{"id":24037,"date":"2023-07-21T04:25:00","date_gmt":"2023-07-20T20:25:00","guid":{"rendered":"http:\/\/csccm.org.cn\/?p=24037"},"modified":"2023-07-21T05:45:35","modified_gmt":"2023-07-20T21:45:35","slug":"nejm%e5%8f%91%e8%a1%a8%e8%ae%ba%e6%96%87%ef%bc%9a%e5%bc%ba%e5%8c%96%e5%85%8d%e7%96%ab%e6%a3%80%e6%9f%a5%e7%82%b9%e5%9c%a8%e7%b1%bb%e9%a3%8e%e6%b9%bf%e5%85%b3%e8%8a%82%e7%82%8e%e4%b8%ad%e7%9a%84","status":"publish","type":"post","link":"https:\/\/csccm.org.cn\/?p=24037","title":{"rendered":"[NEJM\u53d1\u8868\u8bba\u6587]\uff1a\u5f3a\u5316\u514d\u75ab\u68c0\u67e5\u70b9\u5728\u7c7b\u98ce\u6e7f\u5173\u8282\u708e\u4e2d\u7684\u4f5c\u7528"},"content":{"rendered":"\n

EDITORIAL<\/a><\/p>\n\n\n\n

Reinforcing the Checkpoint in Rheumatoid Arthritis<\/h1>\n\n\n\n

Ellen M. Gravallese, Ranjeny Thomas<\/h3>\n\n\n\n

N Engl J Med 2023; 388:1905-1907
DOI: 10.1056\/NEJMe2300734<\/h3>\n\n\n\n

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor in lymphocyte activation, acting as an immune checkpoint to prevent the continued activation of T cells after an immune response and to maintain peripheral immune tolerance. PD-1 is a marker of antigen-experienced T cells. With sustained T-cell stimulation \u2014 as occurs in tumor microenvironments \u2014 PD-1 is expressed by anergic and regulatory CD4+ T cells and by exhausted CD8+ T cells. The expression of PD-1 by helper T cells is necessary for their functional interaction with B cells.1<\/a><\/sup> In this issue of the Journal<\/em>,<\/sup>2<\/a><\/sup> Tuttle and colleagues report findings of a phase 2 trial of peresolimab for the treatment of patients with rheumatoid arthritis. Peresolimab is a humanized monoclonal antibody designed to stimulate PD-1, with the goal of suppressing T-cell activation. This novel approach provides an exciting therapeutic mechanism for the treatment of rheumatoid arthritis and potentially other autoimmune diseases in which antigen-activated lymphocytes play a pathogenic role.<\/p>\n\n\n\n

Successful manipulation of the PD-1\u2013PD-1 ligand (PD-L1) pathway has already revolutionized cancer therapy.3<\/a><\/sup>\u00a0Inhibition of this receptor\u2013ligand interaction (checkpoint inhibition) with the use of antibodies that block PD-1 or prevent the ligation of PD-1 with PD-L1 expressed on the surface of activated antigen-presenting cells and cancer cells augments the inflammatory and cytotoxic capacities of antigen-experienced T cells. The checkpoint inhibitor armamentarium also includes other targets, such as cytotoxic T-lymphocyte\u2013associated protein 4 (CTLA-4), to prevent coinhibition through CD80 and CD86 expressed on antigen-presenting cells. Although checkpoint inhibitors enhance tumor-specific T-cell attack, they may also enhance self-reactive T cells. This approach has come at the cost of inducing many immune-related adverse events, including diseases resembling autoimmune myositis, thyroiditis, colitis, and, of importance, rheumatoid arthritis.4<\/a><\/sup>\u00a0Thus, it was reasonable to envision that activation of PD-1 might be beneficial in patients with rheumatoid arthritis.<\/p>\n\n\n\n

Whereas PD-1 is expressed by many T cells infiltrating rheumatoid arthritis synovial tissues and is up-regulated in synovial tissues from patients with early or established rheumatoid arthritis as compared with tissues from patients with osteoarthritis, expression of PD-L1 in synovial tissues is low. This is seen even though dendritic cells are activated in synovial tissues in rheumatoid arthritis. In contrast, increased levels of soluble PD-1 are hypothesized to bind PD-L1 in patients with rheumatoid arthritis, exposing greater levels of surface CD80 on dendritic cells for immune activation.5,6<\/a><\/sup> Together, these changes in costimulation relative to coinhibition would result in down-regulation of PD-1 inhibitory signaling, which could be restored through stimulation of the PD-1 receptor by peresolimab.<\/p>\n\n\n\n

The phase 2, placebo-controlled trial performed by Tuttle and colleagues included 98 adults with moderate-to-severe rheumatoid arthritis and showed efficacy of the 700-mg dose of peresolimab. This small trial did not determine the optimal dosing of peresolimab, because analysis of the 300-mg dose was exploratory, and the trial focused on one 700-mg dose. A dose-ranging study and a larger, longer phase 3 trial will be important to further assess this promising new approach to the treatment of rheumatoid arthritis. This trial did not identify significant safety signals, but caution is needed, given the short follow-up period and small sample size. Because this therapeutic approach is not antigen-specific, one of the biggest concerns about the treatment relates to the development of cancer, an adverse event that probably would not have been identified during the short time frame of the trial.<\/p>\n\n\n\n

However, this trial has many strengths. Peresolimab had a clinically relevant benefit on the primary outcome \u2014 the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). Of interest, serum levels of CRP did not decrease during the trial despite this clinical response. Although the reasons for the lack of change in CRP levels are not completely clear, CRP is regulated by STAT3, which is activated by both the antiinflammatory molecule interleukin-10 and the proinflammatory molecule interleukin-6; therefore, CRP levels may depend on whether interleukin-10 or interleukin-6 is present.7,8<\/a><\/sup> Nevertheless, the CRP findings in this trial provide validation that the beneficial change in the DAS28-CRP was due to clinical improvement and not simply to a drop in CRP levels. Another strength of the trial is the inclusion of patients who had had an inadequate response to previous treatment with biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs), because these patients typically have lower response rates in rheumatoid arthritis clinical trials.<\/p>\n\n\n\n

Many of the current therapies for rheumatoid arthritis act by blocking proinflammatory pathways, and disease often recurs when these therapies are discontinued. Peresolimab has the potential instead to reset the immune response or restore immune tolerance.9<\/a><\/sup> Although this trial is a promising step forward, many questions remain. Will mechanistic studies validate the prediction that PD-1 agonism enhances T-cell anergy and regulation in rheumatoid arthritis? How long will the effects of peresolimab persist after treatment is withdrawn, and will these effects create a better immune environment for response to other DMARDs? Will administration of peresolimab during the early stage of disease result in a more prolonged immunosuppressive effect than administration in patients with established disease? Although the answers to these questions are unknown, this trial opens a refreshing new chapter in the treatment of rheumatoid arthritis and introduces an approach that might also be applied to the treatment of other autoimmune diseases that are driven by antigen-activated lymphocytes.<\/p>\n","protected":false},"excerpt":{"rendered":"

EDITORIAL Reinforcing the Checkpoint in Rheumatoid Arth […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24037"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=24037"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24037\/revisions"}],"predecessor-version":[{"id":24038,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24037\/revisions\/24038"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=24037"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=24037"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=24037"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}