Abstract Objective To evaluate gene expression in blood of patients with psoriatic arthritis (PsA) versus healthy controls and identify changes associated with guselkumab treatment. Methods Whole blood transcriptome profiling via paired‐end RNA sequencing was conducted using samples from DISCOVER‐1 and DISCOVER‐2 at baseline (n = 673) and at weeks 4 and 24 from a representative subgroup that received placebo or guselkumab (n = 227 [longitudinal PsA cohort]). Baseline samples were compared with demographically matched healthy controls (n = 21). Guselkumab‐mediated changes in gene expression were assessed in participants from the longitudinal PsA cohort who did versus did not achieve at least 20% improvement in American College of Rheumatology response criteria (ACR20) or at least 75% improvement in Psoriasis Area and Severity Index (PASI75). Differential gene expression was analyzed using edgeR. Results At baseline, 355 upregulated and 314 downregulated genes (PsA‐associated genes) were identified in patients with PsA versus healthy controls. Upregulated genes were related to neutrophil, mononuclear cell, and CD11b+ gene sets. No cell type–specific gene sets were identified among downregulated genes. Most PsA‐associated genes were modulated by guselkumab treatment. At week 24, genes downregulated by guselkumab were enriched with neutrophil, monocyte, eosinophil, and macrophage gene sets; genes upregulated by guselkumab were enriched with B cell, T cell, and natural killer cell gene sets. Reductions in expression of upregulated PsA‐associated gene sets were more pronounced in ACR20 and PASI75 responders than in nonresponders. Conclusion These findings suggest a dysregulation of immune cell profiles in blood from patients in the baseline PsA cohort that approached levels in healthy controls after guselkumab treatment. INTRODUCTION Psoriatic arthritis (PsA) is a heterogenous chronic inflammatory disease characterized by inflammation, pain, and structural damage in peripheral joints. Other PsA disease domains include enthesitis, dactylitis, skin and nail lesions, and axial arthritis ([44]1, [45]2, [46]3). Additionally, patients with PsA may experience fatigue, work productivity loss, physical disability, and psychosocial and functional impairments ([47]4, [48]5). Advances in understanding the underlying pathogenesis of psoriasis and PsA, most notably the key role for the interleukin (IL‐23)/IL‐17 axis ([49]6, [50]7), have led to the successful development of disease‐modifying antirheumatic drugs (DMARDs) targeting this pathway, which are now part of standard clinical practice ([51]1, [52]2, [53]3). However, therapeutic decisions remain largely empirical, and many patients fail to respond sufficiently to their current therapy. As such, there remains significant unmet clinical need in PsA. Targeted therapies offer an opportunity to better understand the underlying disease processes in humans and the biomarkers associated with disease response. IL‐23 is a proinflammatory cytokine composed of the p19 and p40 subunits. The p40 subunit is shared with IL‐12, whereas the p19 subunit is unique to IL‐23. As an upstream regulator, IL‐23 promotes the maturation and pathogenicity of Th17 cells, which in turn produce effector cytokines, including IL‐17A, IL‐17F, IL‐22, and tumor necrosis factor ([54]7, [55]8). Guselkumab, a fully human anti‐IL‐23 monoclonal antibody targeting the p19 subunit, is the first such agent to have gained approval to treat adults with moderate‐to‐severe plaque psoriasis or active PsA. Efficacy and safety of guselkumab were demonstrated in the phase 3 DISCOVER‐1 study conducted in patients with PsA who were bio‐ naive or who had previously received up to two TNFi (about 30% of the study population) and in the phase 3 DISCOVER‐2 study in patients with PsA who were bio‐naive. Guselkumab demonstrated significant clinical benefit, consistent safety versus placebo at week 24 in patients with active PsA, with maintenance of clinical response demonstrated up to 1 year in DISCOVER‐1 and through 2 years of treatment in DISCOVER‐2 ([56]9, [57]10, [58]11, [59]12, [60]13). Previous analyses of protein expression from 300 DISCOVER‐1 and DISCOVER‐2 participants revealed that serum levels of C‐reactive protein (CRP), serum amyloid A (SAA), IL‐6, IL‐17A, and IL‐17F were elevated at baseline in patients with active PsA compared with matched healthy controls ([61]14). Guselkumab treatment reduced the levels of these serum proteins by week 4, with further reductions seen at week 24. Although levels of IL‐17A and IL‐17F at baseline were found to correlate with disease activity and therapeutic response in the skin, they did not correlate with disease activity in the joints at baseline or after treatment with guselkumab ([62]14). Furthermore, only weak associations between baseline CRP, SAA, and IL‐6 levels and baseline joint disease activity were observed. Similar results have been reported in other studies, suggesting that these biomarker levels may not predict treatment response ([63]15). Further studies are needed to better understand PsA pathophysiology and to identify reliable disease biomarkers. Results from analyses of transcriptome profiling by RNA sequencing using whole blood samples collected from participants in the DISCOVER‐1 and DISCOVER‐2 studies are reported herein. The objectives of these analyses were to gain insight into the underlying biology of PsA by identifying PsA‐associated genes and to identify gene expression changes associated with guselkumab treatment overall and in treatment responders versus nonresponders. MATERIALS AND METHODS Study design and participants Complete descriptions of the DISCOVER‐1 and DISCOVER‐2 studies have been published ([64]12, [65]13). Briefly, DISCOVER‐1 and DISCOVER‐2 were multicenter, double‐blind, randomized, placebo‐controlled phase 3 studies in adults with active PsA. Both studies enrolled adult participants with active disease (DISCOVER‐1: ≥3 tender and ≥3 swollen joints and a CRP concentration of ≥0.3 mg/dl; DISCOVER‐2: ≥5 tender and ≥5 swollen joints and a CRP concentration of ≥0.6 mg/dl) despite standard treatment (conventional synthetic DMARDs, apremilast, oral corticosteroids, or nonsteroidal anti‐inflammatory drugs). In DISCOVER‐1, participants previously treated with up to two TNFi (about 30% of the study population) could participate; prior biologic therapy was prohibited in DISCOVER‐2. In both studies, participants were randomized 1:1:1 to receive 100 mg of subcutaneous guselkumab every 4 weeks (Q4W), 100 mg of guselkumab at weeks 0 and 4 and subsequently every 8 weeks (Q8W), or the matching placebo. Starting at week 24, participants in the placebo group crossed over to receive 100 mg of guselkumab Q4W. The studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. At each site, study protocols were approved by the governing ethical body. All study participants provided written informed consent. Additional consent was provided for gene expression evaluation. The trials were registered at [66]ClinicalTrials.gov ([67]NCT03162796 [DISCOVER‐1] and [68]NCT03158285 [DISCOVER‐2]). Clinical efficacy assessments The primary endpoint for each study was the proportion of participants achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) ([69]16) at week 24 ([70]12, [71]13). The proportion of patients achieving at least 75% improvement in the Psoriasis Area and Severity Index (PASI75) ([72]17) was also evaluated as a predefined secondary endpoint at week 24 in both studies. PASI75 response was evaluated in participants with 3% or more body surface area with psoriatic involvement and an Investigator's Global Assessment score of ≥2 (mild‐to‐severe PsO) at baseline. Sample collection and processing For biomarker analyses, whole blood samples collected at week 0 (baseline), week 4, and week 24 were analyzed from consenting participants in the DISCOVER‐1 and DISCOVER‐2 studies (baseline PsA cohort). Blood samples collected at weeks 4 and 24 were analyzed from a subgroup of the baseline PsA cohort (227 of 673 [33.7%]), hereafter referred to as the longitudinal PsA cohort. The baseline and longitudinal PsA cohorts were selected after study completion with baseline characteristics, such as demographics, disease activity, and concomitant medication use, representative of the overall cross‐study populations (Supplementary Table 1). Independent of the clinical program, blood was also collected and analyzed from 21 demographically matched (age, sex, and race and ethnicity) healthy controls. RNA was isolated from whole blood collected in PAXgene® Blood RNA Tubes (BD Biosciences). Globin messenger RNA (mRNA) was removed using GLOBINclear (Invitrogen). Whole blood transcriptome profiling by paired‐end RNA sequencing (TruSeq Stranded mRNA; Illumina) was performed using the NovaSeq Sequencing System (Illumina) at a depth of 30 million reads per sample. The samples were run in a single batch. Statistical analysis Treatment group and responder cohort comparisons in baseline demographic and disease characteristics and clinical response (ACR20 and PASI75) at week 24 were assessed via chi‐square test or Kruskal‐Wallis rank sum test. These analyses were not corrected for multiple comparisons. Participants meeting treatment failure criteria (discontinued study treatment, terminated study participation, initiated or increased DMARD or oral corticosteroid doses, or initiated protocol prohibited‐PsA treatment) were considered nonresponders for the ACR20 and PASI75 endpoints ([73]12, [74]13). Differential gene expression was assessed using various functions (eg, estimateDisp, glmQLFit, and glmQLFTest) in edgeR (Version 3.28.1) on log‐transformed counts per million ([75]18, [76]19, [77]20). Transcripts from low‐expressing genes, that is below the minimum count criteria defined by the filterByExpr function from the edgeR package in R ([78]19, [79]20), and nonprotein coding genes were excluded from the analysis. Raw counts were converted to log2 counts per million prior to differential expression analysis. Gene expression distributions were normalized using the trimmed mean of M‐values method (calcNormFactors function) in edgeR ([80]18). Differentially expressed genes were defined by significance (false discovery rate [FDR] <0.05) and |log fold change| greater than 1 using all baseline samples (including those without follow‐up). Differentially expressed genes in the baseline PsA cohort versus healthy controls were assessed for cell type enrichment using SaddleSum ([81]21), with enrichment terms tested using the Gene Expression Barcode database ([82]22). For the longitudinal PsA cohort, the participant was added as a variable into the modeling for differential expression (week 0 vs. week 4 and week 0 vs. week 24) to account for paired comparison between time points from the same participants. FDR <0.05 was considered significant. Overall changes from baseline in guselkumab‐mediated gene expression were examined at week 24 in the longitudinal PsA cohort after pooling the guselkumab Q4W and Q8W groups, with significance defined by an FDR < 0.05; a fold‐change cutoff was not applied for these analyses. Genes whose expression patterns changed with guselkumab treatment at week 24 were tested for cell type enrichment using SaddleSum with enrichment terms from CIBERSORT cell signatures ([83]23). Statistics were based on the generalized linear model using a paired subject design in edgeR (glmQLFit). Gene set enrichment scores were calculated using gene set variation analysis (GSVA) ([84]24). GSVA was performed using the list of PsA‐associated genes defined from differential expression analysis between the baseline PsA cohort and healthy controls to obtain gene set variation enrichment scores. Differences in the mean enrichment scores of disease genes in the guselkumab Q4W or Q8W groups versus placebo at weeks 4 and 24 were assessed using the Wilcoxon signed‐rank test. Guselkumab‐mediated changes in gene set enrichment scores for baseline differentially expressed PsA‐associated genes were also compared between clinical responders and nonresponders within the longitudinal PsA cohort. Responders were defined as participants achieving ACR20 or PASI75 response at week 24. For analyses of PsA‐associated gene expression by PASI75 response, the guselkumab Q4W and Q8W groups were pooled due to the low number of PASI75 nonresponders observed (n = 24 of 227) compared with responders (n = 138 of 227) across both guselkumab treatment groups. Statistical significance was based on a paired t‐test relative to baseline for the respective treatment arms. Additional pathway analyses of the PsA‐associated genes and of the guselkumab‐modulated differentially expressed genes were conducted using the gProfiler tool ([85]https://biit.cs.ut.ee/gprofiler). gProfiler performs gene set enrichment analysis by mapping genes to known functional information sources to detect statistically significantly enriched terms. Inputted genes were selected by an FDR less than 0.05 and |fold change| greater than or equal to 1.25. RESULTS Baseline cohort characteristics Whole blood samples were analyzed from 673 participants across the DISCOVER‐1 and DISCOVER‐2 studies (baseline PsA cohort). This cohort was balanced across treatment groups with respect to age, race, sex, geographic region, PsA onset and duration, and prior PsA therapy, representative of the overall DISCOVER‐1 and DISCOVER‐2 populations (Supplementary Table [86]1). Additionally, as was reflective of the overall primary study populations, among participants in the baseline PsA biomarker cohort, ACR20 and PASI75 response rates at week 24 were significantly greater in the guselkumab groups compared with the placebo group (Supplementary Table [87]1) ([88]12, [89]13). Baseline characteristics and baseline gene expression were similar between the responder and nonresponder cohorts (all P = not significant; data not shown). PsA‐associated genes A total of 669 differentially expressed genes, defined as PsA‐associated genes (disease genes), were identified in the DISCOVER‐1 and DISCOVER‐2 baseline PsA cohort when compared with healthy controls. Of these, 355 genes were upregulated and 314 genes were downregulated in PsA at baseline compared with healthy controls. The top 20 differentially expressed genes are displayed in Figure [90]1. Genes upregulated in PsA were primarily associated with neutrophil, mononuclear cell, and CD11b+ cell gene sets (Table [91]1). In contrast, no cell type–specific gene sets were identified among the genes downregulated in the baseline PsA cohort compared with healthy controls. Pathway analysis conducted using gProfiler indicated that the dysregulated pathways among PsA‐associated genes included the following REACTOME ([92]www.reactome.org) pathways: neutrophil degranulation; NOTCH4 and NOTCH3 signaling, which are associated with inducing Th1/Th17 cells in inflammatory arthritis ([93]25); and IL‐4 and IL‐13 signaling, which are involved in upregulation of the Th1‐driven proinflammatory response and downregulation of Th17‐mediated immune response ([94]26) (Supplementary Table [95]2). Figure 1. Figure 1 [96]Open in a new tab Top 20 differentially expressed genes in the baseline PsA cohort versus healthy controls. LogFC for downregulated and upregulated genes in PsA are shown in blue and red, respectively. Statistics based on generalized linear model using edgeR (glmQLFit). FC, fold change; FDR, false discovery rate, PsA, psoriatic arthritis. Table 1. Cell type enrichment of PsA disease‐associated genes Gene set for cell type GSVA score FDR Genes upregulated in PsA Neutrophils 52.75 3.13 × 10^−6 Mononuclear cells 53.42 1.60 × 10^−5 CD11b+ cells 54.06 3.87 × 10^−5 [97]Open in a new tab Note: Genes upregulated in PsA were identified by comparing gene expression in the baseline PsA cohort vs. healthy controls. Enrichment statistics were derived from SaddleSum ([98]21), and enrichment terms were tested using the Gene Expression Barcode database ([99]22). Abbreviations: CD, Cluster of Differentiation; FDR, false discovery rate; GSVA, gene set variation analysis; PsA, psoriatic arthritis. Modulation of gene expression by guselkumab over time Among participants included in the longitudinal PsA cohort (n = 227; placebo = 65, guselkumab Q4W = 79, guselkumab Q8W = 83), treatment with guselkumab (pooled Q4W and Q8W arms) modulated the expression of PsA‐associated genes (disease genes) at week 24 compared with baseline (Figure [100]2). Of the 355 disease genes shown to be upregulated at baseline in Figure [101]2, 293 (82%) were decreased from baseline with guselkumab treatment (Q4W and Q8W) at week 24. Similarly, for 242 (77%) of the 314 downregulated disease genes at baseline, expression was increased with guselkumab treatment at week 24. Moreover, neither guselkumab nor placebo treatment increased the expression of genes upregulated in disease or decreased the expression of genes downregulated in disease. Genes downregulated from baseline with guselkumab treatment at week 24 were enriched in neutrophil, monocyte, eosinophil, and macrophage gene sets, whereas genes upregulated by guselkumab were enriched in B cell, T cell, and natural killer (NK) cell gene sets (Table [102]2). Figure 2. Figure 2 [103]Open in a new tab Genes modulated by guselkumab treatment and genes differentially expressed in the baseline PsA cohort versus healthy controls. Genes that were downregulated in the baseline PsA cohort and increased with guselkumab treatment at week 24 are shown in blue, whereas genes upregulated in the baseline PsA cohort and decreased with guselkumab at week 24 are shown in red. Black and gray dots on the left‐hand side represent genes that are decreased by guselkumab treatment (but not upregulated in PsA), whereas those on the right‐hand side represent genes increased by guselkumab treatment (but not downregulated in PsA). Significance was defined by an FDR < 0.05 (ie, only genes that were significantly upregulated or downregulated are shown in the figure). FC, fold change; FDR, false discovery rate; GUS, guselkumab; PsA, psoriatic arthritis. Table 2. Gene set enrichment of downregulated and upregulated genes associated with guselkumab (pooled Q4W and Q8W) treatment at week 24 Gene set for cell type GSVA score FDR Downregulated at week 24 vs. baseline Neutrophils 10.76 1.4 × 10^−37 Monocytes 6.78 4.0 × 10^−19 Eosinophils 4.64 2.1 × 10^−9 Macrophages M0 2.87 1.8 × 10^−4 Upregulated at week 24 vs. baseline B cells, naive 5.66 3.5 × 10^−21 B cells, memory 5.46 2.3 × 10^−19 Treg cells 4.43 1.5 × 10^−12 T cells, CD8 4.34 4.1 × 10^−11 T cells, follicular helper 3.97 7.5 × 10^−11 T cells, CD4 naive 3.56 1.9 × 10^−9 T cells, CD4 memory resting 3.85 5.9 × 10^−9 T cells, gamma delta 2.95 6.7 × 10^−5 T cells, CD4 memory activated 2.26 1.1 × 10^−3 NK cells, activated 2.72 1.3 × 10^−3 NK cells, resting 2.66 1.5 × 10^−3 Plasma cells 2.34 3.8 × 10^−3 [104]Open in a new tab Note: Differential expression was assessed using a paired analysis of week 24 versus baseline for the 100 mg of guselkumab Q4W and Q8W treatment arms combined. Results were generated by SaddleSum using logFC as weights for genes with an FDR < 0.05 and the term database of CIBERSORT cell signatures. Abbreviations: FC, fold change; FDR, false discovery rate; GSVA, gene set variation analysis; NK, natural killer; Q4W, every 4 weeks; Q8W, every 8 weeks. As assessed by change from baseline in median GSVA score over time, gene sets upregulated in the baseline PsA cohort were significantly decreased, whereas downregulated gene sets were significantly increased with guselkumab versus placebo treatment at weeks 4 (Q8W only) and 24 (Q4W and Q8W). At week 24, the change in GSVA score for upregulated genes was numerically greater in the guselkumab Q8W arm than in the guselkumab Q4W arm. No significant changes from baseline in median GSVA score were observed over time in participants receiving placebo (Figure [105]3). Pathway analysis of the differentially expressed genes at week 24 of guselkumab treatment indicated that extracellular matrix organization and collagen formation were the top REACTOME pathways modulated by guselkumab (Supplementary Table [106]3). Figure 3. Figure 3 [107]Open in a new tab Change from baseline in median GSVA scores for differentially expressed disease‐associated genes in PsA. Solid lines represent genes upregulated in PsA at baseline compared with healthy controls, and dashed lines represent downregulated genes in PsA at baseline. The statistical significance of the change from baseline in median GSVA score for guselkumab Q4W or Q8W versus placebo was assessed via Wilcoxon signed‐rank test. GSVA, gene set variation analysis; GUS, guselkumab; PBO, placebo; PsA, psoriatic arthritis; Q4W, every 4 weeks; Q8W, every 8 weeks. *P < 0.05; **P < 0.01; ***P < 0.001. Modulation of PsA‐associated gene expression by clinical response Among participants in the longitudinal PsA cohort, gene set enrichment scores for upregulated PsA‐associated genes were significantly decreased from baseline at week 24 in ACR20 responders in the guselkumab Q4W and guselkumab Q8W groups to levels approaching those in healthy controls (ie, normalized) (Figure [108]4A). Median gene set enrichment scores were also lower in the guselkumab Q4W and guselkumab Q8W groups at week 4 than at baseline, but the differences were not significant. No significant changes in the expression of upregulated PsA‐associated genes were observed in ACR20 responders in the placebo group or in ACR20 nonresponders across treatment groups, although median gene set enrichment scores were numerically lower in nonresponders of the guselkumab Q4W and guselkumab Q8W groups at weeks 4 and 24 relative to baseline. Figure 4. Figure 4 [109]Open in a new tab Changes in enrichment score of upregulated disease genes stratified by ACR20 response (A) or PASI75 response (B) at weeks 4 and 24. Statistics for within–treatment group comparisons were based on a paired t‐test relative to baseline for the treatment arms, with the DISCOVER‐1 and DISCOVER‐2 cohorts combined. The guselkumab treatment arms were combined for the PASI75 analysis because of the low number of PASI75 nonresponders observed across both groups. In the box‐and‐whisker plots, the diamond symbol indicates the sample mean. ACR20, ≥20% improvement in the American College of Rheumatology response criteria; BL, baseline; GUS, guselkumab; HC, healthy control; ns, not significant; PASI75, ≥75% improvement in the Psoriasis Area and Severity Index; PBO, placebo; Q4W, every 4 weeks; Q8W, every 8 weeks. *P < 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P < 0.0001. Among PASI75 responders within the longitudinal PsA cohort, gene set enrichment scores for upregulated PsA‐associated genes were significantly decreased from baseline with guselkumab treatment at weeks 4 and 24 (Figure [110]4B). No significant changes were observed in participants who received placebo or in PASI75 nonresponders; in nonresponders, median gene set enrichment scores trended lower at weeks 4 and 24 than at baseline in the combined Q4W and Q8W group. DISCUSSION Whole blood transcriptome profiling revealed differential gene expression in patients with active PsA from the DISCOVER‐1 and DISCOVER‐2 clinical studies in comparison with healthy controls. Genes upregulated in the baseline PsA cohort were primarily related to neutrophil, mononuclear cell, and CD11b+ cell gene sets, whereas downregulated PsA‐associated genes were not related to gene sets specific to any cell types. The pathways identified as enriched among the PsA‐associated genes were neutrophil granulation, NOTCH4 and NOTCH3 signaling, and IL‐4 and IL‐13 signaling. The finding that myeloid gene sets are upregulated in disease is consistent with prior reports of increased myeloid cell types, including CD64+ and CD14+CD16+ monocytes, in the blood of patients with PsA, although further study is needed to better define the immune cells identified to be affected in this analysis ([111]27, [112]28). Gene expression signatures have been previously reported in small studies using microarray analyses of peripheral blood from patients with PsA compared with healthy controls ([113]29, [114]30, [115]31). In a study of 19 patients with PsA and 19 age‐ and sex‐matched healthy controls, the expression of the proinflammatory genes S100A8, S100A12, and thioredoxin was increased, whereas the expression of genes related to B cells and the regulation of immune responses was decreased ([116]29). Another study of 16 patients with PsA and 15 healthy controls reported both upregulated and downregulated genes within several functional categories, including cell adhesion, T and B cell–mediated immunity, and cytokine and chemokine signaling ([117]30). In a separate small study comparing gene expression in patients with PsA versus healthy controls, differentially expressed genes clustered into several functional categories, including immune response, innate immunity, and inflammation. This study also showed similarities between genes differentially expressed in whole blood and in the synovium of patients with PsA ([118]31). Differences in sample size, analysis method (microarray vs. RNA sequencing), and patients’ disease characteristics (eg, level of disease activity required for inclusion in a phase 3 study) may contribute to differences in PsA‐associated genes identified in the present study compared with those previously reported. The expression of most (77%‐82%) PsA‐associated genes identified in the baseline PsA cohort was modulated by guselkumab treatment, as assessed at week 24, with directional changes in gene expression suggestive of normalization toward healthy controls. In particular, genes related to neutrophils, monocytes, eosinophils, and macrophages were downregulated and genes related to B cells, T cells, and NK cells were upregulated with guselkumab treatment at week 24 compared with baseline. These findings suggest that guselkumab treatment suppresses inflammation‐associated pathways and may partially normalize immune cell composition in patients with PsA. The top pathways associated with guselkumab‐modulated changes in PsA‐associated genes included extracellular matrix organization and collagen formation. These results are complementary to protein‐level findings from the DISCOVER‐2 study showing that serum levels of collagen turnover biomarkers associate with PsA disease activity and decrease with guselkumab treatment ([119]32). Greater modulation of upregulated PsA‐associated genes was seen in both joint (ACR20) responders and skin (PASI75) responders than in nonresponders. Among guselkumab‐treated participants in the longitudinal PsA cohort, significant reductions in gene set enrichment scores were observed for upregulated PsA‐associated genes at week 24 in responders only. Together, these findings suggest that inhibition of IL‐23 with guselkumab treatment partially normalizes transcriptomic signatures of immune cell genes in whole blood of patients with PsA, which may in turn contribute to clinical responses in the joints and skin. Further study of these genes is warranted to evaluate their potential as predictors and mediators of response ‐ for example, whether the same gene sets are seen in responders for therapies targeting other cytokines or if changes are specific to guselkumab treatment. A head‐to‐head analysis with other biologic therapies could provide such information. These analyses are strengthened by large sample size, random allocation of therapy, and availability of the placebo‐controlled cohort. However, these analyses have several limitations. Samples were collected from patients with PsA with active disease who met inclusion criteria for participation in either of the DISCOVER studies. Thus, the findings may not be generalizable to all patients with PsA, such as those with less severe disease or disease managed by standard therapies. The analyses are also limited by the relatively short time frame for analysis (24 weeks), given the chronic nature of PsA, which typically requires long‐term treatment. However, clinical changes in response to guselkumab are observed before or by week 24 ([120]12, [121]13). In conclusion, these analyses revealed dysregulation of immune cell profiles in blood from patients with PsA versus healthy controls. Guselkumab treatment partially normalized pathway genes related to specific immune cell populations, suggesting modulation of immune cell composition, which may drive the clinical responses observed in patients with PsA treated with guselkumab. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Chen, Song, Seridi, and Miron had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design Hsia, Kollmeier, Xu, Sweet. Acquisition of data Sweet, Hsia, Kollmeier, Xu. Analysis and interpretation of data Siebert, Sweet, Ritchlin, Seridi, Song, Gao, Chen, Miron. ROLE OF THE STUDY SPONSOR Janssen R&D had a role in the study design, analysis, interpretation of the data, and the decision to submit the manuscript for publication. Supporting information Disclosure Form: [122]Click here for additional data file.^ (961KB, pdf) Supplementary Table 1 Baseline demographic and disease characteristics of patients in the baseline PsA biomarker cohort [123]Click here for additional data file.^ (19.2KB, docx) Supplementary Table 2 Pathway enrichment analysis results from gProfiler for PsA‐associated genes Pathway enrichment analysis of differentially expressed genes from samples obtained from patients with PsA from the DISCOVER‐1 and DISCOVER‐2 studies versus healthy control subjects. Inputted genes selected by FDR <0.05 and |fold change| ≥1.25. FDR, false discovery rate; PsA, psoriatic arthritis. [124]Click here for additional data file.^ (691.7KB, pdf) Supplementary Table 3 Pathway enrichment analysis results from gProfiler for differentially expressed genes at Week 24 of guselkumab treatment Pathway enrichment analysis of differentially expressed genes from Week 24 versus baseline samples obtained from patients with PsA in the guselkumab treatment arms (pooled Q4W and Q8W) of the DISCOVER‐1 and DISCOVER‐2 studies. Inputted genes selected by FDR <0.05 and |fold change| ≥1.25. FDR, false discovery rate; PsA, psoriatic arthritis; Q4W, every 4 weeks; Q8W, every 8 weeks. [125]Click here for additional data file.^ (426.5KB, pdf) ACKNOWLEDGMENTS