Causes of biologic and small molecule therapy failure

Psoriasis is a chronic immune-mediated inflammatory disease for which biologic agents and small-molecule inhibitors have substantially improved therapeutic outcomes; however, treatment failure remains common in clinical practice.Evidence indicates that inadequate or lost responses result from the combined effects of genetic background, age at disease onset, comorbidities, immunogenicity, and drug-related adverse events rather than from a single factor.Genetic predisposition, including HLA-C*06:02, has been associated with favorable responses to earlier biologics; however, its utility as a predictive biomarker is limited with newer therapies.Meanwhile, ongoing genetic studies have identified additional susceptibility genes as potential predictors of treatment response.With respect to age-related factors, late-onset psoriasis is generally associated with more favorable treatment responses; however, patient age independently influences treatment outcomes, with safety concerns predominating in older patients and adherence-related factors in younger patients.Comorbidities, particularly obesity and metabolic disorders, are consistently linked to reduced treatment response, potentially through enhanced innate immune activation.Anti-drug antibody formation and adverse events further contribute to treatment discontinuation in a drug-specific manner.Overall, treatment failure in psoriasis is a multifactorial and context-dependent phenomenon, underscoring the need for individualized treatment strategies.