The Role of Hydroxychloroquine in the Management of Rheumatic Disorders: A Comprehensive Review

Abstract

A drug preferred for its antimalarial effect called hydroxychloroquine (HCQ) has long been used to manage and avoid malaria. Nevertheless, its exact mode of action is still unknown. HCQ works through a variety of strategies to influence distinct molecular and cellular pathways. Additionally, HCQ has been demonstrated to be an effective treatment for rheumatic conditions such as primary Sjögren's syndrome, rheumatoid arthritis, antiphospholipid syndrome and systemic lupus erythematosus. Despite being widely regarded as safe, HCQ has been known to cause adverse responses; thus, doctors should closely evaluate rheumatism patients before taking these medications. The current study aims to emphasize the potential side effects of treatment while supporting the clinical usage of HCQ for autoimmune disorders.

Keywords: effect mechanisms; hydroxychloroquine; organ toxicity; rheumatic disorders.

FIGURE 1

Chemical structures of chloroquine and hydroxychloroquine [8].

FIGURE 2

Possible molecular processes via which hydroxychloroquine contributes to autoimmunity [9]. (a) Across a pH gradient, HCQ penetrates and builds up in lysosomes. By raising the pH to stop lysosomal enzyme function, hydroxychloroquine stops cargo from being broken down in autolysosomes that are derived either internally (through the autophagy route) or externally (via endocytosis or phagocytosis). MHC class II‐mediated autoantigen presentation can be avoided by inhibiting lysosomal action. (b) Hydroxychloroquine can also attach to the minor gap of DNA with double strands and build‐up in endosomes. By changing the pH of endosomes, which are important in TLR processing, and/or blocking TLR7 and TLR9 from attaching their ligands (DNA and RNA, respectively), this medication can suppress Toll‐like receptor (TLR) signalling. By disrupting its ability to bind to cytosolic DNA, hydroxychloroquine may additionally diminish the function of the nucleic acid biosensor cyclic GMP‐AMP (cGAMP) synthase (cGAS). The generation of proinflammatory cytokines, such as type I interferons, can be decreased by hydroxychloroquine through blocking TLR signalling and cGAS–stimulator of interferon genes (STING) signalling.

FIGURE 3

By blocking a number of innate and adaptive immunological pathways, HCQ can disrupt the activation of immunity at different cell stages. In plasmacytoid dendritic cells (pDCs) along with other immunized antigen‐presenting cells (APCs), such as monocytes, macrophages and B cells, cellular debris may stimulate the Toll‐like receptor 7 (TLR7) and TLR7 pathways of signalling throughout autoimmune diseases. This can stimulate various kinds of cells and cause the release of different proinflammatory cytokines. Via lysosomal suppression and decreased MyD88 signalling, HCQ may disrupt TLR7 and TLR9 ligand binding and TLR signalling in APCs, hence impeding TLR‐mediated activation of cells and cytokine generation. This medication also prevents the processing of antigens and subsequent MHC class II presentation to T cells in APCs, including pDCs and B cells. This stops the activation of T cell differentiation, thereby lowering the expression of co‐stimulatory molecules, like CD154, and it also lowers the amount of cytokines, like TNF, IL‐1 and IL‐6, that are produced through both T cells and B cells [9].

FIGURE 4

HCQ's utilization in rheumatism. The degree of proof confirming the administration of HCQ for each ailment is indicated by alternative hue coding. Orange indicates an elevated amount of proof, yellow indicates an average level and blue indicates a low level. APS (antiphospholipid syndrome); DM (dermatomyositis); HCQ (hydroxychloroquine); OA (osteoarthritis); RA (rheumatoid arthritis); SLE (systemic lupus erythematosus); SS (Sjögren's syndrome).

FIGURE 5

Adverse HCQ‐related effects.

FIGURE 6

Hydroxychloroquine in dermatology [83].

FIGURE 7

Hypothesis for combined effects of sarcopenia and CQ/HCQ‐induced myopathy, along with aging and chronic use of drugs [90].

FIGURE 8

Mechanisms of hydroxychloroquine retinopathy [89].

FIGURE 9

Prolonged QT periods due to HCQ treatment [100].