Purpose of reviewTo provide a summary of the recent and expected developments related to the treatment of axial spondyloarthritis.Recent findingsAn increasing number of interleukin-17 blocking agents show efficacy in axial spondyloarthritis including both non-radiographic and radiographic forms. Janus kinase inhibitors showed promising results in phase II studies in radiographic axial spondyloarthritis and have, therefore, a potential to become a therapeutic option in this indication in the future. Inhibition of structural damage progression in axial spondyloarthritis seems to be possible in the case of effective and early anti-inflammatory treatment, although there are still open questions related to particular drug classes. Despite major advances in the field and growing therapeutic options, there are still many open questions related to the optimized treatment strategies and to the individual choice of a drug in axial spondyloarthritis.
| S-EPMC7371669 | biostudies-literature