Sjögren’s syndrome still has no approved disease-modifying treatment, making it one of the most under-served autoimmune conditions in rheumatology. But the pipeline of experimental therapies is fuller now than at any point in the disease’s history, with drugs targeting B cells, interferon signaling, autoantibody levels, and even gene therapy for damaged salivary glands all moving through clinical trials. Several of these approaches have produced early signals of efficacy that earlier drug candidates never managed, and one in particular, a new kind of B-cell depleter called ianalumab, has reached late-stage testing.
Why Earlier Drug Trials Kept Failing
For years, the main hope for a disease-modifying therapy in Sjögren’s was rituximab, a drug that wipes out B cells and had already proven itself in rheumatoid arthritis and certain lymphomas. The logic was straightforward: Sjögren’s is driven in large part by overactive B cells that infiltrate the salivary and lacrimal glands, so removing those cells should help. In practice, the pivotal trials were disappointing. The TEARS trial found no significant difference between rituximab and placebo for dryness, pain, fatigue, or overall disease activity.1PubMed. Treatment of primary Sjögren syndrome with rituximab: a randomized trial The larger phase 3 TRACTISS trial confirmed the pattern, showing no meaningful improvement in fatigue or oral dryness at 48 weeks.2Best Practice & Research Clinical Rheumatology. Novel therapies in Sjögren’s disease: A systematic review of the literature
There was a curious wrinkle, though. Rituximab did improve the structural appearance of salivary glands on ultrasound, even when patients did not feel better. That gap between measurable biological changes and subjective symptoms has haunted Sjögren’s research. Another high-profile failure was abatacept, a drug that blocks the costimulatory signal T cells need to activate. A phase III trial showed virtually identical drops in disease activity scores for the drug and placebo groups, with no clinical benefit despite some encouraging shifts in biomarkers like immunoglobulin levels.3BMJ Journals. Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial The emerging consensus is that hitting just one part of the immune system is not enough when the disease operates through several overlapping pathways at once.
Smarter B-Cell Strategies
The failure of rituximab did not kill interest in B cells as a target. Instead, it pushed researchers toward more refined approaches. A key insight came from work on B-cell activating factor, commonly called BAFF, a protein that acts as a survival signal for B cells. In Sjögren’s, BAFF levels are abnormally high, and the protein appears to keep inflammatory B cells alive in the salivary glands far longer than they should be, fueling a cycle of autoantibody production and tissue damage.4Scandinavian Journal of Immunology. The BAFF/APRIL System in Systemic Autoimmune Diseases with a Special Emphasis on Sjögren’s Syndrome Altered expression of BAFF and its receptors across multiple immune cell types helps explain why B-cell hyperactivity is so persistent in this disease.5Rheumatology. Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome
Ianalumab (also known by its trial name VAY736) was designed to exploit this understanding. Unlike rituximab, which only depletes B cells by targeting the CD20 protein on their surface, ianalumab does two things simultaneously: it blocks the BAFF receptor so B cells lose their survival signal, and it triggers enhanced antibody-dependent cellular cytotoxicity to actively destroy the cells.6Annals of the Rheumatic Diseases. Treatment of primary Sjögren’s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity A phase 2b dose-finding study (BAFSER) showed preliminary efficacy and helped select doses for further testing.7The Lancet. Safety and efficacy of ianalumab (VAY736) in patients with primary Sjögren’s syndrome (BAFSER): a randomised, double-blind, placebo-controlled, phase 2b dose-finding study Ianalumab is now in phase III trials and is widely regarded as the most advanced disease-modifying candidate for Sjögren’s.
Another inventive strategy is to combine existing drugs in sequence. A phase II trial tested giving belimumab (which neutralizes circulating BAFF) before rituximab (which depletes B cells). The reasoning was that when rituximab destroys B cells, free BAFF levels spike, which can fuel a rebound of the very cells you just removed. Pre-treating with belimumab prevented that spike, keeping BAFF suppressed through the critical window after B-cell depletion.8PubMed Central. A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren’s syndrome Whether that biological advantage translates into better symptom control is still being evaluated, but the principle of outsmarting the BAFF rebound is influencing how future combination trials are designed.
Targeting the Interferon System
B cells are not the only culprits. Research has shown that Sjögren’s patients have markedly overactive interferon signaling, with both type I and type II interferon pathways ramped up compared to healthy individuals. The two pathways dominate in different tissues: type I interferon activity is more pronounced in the blood, while type II interferon is more active in the salivary glands themselves.9PubMed Central. Type I and II interferon signatures in Sjogren’s syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren’s related lymphomagenesis This dual signature means that blocking interferon at the right point could dampen both systemic inflammation and the local gland destruction that causes dryness.
Anifrolumab, a drug that blocks the type I interferon receptor and is already approved for lupus, is attracting interest for Sjögren’s. Its mechanism interrupts the feedback loop between interferon-driven inflammation and B-cell dysfunction.10PubMed Central. Marked improvement of oral manifestations in systemic lupus erythematosus after therapy with IFNAR1 blocking antibody (anifrolumab): A case report The evidence so far is limited to case-level observations and extrapolation from lupus data, so controlled trials specifically in Sjögren’s are needed before drawing firm conclusions. Still, the biological rationale is strong, and the drug’s track record in a closely related autoimmune disease makes it a plausible candidate.
JAK inhibitors represent another route into the interferon pathway. The JAK-STAT signaling cascade is a downstream relay system that many inflammatory cytokines depend on, including interferons. Blocking these enzymes could theoretically tamp down multiple pro-inflammatory signals at once.11PubMed Central. JAK/STAT Pathway Targeting in Primary Sjögren Syndrome Several JAK inhibitors are already approved for rheumatoid arthritis and other conditions, and early-phase trials in Sjögren’s are underway. The advantage of these oral pills over injectable biologics is convenience, though they come with their own safety considerations, including infection risk.
Lowering Autoantibody Levels Directly
Most of the strategies above try to shut down the immune cells that produce harmful autoantibodies. A different approach sidesteps the cells entirely and goes after the antibodies themselves. Efgartigimod is an engineered protein fragment that blocks a receptor called FcRn, which normally recycles immunoglobulin G (IgG) antibodies and keeps their levels high. By blocking that recycling machinery, efgartigimod causes circulating IgG to be broken down faster than it is replenished, pulling autoantibody levels down.
A completed phase 2 trial tested efgartigimod in patients with moderate-to-severe Sjögren’s. The drug reduced total IgG levels by roughly 60% and produced a notably higher proportion of responders on a composite disease endpoint compared to placebo, with about 46% responding in the treatment group versus about 11% on placebo.12PubMed Central. Efficacy and safety of efgartigimod PH20 SC for Sjögren’s disease-associated dryness: study protocol for an investigator-initiated, multicenter, phase 2, randomized, double-blind, placebo-controlled trial (OASIS study) Those numbers are early and the trial was small, so they need confirmation, but the response rate gap is the kind of signal that justifies further investment. A newer investigator-initiated trial is specifically testing a subcutaneous formulation of efgartigimod for Sjögren’s-related dryness. This approach is particularly interesting because it does not suppress the entire immune system the way B-cell depleters do; it selectively lowers the antibody levels that are thought to drive the disease.
CAR-T Cell Therapy and the Idea of an Immune Reset
The most dramatic new approach borrows technology from cancer treatment. CAR-T cell therapy involves extracting a patient’s own T cells, engineering them in a laboratory to recognize and destroy B cells, and infusing them back. The result is a far deeper and more thorough B-cell depletion than rituximab or ianalumab can achieve, potentially eliminating even the long-lived, tissue-resident B cells that conventional drugs miss. In autoimmune disease, the goal is not just depletion but what researchers call an “immune reset,” in which the B-cell population that regrows after treatment is free of the autoreactive clones that were driving the disease.13PubMed Central. Advancements and challenges in CAR T cell therapy in autoimmune diseases
CAR-T has already generated remarkable case reports in lupus and inflammatory myopathy, and there is now a published Sjögren’s case as well. A 76-year-old woman who had active Sjögren’s for a decade received anti-CD19 CAR-T therapy to treat a concurrent lymphoma. By 90 days after treatment, her antinuclear antibodies and anti-Ro-52 antibodies were negative for the first time in ten years. Her dry mouth improved, serum cytokine levels normalized, and her disease activity score dropped substantially. Six months out, the lymphoma remained in complete remission and the Sjögren’s improvements held.14PubMed Central. Concurrent remission of lymphoma and Sjögren’s disease following anti-CD19 chimeric antigen receptor-T cell therapy for diffuse large B-cell lymphoma: a case report
A single case report is not proof that CAR-T works for Sjögren’s, and there are serious practical barriers. The manufacturing process is expensive and labor-intensive, the treatment requires a lymphodepleting chemotherapy pretreatment, and cytokine release syndrome is a real risk. For a disease that is rarely life-threatening, the risk-benefit math is harder to justify than it is in cancer. But the case illustrates what a thorough immune reset can accomplish, and several groups are now designing formal trials of CAR-T in autoimmune Sjögren’s, sometimes using newer “off-the-shelf” CAR-T products that could reduce cost and complexity.
Regenerative Approaches for Damaged Glands
All of the therapies discussed so far aim to quiet the immune attack. But by the time many patients are diagnosed, their salivary and lacrimal glands have already sustained real damage, including fibrosis and loss of functional tissue. Calming inflammation may prevent further destruction, but it cannot restore gland function that is already gone. That is where regenerative strategies come in.
Mesenchymal stem cells (MSCs) have shown promise in both animal models and small human studies. A systematic review of the available data found that MSC injections improved salivary secretion, reduced the density of inflammatory cells infiltrating the salivary glands, lowered pro-inflammatory cytokine levels, and raised anti-inflammatory ones.15PubMed Central. Treatment of Sjögren’s Syndrome with Mesenchymal Stem Cells: A Systematic Review Animal studies have provided more detail on how this works, showing that MSC transplantation can reverse pathological changes in the submandibular glands, including fibrosis and the tissue remodeling that erodes gland architecture.16PubMed. Mesenchymal stem cell transplantation alleviates Sjögren’s syndrome symptoms by modulating Tim-3 expression The appeal of MSCs is their dual action: they both quiet inflammation and promote tissue repair. The limitation is that the human evidence is still thin, mostly drawn from small, uncontrolled studies, and standardizing the manufacturing and dosing of cell-based products remains a challenge across medicine.
Gene therapy targeting the salivary glands specifically is a more futuristic approach but has produced striking results in mice. Researchers have tested delivering a gene for aquaporin 1, a water-channel protein, directly into salivary gland tissue. In a mouse model of Sjögren’s, this increased the glands’ water permeability and restored saliva flow, while also reducing disease-associated inflammation.17Proceedings of the National Academy of Sciences. Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice Translating gene therapy from mice to humans involves substantial regulatory and safety hurdles, but the concept of repairing the glands’ fundamental plumbing rather than just fighting the immune system that damaged it offers a genuinely different angle on the disease.
The Problem With How Trials Measure Success
One reason treatments keep failing to reach approval is not necessarily that the drugs do not work. The tools used to measure success in Sjögren’s trials may be too blunt. Disease activity in Sjögren’s is typically scored with composite indices that combine many different organ-system manifestations into a single number. When a drug helps some domains (say, gland inflammation) but not others (say, joint pain or fatigue), the improvement can be diluted in the composite score, making it look like nothing happened. The heterogeneity of Sjögren’s itself complicates matters: one patient’s disease may be driven primarily by B-cell infiltration of the glands, another’s by systemic interferon activation, and a third’s by neurological involvement. Lumping all of them together in the same trial and expecting a single drug to move the same endpoint for everyone is arguably setting the trial up to fail.18Internal Medicine Journal. Evolving treatments for Sjögren disease: current approaches and emerging targets
Work on molecular classification is trying to solve this. Researchers have used gene-expression profiling to sort Sjögren’s patients into distinct biological subgroups, and have identified biomarker panels that machine-learning classifiers can use to assign future patients to these subgroups.19Nature Communications. A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome The practical payoff would be the ability to enrich clinical trials with patients whose disease biology actually matches the drug being tested. If a drug targets BAFF, enroll the patients whose disease is BAFF-driven. If a drug targets interferon, enroll those with a strong interferon signature. This kind of stratification has transformed treatment in oncology and is widely expected to improve the hit rate in Sjögren’s trials over the next decade.
Fatigue and Depression as Treatment Targets
One of the most underappreciated aspects of Sjögren’s is that dryness, the hallmark symptom, is often not the feature that most disrupts patients’ lives. A cohort study found that fatigue and depression were the dominant predictors of physician visits and work disability, far more so than dry eyes and dry mouth. Patients who reported persistent lack of stamina had roughly four times the odds of not being gainfully employed, even after adjusting for other factors.20Rheumatology. Fatigue and depression predict physician visits and work disability in women with primary Sjögren’s syndrome: results from a cohort study This has direct implications for drug development. A treatment that reduces gland inflammation and improves saliva flow but does nothing for fatigue may still leave patients functionally disabled. Trial designers are increasingly recognizing the need to measure fatigue, mental health, and overall functional capacity as endpoints alongside the traditional dryness and disease-activity scores.
The biological relationship between systemic inflammation and fatigue is not unique to Sjögren’s, but it is especially pronounced in this disease. Cytokines circulating in the blood can cross into the central nervous system and produce a sickness-like state of exhaustion and low mood. Some of the newer biologics that dampen systemic cytokine signaling, like interferon blockers and JAK inhibitors, may therefore have an effect on fatigue that older gland-focused treatments lacked. Whether that theoretical advantage holds up in real patients is something the next generation of trials will need to test explicitly.
The Gut Microbiome and Sjögren’s
An unexpected thread in Sjögren’s research is the connection between gut bacteria and disease severity. A pilot study comparing the microbiomes of Sjögren’s patients and healthy controls found distinct differences in both the mouth and the stool. Patients tended to have lower microbial diversity in the mouth and shifts in the relative abundance of certain bacterial genera in the gut, with more potentially harmful species and fewer beneficial commensals. The most striking finding was an inverse correlation between gut microbial diversity and combined ocular and systemic disease severity: the sicker the patient, the less diverse their intestinal microbiome.21Scientific Reports. Altered Mucosal Microbiome Diversity and Disease Severity in Sjögren Syndrome
It is not yet clear whether the disrupted microbiome is a cause of worse disease, a consequence of it, or both. Reduced saliva flow alters the oral ecosystem, which could cascade downstream. Conversely, a less diverse gut microbiome may fail to properly educate the immune system, allowing autoimmune activity to escalate. Teasing apart cause and effect will require larger longitudinal studies. But if the microbiome turns out to be a modifiable factor, interventions like targeted probiotics or dietary changes could eventually complement immune-directed therapies, particularly for the mucosal symptoms that existing drugs handle poorly.
When Sjögren’s Looks Different in Children
Most treatment research focuses on adults, but Sjögren’s also affects children, and it often presents in ways that delay diagnosis. Rather than the classic dry eyes and dry mouth, pediatric patients frequently show up with recurrent parotid gland swelling, sometimes for years before anyone suspects an autoimmune cause.22Pediatrics. Recurrent Parotitis as a Presentation of Primary Pediatric Sjögren Syndrome Sjögren’s is surprisingly common among children with recurrent parotitis, and researchers have urged ear, nose, and throat specialists to maintain a high index of suspicion for the disease in this population.23PubMed. Sjögren’s syndrome in children with recurrent parotitis
This matters for the future of treatment because children diagnosed early have decades of disease ahead of them. They stand to benefit the most from disease-modifying therapies that could prevent cumulative gland damage over a lifetime. Yet pediatric patients are almost never included in the clinical trials now underway. As disease-modifying drugs eventually reach approval for adults, pressure will build to study them in younger patients, a process that typically lags by years. Recognizing the pediatric face of Sjögren’s now helps ensure those children are not an afterthought when effective treatments finally arrive.