The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis

Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02–1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58–0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55–0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65–0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34–0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.

Biologics have revolutionized the treatment of these diseases, although approximately 30% of patients do not respond to treatment, requiring a switch in biologics or treatment approach [18].Today, no biomarkers are available to identify treatment for individual patients, although different biomarkers have been proposed.Indeed, high CRP early in treatment has been associated with the risk of colectomy in patients with ulcerative colitis [19], serum drug concentration has been associated with response [20], certain cytokines have been associated with response [21][22][23], and different genetic variants have been associated with response [24][25][26][27][28][29][30][31][32][33].In general, these genetic markers have been assessed in smaller studies, which by themselves might not be powered for identifying an association, and most have only been assessed in a few studies [24][25][26][27][28][29][30][31][32][33].In this study, we conducted a systematic review and meta-analysis on single nucleotide polymorphism (SNP) genetic markers and their response to biologics in psoriasis, PsA, RA, and IBD, and across all the CIDs due to shared immunology.

Methods and Materials
A systematic review and meta-analysis were conducted according to the guidelines of the Preferred Reporting Items for systematic Reviews and Meta-analyses (PRISMA) statement (Figure 1).Prior to the study, the protocol for the systematic review was registered in PROSPERO (CRD42021282400).

Eligibility Criteria
Published studies in English from any year and any healthcare setting were eligible to be included.All original study types in patients with psoriasis, PsA, RA, or IBD treated with biologics and any SNPs outside the HLA region predicting response were included.Studies had to report an association between SNPs and response/non-response to treatment with biologics.Studies had to be original and report the number of patients receiving the given biologic, the number and/or proportion of patients achieving response, and the number and/or proportion of patients with the SNP and response to treatment.If only haplotypes were presented, the study was excluded.

Search Strategy
Two authors (RA, MS) independently screened Pubmed, Embase, and Web of Science.The databases were screened from inception through November 2021 using numerous alternative search terms for (i) "biologics", (ii) "psoriasis, rheumatoid arthritis, inflammatory bowel disease", and (iii) "polymorphism" (Supplementary Table S1).Screening was conducted using the web-based screening tool Rayyan, which allows collaborative blinded citation screening [34].In Rayyan, users assessed studies for in-or exclusion blinded to the other screeners.Following unblinding, disagreements between screeners were shown.Disagreements were resolved through debate, and the resulting decision was unanimous.If the reviewers could not come to an agreement, the senior author (NL) would make the final decision.Data on drug type, number of participants, age, SNP, assessment of response, time of response, and association with response were extracted from each article.

Eligibility Criteria
Published studies in English from any year and any healthcare setting were eligible to be included.All original study types in patients with psoriasis, PsA, RA, or IBD treated with biologics and any SNPs outside the HLA region predicting response were included.Studies had to report an association between SNPs and response/non-response to treatment with biologics.Studies had to be original and report the number of patients receiving the given biologic, the number and/or proportion of patients achieving response, and the number and/or proportion of patients with the SNP and response to treatment.If only haplotypes were presented, the study was excluded.

Search Strategy
Two authors (RA, MS) independently screened Pubmed, Embase, and Web of Science.The databases were screened from inception through November 2021 using numerous alternative search terms for (i) "biologics", (ii) "psoriasis, rheumatoid arthritis, inflammatory bowel disease", and (iii) "polymorphism" (Supplementary Table S1).Screening was conducted using the web-based screening tool Rayyan, which allows

Statistics
Data synthesis was performed using StatsDirect version 3 (StatsDirect Ltd., Cheshire, UK).All SNPs that were found to be associated with a response to biologics in any of the inflammatory diseases were included (Supplementary Tables S2-S5).Meta-analyses were performed for SNPs assessed in ≥ two studies assessing the same drug and/or drug class for the individual disease with retrievable data on genotypes and treatment response.An odds ratio [OR] meta-analysis was performed to achieve pooled OR using the random effects model (Der Simonian and Laird) due to the substantial heterogeneity of studies.Cochran's Q-test was used to assess the heterogeneity of the studies using a significance level of 0.05 and I2 (inconsistency) statistics.Analyses were conducted for the individual diseases and for SNPs, which could be included in ≥2 meta-analyses for individual diseases for the same drug and/or drug class pooled meta-analyses across all CIDs were conducted.UC and Crohn's disease were categorized together as IBD as this was done in several of the included studies.Odds ratios were calculated for the odds of achieving a response in those with minor alleles compared with those with major alleles.The response was assessed according to criteria set in the study, and only binary response outcomes (i.e., responders/non-responders) were included.If a study reported multiple categorical outcomes (e.g., non-responders, intermediate responders, and good responders), the responders categories were pooled to be non-responders vs. all other types of responders unless otherwise specified in the study.If a study reported a response for multiple time points, the one with the most comprehensive data was selected.Each SNP was categorized according to drug class, treatment response, and the distribution of responders and non-responders according to minor and major alleles.Minor alleles were categorized according to the National Center of Biotechnology Information in the National Institute of Health (NCBI, NIH), unless otherwise specified.

Results
In total, 3104 studies were assessed, of which 267 were included for full-text screening.Of these, 185 studies comprising a total of 62,774 patients met the prespecified inclusion criteria and were included in the systematic review (Figure 1).Of the 185 studies, 32 (17.3%) included patients with psoriasis, 7 (3.8%)included patients with PsA, 100 (54.1%) included patients with RA, and 46 (24.9%) included patients with IBD (Supplementary Tables S2-S5).

Association between SNPs and Response to Biologics in Psoriasis
In total, 32 studies including 4413 patients assessed the association between genetic variants and response to biologics in patients with psoriasis.Of the assessed genetic variants, 126 have been associated with response to treatment with biologics among patients with psoriasis.Most SNPs were assessed in patients treated with TNFi, and most SNPs were only assessed in one study (Supplementary Table S2).

Association between SNPs and Response to TNFi in Psoriasis
In total, 27 studies including 3647 patients assessed the association between genetic variants and response to treatment with TNFi for patients with psoriasis.Of the assessed genetic variants, 118 across 85 genes have been associated with response to treatment with TNFi (Supplementary Table S2).The SNPs assessed several times were primarily in the genes linked to the working mechanism of the TNFi where SNPs in the TNF-α gene, TNF-α receptor, and TNFAIP3 were the most frequently investigated.

Association between SNPs and Response to IL-12/-23i in Psoriasis
In total, seven studies including 572 patients assessed the association between genetic variants and response to treatment of psoriasis with IL-12/23i.Of the assessed genetic variants, 44 SNPs across 36 genes have been associated with response or lack of response to IL-12/23i.Four studies (n = 416 patients) and four genetic variants were assessed in the meta-analysis, none of which were associated with a response to treatment with IL-12/23i (Supplementary Table S6).

Association between SNPs and Response to IL-17i in Psoriasis
Two studies including 194 patients assessed the association between genetic variants and response to treatment with IL-17i.Here, TYK2 (rs2304255), DDX58_v1 (rs34085293), and MICB-DT (rs9267325) were associated with response [43], while IL-17A (rs2275913) was not associated with response [44].

Association between SNPs and Response to Biologics in Psoriatic Arthritis
In total, seven studies including 469 patients assessed the association between genetic variants and response to biologics in patients with PsA.Of the genetic variants, nine SNPs across eight genes have been associated with response (Supplementary Table S3).All variants were assessed in patients treated with TNFi.Only FCGR2A (rs1801274) could be included in the meta-analysis, and no association with a response (OR: 3.29 [95% CI: 0.20-52.96])was observed, including two studies (n = 114 patients [45,46]).

Association between SNPs and Response to Biologics in Rheumatoid Arthritis
In total, 100 studies including 42,886 patients assessed the association between SNPs and response to biologics in RA.Of the assessed genetic variants, 232 have been associated with response to treatment with biologics among patients with RA of which most were assessed for TNFi and most were only assessed in one study (Supplementary Table S4).

Association between SNPs and Response to TNFi in Rheumatoid Arthritis
In total, 77 studies including 38,225 patients assessed the association between genetic variants and response to treatment with TNFi in patients with RA.Of the genetic variants, 211 across 162 genes were associated with response to TNFi (Supplementary Table S4).
The SNPs assessed were primarily in the genes linked to the working mechanisms of the therapeutic targets or in mechanisms important for the RA pathogenesis.

Association between SNPs and Response to Rituximab in Rheumatoid Arthritis
In total, 12 studies including 1998 patients assessed the association between genetic variants and response to treatment of RA patients with rituximab.Of the assessed genetic variants, nine across eight genes were associated with response to rituximab (Supplementary Table S4).Of the genetic variants, three could be included in the metaanalysis, of which two were associated with a response to rituximab in RA.The minor allele of TNFSF13B (rs9514828) was associated with poor response (OR: 0.33 [95% CI: 0.13-0.82]) to rituximab across two studies (n = 267 patients [64,65]).The minor allele of FCGR3A (rs396991) was associated with a good response to rituximab (OR: 1.71 [95% CI: 1.16-2.51])across five studies (n = 602 patients [66][67][68][69][70]).

Association between SNPs and Response to Abatacept in Rheumatoid Arthritis
In total, three studies including 272 patients assessed the association between genetic variants and response to treatment with abatacept in RA patients.Of the six assessed genetic variants, three genetic variants across two genes were associated with response to abatacept (Supplementary Table S4).Only the SNP in FCGR3A (rs396991) could be included in the meta-analysis, showing no association with response to abatacept across two studies including 141 patients [75,76].

Association between SNPs and Response to Biologics in Inflammatory Bowel Diseases
In total, 46 studies including 15,006 patients assessed the association between genetic variants and response to biologics in patients with IBD.Of the genetic variants, 166 were associated with response to treatment with biologics among patients with IBD of which most were assessed for TNFi, and most were only assessed in one study (Supplementary Table S5).

Association between SNPs and Response to TNFi in Inflammatory Bowel Diseases
In total, 46 studies including 14,896 patients assessed the association between genetic variants and response to treatment of IBD with TNFi.Of the genetic variants, 166 across 132 genes were associated with response to TNFi (Supplementary Table S5).Thirteen studies assessed SNPs for TNFi as a class, and 33 studies investigated the individual TNFi.The SNPs were most often assessed in the genes linked to TNF-α signaling or in mechanisms important for the IBD pathogenesis.

Association between SNPs and Response to IL-12/-23i in Inflammatory Bowel Diseases
One study including 110 patients assessed the association between 7 genetic var and response to treatment of IBD with IL-12/-23i.Here, only PTPN2 (rs7234029) associated with a non-response to IL-12/-23i [88] (Supplementary Table S5).

Association between SNPs and Response to IL-12/-23i in Inflammatory Bowel Diseases
One study including 110 patients assessed the association between 7 genetic variants and response to treatment of IBD with IL-12/-23i.Here, only PTPN2 (rs7234029) was associated with a non-response to IL-12/-23i [88] (Supplementary Table S5).

Discussion
In this systematic review and meta-analysis, we identified and systematically reported all SNPs outside the HLA region that were associated with a response to treatment with biologics for patients with psoriasis, PsA, RA, and IBD.In total, 126 SNPs have been associated with response in psoriasis, 9 in PsA, 232 in RA, and 166 in IBD.In the metaanalysis, 5 SNPS showed significant association with a response to the CIDs together, 15 in psoriasis, none in PsA, 9 in RA, and 7 in IBD.
Identification of genetic markers of treatment response is of great importance as a considerable proportion of patients treated with biologics do not respond to the given biologic.As shown in this systematic review and meta-analysis, multiple studies have assessed genetic markers and found them associated with response.Across all CIDs, genetic variants in TNF-α and Fc-γ receptor genes in relation to response to TNFi were the most heavily investigated.
A previous meta-analysis found no association between the minor allele of TNF-α-308 (rs1800629) and response to TNFi among patients with psoriasis or IBD108, but did find an association for patients with RA [121,122].Interestingly, we found the minor allele of TNF-α-308 (rs1800629) to be associated with a poor response to TNFi when assessing all CIDs together, but only for psoriasis when the diseases were examined individually.We did see a similar direction of response across the diseases, and the lack of association might be due to differences in design and the number of patients.The minor allele of TNF-α-238 (rs361525) was not associated with response to TNFi for any of the diseases when examining TNFi together.However, when evaluating etanercept alone, the minor allele was associated with poor response to TNFi in psoriasis and infliximab alone when all diseases were pooled.This could be due to differences in the mode of action of the individual TNFi, as the association with the response to adalimumab appeared to be in the opposite direction than the other TNFis although this was not significant.In agreement with Antonatos et al. [121], the current meta-analysis only found an association between the minor allele of TNF-α-857 (rs1799724) and the poor response to TNFi in patients with psoriasis.The persistent association between genetic variants in the TNF-α genes and response to TNFi underlines the importance of these genes.The genetic variants have been shown to alter the expression and/or levels of TNF-α, which is a plausible mechanism for association [123].However, the conflicting results and potential differences in the drugs warrant further studies differentiating the individual drugs.
The association between genetic variants in the Fcγ-receptors (FCGR3A (rs396991) and FCGR2A (rs1801274)) and response to biologics have been assessed in several studies.The FcγR2A-and FcγR3A receptors play a central role in antibody-dependent immune response.FCGR3A (rs396991) has been associated with the development of RA [124] and FCGR2A (rs1801274) with UC [125].In the meta-analysis, we found the minor allele of FCGR3A (rs396991) to be associated with poor response to TNFi and infliximab alone when pooling all CIDs together; similarly, this was observed for RA and IBD alone but not for psoriasis.For rituximab, the opposite association was observed, with the minor allele being associated with a good response to treatment in patients with RA.Interestingly, the minor allele of FCGR3A (rs396991) has been shown to lead to higher surface expression of FCGR3A [126] and also has a higher affinity to IgG than the major allele [127].For TNFi, the lower response rate has been suggested to be a result of higher FcγR-mediated drug clearance resulting in lower drug levels and, therefore, a worse response [58], while higher levels of FcγRIIIa/CD16 expression leading to higher B-cell depletion have been suggested to be the reason for better response to rituximab in patients having the minor allele [70,128].These results suggest FCGR3A (rs396991) to be a potential variant for choice of drug in patients with RA.However, further investigations into the association between SNPs in the Fcγ receptors, drug levels, and response to biologics are warranted.Some limitations should be considered when interpreting the results of the metaanalyses.First, the included studies were heterogeneous with heterogeneous populations, response criteria, and sample size, which complicates the meta-analysis and interpretation of the results.Furthermore, most studies assessed TNFi as a group, and differences in structure, affinity, and specific target of the individual target might lead to different effects of the SNPs.Few studies have assessed drugs other than TNFi, and to be able to use genetic variants to stratify patients, the association between SNPs and other treatments needs to be conducted.Other factors, including biomarkers like serostatus for RA [129], and clinical factors like smoking and body weight [130][131][132][133][134], can influence response and might dilute the result of the meta-analysis.However, these should not be considered classical confounders as few of the SNPs are believed to be associated with these.Lastly, only individual SNPs could be included, and the inclusion of pathway analyses might have revealed other genetic variants associated with response.Similarly, the identification of underlying biological mechanisms may improve the predictive potential.On the other hand, the identification of markers across several diseases, including heterogeneous studies, underlines the robustness of the observed associations.
Taken together, numerous SNPs have been associated with a response to treatment with biologics in psoriasis, PsA, RA, and IBD.The current systematic review provides an overview of these SNPs.However, most of the studied SNPs have only been assessed once or twice, and in the meta-analysis, only a fraction of the SNPs was significant and primarily in treatment with TNFi.This indicates that several of the SNPs that were found to be associated in individual studies could be due to chance findings and require further investigation and validation in other cohorts as well as assessed for biologics with other targets.Furthermore, the results suggest that none of the assessed SNPs alone can predict whether a patient will respond or not to a given biologic, and collaborations working toward polygenic risk gene scores should be established.
In conclusion, we present a systematic overview of all SNPs that have been associated with response to biologics in the treatment of psoriasis, PsA, RA, and IBD.Genetic variants in TNFα, NLRP3, MYD [88], and FcγR genes are associated with response to TNFi when assessing several inflammatory diseases together.For the individual diseases, 126 genetic variants were found to be associated with a response to biologics in psoriasis, 9 in PsA,

Figure 2 .
Figure 2. Genetic variants significantly associated with response to biologics among patients with psoriasis in the meta-analysis.

Figure 2 .
Figure 2. Genetic variants significantly associated with response to biologics among patients with psoriasis in the meta-analysis.

22 Figure 3 .
Figure 3. Genetic variants significantly associated with response to biologics among patients with rheumatoid arthritis in the meta-analysis.

Figure 3 .
Figure 3. Genetic variants significantly associated with response to biologics among patients with rheumatoid arthritis in the meta-analysis.

9 Figure 4 .
Figure 4. Genetic variants significantly associated with response to biologics among patients inflammatory bowel diseases in the meta-analysis.

Figure 4 .
Figure 4. Genetic variants significantly associated with response to biologics among patients with inflammatory bowel diseases in the meta-analysis.

Figure 5 .
Figure 5. Genetic variants significantly associated with response to biologics among patients acro all indications in the meta-analysis.

Figure 5 .
Figure 5. Genetic variants significantly associated with response to biologics among patients across all indications in the meta-analysis.

Table 1 .
Pooled odds ratio using random effects meta-analysis for all diseases combined.
TNFi combined: includes studies assessing TNFi overall but also individual drugs.TNFi overall: includes only studies assessing TNFi overall as a drug class.* p < 0.05.# odds ratio (OR) of response comparing minor allele with major allele, OR > 1 favors major allele, OR < 1 favors minor allele.