Convergence of Psoriatic Arthritis and Hyperuricemia: A Review of Emerging Data from This New Concept Called “Psout”

Abstract

This review examines the concept of “psout”, an overlap syndrome of hyperuricemic psoriatic arthritis (HU-PsA) and co-existing gout and PsA. The manuscript explores its epidemiology, pathophysiology, clinical implications, and treatment strategies, focusing on emerging data since its first description in 2020. The psout concept is sustained by shared inflammatory and metabolic pathways between gout and PsA, contributing to a broad spectrum of phenotypes and moderate-to-severe clinical manifestations. Monosodium urate crystals and hyperuricemia are central to this overlap, influencing cytokine production, keratinocyte activation, and immune responses, being able to activate both innate and acquired immunity. Clinical management is complex due to diagnostic challenges and therapeutic considerations not yet implemented in international recommendations. Emerging data from clinical trials underscore the significance of hyperuricemia in worsening PsA outcomes while highlighting the potential of personalized treatments. Future research into shared pathophysiological mechanisms, the accurate description of the diversity of phenotypes, innovative imaging assessments, and therapeutic strategies could provide insights into the interplay of these two conditions and enhance patient outcomes.

1. Introduction

Psoriasis is a chronic autoimmune condition characterized by rapid skin cell turnover, leading to the formation of thick, red, scaly patches on the skin [1]. It affects approximately 2–3% of the global population [2] and can significantly impact the quality of life due to its visible symptoms and associated discomfort [3]. Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in about 30% of individuals with psoriasis [4,5]. PsA is a multifaceted disease that can affect peripheral joints, entheses, and the axial skeleton [6]. The clinical presentation of PsA is highly variable, ranging from mild joint pain and stiffness to severe, debilitating arthritis with joint destruction and deformity [6].

Gout is the most prevalent chronic inflammatory arthritis affecting about 1% of the global population with a rising prevalence across the globe [7]. It is characterized by sudden, severe attacks of pain, redness, and swelling in the joints, caused by the deposition and release of monosodium urate (MSU) crystals in the joints and surrounding tissues, which occurs due to hyperuricemia, an elevated level of uric acid in the blood [8]. Uric acid is a byproduct of purine metabolism, and its levels can become elevated due to factors such as diet, genetics, high cell-cycle turn-over, and renal dysfunction [8]. Hyperuricemia is a common metabolic disorder and a significant risk factor for the development of gout. While not all individuals with hyperuricemia develop gout, those with persistently high uric acid levels are at an increased risk [8]. Gout can lead to chronic arthritis, tophi (nodular masses of uric acid crystals), and kidney disease if not properly managed [8]. Gout is also associated with cardiometabolic comorbidities and premature mortality [9].

“Psout” is a recently established term proposed to describe the overlapping conditions ranging from hyperuricemic PsA (HU-PsA) to co-existing gout and PsA in the same patient [10]. This novel concept highlights the intersection of inflammatory and metabolic pathways in these two conditions. Psout is not merely an overlap of PsA and gout, but represents a distinct entity where hyperuricemia plays a significant role in worsening PsA outcomes. Recognizing psout as a separate entity aids in optimizing diagnostic accuracy and treatment selection, as patients may require interventions targeting both inflammatory and metabolic pathways. The growing number of publications about the concept of psout since its first description [10], a few years ago in 2019, underscores the increasing interest and importance of this topic for the rheumatological community.

The objective of this review is to provide a comprehensive analysis of the intersection between hyperuricemia/gout and psoriasis/PsA, emphasizing the concept of “psout”. The significance of psout lies in its potential to complicate the clinical management of patients, as the presence of hyperuricemia in a PsA patient can lead to more severe joint inflammation and damage. Recognizing the coexistence of PsA and hyperuricemia or gout can help clinicians to tailor therapies more effectively, potentially improving patient outcomes. Understanding psout is indeed crucial for developing personalized treatment strategies that address both the inflammatory and metabolic aspects of the disease. This study of psout also provides insights into the shared pathophysiological mechanisms between psoriasis, PsA, and gout, paving the way for future research and therapeutic advancements.

2. Epidemiology

The epidemiological relationship between PsA and gout is increasingly recognized [11,12]. Recent studies have shown that HU occurs in about one third of PsA patients [13,14,15,16,17]. Nevertheless, it is important to note that the thresholds for HU used in these studies vary (Chu et al.: 60 mg/L for women, 70 mg/L for men [15]; Lai et al.: 360 µmol/L for women, 420 µmol/L for men [13]; Gudu et al.: 68 mg/L in both sex [14]; Aljohani et al.: 360 µmol/L for women and 450 µmol/L for men [16] and Widawski et al.: 360 µmol/L in both sex [17]). Thus, the figures would likely be higher if stricter cut-off values were applied. It is then difficult to know if HU is more prevalent in PsA patients than in the general population. Indeed, epidemiological studies have reported low HU prevalence in healthy individuals (13–20%, or even lower), but often using higher thresholds than those currently applied. Using updated criteria, a recent study found a 37% prevalence in healthy men with a cut-off of 56 mg/L [18]. Studies suggested an increased risk of gout in PsA patients. A nationwide population-based study in Taiwan involving 229 246 patients suggested that gout was significantly associated with PsA (OR 2,5, 95%) [11]. Interestingly, there was also an increased prevalence of psoriasis (1.6% vs. 1.1%) and PsA (0.3% vs. 0.1%) among patients with gout compared to those without. In another huge study in US men and women, the risk of gout was five times higher in PsA patients [19]. In a recent review, Sherri et al. nicely summarized existing data, confirming that the prevalence of hyperuricemia is higher in PsA patients and that gout is significantly associated with PsA [12]. Metabolic syndrome and obesity are, indeed, a shared risk factor for both psoriasis and gout, and it may partially explain the increased prevalence of hyperuricemia in PsA patients. However, studies suggest that hyperuricemia itself may independently contribute to the severity of PsA, beyond a metabolic syndrome alone [12]. Additionally, MSU detection in synovial fluid is higher in PsA patients than in other types of arthritis [12].

3. Pathophysiology

The pathophysiological mechanisms underlying this overlap involve complex interactions between inflammatory and metabolic pathways. The deposition of MSU crystals in joints and the systemic effects of hyperuricemia play significant roles in the inflammatory processes. MSU crystals play a significant role in inflammation when gout and PsA co-exist, but their contribution in isolated PsA remains uncertain. While hyperuricemia may influence PsA severity, the direct role of MSU crystals in PsA without clinical gout remains controversial. A particular relationship has been observed between hyperuricemia, gout, psoriasis, and PsA. Some have thought that psoriasis was a risk factor for hyperuricemia, particularly due to the excessive proliferation of keratinocytes and cellular hypercatabolism, causing an excessive release of uric acid, similar to what can be observed in diseases with a high cell turnover such as hematological malignancies (e.g., myeloproliferative and lymphoproliferative syndromes) [20]. However, today, there is growing evidence to suggest that chronic hyperuricemia may constitute an endosomal trigger promoting the development of psoriasis and psoriatic arthritis. Uric acid crystals are powerful cellular activators, and soluble uric acid also has complex immunomodulatory actions [21]. The pathophysiological mechanism of gout attacks is now well established. During a flare, uric acid in a crystal form is internalized by phagocytosis and incorporated into lysosomes, inducing an influx of sodium and intracellular water, thereby activating the inflammasome, an oligomeric protein complex involved in innate immunity [22]. This phenomenon occurs preferentially in macrophages, dendritic cells, and plasmacytoid cells. The intracellular protein complex NOD-like receptor family, pyrin domain-containing 3 (NLRP3), leads to the activation of caspase-1 and allows the cleavage of pro-IL-1β into IL-1β, the activated form of the pro-inflammatory cytokine. The NLRP3 inflammasome is dependent on a two-signal initiation system, which avoids unregulated and inappropriate activation.

Intra-articular microcrystals and those present in tophi are able to activate surrounding cells through various mechanisms. MSU crystals can induce necroptosis or programmed necrosis in neutrophils via the RIPK3 receptor and MLKL protein kinases [23]. Under the influence of MSU crystals, neutrophils can be activated through an alternative mechanism characterized by the release of microparticles organized in networks called Neutrophil Extracellular Traps (NETs); this process is referred to as NETosis. These NETs expose various cellular structures that act as DAMPs (damage-associated molecular patterns), such as histones, mitochondrial DNA, ATP, and uric acid, which in turn stimulate toll-like receptors (TLRs) present in surrounding cells and participate in the release of pro-inflammatory cytokines including IL-1 [24]. Paradoxically, this NETosis is also involved in the resolution of acute gouty arthritis through the use of proteases capable of neutralizing pro-inflammatory mediators, creating a control feedback loop [25].

There is a continuum between hyperuricemia and authentic gout attacks. In patients with gout, outside of gout attacks, certain immune cells remain inappropriately activated. Thus, through the role of uric acid deposits in the joint, gout can also be a chronic inflammatory disease. MSU crystallizes and deposits in local tissues, triggering chronic inflammatory responses. During the intercritical phases, monocyte HLA-DQA1 increases, and HLA-DQA1 has been found to be associated with the pathogenesis of psoriasis [26]. MSU crystals activate systemic inflammation and distinctive immune responses in gout remission with MSU crystal deposition [27]. Additionally, this inflammation contributes to promoting some of the comorbidities classically associated with gout such as obesity, atherosclerosis, hepatic steatosis, diabetes, and likely, PsA.

The role of MSU crystals in psoriasis has long been suggested. MSU crystals have been found in large numbers in psoriatic skin lesions. An experimental animal model of a Boa constrictor fed with high doses of uric acid developed a psoriasis-like dermatosis. In humans, hypouricemic treatment with allopurinol may improve psoriasis in hyperuricemic patients [20]. The origin of uric acid may be local, released by hyperactivated keratinocytes, or systemic in the case of chronic hyperuricemia. MSU induces macrophage tissue migration [28]. MSU crystals have been shown to interact with resident skin cells (keratinocytes) [29] and joints (synoviocytes) [30] via the P2Y6 receptor, inducing the secretion of pro-inflammatory mediators including IL-1α, IL-8/CXCL8, and IL-6. MSU crystals also induce oxidative stress by releasing ROS and RNS in fibroblast-like synoviocytes (FLS) [31]. They are also capable of inducing osteoclast differentiation [32] and have an inhibitory effect on osteoblasts [33], hence explaining bone erosion.

Innate lymphoid cells type 3 (ILC3) are a recently identified group of innate immune cells that participate in the progression of several metabolic diseases by secreting interleukin IL-17 and IL-22. In HU patients, positive correlations have been detected between circulating ILC3 levels, plasma IL-17A, and serum uric acid [34]. In vitro, naïve CD4(+) T cells co-cultured with uric-acid-treated dendritic cells differentiate toward the Th17 lineage in the presence of inflammasome-dependent cytokines IL-1α/β and IL-18 [35].

Interestingly, MSU crystals also act on adaptive immunity, serving as adjuvants in the humoral response to hepatitis B, tuberculosis, and tumors. MSU crystals activate antigen-presenting cells (dendritic cells), promoting their antigenic presentation function [36]. MSU directly activates T cells via the P2X7 receptor [37], inducing a pro-inflammatory response and can stimulate the proliferation of human T cells [38] by activating the c-Myc transcription factor [25]. Additionally, they promote the differentiation of T lymphocytes toward the Th17 pathway [35], which is involved in the pathogenesis of spondyloarthritis and psoriasis.

Plasmacytoid dendritic cells are activated via TLRs by various environmental factors: PAMPs (pathogen-associated molecular patterns) present in large numbers in the psoriatic epithelium, possibly emanating from the exogenous environment (microbial peptides), or hyperactivated keratinocytes (cathelicidin, DNA, and uric acid). Dendritic cells induce T-cell proliferation and differentiation into Th1 and Th17 cells in secondary lymphoid organs. Self-reactive T cells in turn stimulate keratinocytes [39,40] via the release of IL-17 and IFN-γ. In Pso and PsA, there is a deregulation of the IL-23 and IL-17 cytokine axis, as well as an overexpression of TNF-alpha. In a mouse model, it has been shown that at the level of the enthesis, macrophagic and dendritic cells are at the origin of an overexpression of IL-23 [41]. Enthesis-resident γδ T cells express IL-23R on their surface and produce IL-17 and TNF-alpha in response to their activation by IL-23 [42].

As a summary, MSU crystals are a constant source of inflammation triggering both innate and adaptative immunity. MSU crystals activate resident cells, keratinocytes themselves by an autocrine effect, and enthesis synoviocytes. MSU induces the epidermal plasmacytoid dendritic cells by binding to their transmembrane receptor P2Y6, leading to the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-8, IL-23, and IL-12) [25]. This signal on the surface of activated dendritic cells stimulates antigen presentation and the T lymphocyte response [22]. Finally, in an inflammatory environment, these crystals are capable of inducing the secretion of IL-17 by T cells [37]. In psout, the interplay of IL-1β, TNF-α, IL-23, and IL-17 signaling pathways may exacerbate joint inflammation, highlighting the need for tailored management.

4. Clinical Presentation and Diagnosis

4.1. Overlapping Clinical Features

The overlap of certain clinical features between gout and PsA poses significant challenges for both diagnosis and treatment. The shared features often obscure distinctions between the two conditions and imply reciprocal interactions. Notably, the 2015 ACR/EULAR criteria for gout may misclassify some patients with PsA, and conversely, patients meeting the CASPAR criteria for PsA might also satisfy the criteria for gout. This overlap has important implications for both daily clinical practice and clinical trials. This has been highlighted in the first French descriptive monocentric retrospective study, in which our group showed that 30.2% of PsA patients had HU and 6.2% met the gout criteria [17].

The recently established term “psout” describes a wide spectrum of overlapping conditions ranging from hyperuricemic PsA (HU-PsA) to co-existing gout and PsA. The most apparent benefit of recognizing this condition for clinicians is the ability to avoid misclassifying a gout attack as a PsA flare, preventing unnecessary modifications in PsA treatment regimens. Recognizing the psout phenotype ensures that hyperuricemia is appropriately addressed alongside PsA treatment, reducing the risk of uncontrolled joint inflammation and ensuring that clinicians pay more attention to those patients with additional comorbidities.

Similarities and differences can be observed in patients with PsA or gout, compared to those with psout (

Table 1. Features of PsA, gout, and psout.

	PsA	Gout	Psout (Overlap)
Demographics	Male and female equally affected	Predominantly male	Predominantly male
Metabolic Features	May coexist with metabolic syndrome	Strong association with metabolic syndrome	Increased metabolic burden (high BMI, hypertension, dyslipidemia [hypertriglyceridemia])
Skin disease and subsets of psoriasis	All subtypes encountered: psoriasis vulgaris, guttate, nail changes, inverse psoriasis, and pustular psoriasis	Common local inflammatory skin changes occurring upon flares	More extensive, with higher frequency of moderate-to-severe skin disease, predominantly scalp and in plaques psoriasis vulgaris
Rheumatological Involvement	Asymmetric oligo- or polyarthritis; enthesitis; tenosynovitis; dactylitis; axial forms (Ax-PsA)	Monoarthritis; oligoarthritis, (rarely, but possible polyarthritis); MTP I classic; wrists, knees and ankles; tenosynovitis and enthesitis possibly related to intra- or peri-tendinous tophi; sacro-iliitis (rare and with specific radiographic findings: vast irregular and shredded erosions of SI joints)	Asymmetric mono-, oligo- or poly-arthritis Typically peripheral synovitis (wrists; MCP; knees; ankles; MTP I) Enthesitis: similar frequency; Axial PsA rare; Dactylitis, more frequent or severe
Synovitis	Peripheral and axial (in axial PsA)	Peripheral synovitis (axial gout, possible, but very rare)	Predominantly peripheral synovitis
Enthesitis	Common (Achilles, plantar fascia)	Rare, occasionally present	Common at shared sites
Radiographic Features	Marginal erosions, pencil-in-cup deformity, osteitis, osteoconstruction	Tophi-induced erosions, anarchical distribution, soft tissue tophi	Mixed features (PsA erosions + osteoconstruction features and gout tophi)
Comorbidities	Variable, metabolic syndrome, cardiovascular risk	Frequent (renal disease, diabetes); metabolic syndrome; very high cardiovascular risk	High comorbidity burden (high Charlson Comorbidity index score), high to very high cardiovascular risk
HLA-B27 Association	Present, peculiarly in axial PsA (30%)	Classically absent (frequency as the general population, around 9%)	Rarely present (less than 30%)

) [10]. All these conditions commonly present as monoarthritis, oligoarthritis, or polyarthritis, with a predilection for the lower limbs, including the knees, ankles, and first metatarsophalangeal (MTP) joint. Gouty sacroiliitis, which remains rare, can be misdiagnosed as axial-PsA. This can be limited by a careful radiographic assessment and recognition of specific features of gout, including notably large and deep erosions of the sacroiliac joints [10].

MTP I arthritis, a hallmark of gout, is also seen in PsA, often manifesting as dactylitis with concurrent skin changes. This overlap diminishes its diagnostic specificity for either condition. Enthesitis, a hallmark of PsA, frequently involves the calcanean tendon or plantar fascia, which may also occur in gout, though with specific imaging signs for the latter such as peri- or intra-tendinous tophi. The combination of novel imaging modalities such as ultrasonography, MRI, or DECT will likely contribute to decipher the synovitis and enthesitis analysis in the context of psout.

While it has been suggested by epidemiologic associations that psoriatic skin involvement could trigger hyperuricemia through an increased keratinocyte turnover and the associated production of inflammatory cytokines, there is growing evidence to suggest the converse may also be true—hyperuricemia might exacerbate psoriatic skin involvement. Furthermore, specific variations in the skin phenotype of psoriasis depending on the presence or absence of HU or gout is currently not fully established. Although there are limited data on whether specific psoriasis subtypes (vulgaris, scalp, guttate, nail, inverse, or pustular) are more common in psout, some studies suggest that psoriasis vulgaris and scalp psoriasis may be more prevalent in hyperuricemic PsA patients [43]. However, these observations should be mitigated by the higher prevalence of psoriasis in plaques over other psoriasis subsets, which limits the formulation of definitive conclusions. In addition, currently available data on psoriasis skin phenotypes in the HU context are very limited and with no specific dermatological expertise assessment of the skin, since most studies are emanating from mono-centric retrospective rheumatological cohorts, introducing selection bias. Future studies are needed to determine if hyperuricemia influences the severity of specific dermatologic phenotypes.

4.2. Impact of Hyperuricemia on Psoriatic Disease and Vice-Versa: Data from Patient Cohorts (Table 2)

AlJohani et al. [16] were the first to study the characteristics and outcomes of PsA patients with HU. In this study, 31.9% of the 1019 PsA patients were found to have HU, defined as uric acid levels >450 µmol/L for men and >360 µmol/L for women. These HU-PsA patients were followed prospectively, and their disease characteristics and outcomes, particularly regarding cardiovascular disease (CVD) and kidney disease, were analyzed. This study revealed that HU-PsA patients had a longer disease duration and more severe psoriasis (higher PASI scores) compared to normouricemic patients. They also had a higher burden of comorbidities, including CVD, metabolic diseases, and kidney stones. Notably, the prevalence of gout was low (3.4%) in these patients, despite the elevated uric acid levels. Importantly, persistent HU, defined as elevated uric acid levels over two consecutive visits, was associated with an increased risk of myocardial infarction, heart failure, and renal impairment. Multivariate analysis highlighted obesity and longer PsA disease duration as key factors linked to persistent HU and poorer outcomes in these patients.

The study by Widawski et al. [17] then provided foundational insights into the role of HU in PsA, focusing on patients’ characteristics and their articular involvement. Among 242 patients analyzed, 73 (30.2%) had HU (defined by serum uric acid [SUA] ≥360 µmol/L) and 15 (6.2%) met the 2015 ACR/EULAR criteria for gout. HU patients were more frequently male (72.6% vs. 39.1%, p = 1.6 × 10⁻⁶) and had a higher body mass index (30.0 vs. 28.3 kg/m²; p = 0.015). The Charlson Comorbidity Index was higher in HU patients (2.6 vs. 1.8; p = 0.005), indicating more comorbid conditions. PsA onset occurred later in HU patients (49 vs. 44.5 years; p = 0.016), and HU patients were more likely to have polyarticular disease (56.2% vs. 41.9%; p = 0.049), while fewer had axial disease (9.6% vs. 22.8%; p = 0.019). Interestingly, HU patients exhibited more destructive disease, with 52.8% having joint damage compared to 37.4% in normouricemic patients (p = 0.032). Multivariable analysis showed that HU was associated with poorer treatment responses (odds ratio 0.35; 95% CI 0.15–0.87; p = 0.024) and peripheral joint involvement (odds ratio 2.98; 95% CI 1.15–7.75; p = 0.025). These findings suggested that patients with psout are more likely to have severe peripheral joint involvement and more destructive disease, in line with the hypothesis that HU may worsen the clinical course of PsA.

Other authors explored the clinical characteristics of psout, such as Galozzi et al. who similarly observed hyperuricemia in 8.9% of PsA patients, predominantly in those with wrist and metacarpophalangeal (MCP) joint synovitis, typically peripheral PsA [44]. However, more extensive, prospective studies with standardized treatment protocols were needed to better understand the role of HU in the pathogenesis and progression of PsA. To address this gap, post hoc analyses from phase 3 clinical trials such as FUTURE 2–5, MAXIMISE [45], DISCOVER 1 and 2 [46], and SELECT-PsA [47] have provided crucial data. These studies not only offer a more comprehensive examination of the relationship between HU and both psoriasis and PsA severity, but they also provide, for the first time, insights into the impact of HU on treatment responses to a range of biologics and targeted therapies. These include secukinumab [45], guselkumab [46], upadacitinib, and adalimumab [47]—each with distinct mechanisms of action, such as IL-17A inhibition, IL-23 inhibition, JAK inhibition, and TNF-α inhibition, respectively. This broader data set allows for a more nuanced understanding of how HU influences therapeutic efficacy and may inform the development of personalized treatment approaches for patients with PsA.

Across pooled analyses from these phase 3 trials, HU was consistently associated with distinct patient profiles when compared to normo-uricemic ones [45,46,47]. The prevalence of HU in PsA patients was reported as 32.8–43.5% at SUA levels ≥360 µmol/L [45,46,47]. Patients with HU were predominantly male (66.4–76.0% vs. 34.2–39.0% in normouricemic patients) [45,46,47] and had a higher body mass index (BMI) (30.9–32.3 vs. 28.3–29.7 kg/m²) [45,46,47].

HU patients consistently showed more severe psoriasis across the studies. In the DISCOVER 1 and 2 trials, HU patients had significantly higher PASI scores (11.3 ± 12.0 vs. 8.4 ± 9.6; p < 0.001) and a greater proportion of HU patients with body surface area (BSA) involvement > 20% (34.6% vs. 21.8%; p < 0.001) compared to normouricemic patients [46]. Similarly, in the SELECT-PsA study, HU patients demonstrated a higher PASI score (11.6 vs. 9.2) and more extensive skin involvement with 57.1% of HU patients having ≥3% BSA involvement compared to 50.8% in normouricemic patients [47]. In the secukinumab trials, HU patients had a higher mean PASI score at the baseline (13.61 ± 11.03 vs. 10.16 ± 9.13 in normouricemic patients). Additionally, HU patients had more often moderate-to-severe psoriasis (66.0% vs. 51.5%) [45].

Concerning the articular severity of PsA, patients with HU demonstrated a higher prevalence and severity of dactylitis across these phase 3 studies. In the secukinumab trials, HU patients also presented with higher rates of dactylitis (34.5 vs. 25.9) [45]. Interestingly, this rate increase according to the SUA threshold (32% at 300, 34.5% at 360, and 37.9% at 420 µmol/L, respectively). In the DISCOVER 1 and 2 trials, HU patients had a mean dactylitis severity score of 9.5 ± 11.0, significantly higher than the 7.5 ± 8.7 observed in normouricemic patients (p = 0.041) [46]. In the SELECT-PsA trials (upadacitinib), HU patients demonstrated a slightly higher rate of dactylitis involvement (30.1%) compared to normouricemic patients (28.9%) [47]. Nevertheless, this trend towards a more frequent and severe articular involvement in HU patients was limited to the dactylitis and did not extend to articular involvement in general. It is important to note that patients were required to have polyarthritis, defined as at least ≥3 tender joints and ≥3 swollen joints, to be included in the studies. In addition, the mean swollen joints count at the baseline was around 10, which may also account for the lack of difference found in these studies.

HU patients also tended to exhibit more severe radiographic damage. In secukinumab trials, the more severe HU patients (>420 µmol/L) had numerically higher vdH-mTSS scores (17.4 ± 41.46) compared to normouricemic patients (12.3 ± 30.40), suggesting a greater degree of joint destruction in HU patients [45].

Across these multiple studies, articular response rates (ACR20, ACR50, and ACR70), as well as enthesitis and dactylitis resolutions or skin response rates (PASI) were all comparable between HU and normouricemic groups, regardless of the treatment regimen (secukinumab, guselkumab, upadacitinib, or adalimumab). These results indicate that HU does not significantly alter the overall efficacy of these biologics and JAK inhibitors in achieving clinical responses [45,46,47].

The safety profiles of upadacitinib and adalimumab were similar between HU and normouricemic patients, with comparable treatment-emergent adverse event rates observed across both groups [47].

Table 2. Summary of Studies on HU in PsA Patients.

Study	Design	Population	HU Prevalence *	Gout Prevalence	Key Clinical Findings
AlJohani et al., 2018 [16]	Prospective cohort	1019 PsA patients	31.9%	3.4%	in HU-PsA: longer disease duration and more severe psoriasis, higher burden of comorbidities
Widawski et al., 2022 [17]	Retrospective cohort	242 PsA patients	30.2%	6.2%	in HU-PsA: male predominance, poorer response to PsA treatment, more peripheral and destructive joint damage
Galozzi et al., 2022 [44]	Retrospective cohort	213 PsA patients	8.9%	Not reported	in HU-PsA: male predominance, higher prevalence in patients with wrist and MCP joint synovitis monosodium urate crystals were reported only in 5/213 SFs (2.4%)
Geneva-Popova et al. 2022 [48]	Retrospective cohort	156 PsA patients	71%	Not reported	The presence of crystals in SF was observed in 23.71% of PsA patients, associated with high disease activity, with severe disability, and with severe pain
Moukarzel et al., 2024 [43]	Retrospective cohort	122 PsA patients	29.5%	9.8%	Systematic US assessment: 23% had asymptomatic hyperuricemia, 7.4% had US signs of gout
Secukinumab Trials [45]	Post hoc analysis	PsA patients	32.8%	2.5%	in HU-PsA: higher prevalence of hypertension, with more clinical dactylitis, more psoriasis, and more severe skin disease; similar efficacy of secukinumab
Guselkumab Trials [46]	Post hoc analysis	PsA patients	38.2%	Not reported	in HU-PsA: more likely to be male and have high BMI, hypertension, and more severe psoriasis and dactylitis; similar efficacy of guselkumab
Upadacitinib Trials [47]	Post hoc analysis	PsA patients	33.3%	Not reported	in HU-PsA: more likely to be male and have a higher BMI and more severe psoriasis, similar efficacy of upadacitinib or adalimumab, upadacitinib was not associated with an increased risk of adverse events in the HU cohort

* according to each study definition.

Table 2. Summary of Studies on HU in PsA Patients.

Study	Design	Population	HU Prevalence *	Gout Prevalence	Key Clinical Findings
AlJohani et al., 2018 [16]	Prospective cohort	1019 PsA patients	31.9%	3.4%	in HU-PsA: longer disease duration and more severe psoriasis, higher burden of comorbidities
Widawski et al., 2022 [17]	Retrospective cohort	242 PsA patients	30.2%	6.2%	in HU-PsA: male predominance, poorer response to PsA treatment, more peripheral and destructive joint damage
Galozzi et al., 2022 [44]	Retrospective cohort	213 PsA patients	8.9%	Not reported	in HU-PsA: male predominance, higher prevalence in patients with wrist and MCP joint synovitis monosodium urate crystals were reported only in 5/213 SFs (2.4%)
Geneva-Popova et al. 2022 [48]	Retrospective cohort	156 PsA patients	71%	Not reported	The presence of crystals in SF was observed in 23.71% of PsA patients, associated with high disease activity, with severe disability, and with severe pain
Moukarzel et al., 2024 [43]	Retrospective cohort	122 PsA patients	29.5%	9.8%	Systematic US assessment: 23% had asymptomatic hyperuricemia, 7.4% had US signs of gout
Secukinumab Trials [45]	Post hoc analysis	PsA patients	32.8%	2.5%	in HU-PsA: higher prevalence of hypertension, with more clinical dactylitis, more psoriasis, and more severe skin disease; similar efficacy of secukinumab
Guselkumab Trials [46]	Post hoc analysis	PsA patients	38.2%	Not reported	in HU-PsA: more likely to be male and have high BMI, hypertension, and more severe psoriasis and dactylitis; similar efficacy of guselkumab
Upadacitinib Trials [47]	Post hoc analysis	PsA patients	33.3%	Not reported	in HU-PsA: more likely to be male and have a higher BMI and more severe psoriasis, similar efficacy of upadacitinib or adalimumab, upadacitinib was not associated with an increased risk of adverse events in the HU cohort

* according to each study definition.

The wide range of prevalence may be due to differences in HU definitions, patient populations, and study methodologies. Future research should standardize diagnostic thresholds to improve comparability across studies.

These studies have linked HU to increased PsA severity or comorbidities; however, these associations are largely univariate and could lose significance in multivariate analyses, as confounding factors may play a role.

4.3. Diagnostic Challenges: Interest of Synovial Fluid Analyses, Ultrasonography, and Dual-Energy-Computed Tomography (DECT)

Synovial fluid analysis is a critical diagnostic tool for distinguishing between different types of arthritis, especially in patients with PsA who present with acute joint swelling. The study by Galozzi et al. examined synovial fluid (SF) samples from PsA patients over a ten-year period to determine whether joint swelling was due to a PsA flare or an acute gout episode [44]. Among 5478 samples analyzed, 213 complete records from PsA patients were evaluated. The study found that MSU crystals were relatively rare, suggesting that acute joint swelling in PsA is more often due to PsA flares rather than gout. Of note, one third of the patients (n = 76) had non-inflammatory SF. In their cohort, HU was observed in only 8.9% of PsA patients, markedly lower than previously reported in the literature, and MSU crystals were reported only in 5/213 SFs (2.4%). This relatively low amount of patients with HU could be due to the definement of HU the same day of the arthrocentesis, as during inflammatory situations (such as the gouty flare itself), SUA levels could be lower than after inflammation resolution. Interestingly, three cases of MSU crystals were found in normouricemic patients. In addition, even if 97% of patients were treated for their PsA, severe inflammatory SF patterns were more frequent in HU patients than normouricemic ones. This highlights the importance of SF analysis in accurately diagnosing and managing joint swelling in PsA patients.

Another study by Geneva-Popova et al. focused on the relationship between the presence of crystals in the synovial fluid of PsA patients and disease activity [48]. The study analyzed SF samples from 156 PsA patients, compared to 50 patients with knee osteoarthritis. They found that 23.7% of PsA patients had detectable crystals, predominantly MSU (67.6%) and calcium pyrophosphate crystals (21.6%), versus none of the patients with knee osteoarthritis (p < 0.001). In their PsA patient cohort, HU was frequent, seen in 71% of the patients. The PsA patients with and without crystals had a similar age and sex distribution. The diagnosis duration was not significantly associated with the presence or absence of crystals (p = 0.614). No significant differences were observed in relation to polyarticular (p = 0.848) and oligoarticular involvement (p = 0.453), skin psoriasis (p = 0.245), and enthesitis (p = 0.493). Nail involvement and dactylitis were significantly more frequent in the PsA patients with crystals (p < 0.001 for both comparisons). All PsA disease activity scores showed significant associations with the presence or absence of crystals in the SF of the PsA patients. Based on DAPSA, 75.70% of the PsA patients with crystals had high disease activity versus 16% of the PsA patients without crystals, p < 0.001. The presence of crystals was significantly associated with an increased chance for severe pain (OR = 157.25, 95% CI: 39.50 to 625.94, p < 0.001), high disease activity based on DAPSA (OR = 15.96, 95% CI: 5.76 to 44.23, p < 0.001) and severe disability on HAQ-DI (OR = 13.60, 95% CI: 5.09 to 36.31, p < 0.001). These findings suggest that SF analysis for crystal identification should be a routine part of the diagnostic process for PsA patients, particularly those with high disease activity, to determine the need for urate-lowering therapy.

Ultrasonography (US) has emerged as a valuable non-invasive tool for detecting infra-clinical gouty patients. An interesting study by Moukarzel et al. explored the prevalence of gout in a cohort of PsA patients and the utility of US in identifying gout-specific signs [43]. HU, defined as a uric acid level exceeding 360 µmol/L, was detected in 29.5% of patients, with 23% presenting asymptomatic HU (uric acid level > 360 µmol/l without a history of gout attacks). The study found that 9.8% of PsA patients (12/122) had gout (report of a history of gout attacks). Of note, nine patients (7.4%) had US-specific signs of gout, such as the double contour (DC) sign. Among them, three were known to have gout, but six did not present any previous history of gout attack. This represents 5.5% of the PsA in whom were found a specific sign of gout in patients with asymptomatic HU.

Finally, the same kind of study was conducted by Antony et al. and investigated the prevalence of US evidence of gout in PsA patients [49]. This cross-sectional study found that 11.4% of PsA patients (12/105) had US signs of gout, such as the double-contour sign and tophi. These studies emphasized the importance of using US to detect subclinical gout in PsA patients, which can significantly impact the management and treatment outcomes.

Dual-energy CT (DECT) can confirm monosodium urate crystal deposition [49], providing specific findings and helping for definitive diagnosis by discriminating between gout and PsA, especially in atypical sites such as gouty sacroiliitis from axial-PsA [50,51].

5. Comorbidities

PsA and gout share common comorbidities (i.e., myocardial infarction, stroke, hypertension, obesity, type 2 diabetes, dyslipidemia, alcohol consumption, and hyperuricemia) [10]. Recent studies have focused on the cardiovascular burden in patients with either gout or PsA. Indeed, patients with PsA seem to have an excess of cardiovascular (CV) comorbidities [52]. When looking at the CV risk factors, PsA patients show a higher prevalence of dyslipdemia, obesity, insulin resistance, type 2 diabetes mellitus, and arterial hypertension. The prevalence of metabolic syndrome is also higher in PsA, compared to psoriasis or rheumatoid arthritis. A large meta-analysis suggested that patients with PsA had a 43% higher risk of having or developing a CV disease [53]. A recent Canadian study confirmed these findings, showing that although standardized mortality rates decreased significantly in PsA patients over the 20-year study period, it remained significantly higher than in the general population. CV diseases were the second most frequent leading cause of death after cancers [54]. It is not clear yet whether inflammation in PsA has a direct role in CV risk; some data suggest that the frequent coexistence of traditional CV risk factors could prevail to explain the excess of CV risk [55].

Gout has been associated with increased cardiovascular risk for years [56]. A recent case-control study confirmed these findings on 152,663 patients with gout and 709,981 matched controls, showing that gout is associated with an increased risk across several CV and atherosclerotic diseases. Sensitivity analyses adjusting for CV risk factors (a high BMI, dyslipidemia, hypertension, and type 2 diabetes) revealed an attenuation of the associations, but gout remained an independent CV risk factor [57].

A growing number of studies have shown a predictive role of HU in overall and CV-related mortality, myocardial infarction, stroke, and heart failure [58]. However, until recently, the threshold of the SUA level at which it becomes a CV risk factor remained unknown, and was only based on the saturation point of SUA (6 mg/dL or 360 µmol/L). In a multivariate Cox regression analysis, the URRAH study confirmed the independent connection between elevated SUA levels and overall and CV mortality, but also determined the SUA threshold for CV mortality to be 5.6 mg/dL [59].

Despite many confounding factors, the link between hypertension and SUA levels remains suspected [60].

These elements recently lead to an update in the expert consensus for the diagnosis and treatment of patients with HU and a high CV risk [58]. These recommendations suggest to treat HU in patients with at least two among hypertension, diabetes, dyslipidemia, targeted organ damage, or previous CV events. A five-step ladder is suggested, starting with an assessment, education, lifestyle, and physical activity, and it is considered whether to start lowering the level of UA medication in the case of the SUA target not being reached (allopurinol, titrated to target). The role of ULT in CV risk reduction remains debated. While some consensus guidelines support its use, others, such as the European ESC guidelines [61], do not. A nuanced approach considering individual patient risk factors is warranted.

As mentioned previously, patients with psout share comorbidities common to PsA and gout, and we can assume that their CV risk is higher than the general population. On the one hand, in a study of 52 patients, Gancheva et al. found no association between intra-articular MSU deposits and CV burden in patients with asymptomatic HU and patients with HU-PsA [62]. But, on the other hand, in a study by Gudu et al. on 120 patients with PsA, HU was significantly associated with obesity, diabetes, ischemic heart disease, and hypertension [14].

Data from secukinumab [45], guselkumab [46], upadacitinib, and adalimumab [47] gathered interesting information regarding the comorbidities seen in HU PsA versus non-HU ones. HU patients exhibited a higher burden of comorbidities compared to normouricemic patients: hypertension, diabetes mellitus, and hyperlipidemia [45,46]. Notably, in SELECT-PsA post hoc analyses, major adverse cardiovascular events (MACE) occurred at similar rates in both HU and normouricemic groups (0.3% vs. 0.9%; p = 0.32). This suggests that while HU patients may have a higher comorbidity burden, the overall safety profile of these targeted therapies, during the study, remains similar across the groups [47]. In any case, whether CV risk in a patient with psout is increased by HU or the existence of other comorbidities, controlling the latter should be fully part of these patients’ management.

6. Treatment Strategies

6.1. Challenges in Managing Psout

Managing psout, the overlap syndrome of PsA, and hyperuricemia and/or gout presents unique challenges due to the overlapping symptoms and potential treatment conflicts. As previously stated, differentiating between PsA flares and gout attacks can be difficult, requiring accurate diagnosis techniques [44]. Treatment conflicts arise as medications effective for one condition may not be suitable for the other. Additionally, patients with psout often have multiple comorbidities, such as CV disease and metabolic syndrome, complicating treatment plans [52].

All gout patients should be treated with ULT, in line with established guidelines. In psout, ULT may also offer potential benefits for PsA severity and cardiovascular risk, though further studies are needed.

6.2. Potential Benefits of Urate-Lowering Therapies in PsA Patients with Hyperuricemia

Urate-lowering therapies (ULTs) could be beneficial for PsA patients with HU by reducing the frequency and severity of gout attacks, improving renal function, and potentially reducing cardiovascular risks. Given the established CV risks associated with HU, it is logical to consider ULTs for patients with psout primarily for CV protection. Using ULTs could be a pragmatic approach in patients with psout, focusing on CV risk management first. This opens the door to studies exploring the efficacy of these treatments on both articular and cutaneous symptoms, driven by the curiosity to understand their full potential and supported by a well-established rationale for cardiovascular benefits [59].

7. Future Directions

7.1. Importance of Early Diagnosis and Intervention

Early diagnosis and intervention may be crucial in managing psout effectively. Identifying the condition at an early stage allows for timely treatment, which could prevent severe joint damage and improve long-term outcomes. Early diagnosis could help in differentiating between PsA flares and gout attacks, ensuring that patients receive the most appropriate treatment for their specific condition. Implementing routine screening for HU in PsA patients could facilitate the early detection of gout, allowing for the initiation of ULTs before significant joint damage occurs. Additionally, educating healthcare providers about the signs and symptoms of psout could improve the diagnostic accuracy and patient outcomes. Moreover, early intervention with appropriate therapies could reduce inflammation, control symptoms, and slow disease progression, thereby enhancing the quality of life for patients.

7.2. Personalized Medicine Approaches for Treating Psout

Therapeutic education for patients with psout could play a key role in improving disease management and clinical outcomes. By helping patients better understand the disease mechanisms and therapeutic goals, therapeutic education could enhance their ability to differentiate between various manifestations. Moreover, it could improve adherence to complex treatment regimens, a critical issue in gout where adherence is notoriously poor. Such patient-centered educational programs could include information on the benefits of a differentiated approach to flare treatments while also addressing the management of associated comorbidities. A structured and interdisciplinary educational approach could, therefore, contribute to optimizing patients’ quality of life while reducing long-term complications.

Personalized medicine offers a tailored approach to managing psout by considering individual patient characteristics, genetic profiles, and biomarkers. Genetic profiling can help tailor treatments, while biomarker analysis can predict the disease progression and response to therapy [26]. Integrated care plans combining rheumatology and dermatology expertise ensure the comprehensive management of both skin and joint symptoms. Personalized advice on diet, exercise, and weight management can help reduce uric acid levels and improve overall health [17]. By leveraging personalized medicine, clinicians can develop more effective and individualized treatment plans for patients with psout, potentially improving outcomes and quality of life. This approach not only addresses the immediate symptoms, but also considers the long-term health of the patients, particularly in managing comorbidities such as CV disease and metabolic syndrome [52].

7.3. Areas for Further Research

Understanding how monosodium urate (MSU) crystals influence the inflammatory processes in PsA could reveal new therapeutic targets [12]. Additionally, genetic studies could identify specific markers that predispose individuals to both conditions, aiding in early diagnosis and personalized treatment strategies [26].

Another important research area is the long-term outcomes of patients with psout. Longitudinal studies could provide insights into the progression of joint damage and the effectiveness of various treatment regimens over time [17]. Moreover, exploring the impact of comorbidities such as CV disease and metabolic syndrome on psout could help develop comprehensive management plans that address all aspects of patient health [52].

The ongoing French APACHE cohort (NCT03768271) is a multicenter prospective study focusing on recent PsA with peripheral arthritis. This study aims to investigate the clinical, biological, and structural characteristics of PsA over a 5-to10-year period. Among its secondary objectives, such as identifying predictive factors of structural severity (including, but not limited to, biomarker, genetic, environmental, clinical, and therapeutic factors), this study has the potential to clarify the clinical, biological, and structural characteristics and trajectories of patients with PsA and HU or gout, potentially refining the psout landscape.

Finally, there is a need for clinical trials to evaluate the efficacy of ULTs specifically in PsA patients with HU. These studies could determine whether ULTs not only reduce gout attacks, but also improve PsA symptoms and overall disease outcomes [10] and reduce comorbidities.

8. Conclusions

This review highlights the complex interplay between hyperuricemia/gout and psoriasis/PsA. Psout represents a clinical challenge due to the overlapping symptoms and shared pathophysiological mechanisms of gout and PsA. The concept highlights the potential involvement of uric acid crystals in the pathophysiology of PsA and underscores the risk of confusion between gout and PsA. Understanding this overlap is crucial for accurate diagnosis and effective management.

Future research should focus on exploring the long-term outcomes of patients and evaluating the efficacy of ULTs in PsA patients with HU. Early diagnosis and intervention may be crucial to prevent severe joint damage and improve patient outcomes. Routine screening for hyperuricemia in PsA patients and the use of appropriate diagnostic tools like synovial fluid analysis, ultrasonography, or DECT can help clinicians in the early detection and management of psout.

Current treatments for PsA and gout exist, each targeting different aspects of the diseases. However, managing Psout requires a nuanced approach due to the potential conflicts in treatment strategies and the presence of multiple comorbidities. Personalized medicine, which considers individual patient characteristics, genetic profiles, and biomarkers, offers a promising avenue for developing tailored treatment plans that address both conditions simultaneously.

By advancing our understanding of this intersection and integrating personalized medicine approaches, we could improve the quality of life for patients with this overlap syndrome and pave the way for future therapeutic advancements.