Sjögren disease (SjD) is a systemic autoimmune disease in which immune-mediated inflammation of lacrimal and salivary glands drives keratoconjunctivitis sicca and xerostomia, and many patients experience fatigue, pain, and extraglandular organ involvement. Contemporary reviews emphasize that the major unmet need is not the lack of targets, but the difficulty of translating biologic signals into clinically meaningful, patient-relevant outcomes in a heterogeneous population 1. Terminology matters because it shapes how cohorts and endpoints are defined. The 2025 international Rome consensus recommended replacing “Sjögren syndrome” with “SjD” and using “associated” rather than “secondary” when SjD coexists with another systemic autoimmune disease 2. In this editorial, we use “Sjögren disease” as the preferred clinical term, while retaining historical terminology (e.g., “primary Sjögren's syndrome”) when describing older classification criteria or trials. The objective of this editorial is to provide an evidence-informed, critical synthesis of (1) how disease heterogeneity and outcome measures shape interpretation of recent therapeutic trials, and (2) how a “trial-ready” precision approach can be operationalized now—pairing targeted therapies to the dominant treatable axis (“systemic inflammation” vs. “glandular function/damage” vs. “symptom amplification”). We performed a narrative literature appraisal using PubMed/NCBI (January 2014–February 2026; emphasis on 2019–2026). We used search terms including “Sjögren disease” OR “Sjögren syndrome” combined with “randomized,” “Phase 2,” “Phase 3,” “BAFF,” “CD40,” “BTK,” “interleukin 2,” “outcome measure,” “ESSDAI,” “ESSPRI,” and “ultrasound”. We prioritized randomized controlled trials, major cohort/cluster analyses, and consensus guideline or nomenclature papers. As this is an editorial, we did not conduct a formal systematic review; however, we aimed for balance by including both positive and negative interventional studies and interpreting them within a coherent framework of heterogeneity and endpoint selection. The reference list was optimized to remain within the journal's limit (≤ 20 references) while maintaining NCBI/PubMed-indexed evidence where possible. Mechanistically, SjD is often framed as an autoimmune epithelitis in which epithelial and antigen-presenting cells amplify interferon-driven immune activation and B cell hyperactivity, promoting autoantibody production and—in subsets—systemic inflammation and lymphoma risk 1. However, “one-size-fits-all” trial logic underperforms because objective inflammation, glandular damage, and symptom burden overlap only partially. At least three complementary lines of evidence highlight actionable heterogeneity. First, symptom-based clustering in large international cohorts shows that dryness, pain, and fatigue aggregate into distinct groups, and treatment exposure can be discordant with objective organ/laboratory abnormalities, implying that symptom burden alone is an unreliable surrogate for inflammatory activity 3. Second, cluster analysis integrating symptoms with clinical and biological features identified phenotypes (notably B cell active/low symptoms, high-systemic activity, and low-systemic activity/high symptoms) with different trajectories and prognostic signals, supporting stratified monitoring and trial design 4. Third, biomarker-informed work suggests these phenotypes map onto distinct immunobiology (e.g., interferon signature and B/T cell activation markers), strengthening the rationale for endotype-informed stratification and endpoint choice 5. The 2016 ACR/EULAR classification criteria remain foundational for research and are widely adopted clinically 2. Importantly, classification is not identical to early clinical recognition: the criteria were designed to standardize enrollment in trials and cohorts (high sensitivity/specificity in validation), not to function as a screening test across all real-world contexts 2. Therefore, clinicians should still pursue objective ocular/salivary testing and serology when clinical suspicion is high, even early in disease. Salivary gland ultrasound (SGUS) is increasingly supported as a feasible adjunct. A systematic review and meta-analysis found pooled sensitivity around 80% and specificity around 90% for SGUS in Sjögren's syndrome populations, with diagnostic estimates robust across scoring systems and criteria 6. Beyond diagnosis, SGUS offers a repeatable, noninvasive way to quantify gland structural change, which can support counseling and may help distinguish potentially reversible inflammatory gland disease from established damage in “treat-early” strategies. Current management remains anchored in symptom control, organ protection, and selective immunosuppression for systemic disease. The 2019 EULAR recommendations provide an evidence-based sequence that starts with the “central triplet” of symptoms (dryness, fatigue, pain), then escalates to systemic therapy for organ involvement 7. These recommendations also emphasize why trial design matters: Historically, RCTs often failed to meet primary endpoints, contributing to limited licensed systemic therapeutic options in SjD. A key insight from the last decade is that biologic plausibility does not guarantee clinical success when cohorts are heterogeneous and endpoints mismatch the treated axis. Hydroxychloroquine, for example, did not improve key symptoms over 24 weeks in the JOQUER RCT, illustrating that immune modulation alone may not shift patient-reported outcomes in unselected populations over short time horizons 8. This underscores the need for deliberate enrichment, longer follow-up when targeting damage, and explicit endpoint hierarchy. Targeted therapy signals are increasingly clear when enrollment and endpoints align. B cell–directed strategies remain a rational anchor. Ianalumab (anti-BAFF receptor, combining BAFF-R blockade with B cell depletion) met its primary efficacy objective in a Phase 2b dose-finding RCT (dose-related ESSDAI improvement at Week 24) 9. Longer-term results showed sustained improvements through Week 52 with generally favorable safety findings 10. Other B cell pathway approaches also generate signal: Telitacicept (dual APRIL/BLyS inhibitor) showed clinical benefits and reduced immunoglobulins in a Phase 2 RCT, consistent with on-target B cell pathway modulation 11. Sequential belimumab plus rituximab achieved deeper salivary gland B cell depletion and showed sustained ESSDAI reduction over longer follow-up in a Phase 2 trial 12. The CD40/CD40L co-stimulation axis illustrates why cohort definition can be decisive. In the TWINSS program, iscalimab (anti-CD40) demonstrated dose–response effects on systemic activity in a systemic-activity cohort but did not meet the symptom endpoint in a symptom-dominant cohort 13. In contrast, dazodalibep (CD40L antagonist) was evaluated in both systemic-activity and symptom-dominant populations, and phase 2 data support clinically meaningful benefit, reinforcing the CD40/CD40L pathway as a leading co-stimulation target in SjD 14. Oral pathway inhibitors add nuance rather than simple “success/failure” labels. The BTK inhibitor remibrutinib significantly improved systemic activity (ESSDAI) over 24 weeks, but ESSPRI did not improve, emphasizing the systemic–symptom dissociation that often complicates interpretation of SjD trials 15. A multi-arm Phase 2 RCT of filgotinib (JAK1), lanraplenib (SYK), and tirabrutinib (BTK) did not meet its composite primary endpoint, and key secondary endpoints were also not met, highlighting that pathway inhibition requires careful cohort enrichment, endpoint selection, and potentially longer-term designs 16. Finally, immune regulatory strategies may complement targeted inhibition: low-dose IL-2 improved ESSDAI responses and also reduced dryness, pain, and fatigue in a randomized clinical trial, with an immunologic signature consistent with regulatory cell expansion 17. Taken together, these trials highlight the frequent mismatch between systemic-activity endpoints and patient-reported symptom outcomes; the major efficacy and safety signals of recent targeted therapies are summarized in Table 1. Systemic-activity cohort: Extension cohort (continuing to Week 52): Systemic-activity cohort (active pSS, ESSDAI≈11 at baseline): Symptom outcomes (ESSPRI): Systemic-activity cohort (ESSDAI ≥ 5): Symptom outcomes: Iscalimab (CFZ533) Systemic-activity cohort (ESSDAI ≥ 5): Symptom-dominant cohort (ESSDAI < 5 with high ESSPRI): Generally well tolerated Serious AEs similar to placebo IV 1500 mg on Days 1, 15, 29, then every 4 weeks (Days 57, 85, 113, 141, 169) Crossover design thereafter Systemic-activity cohort (ESSDAI ≥ 5): Symptom-dominant cohort (ESSDAI < 5 with high ESSPRI): Overall population (active pSS, ESSDAI ≥ 5): Symptom outcomes (ESSPRI): Overall population (ESSDAI ≥ 5): Symptom outcomes (ESSPRI): Systemic-activity cohort (active pSS): Symptom outcomes (ESSPRI-like domains: dryness, pain, fatigue): Significant symptom improvements at Week 12 versus placebo: Dryness: Δ−18.33 Pain: Δ−10.33 Fatigue: Δ−11.67. To add value beyond enumerating agents, we propose a simple, clinic- and trial-ready framework that integrates heterogeneity with endpoints. At baseline and longitudinally, classify each patient along three parallel axes: (1) systemic inflammatory activity (organ involvement and ESSDAI domains), (2) glandular function/damage (objective tear/saliva tests, SGUS, and/or biopsy when indicated), and (3) symptom amplification phenotype (ESSPRI domains, comorbid sleep disturbance/anxiety/fibromyalgia features, and broader pain mechanisms). Targeted immunotherapies should be prioritized for axis-1–dominant disease (and for early, inflammatory axis-2 gland disease), with endpoints reflecting the treated axis rather than demanding universal improvement in all domains in short trials. Composite endpoints can help, but only if they remain interpretable and aligned with mechanism. The Sjögren's Tool for Assessing Response (STAR) was developed as a composite responder index spanning systemic activity, patient symptoms, lacrimal and salivary function, and biological parameters, and is being validated in NECESSITY-associated programs; STAR provides a structured way to recognize multidomain benefit without allowing a single domain to obscure meaningful change 1, 18. Finally, the pediatric spectrum deserves explicit inclusion. A 2025 nationwide multicenter childhood SjD study reported that a substantial proportion of children with convincing clinical and laboratory features do not fulfill adult-centric 2016 ACR/EULAR criteria, reinforcing the need for pediatric-adapted diagnostic strategies and endpoints as targeted therapies move forward 19. Sjögren disease is entering a transition defined less by “new targets” than by better matching of targets to the right endotypes and the right outcomes. Heterogeneity-aware trial design (stratification, enrichment, endpoint hierarchy) and a precision clinical mindset—aligning immunopathology with patient-prioritized benefit—are now central requirements for the next generation of SjD therapeutics. Y.-R.X., H.-A.Y. and S.R.M. conceived and drafted the manuscript; S.-B.Y. provided valuable discussion; S.-B.Y. and C.-Y.W. reviewed and edited of the manuscript; All authors have read and agreed to the published version of the manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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