Complementing Standard PsA Assessments with an Enthesitis Focused Lens

Key Takeaways:

• The "entheseal organ" is now recognized as the central site of PsA inflammation, triggered by biomechanical stress and the IL-23/IL-17 signaling axis.
• Clinicians should transition to an "enthesis-inclusive" approach using validated indices – such as the Leeds Enthesitis Index (LEI) for clinical efficiency or Power Doppler Ultrasound (PDUS) to differentiate inflammatory enthesitis from mechanical pain.
• Effective treatment requires moving beyond conventional DMARDs.

In the evolving landscape of psoriatic disease, the enthesis is increasingly recognized as the central driver of psoriatic arthritis (PsA) inflammation, functioning as the primary locus for disease initiation rather than a secondary structural site. The "entheseal organ" concept posits that biomechanical stress triggers a localized innate immune response, characterized by the activation of Group 3 innate lymphoid cells (ILC3s) and the subsequent upregulation of the IL-23/IL-17 axis.¹

Despite its central role, enthesitis remains under-detected in routine clinical practice, often overshadowed by synovitis and cutaneous involvement. Transitioning from a joint-centric to an enthesis-inclusive assessment is imperative to achieve comprehensive disease control and improve long-term functional outcomes.

The diagnostic gap: Subclinical enthesitis and disease burden

While the Disease Activity Index for Psoriatic Arthritis (DAPSA) and Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) provide robust frameworks for assessing peripheral joint involvement, they may insufficiently capture the burden of entheseal inflammation. Enthesitis is present in approximately 35 to 50 percent of PsA patients and is a potent predictor of structural damage and poor quality of life. For example, it may cause musculoskeletal chest pain from costochrondritis.²

Furthermore, recent data suggest a significant prevalence of subclinical enthesitis among patients with "skin-only" psoriasis, potentially serving as a marker for the transition to overt PsA. High-sensitivity imaging, such as Power Doppler Ultrasound (PDUS) and MRI, has shown that entheseal inflammation often precedes clinical synovitis, underscoring the need for rigorous physical examination and, where indicated, advanced imaging.^1,2

Clinical utility of validated enthesitis indices

To standardize the assessment of enthesitis, several validated indices are available, each with distinct clinical applications. The integration of these tools into standard PsA monitoring allows for a more granular understanding of therapeutic response.^2,3

• Leeds Enthesitis Index (LEI) – Focused on 6 sites (bilateral lateral epicondyles, medial femoral condyles, and Achilles insertions), the LEI is optimized for efficiency in high-volume clinical settings.
• Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index – A more comprehensive 16-site assessment that offers greater sensitivity to change, particularly in clinical trial settings.
• Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) – While originally developed for axial spondyloarthritis, the 13-site MASES remains a relevant tool for assessing axial-dominant PsA phenotypes.

What does this mean for clinicians treating patients with PsA? The answer lies in the correlation between high enthesitis scores and refractory disease. Patients with persistent enthesitis often achieve lower rates of Minimal Disease Activity (MDA), necessitating re-evaluation of the therapeutic mechanism of action.^1,2

Evolving treatment paradigms

The standard of care is shifting toward therapies that demonstrate specific efficacy at the enthesis. While conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) show limited utility in treating isolated enthesitis, biologic and targeted synthetic agents have reshaped the prognosis.^4-7

IL-17A and IL-12/23 inhibitors

Phase 3 data from the MAXIMISE and DISCOVER trials highlight the efficacy of IL-17A inhibitors (e.g., secukinumab) and IL-23 inhibitors (e.g., guselkumab) in achieving enthesitis resolution. These agents directly intercept the cytokines produced at the entheseal organ, addressing the core IL-23/IL-17 signaling axis.^4,5

JAK inhibitors

JAK inhibitors such as upadacitinib and tofacitinib have shown robust efficacy in enthesitis resolution, providing a potent oral alternative for patients who exhibit an inadequate response to TNF inhibitors.^4,6

TYK2 inhibitors

Deucravacitinib, a first-in-class allosteric tyrosine kinase 2 (TYK2) inhibitor, represents a novel targeted synthetic DMARD (tsDMARD) for PsA. By selectively binding to the regulatory domain of TYK2, it inhibits the signaling of IL-23, IL-12, and Type I interferons.⁷

Analysis of the POETRY-PsA trials indicates that TYK2 inhibition leads to statistically significant improvements in enthesitis scores (measured by LEI and SPARCC) compared to placebo, offering a highly selective mechanism for managing difficult-to-treat peripheral manifestations.⁷

Safety and tolerability considerations

When escalating therapy to address recalcitrant enthesitis, clinicians must balance efficacy with the specific safety profiles of these advanced classes. For instance, while IL-17 inhibitors offer excellent entheseal clearance, they are contraindicated in patients with concomitant inflammatory bowel disease (IBD).⁴

Conversely, JAK inhibitors require vigilant monitoring for thromboembolic events and herpes zoster reactivation, particularly in older populations with cardiovascular risk factors.⁴

Moving forward in PsA treatment

Translating emerging data into longitudinal patient management requires recalibrating the clinical workflow to ensure that entheseal inflammation is not overlooked during periods of apparent articular remission. The following clinical strategies provide a framework for integrating an enthesitis-focused lens into routine practice:^1,4

• Screening – Perform a systematic palpation of entheseal sites at every visit, regardless of the patient's primary complaint of joint pain or skin flares.
• Imaging – Use PDUS to distinguish mechanical enthesopathy from inflammatory enthesitis, particularly when clinical findings are equivocal.
• Therapeutic selection – Prioritize IL-17 or IL-23 inhibitors in patients in whom enthesitis is the predominant manifestation or a significant driver of functional impairment.

Complementing standard PsA assessments with a dedicated enthesitis lens is no longer optional; it is a clinical necessity for precision medicine. By integrating validated indices such as the LEI and using therapies with proven entheseal efficacy, clinicians can address the "hidden" burden of PsA. This holistic approach not only facilitates achieving MDA but also mitigates the long-term structural and functional decline associated with PsA.