Background Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to investigate the relationship of cytochrome P450 (CYP450) gene polymorphisms with blood concentrations of HCQ and its metabolites and adverse drug reactions (ADRs) in patients with SLE and RA. Methods A cohort of 146 patients with SLE and RA treated with HCQ was reviewed. The ADRs of the patients were recorded. The blood concentrations of HCQ and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Genotyping of single nucleotide polymorphisms (SNPs) in CYP450, a metabolic enzyme involved in the HCQ metabolic pathway, was performed using a MassARRAY system. The chi-square test, T-test, and one-way analysis of variance were used to analyse data. Results Among 29 candidate SNPs, we found that CYP3A4 (rs3735451) was significantly associated with blood levels of HCQ and its metabolites in both the unadjusted model and adjusted model (patients taking HCQ for > 10 years) (P < 0.05). For CYP3A5 (rs776746), a greater risk of skin and mucous membrane ADRs was associated with the TT genotype than with the CT + CC genotypes (P = 0.033). For CYP2C8 (rs1058932), the AG genotype carried a greater risk of abnormal renal function than the AA + GG genotype (P = 0.017); for rs10882526, the GG genotype carried a greater risk of ophthalmic ADRs than the AA + AG genotypes (P = 0.026). Conclusions The CYP2C8 (rs1058932 and rs10882526) and CYP3A5 (rs776746) polymorphisms are likely involved in the ADRs of HCQ. Gene polymorphism analysis of CYP450 and therapeutic drug monitoring of HCQ and its metabolites might be useful to optimise HCQ administration and predict ADRs.
Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated vasculitis (AAV) is a necrotizing vasculitis mainly involving small blood vessels. It is demonstrated that T cells are important in the pathogenesis of AAV, including regulatory T cells (Treg) and helper T cells (Th), especially Th2, Th17, and follicular Th cells (Tfh). In addition, the exhaustion of T cells predicted the favorable prognosis of AAV. The immune checkpoints (ICs) consist of a group of co-stimulatory and co-inhibitory molecules expressed on the surface of T cells, which maintains a balance between the activation and exhaustion of T cells. CD28, inducible T-cell co-stimulator (ICOS), OX40, CD40L, glucocorticoid induced tumor necrosis factor receptor (GITR), and CD137 are the common co-stimulatory molecules, while the programmed cell death 1 (PD-1), cytotoxic T lymphocyte-associated molecule 4 (CTLA-4), T cell immunoglobulin (Ig) and mucin domain-containing protein 3 (TIM-3), B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T‐cell Ig and ITIM domain (TIGIT), CD200, and lymphocyte activation gene 3 (LAG-3) belong to co-inhibitory molecules. If this balance was disrupted and the activation of T cells was increased, autoimmune diseases (AIDs) might be induced. Even in the treatment of malignant tumors, activation of T cells by immune checkpoint inhibitors (ICIs) may result in AIDs known as rheumatic immune-related adverse events (Rh-irAEs), suggesting the importance of ICs in AIDs. In this review, we summarized the features of AAV induced by immunotherapy using ICIs in patients with malignant tumors, and then reviewed the biological characteristics of different ICs. Our aim was to explore potential targets in ICs for future treatment of AAV.
Background: Hydroxychloroquine (HCQ) is a cornerstone therapy for systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to investigate the relationship of cytochrome P450 (CYP450) gene polymorphisms with blood concentration of HCQ and its metabolites and adverse drug reactions (ADRs) in patients with SLE and RA. Methods: A cohort of 146 patients with SLE and RA treated with HCQ was reviewed. The ADRs of patients were recorded. The blood concentration of HCQ and its metabolites were measured by liquid chromatography–mass spectrometry analysis. Genotyping of single nucleotide polymorphism (SNP) in CYP450 metabolic enzyme involved in HCQ metabolic pathway was performed using a MassARRAY system. Chi-square test, T-test, and one-way analysis of variance were used to analyze data. Results: Among 29 candidate SNPs, we found that CYP3A4 (rs3735451) was significantly associated with blood levels of HCQ and its metabolites in unadjusted model and adjusted model (patients taking HCQ for >10 years) (P<0.05). For CYP3A5 (rs776746), skin and mucous membrane ADRs associated with the TT genotype were a greater risk than for the CT+CC genotypes (P=0.033). For CYP2C8 (rs1058932), abnormal renal function with the AG genotype carried a greater risk than with the AA+GG genotype (P=0.017); for rs10882526, ophthalmic ADRs of the GG genotype carried a greater risk than for the AA+AG genotypes (P=0.026). Conclusions: The CYP2C8 (rs1058932 and rs10882526) and CYP3A5 (rs776746) polymorphisms are likely involved in the ADRs of HCQ. Gene polymorphism analysis of CYP450 and therapeutic drug monitoring of HCQ and its metabolites might be useful to optimize HCQ administration and predict ADRs.
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