The clinical heterogeneity and insidious onset of spondyloarthritis (SpA) frequently result in diagnostic delays of 6 to 8 years, ultimately leading to irreversible structural damage. Conventional anatomical imaging and fluid-sensitive MRI (which primarily detects bone marrow edema) lack sufficient diagnostic specificity and fail to elucidate the unique uncoupling of inflammation and pathological ossification at the micro-metabolic level. This review aims to explore the core clinical utility of multidimensional molecular imaging  in deciphering the early molecular mechanisms of SpA, assessing systemic disease burden, monitoring targeted therapy metabolism, and facilitating complex phenotypic differential diagnosis, thereby overcoming the limitations of traditional imaging and advancing precision medicine in SpA.

We systematically reviewed recent frontier literature and clinical trial data regarding multidimensional molecular imaging in SpA. We evaluated the imaging characteristics of various targeted radiotracers (including 18F-FDG, 68Ga-FAPI, and 18F-NaF) across distinct pathophysiological stages. Furthermore, we analyzed the diagnostic performance of dual-modality PET/MRI in evaluating the axial skeleton and cardiovascular involvement. We also synthesized the evidence and limitations of molecular imaging in monitoring therapeutic responses to tumor necrosis factor inhibitors (TNFi) and interleukin-17 (IL-17) inhibitors, as well as its application in the differential diagnosis of complex rheumatic conditions, such as tumor-induced osteomalacia (TIO) and polymyalgia rheumatica (PMR).

Molecular Probes for Pathological "Uncoupling": Molecular probes precisely map the pathogenic evolution of SpA. 18F-FDG sensitively captures macrophage-driven occult synovitis and enthesitis. 68Ga-FAPI visualizes stromal remodeling and fibroblast activation, bridging early inflammation and terminal osteogenesis. 18F-NaF confirms that the peak of aberrant osteogenic metabolism does not co-localize with isolated acute bone marrow edema, but predominantly occurs within transitional microenvironments of post-inflammatory fatty metaplasia. Systemic Evaluation and Therapeutic Monitoring: Hybrid PET/MRI accurately identifies specific vertebral corners at high risk for syndesmophyte formation. 18F-FDG quantitatively assesses clinically silent autoimmune aortitis and the accelerated atherosclerotic burden in SpA. Longitudinal metabolic monitoring demonstrates that early intervention with TNFi and IL-17 inhibitors directly and significantly downregulates focal aberrant osteogenic metabolism (e.g., evidenced by a decreased SUVauc). Differential Diagnosis: Molecular imaging acts as a critical gatekeeper to exclude TIO, occult infections, and malignancies. In complex elderly-onset rheumatic diseases, 18F-FDG exposes highly specific metabolic topological fingerprints: PMR is characterized by pronounced prepubic and bursal hypermetabolism; elderly-onset rheumatoid arthritis (EORA) exhibits symmetrical peripheral synovial uptake; and late-onset SpA displays a definitive sacroiliac tropism. Technical Limitations: Although molecular imaging offers health economic value by identifying early therapeutic futility, 18F-NaF PET still faces challenges, including phenotypic heterogeneity, occasional discordance with structural damage on CT, and the absence of a globally unified quantitative threshold for the maximum standardized uptake value (SUVmax).

Multidimensional molecular imaging transcends macroscopic anatomy to capture in vivo cellular metabolism, providing pivotal evidence for the inflammation-ossification uncoupling mechanism in SpA. It demonstrates profound utility in evaluating systemic disease burden, differentiating complex phenotypes, and predicting the early efficacy of biologic therapies. To fully integrate into the routine clinical algorithm for SpA, future efforts must focus on establishing international standardization consensuses, implementing artificial intelligence (AI)-driven automated image segmentation via low-dose CT (LDCT), and developing highly specific next-generation radioprobes (e.g., P2X7 receptor targets), ultimately cementing its role as a core tool in value-based precision medicine.