Multi-omics study identifies protein biomarkers and potential drug targets to improve psoriatic arthritis diagnosis and treatment
Background
Psoriatic arthritis (PsA) has a global incidence of approximately 0.1–0.2% and affects men and women equally. PsA is a chronic, immune-mediated, inflammatory disease, closely linked to psoriasis. Whereas psoriasis is characterized by patches of abnormal skin, PsA affects the joints and often includes damage to the fingernails and or toenails. Around 30% of people with psoriasis are also affected by PsA and approximately 70% of people with PsA already have psoriasis, although some people with PsA never have psoriasis.
Symptoms and classification
PsA usually affects the peripheral joints, and enthesitis (inflammation of the sites where tendons, ligaments and joint capsules attach to the bone) can also occur.
There are five main types of PsA:
1. Oligoarticular
– involves approx. 70% of patients
– generally mild
– usually involves fewer than 3 joints
– does not occur in the same joints on both sides of the body
2. Polyarticular
– involves approx. 25% of patients
– affects 5 or more joints on both sides of the body
– most similar to rheumatoid arthritis
3. Arthritis mutilans
– affects approx. 5% of patients
-progresses to cause severe joint damage
4. Spondyloarthritis
– stiffness of the neck or sacroiliac joint
– can affect the hands and feet
5. Distal interphalangeal predominant
– inflammation and stiffness of the distal joints of the fingers/toes
– marked nail damage.
Causes and diagnosis
The cause of PsA has been hard to pin down. It is often described as an inheritable polygenic disease. Many genes have been identified that are thought to contribute towards developing the disease; notably, several related to the immune system, such as Class 1 MHC genes (particularly HLA-B*27) and central tolerance (interleukin receptor genes). However, genetics is not the sole cause. For example, although approximately 40–50% of people with PsA have the HLA-B27 genotype, the vast majority of people with that genotype do not have PsA. An interplay with environmental factors is usually needed to trigger the autoimmune response that causes the PsA symptoms.
There is no definitive test for PsA, and diagnosis usually involves assessment of a variety of clinical signs, as well as family history. The main blood test is for rheumatoid factor, a biomarker for rheumatoid arthritis, which is done to rule out this condition. A number of other conditions also have very similar symptoms (osteoarthritis, reactive arthritis, gouty arthritis, systemic lupus erythematosus and inflammatory bowel disease-associated arthritis), so it is important to rule out these differential diagnoses.
Disease management
Early diagnosis and treatment is important to prevent and slow the joint damage that results from long-term inflammation. Treatment is aimed at reducing inflammation and so consists of nonsteroidal anti-inflammatories, conventional disease-modifying antirheumatic drugs (DMARDs; e.g. methotrexate, etc), biologic DMARDs (TNF-inhibitors: e.g. infliximab; interleukin inhibitors: e.g. ustekinumab and secukinumab) and synthetic DMARDs (JAK inhibitors: e.g. tofacitinib).
Multi-omics analysis identifies protein biomarkers and potential drug targets
Although studies have identified many proteins as disease biomarkers, most of the studies were limited in one way or another and still no definitive test for PsA exists. Additionally, even though new therapies are emerging, at least 40% of PsA patients have no or only a partial response to treatment. Hence, a better understanding of the causes of this disease is crucial for both diagnosis and improving treatment. Cai et al. in their recent study performed a comprehensive investigation into 4853 plasma proteins and the risk of PsA [1]. The multi-omics analysis involved proteome-wide Mendelian randomization, protein–protein interaction network analysis, druggability assessment, single-cell RNA sequencing analysis and phenome-wide association studies.
This process identified seven protein markers, higher levels of six (IL23R, ERAP2, IFNLR1, KIR2DL3, CLSTN3, and POLR2F) and lower levels of one (NEO1), were associated with an increased risk of PsA and had a causal association. Additionally, PPI network analysis found that five of these seven proteins interacted with established PsA-related drug targets, enabling classification of the proteins into two tiers. Tier 1 contained the five proteins with the most robust evidence (IL23R, ERAP2, IFNLR1, KIR2DL3, NEO1) and Tier 2 the remaining two with strong evidence (CLSTN3 and POLR2F). Interestingly, IL23R has already been developed as a target for treating moderate to severe plaque psoriasis and IFNLR1 gene expression is known to be significantly upregulated in inflammatory conditions and linked by other studies to rheumatoid arthritis and systemic lupus erythematosus. The authors suggest that their findings will allow better diagnosis of PsA and the identification of new drug targets will assist in developing personalized treatment for this condition.
Reference
1. Cai YX, Zheng DS, Chen XL, Bai ZP, Zhang J, Deng W, Huang XF. An integrated multi-omics analysis identifies protein biomarkers and potential drug targets for psoriatic arthritis. Commun Biol 2025;8(1):240 (https://doi.org/10.1038/s42003-025-07698-5).
