Ultra-Low Dose Cytokines in Rheumatoid Arthritis, Three Birds with One Stone as the Rationale of the 2LARTH® Micro-Immunotherapy Treatment

Int J Mol Sci. 2021 Jun 23;22(13):6717. doi: 10.3390/ijms22136717.


Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH® uses ultra-low doses (ULD) of TNF-α, IL-1β, and IL-2, in association with other immune factors, to gently restore the body's homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1β and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1β and TNF-α in 2LARTH® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.

Keywords: IL-1β; TNF-α; anti-inflammatory medicines; chronic inflammation; hormesis; inflammatory cytokines; micro-immunotherapy; rheumatoid arthritis; ultra-low doses.

Publication types

  • Review

MeSH terms

  • Administration, Oral
  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / physiopathology
  • Cytokines / administration & dosage*
  • Dose-Response Relationship, Drug
  • Humans
  • Immunotherapy / methods*
  • Interleukin-1beta / administration & dosage*
  • Interleukin-1beta / adverse effects
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / physiology
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / adverse effects
  • Molecular Targeted Therapy / methods
  • Precision Medicine
  • Tumor Necrosis Factor-alpha / administration & dosage*
  • Tumor Necrosis Factor-alpha / adverse effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / physiology


  • Cytokines
  • IL1B protein, human
  • IL2 protein, human
  • Interleukin-1beta
  • Interleukin-2
  • TNF protein, human
  • Tumor Necrosis Factor-alpha