Predictive clinical‐genetic model of long‐term non‐response to tumor necrosis factor‐alpha inhibitor therapy in spondyloarthritis

Abstract

Aim: Tumor necrosis factor inhibitors (TNFi) are effective in controlling disease activity in spondyloarthritis (SpA). However, in a proportion of patients these treatments are ineffective or lead to adverse events. Recently, alternative therapies, such as interleukin (IL)-17 or IL-23 inhibitors, have emerged in the treatment of these pathologies. This study aimed to determine clinical and genetic predictors of non-response to TNFi treatment in 118 spondyloarthritis patients diagnosed according to Assessment in SpondyloArthritis International Society (ASAS) criteria.Method: From the literature, 41 single nucleotide polymorphisms (SNPs) were selected that had previously been associated with TNFi treatment response in spondyloarthropathies, rheumatoid arthritis and psoriasis. A clinical non-response was defined as a decrease of <50% of initial Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in axial involvement, or a reduction of less than 1.2 of initial Disease Activity Score of 28 joints-C-reactive protein (DAS28-CRP) in patients with only peripheral involvement. Univariate and multivariate hazard ratios (HR) were determined using Cox proportional hazard models to analyze the potential prognostic factors affecting non-response to TNFi treatment. Results:The clinical factors that significantly increased the non-response rate were: global visual analog scale (VAS), CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI), and the number of TNFi used. Only rs11591741 SNP showed an association with non-response. In the multivariate analysis, females had a non-response rate 4.46 times higher than males; each one-point increase in the BASFI index increased the non-response rate by 75%, and being a genotype GG vs GC or CC carrier was associated with an almost 4 times greater non-response rate. Conclusion:We developed a clinical-genetic model to identify SpA patients with a long-term non-response to TNFi therapy. K E Y W O R D Santi-TNF treatment, genetics, single nucleotide polymorphisms, spondyloarthritis

Efficacy and safety of brodalumab, an anti-IL17RA monoclonal antibody, in patients with axial spondyloarthritis: 16-week results from a randomised, placebo-controlled, phase 3 trial

“…18 High CRP levels and HLA-B27 positivity were previously reported as good predictors of response in patients with SpA/AS treated with anti-TNF agents. [32][33][34] In this study as well, HLA-B27 positivity (vs negativity) and CRP levels ≥ULN (vs <ULN) were associated with higher ASAS 40 response rates in brodalumab-treated patients.…”

The Genetic Contribution to Drug Response in Spondyloarthritis: A Systematic Literature Review

“…The main characteristics of the studies are displayed in Table 1 . There were 15 cohort studies (Tutuncu et al, 2005 ; Seitz et al, 2007 ; Chandran et al, 2010 ; Eder et al, 2010 ; Morales-Lara et al, 2010 , 2012 ; Ramírez et al, 2012 ; Julià et al, 2014 ; Schiotis et al, 2014 ; Fabris et al, 2016 ; Chen, 2017 ; Yan et al, 2017 ; Liu et al, 2019 ; Ovejero-Benito et al, 2019 ; Polo Y La Borda et al, 2019 ), eight case-control studies (Manolova et al, 2014 ; Murdaca et al, 2014 ; Ma et al, 2017 ; Wang et al, 2017 ; Zhao et al, 2017 ; Aita et al, 2018 ; Xing-Rong et al, 2018 ; Xu et al, 2020 ; Sokolik et al, 2021 ) and one cross sectional study (Nossent et al, 2014 ). The definition of the populations was heterogeneous, with studies conducted in Europe, USA, and China, and mainly including AS and PsA patients ( Table 1 ).…”

“…According to the NOS for cohort studies, 11 studies were graded as very good or good (Chandran et al, 2010 ; Eder et al, 2010 ; Morales-Lara et al, 2012 ; Ramírez et al, 2012 ; Julià et al, 2014 ; Schiotis et al, 2014 ; Fabris et al, 2016 ; Chen, 2017 ; Yan et al, 2017 ; Liu et al, 2019 ; Polo Y La Borda et al, 2019 ), and were therefore included in the qualitative synthesis. One study was deemed unsatisfactory (Morales-Lara et al, 2010 ) and three were only satisfactory (Tutuncu et al, 2005 ; Seitz et al, 2007 ; Ovejero-Benito et al, 2019 ), thus their results are not discussed in detailed.…”

“…Furthermore, genes encoding for molecules implicated in the signaling transduction cascade (including inflammatory cascade), such as phosphodiesterase (PDE)3A, were shown to have a linear relationship with DAS28 reduction after anti-TNFα therapy (Julià et al, 2014). Other polymorphisms implicated in SpA pathogenesis that were found to be independently associated to non-response were: rs755622 in macrophage migration inhibition factor (MIF), rs917997 in IL18-receptor accessory protein (IL18-RAP), rs3740691 in ADP Ribosylation Factor GTPase Activating Protein 2 (ARFGAP2), rs1800896 in IL-10, 2rs4240847 in Mitogen-Activated Protein Kinase-Activated Protein Kinase (MAPKAPK2), rs11096957 in Toll like receptor-10 (TLR-10), rs11541076 in Interleukin 1 Receptor Associated Kinase 3 (IRAK-3) (Schiotis et al, 2014;Polo Y La Borda et al, 2019). EULAR, European League Against Rheumatism; DAS28, disease activity score for 28 joints; PsA, psoriatic arthritis; MIF, macrophage migration inhibitory factor; IL18RAP, interleukin 18 receptor accessory protein; TNFRSF1B, TNF receptor superfamily member 1B; ACE, angiotensin I converting enzyme; UQCC1, ubiquinol-cytochrome C reductase complex chaperone 1; ARFGAP2, ADP ribosylation factor GTPase activating protein 2; ASPN, asporin; CALM1, calmodulin 1; IL10, interleukin 10; CYP2C9, cytochrome P450 family 2 subfamily C member 9; CYP2D6, cytochrome P450 family 2 subfamily D member 6;CYP3A5, cytochrome P450 family 3 subfamily A member 5; TNFRSF10A, TNF receptor superfamily member 10a; FCGR2A, Fc fragment Of IgG Receptor IIa; FCGR3A, Fc fragment Of IgG receptor IIIa; TNFRSF1A, tumor necrosis factor receptor superfamily member 1A; MEFV, mediterranean fever; MYOM2, myomesin 2; VPS13B, vacuolar protein sorting 13 homolog B; DISP1, dispatched RND transporter family member 1; IL27, interleukin 27; PDE3A, phosphodiesterase 3A; MAPKAPK2, mitogen activated protein kinase activated protein kinase 2; TLR10, Toll-like receptor 10; IRAK-3, interleukin 1 receptor associated kinase 3; TNFRSA1B, tumor necrosis factor receptor superfamily member 1B; ABCB1:ATP binding cassette subfamily B member 1; TNF, tumor necrosis factor alpha; TNFR2, tumor necrosis factor receptor 2; IL6, interleukin 6; IL6R, interleukin 6 receptor; TGF-β, transforming growth factor beta; DHFR, dihydrofolate reductase; NLRP3, NLR family pyrin domain containing 3; MTHFR, methylenetetrahydrofolate Reductase; SLC19A1, solute carrier family 19 member 1; RFC, reduced folate carrier.…”

The Severe Course of Drug Therapy-Resistant Ankylosing Spondylitis

“…Так, среди больных АС, сменивших первый иФНОα, было больше женщин, отмечались меньшая длительность болезни и более высокие индексы BASDAI и BASFI на момент назначения первого препарата, чем у пациентов, продолжающих применение первого иФНОα [9]. Предикторами неэффективности иФНОα у пациентов со СпА являлись женский пол, исходно высокое значение BASFI, а также наличие гена CHUK rs11591741 GG [11].…”