Genetic and clinical biomarkers of tocilizumab response in patients with rheumatoid arthritis

Maldonado-Montoro, Mar; Cañadas-Garre, Marisa; González-Utrilla, Alfonso; Plaza‐Plaza, José Cristian; Calleja-Hernández, Miguel ÿngel

doi:10.1016/j.phrs.2016.06.016

Cited by 42 publications

(44 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, variants in CD69 and GALNT18 are thought to have limited direct effects on tocilizumab. Variants in those genes are more likely to affect the downstream signaling pathways of the immune system in RA patients, which may limit generalization to non-RA patients 47 . At this point there is limited evidence that pharmacogenomic biomarkers would be helpful in determining response to tocilizumab therapy in COVID-19.…”

Section: Interferon (Inf) β-1bmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacogenomics of COVID-19 therapies

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Interferon (Inf) β-1bmentioning

confidence: 99%

Pharmacogenomics of COVID-19 therapies

et al. 2020

View full text Add to dashboard Cite

show abstract

“…[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.…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Another plexin identified as being in close proximity to B7-H4 on the cell surface, PLXNB2, is required for the physiological and pathological functions of angiogenin (ANG) and has significant therapeutic potential in solid and hematopoietic cancers and neurodegenerative diseases (31). In addition, quantitative SILAC demonstrated increased expression of Enox1 that has previously been implicated in immune regulation: As a candidate gene for the autoimmune disease myasthenia gravis (32), and as a biomarker of response to an anti-IL6 mAb in rheumatoid arthritis (33).…”

Section: Discussionmentioning

confidence: 99%

Identification of the cis‑molecular neighbours of the immune checkpoint protein�B7‑H4 in the breast cancer cell‑line SK‑BR‑3 by proteomic proximity labelling

et al. 2020

View full text Add to dashboard Cite

The immune checkpoint protein B7-H4 plays an important role in the positive as well as the negative regulation of immune T-cell responses. When expressed on cancer cells, B7-H4 inhibits T-cell activity, and numerous types of cancer cells use upregulation of B7-H4 as a survival strategy. Thus, B7-H4 is a potential target for anticancer drug therapy. Unfortunately, the cell biology of this molecule has yet to be fully elucidated. Even basic properties, such as the nature of B7-H4 interactors, are controversial. In particular, the cis-interactors of B7-H4 on cancer cell plasma membranes have not been investigated to date. The present study used a proteomic proximity-labelling assay to investigate the molecular neighbours of B7-H4 on the surface of the human breast cancer cells SK-BR-3. By comparison to a comprehensive proteome analysis of SK-BR-3 cells, the proximity method detected a relatively small number of low abundance plasma membrane proteins highly enriched for proteins known to modulate cell adhesion and immune recognition. It may be inferred that these molecules contribute to the immunosuppressive behaviour that is characteristic of B7-H4 on cancer cells.

show abstract

Genetic and clinical biomarkers of tocilizumab response in patients with rheumatoid arthritis

Cited by 42 publications

References 35 publications

Pharmacogenomics of COVID-19 therapies

Pharmacogenomics of COVID-19 therapies

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

Identification of the cis‑molecular neighbours of the immune checkpoint protein�B7‑H4 in the breast cancer cell‑line SK‑BR‑3 by proteomic proximity labelling

Contact Info

Product

Resources

About