Influence of IL6R gene polymorphisms in the effectiveness to treatment with tocilizumab in rheumatoid arthritis

Maldonado-Montoro, Mar; Cañadas-Garre, Marisa; González-Utrilla, Alfonso; Calleja‐Hernández, Miguel Ángel

doi:10.1038/tpj.2016.88

Cited by 34 publications

(41 citation statements)

References 32 publications

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“…This variant may affect the affinity of the Fc fragment of IgG receptor to tocilizumab and alter its systemic clearance 45 . Polymorphisms of IL6R are considered to affect intracellular signaling pathway of IL-6 receptor bound to tocilizumab, which may also be applicable to other conditions with upregulated IL-6 pathway 46 . In contrast, variants in CD69 and GALNT18 are thought to have limited direct effects on tocilizumab.…”

Section: Methodsmentioning

confidence: 99%

“…Tocilizumab, an inhibitor of the IL-6 receptor, is commonly used for rheumatoid arthritis (RA) and cytokine-release syndrome induced by chimeric antigen receptor-T cell therapy, and now it is under investigation for COVID-19. Although several genetic biomarkers have been reported in the efficacy of tocilizumab in RA, including FCGR3A, IL6R, CD69, GALNT18 [45][46][47] , potential translation of these data to COVID-19 is highly speculative. No studies have addressed pharmacogenomics of tocilizumab in patients with cytokine-release syndrome, which is similar to the physiology in COVID-19.…”

Section: Interferon (Inf) β-1bmentioning

confidence: 99%

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Pharmacogenomics of COVID-19 therapies

et al. 2020

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A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB ®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β-1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

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Section: Methodsmentioning

confidence: 99%

Section: Interferon (Inf) β-1bmentioning

confidence: 99%

Pharmacogenomics of COVID-19 therapies

et al. 2020

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“…However, sensitivity to tocilizumab may vary; for instance, the replacement of asparagine with alanine in the 358 codon of the IL6R gene increases the relative concentration of the soluble receptor form by 35%. According to an original RA study in Spain, patients with the AA rs12083537 and CC rs11265618 genotypes respond better to targeted tocilizumab therapy [ 80 ]. Tocilizumab efficacy is associated with the IL6R gene polymorphisms rs12083537, rs2228145, and rs4329505, as shown by various sources [ 11 ].…”

Section: Genetic Predictors Of Response To Rheumatoid Arthritis Drmentioning

confidence: 99%

Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response

Mikhaylenko

Немцова

Bure

et al. 2020

IJMS

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Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide. Possible manifestations of RA can be represented by a wide variability of symptoms, clinical forms, and course options. This multifactorial disease is triggered by a genetic predisposition and environmental factors. Both clinical and genealogical studies have demonstrated disease case accumulation in families. Revealing the impact of candidate gene missense variants on the disease course elucidates understanding of RA molecular pathogenesis. A multivariate genomewide association study (GWAS) based analysis identified the genes and signalling pathways involved in the pathogenesis of the disease. However, these identified RA candidate gene variants only explain 30% of familial disease cases. The genetic causes for a significant proportion of familial RA have not been determined until now. Therefore, it is important to identify RA risk groups in different populations, as well as the possible prognostic value of some genetic variants for disease development, progression, and treatment. Our review has two purposes. First, to summarise the data on RA candidate genes and the increased disease risk associated with these alleles in various populations. Second, to describe how the genetic variants can be used in the selection of drugs for the treatment of RA.

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“…[24][25][26][27][28] However, for rheumatoid arthritis patients treated with rituximab, the FCGR3A rs396991-V158 allele has been associated with better response, 29,30 but the influence of FCGR2A rs1801274 on rituximab efficacy has not been studied. The role of genetic alterations on tocilizumab response has only been studied in a genome-wide association study 31 and 3 other studies, [32][33][34] the polymorphisms in GALNT18, CD69, and IL-6 genes being statistically significant. Tocilizumab is a structural analogue of IgG1, and its constant fraction interacts with the FCGR2A and FCGR3A receptors.…”

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confidence: 99%

FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis

Morales

Maldonado-Montoro

Plata

et al. 2018

The Journal of Clinical Pharma

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We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991‐TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20–21.33; P = .027) at 12 months, those who were naive for biological disease‐modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274‐TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11–21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90–24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35–17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI95%: 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, −0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19–2.63; P = .025). The FCGR3A rs396991‐G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84–28.48; P = .077) and greater improvement in DAS28 (B = −1.083; 95%CI, −1.98 to −0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991‐TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274‐TT genotype, the FCGR3A rs396991‐G allele, and lower number of previous biological therapies.

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Influence of IL6R gene polymorphisms in the effectiveness to treatment with tocilizumab in rheumatoid arthritis

Cited by 34 publications

References 32 publications

Pharmacogenomics of COVID-19 therapies

Pharmacogenomics of COVID-19 therapies

Genetic Polymorphisms Associated with Rheumatoid Arthritis Development and Antirheumatic Therapy Response

FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis

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