New insights into the pathophysiology of achalasia and implications for future treatment

Table 2 Pathophysiology mechanisms and potential therapeutic targets in achalasia

Physiopathology mechanism	Therapeutic target
Incomplete relaxation of lower esophageal sphincter	3Botulinum toxin injection[3,8,74-77]
	3Pneumatic dilatation[3,8]
	3Heller myotomy[8,74,81-84]
	3Self-Expanding metal stent[79,80]
	3POEM[85,86,91]
Loss of inhibitory ganglion neurons and decrease of NO and VIP	3Nitrates administration (isosorbide dinitrate and nitroglycerin)[3,7,8]
	1Treatment with immunosuppressive drugs (prednisolone, methylprednisolone, beclomethasone, methotrexate, azathioprine or cyclophosphamide) in the early stage of the disease[39,42,87,88]
	2Transplantation of neural progenitor cells[69,89]
Immune-mediate response, inflammation, organ-specific autoimmune disease, and autoantibodies that causes neuritis and glanglionitis	1Treatment with immunosuppressive drugs (prednisolone, methylprednisolone, beclomethasone, methotrexate, azathioprine or cyclophosphamide) to avoid immune-mediate insult damaging the enteric innervation. Suppress the whole activated immune system, exerts antiproliferative and pro-apoptotic effects, particularly on activated T cells and suppress antibody formation by B cells[39,42,87,88]
	2Biologic therapy (monoclonal antibodies: TNF-α inhibitors, IL-6 inhibitor, anti-CD20 antibody, CTLA-4 antibody, IFN-g antibody, etc) in the early stage of the disease[48,93]
	2Administration of regulatory cells to downregulate inflammation and to induce immunological tolerance[50-52]
Fibrosis	2Extracellular matrix remodeling (Polymerized type I collagen)[94]
Neurotrophic viral infection (Herpes simplex virus, varicella zoster, measles, etc.), molecular mimicry, bystander activation, viral persistence and polyclonal activation	2Antiviral therapy in patients with recent-onset achalasia[6,34-36,72,73]
Genetics	2Genomic medicine for decrease the effect of certain environmental factors, such as infectious agents, on the burden of disease[61-66]

¹Drugs or experimental procedures with therapeutic benefit;

²Drugs or experimental procedures with potential therapeutic;

³Therapies with marginal benefit.