Why Does MCAS Not Respond to Standard Treatment? The Four Mechanistically Distinct Patterns — Why the standard MCAS model produces inconsistent results

The standard MCAS model rests on a specific causal claim. The mast cell is the primary lesion. Mast cells are inappropriately activated. The treatment goal is to stabilize the mast cell so it does not activate inappropriately. If this account is correct, mast cell stabilizers should produce reliable remission, and most patients should respond. The data do not support this prediction. The clinical literature documents wide variability in response to mast cell stabilizers. Some patients respond well. Some respond partially. A substantial fraction respond minimally or not at all. The variability is too large to be explained by dose titration or compliance. The most parsimonious explanation for this heterogeneity is that the patients labeled "MCAS" are not a single clinical entity. They share a phenotype because mast cell activation is the final common pathway of multiple distinct upstream drivers. Stabilizing the mast cell is appropriate symptomatic care, but it does not address the driver in cases where the driver is upstream of the cell itself. In those cases, the mast cell keeps getting the signal to activate because the signal is still being sent. Suppressing the cell while the signal continues produces the pattern of fluctuating, incomplete, escalating response that the literature documents. The Host Capacity Model approach to MCAS begins from this observation. Before stabili