Beyond Synovitis: Molecular and Neuroimmune Mechanisms Informing Target-Joint Attribution and Pain Phenotyping for...

Arthroplasty can provide substantial pain and functional improvement in inflammatory arthritis, but structural indications alone do not determine how much of a patient's overall symptom burden will respond to surgery. Persistent or widespread pain may reflect active inflammation, irreversible joint damage, neuropathic or extra-articular generators, and distributed pain amplification, which we use as a descriptive term for pain extending beyond the target joint and influenced by broader sensory, symptomatic, and contextual processes. This critical structured narrative review integrates direct inflammatory-arthritis arthroplasty evidence, disease-specific pain-phenotyping studies, indirect osteoarthritis perioperative data, and molecular and mechanistic literature. We link cytokine/prostaglandin signalling, neurotrophin- and ion-channel-mediated nociceptor sensitisation, immunosensory signalling, and spinal neuron-glia plasticity to peripheral and central nociceptive amplification. We then propose the Target-Joint Attribution and Pain-Amplification Framework, comprising four provisional clinical phenotypes (A-D): structural-concordant, inflammation-dominant, mixed target-joint/distributed pain-amplification, and distributed pain-dominant. Questionnaire or sensory-test thresholds do not establish mechanisms or surgical eligibility. The framework translates these molecular and neuroimmune mechanisms into testable hypotheses for perioperative phenotyping, biomarker validation, and interpretation of postoperative pain trajectories. Direct phenotype-specific evidence in inflammatory-arthritis arthroplasty remains sparse; prospective validation integrating joint-specific outcomes with molecular and sensory measures is required.