Review

Epidemiology and the burden of disease

SjD is widely cited as the second most prevalent systemic autoimmune rheumatic disease after rheumatoid arthritis, although true population prevalence estimates vary considerably depending on the classification criteria and case-ascertainment method applied. Estimates derived from rigorous population-based studies using current classification criteria place the prevalence of primary SjD in the range of approximately 0.01-0.05%, whereas broader physician-diagnosed estimates used by patient advocacy groups are substantially higher, illustrating the persistent ambiguity created by inconsistent diagnostic criteria and underrecognition in primary care [9,10]. A 2024 American College of Rheumatology abstract analysis estimated a 2024 United States prevalence of approximately 10.6 per 10,000 for physician-diagnosed disease compared with only 1.98 per 10,000 for clinically confirmed cases applying current classification criteria, a discordance that highlights both overdiagnosis in some settings and underdiagnosis in others [10]. SjD predominantly affects women, with a female-to-male ratio frequently cited near 9:1, and most commonly presents in the fourth to sixth decades of life, although pediatric-onset disease, while rare, is increasingly recognized and associated with even greater diagnostic delay and a distinct phenotype dominated by fatigue, arthralgia, and glandular swelling rather than classic sicca symptoms [11].

The diagnostic odyssey: causes and consequences of delay

Several converging factors explain the prolonged diagnostic interval characteristic of SjD. First, sicca symptoms are insidious and frequently normalized by patients and primary care providers alike; objective salivary hypofunction may precede clinically apparent sicca symptoms by a substantial margin. Second, the serological and clinical overlap between SjD and other connective tissue diseases, particularly systemic lupus erythematosus and rheumatoid arthritis, often leads clinicians to anchor on an alternative diagnosis. Third, access to confirmatory testing, including minor salivary gland biopsy, ocular staining scores, and unstimulated salivary flow measurement, is unevenly distributed and underutilized outside specialized rheumatology or oral medicine centers [4,5,9].

The clinical consequences of delayed diagnosis are not merely academic. Longer diagnostic latency has been associated with significantly poorer self-reported general health, greater healthcare utilization, and a higher burden of systemic and extraglandular symptoms at the time of eventual diagnosis [4]. In children and adolescents, diagnostic delay of more than three years from symptom onset has similarly been associated with a significantly higher prevalence of established dryness symptoms at diagnosis, suggesting that earlier recognition could meaningfully alter the trajectory of glandular damage even in younger populations [11]. These findings collectively argue for incorporation of validated screening tools and a lower threshold for rheumatology referral in patients presenting with unexplained sicca symptoms, fatigue, or polyarthralgia, particularly in the presence of positive antinuclear antibodies or anti-Ro/La antibodies.

The systemic and symptomatic burden: fatigue, cognitive dysfunction, and pain

Although SjD is classically defined by glandular dryness, patients consistently rank fatigue, cognitive dysfunction ("brain fog"), and chronic widespread pain among their most disabling symptoms, frequently rating these domains as more burdensome than dryness itself [3,8]. These symptoms correlate poorly with conventional measures of glandular dysfunction or systemic organ involvement, and their pathophysiology is incompletely understood, though proposed mechanisms include central and peripheral cytokine-mediated neuroinflammation, small-fiber neuropathy, autonomic nervous system dysfunction, and disrupted hypothalamic-pituitary-adrenal axis signaling [3]. Importantly, fatigue and pain in SjD are not reliably captured by the ESSDAI, which is weighted toward objective systemic organ involvement, underscoring why patient-reported instruments such as the ESSPRI were developed as a complementary, rather than redundant, measure (discussed further below) [12,13].

Management of this symptomatic triad remains almost entirely non-pharmacologic and supportive, comprising graded exercise, cognitive-behavioral strategies, sleep hygiene optimization, and treatment of comorbid conditions, such as fibromyalgia, depression, and obstructive sleep apnea, which frequently coexist with and amplify SjD-related fatigue [3,8].

Lymphoproliferative risk and other extraglandular manifestations

Among the systemic complications of SjD, the risk of non-Hodgkin lymphoma, particularly mucosa-associated lymphoid tissue (MALT) lymphoma arising within affected salivary glands, represents one of the most clinically consequential unmet needs, as no validated pharmacologic strategy reliably prevents lymphomagenesis in high-risk patients [2,3]. Recognized risk factors include persistent salivary gland enlargement, palpable purpura, low C4 complement levels, cryoglobulinemia, and monoclonal gammopathy, and several of these features are explicitly incorporated into the ESSDAI biological and hematological domains, reinforcing the importance of structured, longitudinal disease activity assessment rather than symptom-directed visits alone [2,12,13]. Other extraglandular manifestations contributing substantially to morbidity include interstitial lung disease, peripheral and autonomic neuropathy, cutaneous vasculitis, and renal tubulointerstitial disease, each of which may be clinically silent in early stages and is therefore liable to be missed without systematic, instrument-based screening [2,3].

Clinimetric tools: utility of the ESSDAI and ESSPRI

A central theme uniting the diagnostic and therapeutic unmet needs in SjD is the historical absence of validated, standardized outcome measures suitable for both clinical trials and routine practice. This gap has been substantially addressed by the development of two complementary EULAR-endorsed instruments: the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) and the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI).

The ESSDAI, first described in 2010, is a clinician-completed, weighted composite index assessing systemic disease activity across twelve organ-specific domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematologic, and biological (immunological) domains [12]. Each domain is scored according to a graded activity scale (typically none, low, moderate, or high activity), and domain scores are weighted by clinical importance and summed to produce a total score ranging from 0 to 123, with higher scores reflecting greater systemic disease activity. The ESSDAI has been validated as sensitive to change and capable of discriminating between active and inactive systemic disease, and analysis of 921 Spanish patients within the GEAS-SS registry demonstrated its utility in characterizing the pattern and prevalence of systemic involvement across a large, real-world primary SjD cohort [13].

The ESSPRI, developed in 2011, is a brief, three-item patient-reported instrument capturing the severity of dryness, fatigue, and pain (joint and muscle pain) over the preceding two weeks, each scored on an 11-point (0-10) numerical rating scale, with the total ESSPRI score calculated as the mean of the three domain scores [14]. Subsequent validation work jointly assessing the ESSDAI and ESSPRI confirmed both instruments' sensitivity to change and established clinically meaningful improvement thresholds, while also demonstrating that the two measures capture largely non-overlapping dimensions of disease: ESSDAI reflects clinician-assessed, objective systemic organ activity, whereas ESSPRI reflects the subjective symptomatic burden that patients themselves identify as most impactful on quality of life [15]. This dissociation has important clinical implications, as patients with low ESSDAI (objectively quiescent systemic disease) frequently report persistently high ESSPRI scores driven by fatigue and pain, a pattern now explicitly recognized in symptom-based cluster analyses that stratify SjD patients into systemic-activity-dominant versus symptom-burden-dominant phenotypes. In routine clinical practice, regular application of both instruments, even in abbreviated form, allows clinicians to distinguish patients who require escalation of systemic immunosuppressive therapy (high ESSDAI) from those whose unmet need is predominantly symptomatic (high ESSPRI with low ESSDAI), informing fundamentally different management strategies and helping to set realistic expectations regarding which emerging therapies are most likely to benefit a given patient phenotype [12-15].

Emerging therapeutic frontiers

The therapeutic landscape for SjD has shifted markedly over the past several years, moving from a near-exclusive reliance on symptomatic and off-label immunosuppressive therapy toward a maturing pipeline of immunoselective biologic agents, several of which have now reported positive phase 2 or phase 3 data.

BAFF/BAFF-Receptor Blockade: Ianalumab

Ianalumab is an afucosylated IgG1 monoclonal antibody with a dual mechanism of action, combining enhanced antibody-dependent cellular cytotoxicity-mediated B-cell depletion with direct blockade of the B-cell activating factor receptor (BAFF-R), thereby targeting both existing autoreactive B cells and the survival signaling that sustains them [16,17]. Recent late-stage clinical studies have demonstrated clinically meaningful improvements in systemic disease activity, supporting further development of ianalumab as a promising therapy for SjD [16,17]. In the paired, global phase 3 NEPTUNUS-1 (N = 275) and NEPTUNUS-2 (N = 504) trials, ianalumab 300 mg administered subcutaneously monthly met its primary endpoint in both studies, demonstrating a statistically significant improvement in ESSDAI change from baseline at week 48 compared with placebo, representing the first phase 3 programs in SjD to demonstrate statistically significant improvement in systemic disease activity. Secondary endpoints, including Patient and Physician Global Assessment scores, also showed numerical improvement, and the safety profile was comparable to placebo [17-19].

FcRn Blockade: Nipocalimab

Nipocalimab is a fully human monoclonal antibody that selectively blocks the neonatal Fc receptor (FcRn), preventing IgG recycling and thereby reducing circulating IgG autoantibodies, including disease-associated antibodies such as anti-Ro52 and anti-Ro60, without broadly suppressing protective immunity. In the phase 2 DAHLIAS trial, a global, double-blind, placebo-controlled study enrolling 163 anti-Ro-seropositive adults with moderate-to-severe SjD, nipocalimab met its primary endpoint with a statistically significant improvement in ClinESSDAI score at week 24 compared with placebo, accompanied by a dose-dependent reduction in total IgG exceeding 77% at the highest studied dose, and numerical improvements in patient-reported dryness, fatigue, and joint pain [20]. These findings support a mechanistic link between autoantibody burden and systemic disease activity and have informed initiation of the phase 3 DAFFODIL program [20].

CD40-CD40L Costimulation Blockade: Dazodalibep

Dazodalibep is a novel non-antibody fusion protein that functions as a CD40 ligand antagonist, blocking the CD40-CD40L costimulatory interaction between T cells and CD40-expressing B cells and antigen-presenting cells, a pathway implicated in ectopic germinal center formation and class-switched autoantibody production within SjD-affected glands. In a phase 2, randomized, double-blind, placebo-controlled crossover trial enrolling two distinct SjD populations, dazodalibep met its primary endpoint in both cohorts: a significant reduction in ESSDAI in patients with moderate-to-severe systemic disease activity (least-squares mean change -6.3 versus -4.1 with placebo; p = 0.0167), and a significant reduction in ESSPRI in patients with high symptom burden but limited systemic organ involvement (-1.8 versus -0.5 with placebo; p = 0.0002) [21]. Dazodalibep also significantly reduced serum CXCL13 and rheumatoid factor levels, biomarkers reflective of germinal center activity, and was generally well tolerated, without the thrombotic signal previously observed with some anti-CD40L antibodies that bind the FcγRIIa-activating Fc domain [21].

Together, these three programs illustrate convergent but mechanistically distinct strategies for interrupting the B-cell-centric immunopathology of SjD (Table 1). Their differing primary endpoints-ESSDAI-driven for ianalumab and nipocalimab, and dual ESSDAI/ESSPRI-driven for dazodalibep-also exemplify the practical trial-design utility of the clinimetric framework discussed above. Other agents under earlier-phase investigation, including the anti-CD40 monoclonal antibody iscalimab and additional FcRn- and BAFF-pathway-targeting agents, further reflect the breadth of immunoselective approaches now being pursued for a disease that, until recently, lacked any late-stage disease-modifying candidate [16,22].

Agent | Mechanism | Trial/Phase | Primary Endpoint Met | Key Findings
Ianalumab | Afucosylated anti-BAFF-R mAb; B-cell depletion + BAFF-R blockade | Phase 3 (NEPTUNUS-1/2) | Yes - ESSDAI CFB at week 48 | Statistically significant ESSDAI reduction in both replicate trials; favorable safety; FDA Breakthrough Therapy designation (2026)
Nipocalimab | Anti-FcRn mAb; reduces IgG/autoantibody recycling | Phase 2 (DAHLIAS) | Yes - ClinESSDAI at week 24 | ≥77% IgG reduction at 15 mg/kg; numerical improvement in dryness, fatigue, pain; published in The Lancet (2025); phase 3 DAFFODIL ongoing
Dazodalibep | CD40 ligand antagonist (fusion protein); blocks T-B costimulation | Phase 2 crossover (two cohorts) | Yes - ESSDAI (pop 1); ESSPRI (pop 2) | Significant reduction in both ESSDAI and ESSPRI across two distinct phenotypic populations; reduced CXCL13/RF; well tolerated

Limitations and future directions

Several gaps remain even as the therapeutic and clinimetric landscape matures. First, no validated biomarker reliably predicts which patients will respond to a specific mechanism of action; baseline autoantibody titers have shown promise in nipocalimab trials but require prospective validation [20]. Second, the relative contributions of central sensitization, fibromyalgia overlap, and true SjD-specific neuroinflammation to the fatigue-pain-cognitive dysfunction triad remain incompletely disentangled, complicating both trial design and patient counseling [3,8]. Third, real-world implementation of ESSDAI and ESSPRI outside clinical trials remains inconsistent, and abbreviated or digitally administered versions may be needed to facilitate routine adoption in busy rheumatology practices [12-15]. Finally, as multiple late-stage agents approach potential approval, head-to-head comparisons and biomarker-guided sequencing studies will be required to rationally position these therapies relative to one another and to existing off-label immunosuppressive strategies [16].