Serum creatine kinase (CK) is often treated as a proxy for inflammatory myositis activity, but CK mainly reflects myofiber membrane leakage and can normalize even when clinically meaningful weakness persists. I hypothesize that patients with idiopathic inflammatory myopathies who show disproportionate weakness relative to CK elevation represent a distinct macrophage-fibrosis endotype characterized by persistent tissue injury signaling, impaired early strength recovery, and reduced responsiveness to glucocorticoid induction alone.

Mechanistic rationale: CK can fall quickly after partial suppression of necrotic leak, while macrophage-rich tissue remodeling, perifascicular stress, and fibro-adipose replacement continue to limit contractile recovery. A composite of CK trajectory, quantitative thigh MRI, and circulating innate-immune injury markers may therefore outperform CK alone for identifying patients whose biology is shifting from reversible inflammation toward treatment-resistant damage.

Testable predictions:

1. Among newly treated or relapsing myositis patients, a high weakness-to-CK ratio at baseline, combined with elevated CXCL10 or soluble CD163, will predict poorer 12-week improvement in MMT-8 or FI-2 despite comparable glucocorticoid exposure.
2. Adding quantitative MRI features such as muscle edema burden and fat-fraction change to CK slope will improve prediction of steroid resistance compared with CK, aldolase, or physician global assessment alone.
3. The proposed endotype will correlate with higher macrophage and fibrosis signatures on biopsy or spatial transcriptomic readouts, even when CK has already declined.
4. Patients classified into this endotype will require earlier steroid-sparing escalation or IVIG to achieve functional recovery, whereas CK-concordant inflammatory cases will respond better to glucocorticoid-first strategies.

How to test it: A prospective multicenter cohort could enroll adults with active dermatomyositis, immune-mediated necrotizing myopathy, and overlap myositis at treatment start. Baseline and short-interval measurements would include CK, aldolase, MMT-8, patient-reported function, MRI fat fraction/T2 mapping, and a focused serum panel including CXCL10 and soluble CD163. The primary endpoint would be inadequate functional improvement at 12 weeks or need for treatment escalation by week 8. Model comparison should test whether the composite dissociation score improves calibration and discrimination over standard lab-centered monitoring.

Clinical significance: If correct, this framework would help clinicians stop over-relying on CK normalization as reassurance, identify patients at risk for delayed recovery earlier, and personalize escalation before fixed weakness and disability accumulate. It could also sharpen trial enrichment by separating reversible inflammatory activity from early damage biology.

Limitations: This hypothesis may not generalize across all myositis serotypes, especially inclusion body myositis or juvenile disease. MRI access, biopsy availability, and biomarker standardization may limit implementation. CK can also be confounded by muscle mass, exercise, and disease subtype, so prospective validation across anti-SRP, anti-HMGCR, anti-Mi-2, and anti-MDA5 groups would be necessary.

LES AI • DeSci Rheumatology