The causal relationship between uveitis and psoriatic arthritis: A bidirectional Mendelian randomisation study

Introduction

Psoriatic arthritis (PsA) represents a chronic, immune-mediated inflammatory joint disease characterised by musculoskeletal inflammation, predominantly occurring among patients with psoriasis. The onset of PsA is most common between the ages of 30 and 50, with no significant disparity between the sexes.¹ Over half of the individuals diagnosed with PsA report at least one comorbidity, such as cardiovascular disease, uveitis, depression, inflammatory bowel disease, and metabolic syndrome.² This complex association underscores the necessity for a comprehensive understanding of PsA pathogenesis. Genetic studies have provided valuable insights into the pathways and susceptibility loci associated with PsA development.^3,4 Exploring the genetic connections between PsA and these comorbidities holds promise for enhancing management strategies and developing targeted therapies, offering hope for future management of this challenging and burdensome condition.

Uveitis is characterised by intraocular inflammation occurring in the uveal tract and adjacent ocular structures. It stands as a leading cause of blindness and visual impairment, significantly impacting the quality of life of affected individuals.⁵ Approximately 10 to 15% of uveitis cases lead to complete vision loss, while reversible vision loss occurs in up to 35% of cases. The causes of uveitis are diverse, encompassing infections, systemic diseases, and autoimmune conditions. Additionally, between 1/4 and 1/3 of individuals with uveitis may exhibit extraocular or systemic manifestations, such as PsA.^6-8 In recent years, despite numerous studies having proven the association between uveitis and PsA, the causal relationship and underlying mechanisms remain unclear.^9-11 Previous studies were predominantly observational in nature, making them susceptible to various biases.

Mendelian randomisation (MR) is a genetic epidemiological research methodology that employs single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to discern potential causal relationships between exposure factors and outcomes based on the Mendelian laws of heredity.^12,13 In contrast to observational studies, MR studies possess several advantages. As genetic variation is determined at the time of conception, it predates disease development and is generally unaffected by confounding factors, such as acquired factors and the social environment. Consequently, the inferred causal associations from MR studies exhibit more cogent temporality, diminish confounding bias, and mitigate reverse causation.¹⁴ This study employed a two-sample bidirectional MR analysis utilising publicly available genome-wide association studies (GWAS) databases to investigate the causal relationship between uveitis and PsA. Although previous observational studies have reported an association between uveitis and PsA, their findings are subject to potential confounding, reverse causation, and measurement bias. These inherent limitations of observational designs highlight the importance of employing causal inference approaches such as MR, which can provide more robust evidence by minimising such biases.

Methods

Study design

To ascertain a causal relationship between uveitis and PsA, a two-sample bidirectional MR analysis was conducted utilising a combined dataset sourced from GWAS.^15,16 In forward MR analysis, uveitis is regarded as the exposure, while PsA serves as the outcome. Conversely, in reverse MR analysis, PsA is treated as the exposure, and uveitis as the outcome. The data utilised in this investigation were acquired from previously published studies, which received ethical approval from the respective committees, thereby obviating the need for additional ethical clearance. The pictorial representation of the study design has been shown in Figure 1. This MR analysis rests upon three core assumptions: (1) relevance, where selected SNPs are strongly associated with the exposure; (2) independence, meaning the SNPs are not associated with any confounders; and (3) exclusion restriction, implying the SNPs affect the outcome only through the exposure. These assumptions were addressed through stringent SNP selection criteria, pleiotropy screening using PhenoScanner, and validation through MR-Egger intercept sensitivity analyses.

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Figure 1:

Study design overview. MR analyses depend on three core assumptions.

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Results

Causal effect of uveitis on PsA

Meta-analysis results for the forward MR outcomes have been shown in Figure 2a. We discerned a causal association between uveitis and PsA, as indicated by the IVW method (OR=1.63, 95% CI: 1.22-2.19, P-value = 0.001). The reverse MR outcomes have been shown in Figure 2b (OR=1.55, 95%CI: 1.07-2.24, P-value = 0.02). The effects of a single SNP on uveitis and PsA has been depicted in the scatter plot [Supplementary Figure S1-S6 (A)] and forest plot [Supplementary Figure S1-S6 (B)]. Detailed results of the MR analysis have been shown in Supplementary Table S3.

Supplementary Figure S1

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Supplementary Figure S2

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Supplementary Figure S3

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Supplementary Figure S4

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Supplementary Figure S5

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Supplementary Figure S6

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Supplementary Figure S7

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Supplementary Table S3

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Figure 2:

Meta-analysis results for the forward MR outcomes and reverse MR outcomes. The causal estimates are presented as odds ratios (ORs) along with their corresponding 95% confidence intervals (CIs).

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Discussion

Multiple investigations have demonstrated an association between uveitis and PsA, with the prevalence of uveitis being significantly higher in patients with PsA compared to the control group.²⁴ Chen et al.¹⁰ found an increased risk of subsequent PsA in uveitis patients. Additionally, a nationwide cohort study in Korea revealed a higher risk of uveitis in patients with PsA.²⁵ These findings suggest a bidirectional association between uveitis and PsA. Interestingly, a nationwide study in Denmark demonstrated a similar bidirectional relationship, indicating an increased risk of PsA in uveitis patients, and an increased risk of uveitis in patients with PsA.²⁶ It is important to note that MR estimates reflect the effects of lifelong genetic predisposition to a trait, rather than the impact of short-term exposures or treatments. This should be considered when interpreting the directionality and clinical relevance of the observed associations.

In our MR analysis, we explored the causal relationship between uveitis and PsA. Our findings suggest that uveitis may serve as a risk factor for the development of PsA. The reverse MR analysis also suggested that PsA might also predispose individuals to uveitis, indicating a bidirectional causal relationship between the two conditions. This discovery aligns with previous observational studies.

More and more evidence suggests that some loci significantly associated with PsA are unrelated to psoriasis at the genome-wide significance threshold, including loci at CSF2, PTPN22, TNFAIP3, and HLA-B. Interestingly, a meta-analysis revealed that PTPN22 rs2488457 conferred strong susceptibility to uveitis in general.²⁷ Numerous studies have demonstrated a close association between HLA-B27 and PsA, with HLA-B27 playing a significant aetiological role in PsA. Haroon et al. found that HLA-B27 and HLA-B39 are significantly associated with psoriatic arthritis.²⁸ In addition to its strong association with PsA, HLA-B27 is closely associated with anterior uveitis, representing 18% to 32% of cases, while anterior uveitis constitutes 50% to 92% of total uveitis cases.²⁹ Furthermore, a transcriptomic study found an upregulation of immunoglobulin genes in PsA patients compared to those with psoriasis, potentially promoting the spread of inflammation from the skin compartment to other tissues. Considering previous research and our study results, we propose a hypothesis that the bidirectional positive causal relationship between uveitis and PsA may be associated with HLA-B27, PTPN22, and the upregulation of immunoglobulin genes. The precise underlying mechanisms require further confirmation.

The primary strength of this study lies in its pioneering application of MR to explore the causal relationship between genetically predicted uveitis and PsA. By leveraging the principle of random allele allocation at conception, MR helps mitigate confounding and reverse causation—two major limitations of observational studies. Additionally, all participants were of European ancestry, which minimises the impact of population stratification within the analysed datasets.

However, several limitations should be acknowledged. First, the study population was restricted to individuals of European descent, which may limit the generalisability of the findings to non-European populations. Second, uveitis is a heterogeneous condition encompassing various subtypes, such as anterior, intermediate, posterior, and panuveitis. Due to the lack of subtype-specific GWAS datasets, subgroup analyses were not feasible. Third, although we applied sensitivity analyses such as MR-Egger and heterogeneity tests, residual horizontal pleiotropy cannot be fully ruled out. Fourth, some analyses used a relatively small number of instrumental SNPs, which may raise concerns regarding weak instrument bias. Lastly, this study relied on summary-level GWAS data, precluding adjustment for individual-level confounders such as medication use, disease duration, or clinical severity. These methodological limitations are inherent to the MR framework and should be considered when interpreting the results.

Limitations

Restricted to European ancestry, lack of uveitis subtypes, potential pleiotropy, limited SNPs, and no individual-level adjustment.

Conclusion

In summary, this study concludes that the presence of uveitis increases the risk of PsA, and conversely, the onset of PsA also promotes the occurrence of uveitis, indicating a bidirectional causal relationship between the two. This research provides new insights into understanding the relationship and potential mechanisms between uveitis and PsA, offering clues for the prevention and treatment of both uveitis and PsA.