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Psoriatic arthritis (PsA) is a heterogeneous, progressive inflammatory disease that often arises in patients with psoriasis. Increasing evidence highlights potential critical windows of opportunity during which early recognition and appropriate therapeutic intervention can alter long-term outcomes.
Methods
This review summarizes evolving treatment strategies for PsA across the disease continuum—from psoriasis and very early PsA through to established disease—focusing on the rationale for rapid intervention and risk-stratified use of biologics and emerging therapies.
Results
Data from many recent trials support the principle that earlier use of effective targeted therapy can improve outcomes, including controlling psoriasis and arthritis, inducing remission and even drug-free remission. Treat-to-target strategies, with close monitoring and timely escalation, are central to optimizing outcomes. In this recent literature, biologics targeting TNF, IL-17, and IL-23 have reshaped our understanding of the treatment landscape. Novel oral cytokine-signaling inhibitors, such as TYK2 and IL-23 receptor antagonists, represent promising future options but require long-term safety and head-to-head data in PsA. Comorbidities, patient preference, and safety considerations remain essential in tailoring therapy.
Conclusions
PsA management is shifting from reactive to proactive care. Aligning clinical practice toward early detection of skin and joint disease, rapid access to appropriate biologics, and disciplined treat-to-target approaches offer the best prospect for durable remission and improved quality of life. The next challenge lies in defining early PsA, predicting progression from psoriasis, and integrating new therapeutic classes into evidence-based treatment algorithms.
Key Summary Points
PsA develops along a continuum from psoriasis through very early and early disease to established multidomain inflammation, highlighting potential windows of opportunity for intervention.
Early recognition and timely access to effective biologics, particularly those targeting TNF, IL-17, and IL-23, can improve long-term outcomes by preventing irreversible damage and sustaining disease control.
Introduction
Psoriatic disease is a heterogeneous systemic inflammatory disorder that includes psoriasis, psoriatic arthritis (PsA), and a broad spectrum of comorbidities [1, 2]. Up to one-third of individuals with psoriasis eventually develop PsA, although the onset of arthritis may follow a variable latency period [3, 4]. Emerging data suggest a continuum that includes subclinical inflammation and a prodromal phase with non-specific musculoskeletal symptoms before overt arthritis appears [5]. This evolving understanding highlights the systemic nature of psoriatic disease and underscores the importance of early recognition and intervention to limit irreversible joint damage and comorbidity burden [6].
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Over the last two decades, major advances in therapeutics have transformed the management of psoriatic disease. Tumor necrosis factor (TNF) inhibitors were the first biologic agents to demonstrate efficacy across both skin and joint domains. The subsequent introduction of Interleukin (IL)-17 and IL-23 inhibitors has expanded treatment options, offering high efficacy in psoriasis and PsA [7‐9]. Nevertheless, treatment response remains heterogeneous, and key questions remain regarding the optimal timing and sequencing of therapies.
The concept of a “window of opportunity” in PsA is now being explored. Across the psoriatic disease spectrum, accumulating evidence indicates that earlier recognition and initiation of effective therapy can modify disease trajectory, reducing irreversible joint damage and preserving long-term function [10, 11]. In psoriasis, this has prompted evaluation of whether early systemic treatment can change psoriasis outcomes, delay or prevent transition to clinically manifest PsA; in early PsA, timely therapy increases the likelihood of remission or minimal disease activity, whereas in established or refractory disease, the same interventions are more likely to stabilize than to reverse accrued damage. Therapeutic decisions must also account for comorbidities—cardiometabolic disease, obesity, and extra-articular manifestations such as inflammatory bowel disease (IBD) or uveitis—which influence both efficacy and safety and therefore shape drug choice alongside disease stage [9]. In practice, such considerations are highly consequential: patients with recurrent uveitis derive greatest benefit from TNF monoclonal antibodies with proven ocular efficacy, while those with concomitant IBD are also preferentially managed with TNF monoclonal antibodies, given both their established efficacy in Crohn’s disease and ulcerative colitis and the potential for IL-17 inhibition to worsen intestinal inflammation [9, 12]. Similarly, heightened cardiovascular risk—particularly in older adults—necessitates caution with Janus kinase (JAK) inhibitors, where safety signals have emerged in adults aged ≥ 50 years with cardiovascular or malignancy risk factors [13]. These examples underscore that psoriatic disease management cannot be reduced to joint and skin outcomes alone. Instead, treatment must be tailored to the individual patient, integrating disease stage with comorbidity profile to achieve durable remission and to minimize systemic morbidity. Early intervention, therefore, is not only about halting structural joint damage but also about choosing the safest and most effective therapy for each patient within the broader context of psoriatic disease.
In this review, we summarize evidence supporting multiple therapeutic windows across the psoriatic disease spectrum (Fig. 1; Table 1), examine the strengths and limitations of available therapies, highlight the impact of comorbidities, and discuss how emerging strategies, including precision medicine, may reshape treatment paradigms in the future. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Fig. 1
Psoriatic disease continuum and opportunities for early intervention. The figure illustrates the progression from psoriasis to early and established psoriatic arthritis (PsA), highlighting potential intervention points across stages. Evidence suggests biologics may reduce systemic inflammation in psoriasis (though prevention remains uncertain), interception strategies are under study in at-risk individuals, early treat-to-target therapy improves outcomes in recent-onset PsA, and biologics remain effective in established disease
Therapeutic descriptions across the psoriatic disease continuum
Stage
TNF inhibitors
IL-17 inhibitors
IL-23 inhibitors
Key notes/outcome considerations
Psoriasis without clinical arthritis
Broad class efficacy for psoriasis; observational signals for lower incident PsA are hypothesis-generating only
Rapid skin efficacy. Histologic resolution signals in early PsO with secukinumab skin biopsy study (mechanistic) [28]
GUIDE (guselkumab) suggests earlier treatment yields more stable control/remission in psoriasis [27]. Highest skin efficacy; disease-modification hypothesis in early PsO
Up to one-third of PsO develop PsA over time. TRM cell biology may underlie recurrence; prevention evidence is preliminary and limited by surveillance/immortal-time/confounding biases
Very early/subclinical PsA (interception window)
No RCT in purely subclinical PsA; class has a strong anti-inflammatory profile conceptually suitable for interception
IVEPSA: secukinumab reduced MRI-detected inflammation and improved symptoms over 24 weeks in high-risk PsO [5]. Not true prevention; reversal of subclinical activity
PAMPA: ongoing RCT testing guselkumab for interception in high-risk PsO with imaging abnormalities [39]
Imaging-positive (MRI/US) without clinical arthritis; distinct from true prevention and from early clinical PsA
Early PsA
GOLMePsA: no significant difference at 24 weeks vs. MTX + CS (negative primary) [42]. SPEED (TWiCs): early aggressive strategies (adalimumab induction and combination csDMARDs) outperformed step-up in poor-prognosis early PsA [44]
CONTROL (open-label): early TNFi superior to conventional step-up in poor-prognosis early PsA [40]
STAMP: early secukinumab + MTX showed faster improvement by 12 weeks but no difference at 24 weeks by ACR outcomes [41]
Direct early PsA RCT evidence: none
No early intervention RCT has directly tested radiographic progression; structural protection evidence largely from established disease. Outcome choice (PASDAS vs. ACR/DAPSA) may influence conclusions
Established PsA
Broadest domain coverage incl. axial and uveitis; strong radiographic and long-term data; flexible switching/combination
Adalimumab—ADEPT [46] significant ACR/PASI responses; radiographic inhibition sustained in LTE
Bimekizumab—BE OPTIMAL[54]/BE COMPLETE [55] Rapid multidomain responses; safety consistent with IL-17 class
Good skin and joint efficacy; radiographic inhibition demonstrated and good tolerability; peripheral joint onset may be slower vs. IL-17 (e.g., DISCOVER-2 [56]). Favorable persistence/tolerability in registries
significant joint and skin efficacy, durable safety
GRAPPA domain-driven selection: TNF or IL-17 for axial; monoclonal TNF for uveitis; IL-23 or TNF for concomitant IBD. Structural reversal is rare; aim is stabilization and function preservation
Refractory/late-stage PsA (D2T concepts)
Remains an option for axial/uveitis even after multiple failures; durability may be reduced with prior exposure
Effective after TNF failure
Stronger/faster skin, nail, enthesitis control vs. IL-23
Evidence for axial disease and radiographic protection
Durable skin control with favorable long-term safety (vs. TNF, IL-17); Less immunogenicity and convenient dosing (q8–12 weeks)
Potential to sustain efficacy despite prior biologic exposure
Goals shift to symptom control, maintenance of function, and comorbidity management; multidisciplinary care essential. Other options after biologic failure include tsDMARDs with class-specific label cautions
Label-aligned cautions (summary)
Risk of serious infections and tuberculosis reactivation; screen and vaccinate per guidelines
Use with caution in active IBD; monitor for mucocutaneous candidiasis
Limited/uncertain efficacy for axial disease and uveitis; slower joint onset than IL-17 in some studies
Summaries only—verify exact wording with current product labels and regulatory guidance
Stages are ordered from cutaneous-only disease to refractory PsA. Evidence items prioritize trial signals mentioned in the text. Safety notes are summarized generically; cross-check current product labels for exact wording. Reference tags as per draft numbering: IVEPSA [5]; GUIDE [27]; PAMPA [39]; CONTROL [40]; STAMP [41]; GOLMePsA [42]; SPEED [44]; PRESTA [50]; ADEPT [46]; IMPACT [49]; GO-REVEAL [47]; RAPID-PsA [48]; FUTURE [51]; SPIRIT P1/P2 [52, 53]; BE COMPLETE [55]; BE OPTIMAL [54]; DISCOVER [56]; KEEPsAKE [57, 58]
PsO psoriasis, PsA psoriatic arthritis, RCT randomized controlled trial, csDMARD conventional synthetic disease-modifying anti-rheumatic drug, bDMARD biologic DMARD, tsDMARD targeted synthetic DMARD, T2T treat-to-target, TRM tissue-resident memory, MRI magnetic resonance imaging, US ultrasound, ACR American College of Rheumatology, DAPSA Disease Activity Index for Psoriatic Arthritis, PASDAS Psoriatic Arthritis Disease Activity Score, IBD inflammatory bowel disease, D2T difficult-to-treat
Pathophysiology and Potential Treatment Targets
The skin represents the initial site of inflammation in psoriatic disease, where early immune activation may be reversible with timely intervention. In PsA, this inflammatory potential extends beyond the skin to musculoskeletal structures [14, 15]. The enthesis represents a key anatomical site in PsA, where mechanical stress and microdamage can trigger local immune activation [16]. Early inflammation at this interface is often transient and reversible, whereas chronic synovial proliferation and structural remodeling that develop later are far less amenable to treatment [1, 2].
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Central to these processes are the IL-23/IL-17 and TNF pathways, which orchestrate both cutaneous and musculoskeletal inflammation [7, 8]. These cytokine circuits underpin the rationale for biologic therapies, but their clinical impact differs according to disease stage. In early disease, blocking these pathways can suppress inflammation before irreversible joint or entheseal damage accrues; in long-standing disease, cytokine blockade may still control inflammation but is less likely to restore function [1, 9]. TNF inhibitors, the first biologics approved for PsA, have demonstrated consistent efficacy across peripheral arthritis, skin disease, enthesitis, and axial involvement, with long-term data confirming inhibition of radiographic progression [17, 18]. Importantly, their effectiveness appears greater when introduced early in the course of the disease. Randomized trials and observational cohorts indicate that patients treated soon after symptom onset are more likely to achieve remission or minimal disease activity, whereas those with established PsA often experience residual disability despite adequate inflammatory control [9, 19]. These findings support the concept that TNF blockade is most impactful before irreversible structural change becomes dominant. IL-17 inhibitors directly target the effector cytokine most closely linked to keratinocyte activation and entheseal inflammation, accounting for their strong efficacy in both skin and joint domains [8]. Their maximal benefit is also observed when given before chronic remodeling dominates, consistent with the central role of IL-17 in acute inflammation rather than tissue repair [20]. IL-23 inhibitors, in contrast, act more “upstream” by modulating the survival and expansion of pathogenic IL-23R⁺ lymphocytes. While highly effective in psoriasis, their impact in PsA appears stronger earlier in disease, when enthesitis and skin inflammation predominate, than in long-standing arthritis with structural change [21‐23].
JAK inhibitors offer an oral targeted approach for PsA by modulating multiple cytokine pathways simultaneously. They have shown efficacy across joint and skin manifestations, providing an alternative to biologic therapies. Clinical experience suggests that their benefit is most pronounced when inflammation remains the dominant driver of disease, rather than when irreversible structural changes have developed [24]. TYK2 inhibitors represent a newer strategy, selectively targeting signaling pathways such as IL-23/IL-12 and type I interferons. They have demonstrated efficacy in psoriasis and early evidence indicates potential benefit in PsA as well. As with other targeted agents, their role is likely to be greatest when introduced early in the disease course, before chronic tissue remodeling limits the impact of therapy, but there are more limited data with oral therapies [25‐27].
Together, these observations across biologics disease-modifying anti-rheumatic drugs (DMARDs) reinforce a common principle: therapies are most effective when inflammation is the dominant driver of disease activity, whereas efficacy plateaus once structural remodeling, chronic pain sensitization, and comorbidities take precedence.
Windows of Opportunity Across the Psoriatic Disease Spectrum
Early Intervention in Psoriasis
In recent years, biologic therapies have offered intriguing signals of modifying this trajectory. The GUIDE study with guselkumab in psoriasis highlighted that patients treated earlier in their disease course were more likely to achieve stable disease control and sustain drug-free remission compared with those with longer disease duration [28]. This trial demonstrated that patients with shorter disease duration (≤ 2 years) achieved complete skin clearance (PASI = 0) more frequently and faster than those with longer disease duration (51.8% vs. 39.4%; median 141 vs. 200 days). This finding supports the concept that early disease control may induce a more stable immunologic remission. Similarly, a skin biopsy study with secukinumab demonstrated resolution of histologic abnormalities in early psoriasis, but not in participants with more established skin disease, further underscoring the potential for disease modification when intervention is initiated promptly [29]. These findings align with emerging insights into T resident memory (TRM) cells, which may act as a reservoir for recurrent inflammation and are increasingly recognized as key players in both dermatology and rheumatology [30‐32]. Collectively, these observations support the broader concept that very early systemic intervention offers the greatest potential to alter the natural history of psoriatic disease and improve long-term outcomes, while highlighting the need for prospective studies to confirm whether such early signals can be translated into durable remission in clinical practice.
Psoriasis at Risk of Developing Arthritis
Patients with psoriasis but without musculoskeletal involvement represent the earliest stage where therapeutic intervention may modify the course of arthritis. Epidemiological studies consistently demonstrate that up to one-third of patients with psoriasis eventually develop PsA, and longitudinal cohorts identify subclinical enthesitis or synovitis in a significant proportion of patients with psoriasis at risk [33, 34].
Observational studies evaluating systemic therapies in psoriasis cohorts have also suggested a reduced risk of incident PsA, particularly with biologic agents when compared to topical therapy, phototherapy, or conventional systemic treatments [35‐37]. Singla et al. further compared different classes of biologics and reported differential effects on PsA incidence, raising the possibility that targeted pathways may not be equivalent in their capacity to modify disease progression [38]. Collectively, these findings support the intriguing concept that effective suppression of cutaneous inflammation could alter the natural history of psoriatic disease. However, interpreting such data is far from straightforward. Meer et al. noted that common biases in observational datasets—such as more intensive monitoring in treated patients (surveillance), misclassification of pre-exposure “immortal” time, reverse causation when early PsA symptoms prompt therapy (protopathic), and treatment selection linked to disease severity (confounding by indication)—can distort apparent associations [39]. Consequently, signals that systemic therapy might delay or prevent transition from psoriasis to PsA should be viewed as preliminary and hypothesis-generating, pending confirmation in validation through prospective trials [35].
Very Early or Subclinical PsA
A second therapeutic window exists in patients with psoriasis who show subclinical musculoskeletal inflammation on imaging or biomarker testing but have not yet developed clinical arthritis. This group represents a transition between pure psoriasis and early PsA, and may provide an opportunity for disease interception.
At the pre-arthritis end of the spectrum, an interception strategy targets patients with psoriasis who already have subclinical musculoskeletal inflammation on imaging (magnetic resonance imaging (MRI) or ultrasound) but no clinical arthritis. In the prospective IVEPSA (Interception in Very Early PSA) study, 24 weeks of secukinumab reduced MRI-detected musculoskeletal inflammation and improved symptoms in high-risk psoriasis, indicating that pharmacologic intervention can reverse subclinical disease activity before overt PsA develops [5]. This stage should not be regarded as true prevention—because inflammatory changes are already demonstrable—nor is it equivalent to early PsA, since patients do not yet meet clinical criteria; rather, it constitutes a distinct “interception window” within the psoriatic disease continuum in which targeted therapy may modify downstream clinical expression. From an imaging perspective, findings consistent with subclinical PsA typically include bone marrow oedema at entheseal or periarticular sites, active synovitis or tenosynovitis on MRI, or power doppler signal at entheseal insertions on ultrasound—features that are infrequent in healthy individuals and more likely to indicate genuine inflammatory activity rather than nonspecific mechanical change.
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Building on this proof-of-concept, IL-23 blockade is now being investigated in larger, more definitive interception-focused trials. The randomized, double-blind, placebo-controlled PAMPA (Preventing Arthritis in a Multicenter Psoriasis At Risk cohort) study of guselkumab is testing whether intervening at the interception stage can delay or even prevent transition to clinical PsA [40]. Unlike IVEPSA, which demonstrated short-term biological reversibility, PAMPA is designed to establish whether sustained interception alters long-term clinical outcomes. Together, these complementary approaches frame interception not as true prevention nor as established PsA management, but as a distinct and actionable therapeutic window with potential to reshape the psoriatic disease course.
This interception paradigm applies predominantly to the common adult psoriasis-first trajectory in which cutaneous disease precedes musculoskeletal involvement. Adult patients who present with arthritis before psoriasis likely follow a less frequent and distinct pathogenic pathway, and thus are not the primary target of interception strategies. Similarly, juvenile psoriatic arthritis more often presents with arthritis first, reflecting age-dependent differences in immune maturation rather than the adult psoriasis-first model on which interception approaches are based.
Early PsA
The third and most critical window is in early clinical PsA, usually defined as within the first two years of symptom onset. Multiple studies demonstrate that early diagnosis and treatment improve the likelihood of remission, reduce radiographic progression, and may fundamentally alter long-term outcomes [10].
The CONTROL (Comparison of Optimal Novel Therapies for ROLe in early PsA) study, was an open-label, multicenter trial comparing early TNF inhibitor therapy with conventional step-up care in patients with early PsA and poor prognostic features. This study showed that early intensive therapy with adalimumab plus methotrexate achieved MDA in 41% of patients at week 16 compared with 13% for methotrexate escalation (p < 0.0001), demonstrating that early biologic combination therapy yields markedly faster and higher rates of treatment target attainment than conventional step-up approaches. Early initiation of biologics was associated with superior disease control, supporting the concept that aggressive intervention in the first years of disease may maximize the potential for long-term remission [41]. However, participants were chosen based on an inadequate response to methotrexate, excluding many patients who may respond well to methotrexate as a first-line option. This limits the generalizability of the findings to the broader early PsA population.
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The STAMP trial (Treatment Strategies Aiming at Minimal Disease Activity in PsA) is a randomized, open-label, multicenter study comparing early initiation of secukinumab with a conventional treat-to-target approach using standard-of-care csDMARD escalation in patients with newly diagnosed PsA. At week 12, early secukinumab achieved American College of Rheumatology 50% response (ACR50) in 38% of patients versus 17% with standard care (p = 0.009), demonstrating that early biologic initiation leads to a faster and higher rate of clinical response. Although by week 24 overall efficacy between groups became comparable, the secukinumab arm showed more rapid attainment of treatment targets and a lower need for therapy escalation—supporting early intervention strategies within a treat-to-target (T2T) framework [42].
Within the early PsA window, the GOLMePsA (Golimumab Methotrexate Psoriatic Arthritis) trial was designed to test whether an up-front, intensive induction strategy—golimumab in combination with methotrexate and short-course corticosteroids—could outperform a conventional methotrexate-plus-corticosteroids regimen in treatment-naïve patients with early psoriatic arthritis (disease duration ≤ 24 months). This randomized, double-blind study applied composite clinical and imaging endpoints at 24 weeks to examine whether rapid suppression early in the disease course could change outcomes. At 24 weeks, no statistically significant difference was observed in the primary composite endpoint between the combination (golimumab + methotrexate + short-course corticosteroids) and methotrexate + corticosteroids alone (adjusted mean difference in PASDAS = − 0.55 [95% CI − 1.12 to 0.03]; p = 0.064). Both groups improved substantially, but the addition of golimumab did not confer clear superiority. Importantly, relative corticosteroid use differed between groups (21% vs. 49%; p = 0.009), highlighting how induction intensity and glucocorticoid exposure can shape both efficacy signals and safety [43]. Although conceived as a “hit-hard-early” proof-of-concept trial, GOLMePsA ultimately showed that intensive biologic induction did not outperform standard MTX-based therapy in unselected early PsA. Differences in corticosteroid exposure, modest sample size, and broad inclusion criteria may have diluted treatment contrast, emphasizing the need for refined patient selection and controlled steroid use in future early intervention studies. In a recent accompanying editorial, Gladman contextualizes GOLMePsA within the broader early intervention paradigm, stressing that a negative primary outcome does not undermine the principle of early control. Rather, the trial highlights the need to refine study designs, minimize steroid confounding, optimize endpoints, and better identify patient subsets most likely to benefit from intensified early therapy [44].
The SPEED (Severe Psoriatic arthritis − Early intervEntion to control Disease) trial applied a trial-within-cohort design, randomizing patients with early poor-prognosis PsA to early TNF inhibitors, combination csDMARDs, or standard care. A total of 192 patients with moderate-to-severe PsA were randomized to standard step-up care, combination csDMARDs, or early TNF inhibitor therapy. At week 24, both early intensive arms achieved significantly greater improvements in PASDAS compared with standard care—mean difference − 1.09 (95% CI − 1.72 to − 0.46; p < 0.001) for early TNFi and − 0.69 (95% CI − 1.28 to − 0.10; p = 0.02) for combination DMARDs. Primary results indicated that aggressive early intervention strategies achieved higher remission rates and better function compared with conventional step-up therapy [45]. Importantly, unlike GOLMePsA and STAMP, SPEED specifically selected patients with poor prognostic features—including high baseline disease activity, elevated acute-phase reactants, functional impairment, or early erosive changes—thereby enriching the cohort for individuals with more severe early PsA. This trial-level distinction supports the interpretation that patients with these features may derive particular benefit from early aggressive therapy, whereas broader early PsA populations may not require such an approach. These nuances emphasize the importance of patient stratification in designing early intervention strategies. In addition, the superior outcomes with combination csDMARDs highlights their potential role as a pragmatic option in settings where biologics are unavailable, underscoring that early strategies must consider treatment access.
Taken together, trials in early PsA highlight both the promise and the complexity of intervening within the first years of disease. CONTROL and SPEED suggest that early biologic therapy can enhance outcomes, whereas STAMP and GOLMePsA remind us that benefits are not uniform and may depend on trial design, concomitant therapy, and patient selection. The overall lesson is that the early PsA window remains a nuanced stage where timely intervention is essential—embodying the ‘window of opportunity’ in which inflammation can be reversed before irreversible damage occurs. Beyond this timely intervention, the additional benefit of more aggressive medication regimens may be beneficial in those with poor prognostic factors.
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Established PsA
When PsA is well established, the opportunity for true disease modification begins to narrow, yet therapeutic decisions remain critical to optimize long-term outcomes. At this stage, treatment remains focused on treat to target but thinking about escalation, cycling, and domain-specific tailoring. Real-world registry studies demonstrate heterogeneous drug survival, with persistence rates varying between biologic classes and across patient populations. For example, IL-23 inhibitors have shown potential for favorable persistence compared with TNF inhibitors in some registries, while secondary loss of efficacy remains a common driver of switching [46].
Domain-driven treatment decisions are increasingly emphasized in clinical practice. The updated Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations propose therapy selection based on musculoskeletal (peripheral arthritis, enthesitis, dactylitis, axial disease) and extra-musculoskeletal domains (skin, nails, IBD, uveitis) [9]. For example, TNF or IL-17 inhibitors are recommended for axial disease, monoclonal TNF antibodies for uveitis, and IL-23 or TNF inhibitors for concomitant IBD. This individualized approach reflects both disease heterogeneity and the high prevalence of related conditions and comorbidities in established PsA.
Beyond symptomatic control, extensive RCT evidence across TNF inhibitors (ADEPT, GO-REVEAL, RAPID-PsA, IMPACT, PRESTA) [18, 47‐51], IL-17 inhibitors (FUTURE, SPIRIT, BE OPTIMAL/COMPLETE) [52‐56], and IL-23 inhibitors (DISCOVER, KEEPsAKE) [21, 57‐59] has consistently demonstrated multidomain efficacy and, in several trials, attenuation of radiographic progression. Long-term extension studies confirm that sustained suppression of inflammation translates into structural protection, although the magnitude of benefit varies between classes and patient subsets [47, 60‐62]. Radiographic progression can still be attenuated by biologics at this stage, and substantial functional improvement—including achievement of minimal disease activity in many patients—can be observed even in established disease. However, once structural damage has occurred, complete reversibility remains uncommon, underscoring the rationale for early intervention.
Refractory or Late-Stage PsA
By the time patients reach refractory or late-stage PsA, the window of opportunity has largely closed. These individuals often present with accumulated joint damage, irreversible functional impairment, and a history of multiple biologic failures. The concepts of difficult-to-treat (D2T) and complex-to-manage (C2M) PsA have been introduced to capture this population, characterized by persistent disease activity despite ≥ 2 biologic or targeted synthetic DMARDs, combined with pain amplification, obesity, fibromyalgia, and psychiatric comorbidities [63]. In this context, the goals of therapy shift from disease modification to symptom control, maintenance of residual function, and management of comorbidities. Multidisciplinary approaches—including pain management, rehabilitation, psychological support, and cardiovascular risk reduction—are essential. Despite ongoing therapeutic advances, reversal of structural damage remains elusive, and unmet needs are substantial.
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Future Directions: Newer Therapies
Next-Generation IL-17 Pathway Agents
Dual IL-17A/F blockade has advanced from promise to practice. Bimekizumab is now FDA-approved for PsA, offering rapid multidomain control where skin and entheseal burden are high. Phase 3 trials (BE OPTIMAL/BE COMPLETE) demonstrated early, sustained efficacy across joint, skin, enthesitis, and dactylitis domains, with manageable class-typical candidiasis risk; active IBD remains a key contraindication. These features make bimekizumab particularly attractive for early intensive strategies prioritizing fast skin clearance and enthesitis resolution [55, 56, 64]. Emerging IL-17 agents may further broaden options. Sonelokimab, a trivalent nanobody targeting IL-17A/F, showed robust joint and skin signals in the phase 2 ARGO trial, with phase 3 programs underway. Izokibep, a small-protein high-affinity IL-17A inhibitor, improved arthritis, psoriasis, and enthesitis in its phase 2 study, with acceptable safety [65, 66]. Compared with currently approved IL-17 inhibitors, these next-generation agents offer potential advantages such as dual IL-17A/F blockade, smaller molecular size enabling better tissue penetration, which may translate into enhanced efficacy or patient acceptability.
IL-23 Pathway Agents
IL-23p19 inhibitors are firmly established across psoriasis and PsA, with guselkumab and risankizumab approved and tildrakizumab in late-phase trials. Long-term extensions of DISCOVER and KEEPsAKE confirmed sustained efficacy and favorable safety, supporting IL-23 blockade as a backbone strategy beyond the established setting [67‐69]. Beyond these approved agents, future directions include evaluating IL-23 blockade in earlier disease stages and across extra-musculoskeletal domains. Looking forward, the focus is shifting toward earlier disease interception (e.g., PAMPA in subclinical psoriasis), program expansion with risankizumab and tildrakizumab, and exploration of next-generation IL-23 modulators to enable stage-specific and phenotype-tailored management [40, 70].
Oral Cytokine-Signaling Targets
Among oral agents, selective TYK2 inhibition has emerged as a promising next-generation approach. Deucravacitinib, an allosteric TYK2 inhibitor that avoids direct JAK1/2/3 blockade, met its primary endpoints in a phase 2 PsA trial, achieving dose-responsive improvements across joint, skin, enthesitis, and dactylitis domains [71]. Phase 3 programs are ongoing, and results will clarify whether its distinct selectivity translates into a differentiated long-term safety profile. In parallel, another oral TYK2 inhibitor, TAK-279 (zasocitinib), has also shown encouraging phase 2 results in PsA, with phase 3 trials underway [72]. Although slightly behind deucravacitinib in clinical development, zasocitinib shares the same allosteric mechanism targeting the TYK2 pseudokinase domain and may further validate TYK2 inhibition as a therapeutic class in psoriatic disease. Compared with conventional JAK inhibitors, TYK2’s allosteric mechanism may mitigate risks linked to broader JAK blockade, but head-to-head data and longer follow-up in PsA remain limited. In parallel, novel oral cytokine antagonists are being developed, extending beyond kinase inhibition. Icotrokinra, a novel first-in-class oral IL-23 receptor antagonist, has also demonstrated efficacy in randomized controlled trials in psoriasis, with PsA studies currently underway [73]. Unlike existing monoclonal antibodies that target the IL-23p19 cytokine, icotrokinra blocks the IL-23 receptor itself, potentially broadening the mode of IL-23 pathway inhibition. Early findings suggest that oral IL-23 blockade may provide an additional pathway to expand treatment options in psoriatic disease, complementing biologic agents while offering the convenience of oral administration.
Early dual blockade approaches—such as ABT-122 (TNF + IL-17A)—were biologically plausible but failed to show incremental benefit over adalimumab in phase 2 PsA trials [74], underscoring the complexity of translating cytokine synergy into clinical gain. These results highlight that “more targets” does not necessarily equate to “more efficacy.” By contrast, the newer dual IL-17A/F inhibitor bimekizumab has shown robust efficacy across musculoskeletal and skin domains, reflecting how simultaneous inhibition of both IL-17 isoforms—mechanistically relevant in PsA pathogenesis—can enhance therapeutic response. These examples illustrate that rational target selection remains central to advancing next-generation bispecific and receptor-targeted strategies [55].
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Future Therapeutic Directions of PsA: Toward Individualized Care
The future of PsA therapeutics lies not in an endless expansion of available agents, but in using them wisely—at the right time, in the right patient, for the right purpose. The “window of opportunity” framework provides a lens for this shift. In very early PsA, timely initiation of effective therapy increases the chance of remission and long-term stability, whereas delayed treatment risks irreversible joint damage. Ultimately, individualized care means different things for different patients: for those who fail to respond to first-line therapy, precision medicine offers the chance to guide them to the right mechanism within the early window; for those with comorbidities such as uveitis, IBD, or heightened cardiovascular risk, the therapeutic window is defined as much by safety as by efficacy; and in resource-limited settings, pragmatic strategies such as early combination csDMARDs demonstrate how access itself can shape opportunities for intervention. Framed in this way, individualized care and windows of opportunity are not competing concepts but complementary expressions of the same principle: intervening early, and intervening wisely, to alter the course of psoriatic disease.
Conclusions
PsA should be understood as a continuum that begins in psoriasis and may progress through very early and early stages to established multidomain disease. Mounting evidence demonstrates that early recognition and timely, mechanism-based intervention can substantially alter the disease trajectory—reducing inflammation, preventing structural damage, and preserving long-term function.
The current therapeutic strategies—particularly biologics targeting TNF, IL-17, and IL-23—have redefined standards of care. Within this context, treat-to-target strategies and risk-stratified approaches are central: high-risk patients warrant early escalation to targeted therapy, while others may follow a stepwise pathway provided that close monitoring and rapid adjustment are ensured. Comorbidities, safety considerations, and patient preference remain critical for tailoring treatment decisions, and thoughtful de-escalation should be considered once sustained disease control is achieved.
Looking forward, the field must refine definitions of “very early” PsA, identify predictors of progression from psoriasis, and develop evidence-based algorithms for sequencing and combination strategies. Novel oral cytokine-signaling inhibitors—including TYK2 and IL-23 receptor antagonists—may broaden convenient options, but their place will depend on long-term safety and comparative data in PsA. Ultimately, the priority is to align healthcare systems around earlier detection, rapid access to effective mechanisms, and disciplined treat-to-target care, thereby transforming therapeutic abundance into durable remission and improved quality of life for patients.
Medical Writing/Editorial Assistance
The authors received no specific assistance in the preparation of this manuscript.
Declarations
Conflict of Interest
Laura Coates is an Editorial Board member of Rheumatology and Therapy. Laura Coates was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ji-Hyoun Kang has nothing to disclose. Laura C Coates has received grants/research support from AbbVie, Amgen, Janssen, and UCB; worked as a paid consultant for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Enlivex, Janssen, Moonlake, Novartis, Pfizer, Proximi-T, Takeda and UCB; and has been paid as a speaker for AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer and UCB.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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