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

Abstract

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.

Pharmacogenomics of COVID-19 therapies

“…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 – 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.…”

“…In 87 patients with RA treated with tocilizumab, FCGR3A rs396991TT genotype showed higher response at 12 months (vs. GT; OR: 5.1; 95% CI: 1.2–21.3; p = 0.03). 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 .…”

Important Pharmacogenetic Information for Drugs Prescribed During the SARS‐CoV‐2 Infection (COVID‐19)

“…Patients with the CD69 rs11052877 AA genotype may have an increased response to tocilizumab compared to patients with the AG and GG genotypes 90 . In addition, patients with the FCGR3A rs396991 AA genotype may have an increased response to tocilizumab as compared with patients with the AC or CC genotypes 91 . Finally, GALNT18 rs4910008 CC individuals may have increased response to tocilizumab compared with patients with the CT and TT genotypes 90 .…”

Interleukin-6 receptor genetic variation and tocilizumab treatment response to COVID-19

“…Patients with the CD69 rs11052877 AA genotype, for example, can have an increased response to tocilizumab compared to patients with the AG and GG genotypes [32]. Also, patients with the FCGR3A rs396991 AA genotype may have an increased response to tocilizumab as compared with patients with the AC or CC genotypes [33]. Finally, GALNT18 rs4910008 CC individuals may also have an increased response to tocilizumab compared with patients with the CT and TT genotypes [32].…”