Inflammatory Flux and Disease Progression in Hidradenitis Suppurativa: A Multi-Compartment Deterministic Model Simulating Lifestyle and Pharmaceutical Interventions in In Silico Cohorts

While recent reviews have firmly established hidradenitis suppurativa (HS) as a systemic inflammatory disorder inextricably linked to metabolic comorbidities, the investigation of lifestyle determinants remains a fraction of the research effort compared to the pursuit of pharmaceuticals. Consequently, current clinical approaches may not fully leverage natural modulators of systemic environmental inflammatory influx, a potential driver of the disease. The central premise of this study posits that the compromise of follicular integrity is directly coupled to lifestyle-driven systemic inflammation exceeding a critical threshold. While previous studies have relied on statistical regression and probabilistic frameworks for HS, this study establishes a deterministic multi-compartment ordinary differential equation framework to simulate the longitudinal kinetics of systemic and local lesion inflammation. Represented in this framework is the first mathematical formalization of the 2025 European S2k guideline interventions, explicitly modeling the resistance kinetics of antibiotics, the immunogenic decay of biologics, and the tapering dynamics of corticosteroids to simulate their longitudinal efficacy in HS. Furthermore, we introduce an abstractified framework that applies the laws of mass balance and pharmacokinetics directly to the disease state and key biologically relevant parameters, rather than focusing on cell types, targets, and individual cytokines. In this HS PK model, the lesion is connected to the systemic inflammation and acts as an integrator and amplifier, recording transient systemic spikes as permanent structural debt through an effect of hysteresis that progressively decouples the lesion from the systemic driver. Simulation studies suggest biologic agents provide a buffering capacity that creates a therapeutic equilibrium, which differs from resolving the underlying inflammatory mass balance. When evaluated across a virtual cohort, this reveals distinct kinetic populations. We demonstrate that clinical rebound is mathematically governed by phase space topology, where the disease state acts as a stable natural equilibrium. Upon pharmaceutical cessation, the therapeutic equilibrium collapses, causing the system to shift rapidly back to the disease state, driven by the underlying inflammatory load. Consequently, a comparative rescue trial demonstrated that pharmacological escalation encounters a saturation ceiling. This suggests that sustainable remission in HS may require a transformation that shifts the equilibrium itself, redefining lifestyle modification from an adjuvant option to the fundamental variable required to treat HS effectively.