Mechanism of action of hydroxychloroquine as an antirheumatic drug

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The antimalarial agents chloroquine and hydroxychloroquine have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. These compounds lead to improvement of clinical and laboratory parameters, but their slow onset of action distinguishes them from glucocorticoids and nonsteroidal antiinflammatory agents. Chloroquine and hydroxychloroquine increase pH within intracellular vacuoles and alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and posttranslation modification of proteins in the Golgi apparatus. It is proposed that the antirheumatic properties of these compounds results from their interference with “antigen processing” in macrophages and other antigen-presenting cells, Acidic cytoplasmic compartments are required for the antigenic protein to be digested and for the peptides to assemble with the α and β chains of MHC class II proteins. As a result, antimalarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against autoantigenic peptides. Because this mechanism differs from other antirheumatic drugs, antimalarials are well suited to complement these other compounds in combination drug therapy.

References (48)

  • SE Tett et al.

    A dose-ranging study of the pharmacokinetics of hydroxychloroquine following intravenous administration to healthy volunteers

    Br J Clin Pharmacol

    (1988)
  • DR Miller et al.

    Steady-state pharmacokinetics of hydroxychloroquine in rheumatoid arthritis patients

    Ann Pharmacother

    (1991)
  • M Kubo et al.

    Metabolic basis of diethylami-noethoxy-hexestrol-induced phospholipid fatty liver

    Am J Physiol

    (1987)
  • M Frisk-Holmberg et al.

    Chloroquine serum concentration and side effects: Evidence for dose-dependent kinetics

    Clin Pharmacol

    (1979)
  • CA Homewood et al.

    Lysosomes, pH and the antimalarial action of chloroquine

    Nature

    (1972)
  • DJ Krogstad et al.

    Acid-vesicle function, intracellular pathogens, and the action of chloroquine against Plasmodium falciparum.

    N Engl J Med

    (1987)
  • DJ Krogstad et al.

    Efflux of chloroquine from Plasmodium falciparum: Mechanism of chloroquine resistance

    Science

    (1987)
  • AFG Slater et al.

    Inhibition by chloroquine of a novel heme polymerase enzyme activity in malaria trophozoites

    Nature

    (1992)
  • I Mellman et al.

    Acidification of the endocytic and exocytic pathways

    Annu Rev Biochem

    (1986)
  • P Stahl et al.

    Receptor-mediated endocytosis

    J Clin Invest

    (1986)
  • AL Schwartz et al.

    Recycling of the asialoglycoprotein receptor and the effect of lysosomotropic amines in hepatoma cells

    J Cell Biol

    (1984)
  • IH Pastan et al.

    Receptor-mediated endocytosis of hormones in cultured cells

    Annu Rev Physiol

    (1981)
  • WP Tsai et al.

    Inhibition of human immunodeficiency virus infectivity by chloroquine

    AIDS Res Hum Retroviruses

    (1990)
  • LE Guagliardi et al.

    Co-localization of molecules involved in antigen processing and presentation in an early endocytic compartment

    Nature

    (1990)
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