Symptom-Based Cluster Analysis Categorizes Sjögren's Disease Subtypes: An International Cohort Study Highlighting Disease Severity and Treatment Discordance

Abstract

Objective: Although symptom relief is a critical aspect for successful drug development in Sjögren's disease, patient experiences with Sjögren's-related symptoms are understudied. Our objective was to determine how pain, dryness, and fatigue, the cardinal symptoms of Sjögren's disease, drive cluster phenotypes.

Methods: We used data from the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry and a Sjögren's Foundation survey. We performed hierarchical clustering of symptoms by levels of dryness, fatigue, and pain. Using international and US cohorts, we performed multiple logistic regression analysis to compare the clusters, which included comparisons of differences in symptoms, quality of life (QoL), medication use, and systemic manifestations.

Results: Four similar clusters were identified among 1,454 SICCA registrants and 2,920 Sjögren's Foundation survey participants: 1) low symptom burden in all categories (LSB); 2) dry with low pain and low fatigue (DLP); 3) dry with high pain and low to moderate fatigue (DHP); and 4) high symptom burden in all categories (HSB). Distribution of SICCA registrants matching the symptom profile for each cluster was 10% in the LSB cluster, 30% in the DLP cluster, 23% in the DHP cluster, and 37% in the HSB cluster. Distribution of survey participants matching the symptom profile for each cluster was 23% in the LSB cluster, 14% in the DLP cluster, 21% in the DHP cluster, and 42% in the HSB cluster. Individuals in the HSB cluster had more total symptoms and lower QoL but lower disease severity than those in the other clusters. Despite having milder disease as measured by laboratory tests and organ involvement, individuals in the HSB cluster received immunomodulatory treatment most often.

Conclusion: We identified 4 symptom-based Sjögren's clusters and showed that symptom burden and immunomodulatory medication use do not correlate with Sjögren's end-organ or laboratory abnormalities. Findings highlight a discordance between objective measures and treatments and offer updates to proposed symptom-based clustering approaches.

Figure 1

Heatmaps showing hierarchical clustering of Sjögren's disease symptoms according to severity level. A, Sjögren's International Collaborative Clinical Alliance (SICCA) Registry sample clusters generated by unsupervised hiararchical clustering based on evaluation of the following symptoms: oral and ocular dryness according to a weighted composite score of 5 items (presence of dry mouth, need sips of liquid to swallow food, presence of dry eye, presence of a gritty sensation in the eyes, and use of tear substitutes), fatigue (on a 4‐point Likert scale), and pain (on a 5‐point Likert scale). B, Sjögren's Foundation sample clusters generated by unsupervised hierarchical clustering based on evaluation of the following symptoms: oral and ocular dryness (on a 0–10‐mm visual analog scale [VAS]), fatigue (on a 0–10‐mm VAS), and pain (on a 0–10‐mm VAS).

Figure 2

Depression, quality of life, and medication use in patients from the Sjögren's International Collaborative Clinical Alliance Registry (n = 1,454) categorized according to Sjögren's disease symptom–based clusters. A, Depression, measured by the Patient Health Questionnaire 9 (PHQ‐9), and health–related quality of life, measured by the physical and mental components of the Short Form 12 (SF‐12). Bars show the mean. B, Frequency of medication use. * = P ≤ 0.05; ** = P ≤ 0.01; *** = P ≤ 0.001, by one‐way analysis of variance or chi‐square test. Biologic = tumor necrosis factor inhibitor or anti‐CD20 antibody; NSAID = nonsteroidal antiinflammatory drug; DMARD = disease‐modifying antirheumatic drug.

Figure 3

Oral and ocular dryness measurements, organ involvement, and abnormal laboratory and pathology results in patients from the Sjögren's International Collaborative Clinical Alliance Registry according to Sjögren's disease symptom–based clusters (n = 1,454). A, Frequency of patients with each laboratory or disease‐relevant feature according to dryness measurements, organ involvement, and abnormal laboratory results. B, Mean platelet and white blood cell (WBC) counts. C, Mean IgG levels. D, Mean focus score. Bars show the mean. * = P ≤ 0.05; ** = P ≤ 0.01, *** = P ≤ 0.001, by one‐way analysis of variance or chi‐square test. PBC = primary biliary cholangitis; RF = rheumatoid factor.

Figure 4

Medication use and cost of health care among participants of the Sjögren's Foundation survey according to Sjögren's disease symptom–based clusters (n = 2,920). In the survey, current medication use and exercise (A) and ever use of medications and exercise (B) were assessed, along with cost (in dollars) of specific aspects of health care for Sjögren's disease (C). Bars show the mean. Eye drops include artificial tears or eye ointments (nonprescription); prescription painkillers include, e.g., oxycodone, hydrocodone, tramadol; disease‐modifying antirheumatic drugs (DMARDs) include, e.g., hydroxychlroqouinme, methotrexate, azathioprine, mycophenolate, leflunomide, sulfasalazine; nerve pain medications include, e.g., gabapentin, pregabalin; injectable/infusible biologics include, e.g., rituximab, abatacept, tumor necrosis factor inhibitors. * = P ≤ 0.05; ** = P ≤ 0.01, *** = P ≤ 0.001, by one‐way analysis of variance or chi‐square test. OTC = over‐the‐counter; apt. = appointment.