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Background: Knee osteoarthritis (OA) is associated with substantial disability and impaired quality of life. Treatment aims at decreasing pain and improving function combining non-pharmacological (education, exercise, and weight reduction) and pharmacological modalities (topical, oral NSAIDs, and intraarticular corticosteroids). A challenge is to reduce the consumption of oral NSAIDs due to their side effects. Oral enzyme combination (OEC) therapy with bromelain, trypsin, and flavonoid rutin has proven to be efficacious in several painful musculoskeletal disorders and OA, but its mechanism of action is not fully known. Objectives: We assessed whether OEC could modulate pathways involved in the reduction of inflammation, and consequently improve clinical symptoms, in people with knee OA. Methods: This was a randomized, double-blind, placebo (PBO)-controlled, 8-week crossover, multicenter, exploratory study (NCT05038410) involving patients (age ≥ 40 years, BMI ≤35 kg/m2) with symptomatic knee OA (radiological Kellgren Gmean (95% CI) OEC/PBO 138% (118%, 162%); pmean(95% CI)OEC/PBO 103% (100%, 105%); p=0.038). The urinary cartilage biomarker CTX-II (BL OEC/PBO 485/495 ng/mL) was significantly reduced with OEC (Gmean(95% CI)OEC/PBO 88% (79%, 99%); p=0.038), whereas serum collagen markers remained unchanged. OEC significantly improved the KOOS subdomain scores "Symptoms" (p=0.026) and "Pain" (p=0.046), but not total or other KOOS subscores as compared to PBO. Adverse events were overall balanced between groups, and no clinically relevant changes in clinical biology and hemorheological parameters were observed in either group. Conclusion: This is the first clinical study rigorously exploring the underlying mechanisms of action of OEC in OA. OEC significantly increased IL-10, an anti-inflammatory cytokine, and reduced CTX-II level, a marker of cartilage degradation. Together with the reduction of OA symptoms, these findings suggest that OEC could have disease-modifying potential in knee OA. Future clinical research could leverage MRI to evaluate long-term symptomatic and structural effects of OEC in appropriate OA populations. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Yves Henrotin Wobenzym, Tilman, Artialis, Kiomed Pharma, Grunenthal, Genquine, Allegro, Expanscience, Nestlé, Tilman, Expanscience, Heel, Valérie Badot: None declared, Siddhartha Lieten: None declared, Didier Urbin-Choffray: None declared, Carl Brabant: None declared, Jean-Emile Dubuc: None declared, Stefanie Rau Nestlé Health Science, Odd Erik Johansen Nestlé Health Science, Maximilian Eynatten Nestlé Health Science.
Henrotin et al. (Sat,) studied this question.