Lisco Giuseppe, De Tullio Anna, Zupo Roberta, Prete Marcella, Piazzolla Giuseppina, Racanelli Vito, Triggiani Vincenzo
Interdisciplinary Department of Medicine, School of Medicine, University of Bari "Aldo Moro", Piazza Giulio Cesare 11, 70124, Bari, Italy.
Rheumatic and Systemic Autoimmune Diseases Unit, Department of Interdisciplinary Medicine, University of Bari Medical School, Bari, Italy.
Immunol Res. 2025 Jul 11;73(1):106. doi: 10.1007/s12026-025-09655-0.
Entheses are specialized tissues that connect ligaments and tendons to the bone surface and are frequently involved in seronegative spondyloarthritis. Enthesitis can also be detected in patients with metabolic disorders (MD), regardless of baseline autoimmune rheumatic disease, posing real diagnostic challenges. The present review discusses the pathophysiology of enthesitis and metabolic-associated enthesitis, the clinical relevance of metabolic disorders on enthesitis-related outcomes, diagnostic challenges for adequate differential diagnosis, and possible therapeutic strategies to improve clinical outcomes. PubMed/MEDLINE and the Cochrane Library were searched for original articles, systematic reviews, and meta-analyses. References were screened according to a hierarchical analysis of studies by title, abstract, and full text, collected, presented, and discussed. Metabolic-associated enthesitis is attributable to mechanical stress/overload due to weight excess typically observed in metabolic disorders (MD), such as overweight/obese comorbid patients, metabolic syndrome (MS), and type 2 diabetes (T2D). Interleukin 1β, 6, 17, 18, and 23 and tumor necrosis factor-α play a crucial role in initiating and maintaining entheseal inflammation. Chronic hyperglycemia and insulin resistance lead to a vicious circle as they stimulate, upon activated, specialized T cells to produce these specific cytokines, thus maintaining entheseal inflammation chronically. MD is associated with more severe clinical presentation, worse response to pharmacological treatments, and poor entheseal outcomes also in patients with existing seronegative spondyloarthritis. Non-immune-mediated metabolic-associated enthesitis poses a real diagnostic challenge, possibly underestimating cases and potential misdiagnoses. From a therapeutic viewpoint, glucose control improvement and weight loss are associated with relevant amelioration of entheseal-related outcomes. Pharmacological and non-pharmacological interventions aiming to reduce body weight, improve glucose control and insulin sensitivity, and attenuate inflammation are desirable to achieve the therapeutic target. Glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter type 2 inhibitors, in add-on to non-steroidal anti-inflammatory drugs and immunomodulators when necessary, may have a therapeutic rationale in patients with metabolic-associated enthesitis. Awareness of metabolic-associated enthesitis is essential to improve the accuracy of differential diagnosis in patients with MD and prescribe appropriate therapeutic strategies. However, basic and clinical research is needed to understand the role of "antihyperglycemic" agents in better managing metabolic-associated enthesitis.
附着点是将韧带和肌腱连接到骨表面的特殊组织，并且经常与血清阴性脊柱关节炎相关。无论基线自身免疫性风湿疾病如何，在患有代谢紊乱（MD）的患者中也可检测到附着点炎，这带来了真正的诊断挑战。本综述讨论了附着点炎和代谢相关附着点炎的病理生理学、代谢紊乱对附着点炎相关结局的临床意义、进行充分鉴别诊断的挑战以及改善临床结局的可能治疗策略。检索了PubMed/MEDLINE和Cochrane图书馆以查找原始文章、系统评价和荟萃分析。根据对研究的标题、摘要和全文的分层分析筛选参考文献，收集、呈现并讨论。代谢相关附着点炎归因于代谢紊乱（如超重/肥胖合并症患者、代谢综合征（MS）和2型糖尿病（T2D））中通常观察到的体重过重导致的机械应力/过载。白细胞介素1β、6、17、18和23以及肿瘤坏死因子-α在引发和维持附着点炎症中起关键作用。慢性高血糖和胰岛素抵抗导致恶性循环，因为它们在激活后刺激特殊的T细胞产生这些特定细胞因子，从而长期维持附着点炎症。代谢紊乱还与更严重的临床表现、对药物治疗的反应较差以及现有血清阴性脊柱关节炎患者的附着点不良结局相关。非免疫介导的代谢相关附着点炎带来了真正的诊断挑战，可能会低估病例并导致潜在的误诊。从治疗角度来看，改善血糖控制和减轻体重与附着点相关结局的显著改善相关。旨在减轻体重、改善血糖控制和胰岛素敏感性以及减轻炎症的药物和非药物干预措施对于实现治疗目标是可取的。胰高血糖素样肽1受体激动剂和钠-葡萄糖协同转运蛋白2抑制剂，在必要时与非甾体抗炎药和免疫调节剂联合使用，可能对代谢相关附着点炎患者具有治疗依据。认识代谢相关附着点炎对于提高代谢紊乱患者鉴别诊断的准确性和制定适当的治疗策略至关重要。然而，需要基础和临床研究来了解“降糖”药物在更好管理代谢相关附着点炎中的作用。
