Tumour Necrosis Factor Inhibitors
Biologic agents are being used increasingly to treat moderate to severe PsA patients in whom conventional treatments have failed. There are two broad classes of TNFis approved for use in PsA: monoclonal antibodies to TNF (infliximab, adalimumab, golimumab, certolizumab pegol) and the TNF fusion protein receptor inhibitor (etanercept). A limited number of pharmacogenetic studies to predict TNFi treatment response have been conducted to date specifically in PsA. All such studies in PsA have used a candidate gene approach, where genes are selected for investigation based on knowledge of the biological pathways they lie on and the therapeutic agent to which response is being assessed.
Polymorphisms within the
TNF promoter region have been identified to influence clinical efficacy of etanercept in a study that combined patients with rheumatoid arthritis (RA), ankylosing spondylitis and PsA [
11] (Table
1). In this study, the −308 G/G (rs1800629) genotype in the promoter of the TNF gene conferred a better response to treatment than A/A or A/G genotypes. Only 10 patients with PsA were included; however, it is promising to note a meta-analysis of similar studies of this polymorphism, which included 692 RA patients treated with infliximab, adalimumab or etanercept, showed that the −308(A) variant predicts poor response to TNFis. In the latter analysis, irrespective of the prescribed TNFi, the frequency of the
TNF –
308A variant was 22 % in responders, compared with 37 % in non-responders [OR = 0.4, 95 % confidence interval (CI) 0.4–0.7;
P = 0.000245]. In another small PsA study (
n = 58), which assessed single-nucleotide polymorphisms (SNPs) at positions −238 (rs361525), −308 and −489 (rs80267959) of the TNF-α gene in response to TNFis, the −489A allele showed a trend of association with PsA response to etanercept (not significant). However, in that Italian Caucasian population, the association with the −308 G/G genotype was not replicated [
12].
Table 1
Impact of candidate genes on treatment response in psoriatic arthritis
Biologic therapies |
Etanercept | |
TNF-α-308
| 54 (n = 10 PsA patients) | DAS28 | 6 |
TNF-α-308GG > A associated with better response | TNF |
Infliximab, adalimumab, etanercept | |
TNF-α-489A
| 58 | ACR 20 | 6 |
TNF-α-489A non-significantly associated with better response to etanercept only | TNF |
Infliximab | |
TNF R1A
| 55 | EULAR response | 3 |
TNFR1 AA > AG/GG associated with better response | TNFR1 |
| |
TRAIL-R1
| 55 | EULAR response | 6 |
TRAILR1 CC > CG/GG associated with better 6-month response | TNF-related apoptosis-inducing ligand receptor 1 |
Infliximab, adalimumab, etanercept | |
FCGR2A
| 103 | EULAR response | 6 | High-affinity FCGR2A-131H allele (HH + HR) associated with better response to etanercept only | FCGR |
Infliximab | |
FCGR3A
| 90 (n = 16 PsA) | ACR20 | 3 | High-affinity FCGR3A V158F (FV + VV > FF) non-significantly in PsA patients only | FCGR |
Non-biologic DMARDs |
Methotrexate | |
DHFR
| 119 | 50 % reduction in swollen joint count | 6 |
DHFR 35289A associated with better response | Dihydrofolate reductase |
The TNF receptor 1A (TNFR1A) variant rs767455/G36A in PsA patients has been associated with a better European League Against Rheumatism (EULAR) response at 3 months to infliximab both with the AA genotype (AA 85 % vs. AG/GG 58.9 %;
P = 0.04) and with the A allele (A 76.7 % vs. G 58.3 %;
P = 0.03) [
13]. Interestingly, this was in the opposite direction to RA patients in the same study, whilst a Crohn’s disease cohort also found biological response to infliximab was lower in patients carrying TNFR1 36G mutation in the
TNFR1 gene [
14]. In the same study [
13], TNF-related apoptosis-inducing ligand receptor 1 (
TRAIL-
R1) rs20575 CC genotype was also associated with a 6-month EULAR response to infliximab in PsA (Table
1). In psoriasis, polymorphisms in
TNFAIP3 are associated with response to TNFis, with the SNPs (rs2230926 and rs610604) acting as markers of beneficial response to three TNFis tested [
15].
TNFAIP3, which has also been identified as a susceptibility locus for PsA [
16], is a gene encoding the A20 protein, a TNF-α-inducible zinc finger protein thought to limit NF-κB-mediated immune responses. Therefore, there is some evidence that polymorphisms affecting TNF may affect treatment response to TNFis in PsA patients; however, this may vary according to disease and drug subtype, and larger validation studies are required to confirm these associations.
The presence of the high-affinity
FCGR2A-
131H allele in either homo/heterozygous combinations (HH and HR) in PsA patients receiving etanercept showed a strong trend to a higher rate of EULAR response compared with those without a response (93 vs. 67 %;
P = 0.034) [
17].
FCGR2A, located on chromosome 1, encodes one member of a family of immunoglobulin Fc receptor genes found on the surface of many immune response cells. The protein encoded by this gene is a cell surface receptor and is involved in the process of phagocytosis and clearing of immune complexes. A smaller PsA study, which evaluated the specific distribution of the
FCGR3A V158F polymorphism in relation to infliximab response at 3, 6, and 12 months, found that more patients with a high-affinity genotype (FV + VV) achieved a EULAR response at 3 months (20 % FF vs. 83.3 % FV-VV;
P = 0.036,
P = 0.067) [
18]. This association however was not significant, limited by the small numbers of patients in the study and hence study power.
The prevalence of axial involvement amongst patients with PsA has been reported to be between 25 and 70 %, depending on the criteria used for its definition [
19], and PsA is also known to share susceptibility loci with ankylosing spondylitis (AS) [
20,
21•]. Few studies have analysed the role of genetic markers in the response to TNFi therapy in AS patients, but the majority have shown an association of favourable response with HLA-B27 status [
22,
23]. Outside the MHC, one study suggested variants within macrophage migration inhibitory factor (
MIF) gene (rs755622), interleukin 18 receptor accessory protein (
IL18RAP) gene (rs917997),
IL10 (rs1800896), TNF receptor superfamily member 1B [(
TNFRSFB1); rs4355801] and ADP-ribosylation factor GTPase-activating protein 2 (
ARFGAP2) gene (rs3740691), were associated with non-response in 121 AS patients [
24]. These results are yet to be replicated independently.
In RA, only two associations with TNFi treatment response have approached genome-wide significance (
P < 5 × 10
−8) and/or have been replicated in independent cohorts. These include a polymorphism in the
CD84 gene (rs6427528; G > A) which encodes SLAM family member 5 and has been associated with reduced response to etanercept [
25]; the
PDE3A‐
SLCO1C1 locus (rs3794271; C > T) was associated with reduced efficacy to the TNFis etanercept, infliximab and adalimumab [
26]. Larger homogenous cohorts are required to more accurately assess and replicate these variants to evaluate if they can predict response to TNFis specifically in PsA patients, to inform future clinical decisions regarding treatment selection.