免疫检查点抑制剂相关关节痛与炎症性关节炎的全身体MRI表型研究：揭示亚临床炎症负担与临床管理新策略

本研究针对免疫检查点抑制剂（ICI）引发的肌肉骨骼不良事件（如关节痛和炎症性关节炎），通过前瞻性全身体MRI成像，首次系统揭示了亚临床炎症和骨侵蚀在两类患者中的同等高发性，并鉴定出三种炎症模式（外周炎症性关节炎、风湿性多肌痛及重叠表型）。结果提示当前ICI相关肌肉骨骼毒性被严重低估，为临床分层治疗（如DMARDs选择）提供了影像学依据，对优化肿瘤免疫治疗并发症管理具有重要意义。

　　

免疫检查点抑制剂（Immune checkpoint inhibitors, ICI） revolutionized cancer treatment by unleashing T-cell antitumor activity, but this breakthrough comes with a price – immune-related adverse events (irAEs). Among these, musculoskeletal complications like inflammatory arthritis and arthralgia are increasingly recognized, affecting up to 43% of patients. However, a critical knowledge gap persists: why do some patients develop overt joint swelling while others experience only pain? More intriguingly, could "benign" arthralgia harbor hidden inflammation? Current clinical assessments relying on physical exams may miss subclinical damage, potentially delaying interventions.

To unravel this enigma, researchers from the Leeds Rheumatology department conducted a pioneering prospective imaging study. They employed gadolinium-enhanced whole-body MRI to map inflammatory patterns in 60 patients with ICI-induced arthralgia or inflammatory arthritis, alongside 20 healthy controls. Their findings, published in The Lancet Rheumatology, challenge conventional classifications and offer a paradigm shift in managing these complications.

The study leveraged three key methodologies: (1) Standardized whole-body MRI protocols covering joints, tendons, entheses, and spine, scored by masked assessors; (2) Semi-quantitative grading systems (e.g., RAMRIS for erosions) adapted for global inflammation assessment; (3) Prospective 6-month clinical follow-up tracking treatment responses. Patient cohorts included those receiving anti-PD-1/PD-L1 (70%) or combination ICI therapy (30%), with melanoma (50%) being the predominant malignancy.

Results

Baseline Characteristics
The cohort (mean age 65 years) comprised 35 arthralgia and 25 inflammatory arthritis patients. Notably, 58% of arthralgia patients showed polymyalgia rheumatica (PMR)-like features. Autoantibodies (RF, anti-CCP) were rare (7%), underscoring the seronegative nature of ICI-induced arthropathy.

Imaging Phenotypes
Strikingly, arthralgia patients exhibited comparable MRI inflammation burdens to inflammatory arthritis groups:

• Median synovitis scores: 9.0 vs 10.0 (controls: 2.0)
• Erosion scores: 2.0 vs 2.0 (controls: 0.0)
  Acromioclavicular (77%) and glenohumeral (75%) joints were most frequently affected. Three distinct patterns emerged:

1. Peripheral inflammatory arthritis (37%): Predominant in DMARD-requiring patients (4/5 cases)
2. PMR pattern (12%): Characterized by bilateral trochanteric bursitis/enthesitis
3. Overlap phenotype (20%): Combined erosive synovitis and PMR features

Novel Discoveries

• Myofascial inflammation was identified in 4 patients, suggesting a new toxicity subtype
• Weak correlation (φ<0.3) between MRI findings and clinical exams highlighted imaging's diagnostic value

Discussion
This study shatters the myth that arthralgia represents "mild" ICI toxicity – MRI reveals equivalent structural damage to inflammatory arthritis. The high prevalence of erosions within months of symptom onset suggests aggressive pathophysiology distinct from classical autoimmune diseases. The overlap phenotype (PMR + synovitis + tenosynovitis) may represent a unique ICI-driven entity, warranting tailored management.

Clinically, the data advocate for:

1. Routine rheumatology referral even for arthralgia patients
2. Early imaging to guide immunosuppression intensity (e.g., DMARDs for peripheral arthritis pattern)
3. Recognition of myofascial inflammation as a potential new irAE

Methodologically, whole-body MRI emerges as an indispensable tool, detecting subclinical lesions that predict disease severity – 80% of DMARD recipients had peripheral arthritis pattern on initial MRI.

Conclusion
By illuminating the hidden landscape of ICI-induced musculoskeletal toxicity, this work redefines therapeutic paradigms. The discovery that arthralgia and inflammatory arthritis share similar pathological burdens mandates a radical shift from symptom-driven to imaging-informed management. Future studies should explore whether subclinical inflammation correlates with enhanced antitumor responses, potentially unlocking dual diagnostic and prognostic value for whole-body MRI in immuno-oncology.