Sjögren's disease (SjD) is a systemic autoimmune disease primarily characterized by sicca symptoms due to glandular involvement, often accompanied by extraglandular manifestations. Disease-modifying antirheumatic drugs (DMARDs) are cornerstones in the treatment of autoimmune diseases, currently used in SjD for systemic involvement such as interstitial lung disease. However, due to the high heterogeneity of SjD, there is no unified consensus on the individualized application of DMARDs. This study conducted a case-control investigation to preliminarily compare the efficacy of hydroxychloroquine (HCQ), mycophenolate mofetil (MMF), and tacrolimus (TAC). Furthermore, transcriptome analysis was performed to examine the impact of MMF and TAC treatments on signaling pathways in peripheral blood mononuclear cells (PBMCs) of SjD patients, aiming to provide a theoretical basis for individualized DMARD selection in SjD.

Based on the Sjögren's disease follow-up cohort at Peking University People's Hospital, clinical information of newly diagnosed SjD patients was collected. Patients were divided into HCQ, MMF, and TAC groups and each group included 40 cases. Non-parametric tests were used for paired comparisons of baseline clinical indicators and those after 24 weeks of treatment. Simultaneously, PBMCs were collected at baseline and after 24 weeks of treatment (4 pairs for HCQ, 4 pairs for MMF, and 6 pairs for TAC) for RNA sequencing. Differentially expressed genes were identified, and GO/KEGG enrichment analyses were performed to screen for differential pathways. Clinical efficacy was assessed using the EULAR Sjögren's disease Disease Activity Index (ESSDAI) score.

After 24 weeks of treatment, all three groups (HCQ, MMF, and TAC) presented a significant downward trend in ESSDAI scores. The MMF and TAC groups showed more pronounced improvement compared to the HCQ group (Figure 1). The KEGG enrichment results demonstrated that TAC (Figure 2) and MMF (Figure 3) groups shared significantly enriched pathways, including endocytosis, autophagy, apoptosis, and T cell receptor signaling pathways. The MMF treatment group significantly enriched immune-related pathways such as MAPK, NF-kappa B, p53 signaling pathway, Ferroptosis, as well as TNF, Chemokine, and NOD-like receptor signaling pathways. This reflects the impact of MMF on inflammatory signals, cellular stress, and ferroptosis. Additionally, its influence on protein synthesis pathways in the endoplasmic reticulum suggests MMF may affect autoantibody production. The TAC treatment group enriched pathways such as JAK-STAT, HIF-1 signaling pathway, Cytokine-cytokine receptor interaction, and Th1/2 differentiation, indicating that TAC focuses more on cytokine and T cell differentiation. GO enrichment analysis further confirmed this difference. Processes enriched in the MMF group concentrated on innate immune receptor signaling, while those in the TAC group were dominated by adaptive T cell activation and cell killing.

Compared with HCQ, both MMF and TAC more effectively improved systemic activity (ESSDAI) in Sjögren's disease. Transcriptome enrichment analysis further revealed that MMF was more inclined to regulate innate immunity and inflammatory stress pathways, and potentially intervene in autoantibody production by affecting endoplasmic reticulum protein synthesis. TAC, on the other hand, focused more on adaptive immune pathways. This suggests that MMF may be more suitable for patients with prominent hypergammaglobulinemia, overactive innate immunity, or ferroptosis-related inflammation, while TAC might be a better choice for patients with abnormally active B cell function or significant T cell differentiation abnormality. Furthermore, the common impact of MMF and TAC treatment on T cell receptor signaling suggests the potential of targeting TCR therapies in Sjögren's disease treatment.