JAK Inhibitors: Therapeutic Prospects and Clinical Challenges in Sjögren's Syndrome

Abstract

Sjögren's syndrome (SS) is a systemic autoimmune disorder primarily characterized by lymphocytic infiltration of exocrine glands, resulting in hallmark clinical manifestations such as keratoconjunctivitis sicca and xerostomia. Beyond glandular involvement, SS frequently presents with various extraglandular complications, including nephropathy, neuropathy, and interstitial lung disease (ILD). It is classified into primary and secondary subtypes. Secondary SS typically occurs secondary to other connective tissue diseases, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). This article focuses primarily on the pSS, with only partial discussion of the sSS. The pathogenesis of SS is multifactorial, involving an intricate interplay among genetic susceptibility, environmental exposures, and immune dysregulation. Current therapeutic strategies for SS predominantly emphasize symptomatic relief and immunomodulation. However, rigorous, evidence-based guidelines and well-validated criteria for assessing therapeutic efficacy remain inadequately established [1].

Emerging insights into the pathogenic mechanisms underlying SS have opened novel therapeutic directions. Cytokines are central to the pathogenesis of SS, mediating immune activation and lymphocyte proliferation. Upon binding to their corresponding receptors, cytokines such as type I interferon (IFN-I), interleukins (IL), and transforming growth factor (TGF) can activate associated Janus kinases (JAK) [2]. Activated Janus kinases subsequently phosphorylate specific tyrosine residues on cytokine receptors, facilitating the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins. Phosphorylated STAT proteins form homodimers or heterodimers through their Src homology 2 (SH2) domains, translocate into the nucleus, and bind to specific DNA sequences to modulate gene transcription and subsequent expression of target genes [3].

JAK inhibitors represent a promising therapeutic class, capable of concurrently modulating multiple cytokine pathways via inhibition of the common JAK–STAT signaling cascade. Thus, they hold potential for treating several systemic autoimmune diseases, including SS, systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), and systemic sclerosis (SSc).

The JAK kinase family comprises four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAK inhibitors primarily target the catalytic kinase (JH1) and regulatory pseudokinase (JH2) domains. Both first-generation (tofacitinib, baricitinib, and ruxolitinib) and next-generation inhibitors bind to the ATP-binding pocket of JH1, competitively preventing ATP binding and blocking the JAK–STAT pathway [3]. There are seven known members of the signal transducer and activator of transcription (STAT) family. Among them, phosphorylated STAT1 (pSTAT1) and phosphorylated STAT3 (pSTAT3) are found to be upregulated in salivary gland epithelial cells (SGECs), T cells, NK cells, and monocytes of patients with Sjögren's syndrome (SS). Tofacitinib, a selective JAK1/3 inhibitor, can interfere with interferon (IFN)-β–mediated signaling and reduce pSTAT1 levels in the nucleus and cytoplasm of SGECs in SS patients, suggesting its therapeutic potential in SS. Both retrospective and prospective studies have demonstrated that tofacitinib improves disease activity and modulates the EULAR SS Disease Activity Index (ESSDAI) in SS [4]. However, this study did not employ a double-blind randomized controlled design, and it had a small sample size, short observation period, and incomplete control for confounding factors, all of which may have influenced the outcomes. Indeed, one case report documented an SS patient with renal tubular acidosis and comorbid psoriasis who responded favorably to tofacitinib, with good safety outcomes [5]. However, this is merely an isolated case report. In addition, tofacitinib has shown both anti-inflammatory and antifibrotic properties in treating interstitial lung disease (ILD) associated with anti–melanoma differentiation–associated gene 5 (anti-MDA5) antibody–positive dermatomyositis, significantly improving lung function and chest CT manifestation [6]. SS and dermatomyositis share the serological feature of anti-Ro52 antibodies [7], which exhibit high sensitivity and specificity for the diagnosis of ILD [8], so JAK inhibitors have guiding significance in the treatment of SS. Baricitinib targets JAK1/2 and has been shown to reduce IFN-γ–induced CXCL10 production in human salivary gland duct cells, thereby attenuating inflammation. Clinical studies indicate that baricitinib can reduce ESSDAI and the EULAR SS Patient Reported Index (ESSPRI), while improving arthritis, skin rash, and ILD manifestations in SS patients [9, 10]. Similarly, this study employed a non-double-blind randomized controlled design, with additional limitations including high heterogeneity in the study population, small sample size, short observation period, and incomplete control for confounding factors. Filgotinib, a selective JAK1 inhibitor, diminishes the expression of multiple IFN-related genes (e.g., IFIT1, IFIT2, IFI44L, ISG15, RSAD2, and IFNG) and BAFF in the SGECs of SS patients, and has been shown to increase salivary flow rates in non-obese diabetic (NOD) mice [11]. In a phase II clinical trial for SS that included patients with both primary Sjögren's syndrome and secondary Sjögren's syndrome associated with SLE, RA, or other autoimmune disorders, although the proportion of patients in the filgotinib group reaching the primary endpoint, based on high-sensitivity C-reactive protein (hsCRP) levels and patient-reported SS symptoms (assessed via visual analog scale for global disease, pain, oral dryness, ocular dryness, and fatigue), was 16.6% higher than that in the placebo group, the difference did not reach statistical significance. Moreover, the trial did not meet the secondary endpoints (ESSDAI and ESSPRI), warranting further investigation [12]. This study has several limitations, including flaws in the design of primary endpoints, high heterogeneity in the study population, confounding effects from concomitant medications, and unreliable subgroup analyses. Beyond these agents, studies in healthy human salivary gland cell lines have demonstrated that AG490 and ruxolitinib can block the H₂O₂-induced JAK–STAT3–TET3 pathway, suggesting additional therapeutic possibilities for SS [13]. Deucravacitinib, an allosteric inhibitor of TYK2, mediates the phosphorylation of STAT in type I IFN, IL-12, and IL-23 signaling pathways. It has shown remarkable efficacy in phase III clinical trials for psoriasis and may also serve as a novel treatment for SS [14, 15]. Phase III clinical trials are currently underway to further evaluate its efficacy and safety in patients with active SS (Table 1, Figure 1).

A significant clinical challenge lies in exploring combination therapies of JAK inhibitors with disease-modifying antirheumatic drugs (DMARDs) or other immunosuppressants in patients with severe or refractory Sjögren's Syndrome (SS). Theoretically, targeting multiple pathways through such combinations may enhance therapeutic efficacy. This is supported by evidence that tofacitinib combined with hydroxychloroquine demonstrated significantly greater improvements in both disease activity and immunological parameters compared to hydroxychloroquine monotherapy in SS patients [9]. JAK inhibitors may also be associated with some adverse events, such as infections, hematologic abnormalities, dyslipidemia, cardiovascular or thromboembolic risks, and a potential increase in malignancy risk [16]. Close monitoring of patients and appropriate dose adjustments are crucial to mitigate these issues. Different routes of administration can significantly impact drug bioavailability and therapeutic efficacy. Transdermal administration, exemplified by to facitinib patches evaluated in rheumatoid arthritis, facilitates continuous drug delivery and may reduce systemic adverse effects compared to oral administration [17]. Inhalation administration directly targets the respiratory tract, allowing for rapid onset of action and represents a promising approach for pulmonary inflammatory conditions such as asthma [18]. Currently, a clinical trial is investigating AZD4604 as add-on therapy administered via inhalation to assess its efficacy and safety in patients with moderate to severe asthma [19]. These alternative administration methods could potentially benefit patients with Sjögren's Syndrome (SS), particularly those with glandular or pulmonary manifestations; however, further research is required to establish their clinical utility in this patient population. Precision stratification for JAK inhibitor therapy in Sjögren's Syndrome requires subtyping based on anti-Ro52 status, interferon signature, and ILD phenotype. Concurrent integration of biomarkers such as IFN activity, BAFF levels, and potential candidates (e.g., LY6E, EIF2AK2, IL15, CXCL10) may further clarify therapeutic efficacy, thereby guiding clinical decisions. These biomarkers offer novel therapeutic possibilities for SS management [20].

While JAK inhibitors exhibit promising therapeutic potential for SS, significant challenges persist concerning optimal dosing regimens (including induction and maintenance phases), appropriate routes of administration, treatment duration, and effective integration into routine clinical practice. Large-scale, well-designed randomized controlled trials are required to establish their efficacy and safety profiles in SS patients, thereby generating evidence-based guidance for the safe and effective clinical use of JAK inhibitors. Such evidence will ultimately inform clinical guidelines, ensuring their safe, effective, and standardized application in clinical practice.

Xiaoyu Tang and Po-Cheng Shih were responsible for the conception and original draft writing of this paper; Jingjin Hu participated in the original draft writing, while Dan Ma and Liyun Zhang contributed to the conception, writing, review, and editing of the manuscript.

Permission to Reproduce Material From Other Sources: All materials used in this study are original, and no third-party copyrighted materials were reproduced.

This study does not involve human participants, animals, or any other research requiring ethical approval.

This study does not involve human participants, and therefore patient consent is not required.

The authors declare no conflicts of interest.