Introduction
A 39‐year‐old woman presented with a 15‐year history of Sjögren disease (SjD) that was complicated by leukocytoclastic vasculitis and inflammatory arthritis. One year earlier, she had developed recurrent parotid swelling and required extensive dental work. She treated her parotid gland swelling with massage, warm compresses, and sugar‐free lozenges. She also had mild arthralgias of her metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints associated with one hour of morning stiffness. Her EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score was 3. She had three pregnancies, with one complicated by congenital heart block. Her examination revealed diminished salivary pooling and a whole unstimulated salivary flow of 0.03 mL/5 min (SjD classification criteria 1 normal >0.5 mL/5 min). She had normal Schirmer's testing (right: 17 mm/5 min, left: 35 mm/5 min; classification criteria normal >5 mm/5 min). Her bilateral parotid glands were enlarged (3 cm bilaterally) without enlargement of her submandibular glands. No cervical lymphadenopathy was appreciated on examination. She had no overt synovitis, but her bilateral index and long finger MCP and PIP joints of both hands were tender to palpation. Laboratory tests showed positive antinuclear, anti‐Ro/SSA, and anti‐La/SSB antibodies and rheumatoid factor (RF). Complete blood counts, metabolic panel, and anti‐Cyclic Citrullinated Peptide antibody were normal. Hand and foot x‐rays did not show any erosive changes. Salivary gland ultrasound showed hypoechoic and anechoic foci diffusely through the gland (Figure 1A ). A core needle biopsy of the parotid gland showed lymphoepithelial lesions and germinal center (GC)‐like structures but no evidence of lymphoma (Figure 1 , 2 ). Flow cytometry was negative for monoclonality. She was advised to start hydroxychloroquine for her inflammatory arthralgias and intermittent salivary gland swelling and to follow up in six months.
Heterogeneity in SjD: endotyping as a tool to improve characterization and guide clinical care
SjD is highly heterogeneous. Although dryness, pain, and fatigue are hallmark features of SjD, a wide range of additional symptoms reflect the disease's impact on diverse organ systems. SjD causes a lymphocytic exocrinopathy, most notably of the lacrimal and salivary glands, resulting in profound dryness of the eyes and mouth. Beyond these hallmark symptoms, the individual patient experience in SjD varies widely, ranging from minimal dry eyes and dry mouth to life‐altering fatigue, cognitive difficulties, and a myriad of other symptoms. Beyond the lacrimal and salivary glands, SjD can affect multiple organ systems. A total of 30% to 50% of patients with SjD have extraglandular manifestations, including hematologic, pulmonary, renal, and neurologic involvement, among others. The variability of symptoms and organs impacted in patients with SjD results in several limitations to understanding and treating the disease. First, the heterogeneous presentation might reflect divergent pathogenic processes. As such, grouping phenotypically similar patients might provide improved insight into what drives these disparate presentations. Second, the variable presentations and natural history of SjD make it difficult to develop a treatment plan. 2 Although most immunologic serology abnormalities predate SjD and these abnormalities tend not to change over time, 3 the natural history of organ involvement is highly variable. For example, some patients with SjD present with dryness, and others present with organ‐threatening illness like interstitial lung disease, nephritis, neuropathy, or lymphoma. Each of these manifestations or combinations of manifestations might require a different approach to therapy. If a specific combination of clinical characteristics is well defined, then the disease course and treatment plan may become more predictable. Clear expectations regarding the disease's natural history and management will enhance clinicians’ understanding and enable them to communicate more effectively with patients. Thus, the improved characterization of SjD subtypes might lead to better clinician–patient relationships. A similar paradigm exists in systemic lupus erythematosus (SLE), another highly heterogeneous autoimmune disease. 4
To address these limitations in studying and treating SjD, the research and clinical communities have moved to define endotypes. Endotypes are pathobiologically similar subgroups. Endotype generation in SjD is an evolving field of research, 5 with approaches ranging from symptom based 6 , 7 to peripheral blood transcriptomics or proteomics 8 , 9 and glandular transcriptomics. 10 Recently, Nguyen et al proposed a combined approach using symptoms, clinical disease activity, and laboratory studies to endotype patients with SjD. 11 They identified three main endotypes of SjD: (1) a group with low systemic disease activity and high symptom burden (LSAHS), (2) a B cell active disease and low symptom burden (BALS) endotype, and (3) a high systemic activity (HSA) endotype. The HSA endotype had the highest disease activity burden, whereas the BALS endotype had the highest levels of immunoglobulins and RF, akin to the patient presented in our case. The LSAHS endotype had the highest symptom burden and lowest systemic disease activity and frequency of laboratory abnormalities. Each endotype displayed unique longitudinal features. The BALS endotype developed higher disease activity over time. In contrast, the HSA endotype demonstrated decreases in disease activity over time. Finally, there was no difference in the LSAHS endotype in either symptoms or signs over time. In addition to disease trajectory, we can glean prognosis from endotyping. Lymphoma exclusively occurred in the BALS and HSA groups. Thus, endotypes akin to those of Nguyen et al might help anticipate the disease course in SjD.
Though endotypes hold promise to improve patient care, this is an ongoing field of study. Future work includes longitudinal natural history studies to determine endotype evolution and prospective validation of endotypes in diverse independent cohorts. Furthermore, more prospective research is needed to determine if endotype classifications can be used to select effective therapeutics. Though endotype evaluation is an active field of research, greater understanding of this field is required before deploying these findings clinically.
B cells as critical contributors to SjD pathogenesis
B cells play a crucial role in SjD pathogenesis by producing autoantibodies, presenting self‐antigens to autoreactive T cells, and releasing cytokines (Figure 2 ). 12 The identification of genetic risk loci associated with SjD further underscores B cells as central mediators of disease. For example, genome‐wide association studies have identified polymorphisms in key B cell–related genes, including PR/SET domain 1, tumor necrosis factor alpha–induced protein 3 (TNFAIP3), B lymphoid tyrosine kinase, and C‐X‐C motif chemokine receptor 5 (CXCR5), that are associated with SjD. 13
Beyond genetic predisposition, patients with SjD display distinct alterations in B cell subsets and tissue localization. Increased numbers of plasmablasts in the blood of patients with SjD correlate with elevated autoantibodies, higher disease activity, and lymphoma risk. 14 , 15 B cells, including activated B cells, are also found in the exocrine glands of patients with SjD. 12 Interestingly, circulating memory B cells are decreased in patients with SjD compared to healthy individuals but are elevated in the salivary glands, suggesting that memory B cells may migrate to target tissues. 14 , 15 , 16 , 17 , 18 , 19 Antibody‐forming cells, including fully differentiated plasma cells, are also increased in the glands of patients with SjD. 14 , 20 Approximately 10% to 30% of patients with SjD have GC‐like structures in the salivary glands. 21 Bonafide GCs in these glands express activation‐induced cytidine deaminase and CXCR5, whereas B cell aggregates do not. 22 However, both GCs and B cell aggregates contain autoreactive B cells. 22 An increased ratio of IgG‐/IgA‐producing B cells within the glands is associated with SjD and correlates with greater lymphocytic infiltration, as measured by the focus score. 23 , 24 More recently, “atypical memory B cells” in humans and “age‐associated B cells” in mice—proinflammatory B cell subsets linked to systemic autoimmunity and infections—have been identified in patients with SjD and mouse models. 25 , 26 , 27 , 28 , 29 , 30 The role of these inflammatory B cell populations in driving SjD pathogenesis remains an active area of investigation. The implementation of single‐cell multiomic technologies, such as single‐cell RNA sequencing and spatial transcriptomics, will enable investigators to better characterize B cell infiltration, spatial organization, and interactions within target organs affected by SjD.
Dysregulated B cell signaling and survival pathways contribute to SjD pathogenesis, highlighting key therapeutic targets under investigation. For example, BTK, a critical mediator of B cell receptor signaling, is elevated in B cells from patients with SjD. 31 Additionally, levels of BAFF—a cytokine essential for B cell maturation, proliferation, and survival—are increased in both the serum and salivary glands of patients with SjD. 32 , 33 , 34 , 35 BAFF transgenic mice, who overproduce BAFF, develop systemic autoimmunity, including sialadenitis, and have an increased risk of lymphoma. 32 , 36 BAFF is not only produced by the myeloid compartment but also secreted by salivary gland epithelial cells, suggesting that the glandular epithelium is not a passive bystander in SjD pathogenesis but an active contributor to B cell activation and disease progression. 32 , 34 , 35 , 37 Together, these findings highlight B cells as key drivers of SjD pathogenesis and provide a strong rationale for targeting BAFF, BAFF receptor, and BTK in ongoing phase II/III clinical trials.
When B cells go rogue: pathogenesis, risk factors, and clinical considerations in Sjögren lymphomagenesis
Non‐Hodgkin lymphoma is one of the most serious complications of SjD, affecting 5% to 10% of patients and significantly contributing to increased mortality rates. 38 , 39 , 40 , 41 Individuals with SjD have a 5 to >20 times higher risk of developing lymphoma compared to the general population, the highest among all autoimmune diseases—a wide range likely reflecting the heterogeneity of the populations studied. 38 Notably, 98% of SjD‐associated lymphomas originate from B cells, further underscoring the critical role of B cells in SjD pathogenesis. 42 The majority (>90%) of hematologic malignancies in SjD are mucosa‐associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma. 42 , 43 Among these, low‐grade MALT lymphoma is the most common, with the salivary glands being the primary extranodal site (70%), though it can also arise in other locations, including the lungs, stomach, and ocular adnexal structures. 42 , 43
A leading hypothesis for lymphomatous transformation in SjD is that chronic antigen stimulation drives polyclonal B cell expansion, whereas the acquisition of driver mutations promotes monoclonal B cell proliferation. Intriguingly, using single‐cell DNA and RNA sequencing, Singh et al demonstrated that in SjD‐associated cryoglobulinemic vasculitis, RF B cells acquire lymphoma driver mutations before developing pathogenic V(D)J mutations that transform benign RF into pathogenic RF. 44 This suggests that lymphoma driver mutations enable autoreactive pathogenic B cells to evade tolerance checkpoints, potentially explaining the link between cryoglobulinemic vasculitis and lymphoma development in patients with SjD. 44 Additionally, both germline and somatic mutations in TNFAIP3 , a key regulator of B cell activation, have been implicated not only in multiple autoimmune diseases but also in the increased lymphoma risk observed in SjD. 13 , 45 , 46 Functional abnormalities in A20, the protein encoded by TNFAIP3 , were detected in 77% SjD patients with MALT lymphoma and 29% of those with other histologic subtypes of lymphoma, further supporting its role in disease pathogenesis. 45
Although these genetic and molecular insights highlight key mechanisms underlying lymphomagenesis in SjD, multiple clinical studies have also identified predictive factors that may help stratify patients at higher risk for lymphoma development. Several models identified factors or combinations of factors that are most predictive of lymphoproliferative disease. The first used a cohort of 723 patients with SjD, 38 of whom developed lymphoproliferative disease. 47 Identified predictors of lymphoproliferative disease included parotid enlargement, palpable purpura, and low C4 levels at baseline. 47 In a second cohort of 536 patients with SjD, 40 patients developed lymphoproliferative disease. 48 In this cohort, neutropenia, cryoglobulinemia, splenomegaly, lymphadenopathy, and low C4 levels predicted non‐Hodgkin lymphoma. 48 In a third cohort of 661 patients with SjD, 40 patients developed non‐Hodgkin lymphoma 49 ; the investigators identified low C4, cryoglobulins, anti‐La/SSB antibodies, and leukopenia as predictors of lymphoproliferative disease. Finally, a fourth cohort of 381 patients with SjD, 92 of whom had non‐Hodgkin lymphoma, identified salivary gland enlargement, lymphadenopathy, Raynaud phenomenon, anti‐Ro/SSA and/or anti‐La/SSB autoantibodies, RF, monoclonal gammopathy, and low C4 as predictors for non‐Hodgkin lymphoma development. 50 Beyond these models, high focus score and GCs on labial salivary gland biopsies also predict the risk of lymphomagenesis. 51 , 52 High disease activity, excluding lymphoma, also is associated with increased risk of lymphoma. 53 Furthermore, imaging such as salivary gland ultrasound and computed tomography (CT)/positron emission tomography (PET) might also help predict glandular lymphoma risk, 54 , 55 particularly in the setting of a parotid PET‐CT standardized uptake value maximum ≥4.7. 56 For example, parotid lymphomas seem to occur in salivary glands with hypoechoic or anechoic lesions (grade 2 or 3 using the Outcome Measures in Rheumatology [OMERACT] salivary gland ultrasound scoring system). 55 , 57 Our patient had salivary gland enlargement, high disease activity, positive anti‐Ro/SSA and La/SSB antibodies, positive RF, and a high OMERACT salivary gland ultrasound score. These features indicate that she might be at higher risk for developing lymphoma.
Lymphoma suspicion should be rooted in the history and physical examination of our patients and supplemented with supportive laboratory and imaging findings. MALT lymphoma of the gland is the most common lymphoproliferative disease in SjD and characteristically presents with recurrent or persistent swelling of salivary glands. Patients who have B symptoms, lymphadenopathy, or recurrent parotitis with a laboratory profile suggestive of higher risk for lymphomatous transformation warrant an evaluation. Salivary gland ultrasound or CT/PET can help identify ideal biopsy sites. Ultimately, treatment decisions should be made collaboratively between the patient and hematology/oncology and rheumatology providers.
Advancing SjD treatment: B cell–targeted therapies and the evolving therapeutic landscape
Successful phase II trials: a new era in SjD treatment
As discussed above, B cells play a central role in SjD pathogenesis, even more so when focused on B cell–enriched endotypes. Despite the mechanistic promise of B cell–targeted therapies, past randomized placebo‐controlled trials with the anti‐CD20 therapy, rituximab, did not achieve their primary endpoints. 58 , 59 It is hypothesized these early failures might have been related to the clinical trial design, including broad inclusion criteria and endpoints that were not sensitive to therapeutic intervention. Alternatively, rituximab might fail to deplete B cells in salivary gland tissue. 60 In recent years, however, the SjD treatment landscape has shifted, and multiple putative drugs have achieved their primary endpoint in phase II trials, many of which target B cell–related pathways (Table 1 ). These early successes represent a potential paradigm shift in SjD, from symptomatic management to therapies that might treat or even prevent the progression of the disease. Some of these recent trial successes may be partly explained by the significant evolution of inclusion criteria and endpoints of SjD clinical trials over time. Most trials now require moderate to high systemic disease activity, as measured by the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) 61 , 62 and positive anti‐SSA antibody, for entry.
Table 1
Successful SjD phase II randomized controlled trials targeting B cells * .
* ACR, American College of Rheumatology; AECG, American‐European Consensus Group; CI, confidence interval; clinESSDAI, Clinical EULAR Sjögren's Syndrome Disease Activity Index; ESSDAI, EULAR Sjögren's Syndrome Disease Activity Index; ESSPRI, EULAR Sjögren's Syndrome Patient Reported Index; FcRN, neonatal Fc receptor; LSM, least squares mean; RF, rheumatoid factor; SjD, Sjögren disease. a The cohort who took 300 mg did not meet its primary endpoint and is therefore not shown.
| Drug | Target | Inclusion | Primary endpoint | Primary endpoint data | P value |
| Dazodalibep | CD40 ligand | SjD by ACR/EULAR Positive anti‐SSA antibody or positive RF | – | LSM ± SE | – |
| Cohort 1 | – | ESSDAI ≥5 | Change from baseline in ESSDAI | LSM ± SE Dazodalibep, −6.3 ± 0.6; placebo, −4.1 ± 0.6 | 0.0167 |
| Cohort 2 | – | ESSDAI <5 ESSPRI ≥5 >0.1 mL/min salivary flow | Change from baseline in ESSPRI | LSM ± SE Dazodalibep, −1.8 ± 0.2; placebo, −0.5 ± 0.2 | 0.0002 |
| Ianalumab | BAFF receptor | SjD by AECG ESSDAI ≥6 ESSPRI ≥5 Anti‐SSA antibody positive >0.1 mL/min salivary flow | Change from baseline in ESSDAI and dose‐dependent response at week 24 of placebo‐subtracted ESSDAI change from baseline | Placebo‐adjusted LSM (95% CI) from baseline 300 mg ianalumab: −1.92 (−4.15 to −0.32) | Dose–response change in ESSDAI from baseline P < 0.025 in four models; P = 0.06 in one model |
| Iscalimab | CD40 | SjD by ACR/EULAR Positive anti‐SSA antibody >0.1 mL/min salivary flow | – | Placebo‐adjusted LSM from baseline (95% CI) | Dose–response change in ESSDAI from baseline P = 0.0041 in one of four models |
| Cohort 1 | – | ESSDAI ≥5 ESSPRI ≥5 Anti‐SSA antibody positive | Dose–response change from baseline in ESSDAI a Cohort who took 150 mg Cohort who took 600 mg | Placebo‐adjusted LSM from baseline (95% CI) 150 mg: −3.0 (−4.9 to −1.1) 600 mg: −2.9 (−4.9 to −1.0) | – |
| Cohort 2 | – | ESSDAI <5 ESSPRI ≥5 Impact of Dry Eye on Everyday Life score ≥ 30 | Change from baseline in ESSPRI did not achieve its primary endpoint | Placebo‐adjusted LSM from baseline (95% CI), 600 mg: −0.57 (−1.3 to 0.15) | – |
| Nipocalimab | FcRN | SjD by ACR/EULAR clinESSDAI ≥6 Anti‐SSA antibody positive | Change from baseline in clinESSDAI | LSM change from baseline (90% CI): 5 mg/kg nipocalimab, −0.34 (−1.71 to 1.03) 15 mg/kg nipocalimab, −2.65 (−4.03 to −1.28) | 5 mg/kg, P = 0.681 15 mg/kg, P = 0.002 |
| Remibrutinib | BTK | SjD by ACR/EULAR ESSDAI ≥5 ESSPRI ≥5 Anti‐SSA antibody positive >0 mL/min salivary flow | Change from baseline in ESSDAI | LSM change from baseline (95% CI): −2.86 (−4.71 to −1.01) | 0.003 |
| Telitacicept | BAFF and APRIL | SjD by ACR/EULAR ESSDAI ≥5 Anti‐SSA antibody positive | Change from baseline in ESSDAI | Placebo‐adjusted LSM change from baseline (90% CI): 160 mg, −4.3 (−7.0 to −1.6) 240 mg, −2.7 (−5.6 to 0.1) | 160 mg, P = 0.002 240 mg, P = 0.056 |
One such trial evaluated ianalumab, an anti‐BAFF receptor antibody that can deplete B cells, in patients with anti‐SSA positivity and SjD with moderate to high symptom burden and disease activity. It achieved its primary outcome of dose–response improvement in disease activity from baseline. 63 Ianalumab appears to improve salivary flow but did not show clear benefit on SjD symptoms. In the extension study to 52 weeks, ianalumab seemed to maintain efficacy. 61
The anti‐neonatal Fc receptor (FcRN) antibody nipocalimab reported promising phase II clinical trial results at the 2024 American College of Rheumatology (ACR) annual conference. Anti‐FcRN antibodies prevent IgG recycling, reducing circulating autoantibodies. Nipocalimab treatment of patients with SjD with moderate or severe disease activity and positive anti‐Ro/SSA antibodies resulted in improved disease activity. The resulting paper was recently published. 64
Remibrutinib is a BTK inhibitor 65 that was tested in a phase II study of patients with anti‐SSA positivity and SjD with moderate to high disease activity. BTK inhibitors reduce B cell proliferation and drive B cell apoptosis. Remibrutinib improved disease activity but did not significantly improve symptoms or objective measures of salivary flow.
Telitacicept is a humanized protein that binds and inhibits B lymphocyte stimulator (BLyS; ie, BAFF) and APRIL. Through inhibition of BLyS and APRIL, telitacicept inhibits differentiation, maturation, and survival of B cells. In a phase IIb study of patients with anti‐Ro/SSA antibody positivity and SjD with moderate to high disease activity, 160 mg telitacicept significantly improved ESSDAI compared to placebo; however, the 240‐mg dose did not improve ESSDAI significantly compared to placebo. 66 Fatigue assessments, as measured through the multidimensional fatigue inventory, improved significantly in both doses.
In contrast to the aforementioned studies, the iscalimab and dazodalibep trials stratified patients by endotype. These drugs target the CD40–CD40 ligand interaction that drives GC formation, Ig class switching, and inflammatory cytokine production. Iscalimab is a humanized monoclonal antibody against CD40 with a modified Fc domain that makes its Fcγ‐dependent effects nonfunctional. 67 Iscalimab was tested in two cohorts of patients with anti‐Ro/SSA positivity and SjD: a cohort with high disease activity or a cohort with high symptom burden who also had significant dryness or fatigue burden. 68 The cohort with high disease activity achieved its primary endpoint of dose–response improvement of disease activity. The cohort with high symptom burden did not meet its primary endpoint of symptom improvement but did show significant improvement in the ESSPRI dryness domain. Dazodalibep is an anti‐CD40 ligand antagonist 69 that was uniquely also tested in two populations with anti‐Ro/SSA positivity or RF positivity: (1) a cohort with high disease activity, and (2) a cohort with low disease activity and high symptom burden. Dazodalibep achieved its primary endpoint for each respective cohort. It improved disease activity among patients with high disease activity and it improved symptom burden in patients with low disease activity and high symptom burden. Salivary flow did not improve significantly in either group. These successful phase II studies offer a promising glimpse into a growing therapeutic landscape, highlighting the potential for transformative advances in SjD treatment.
Novel emerging therapeutic strategies in SjD
Chimeric antigen receptor (CAR) technology has revolutionized targeted immunotherapy, offering new avenues for treating both malignancies and autoimmune diseases. 70 CARs are genetically engineered transmembrane receptors inserted into immune cells, like T cells. 70 They typically consist of an antigen‐binding domain, hinge, transmembrane, and intracellular signaling domains. 70 CAR‐T cells, which can be autologous or allogeneic, have shown remarkable efficacy in treating cancers, particularly hematologic malignancies, by specifically binding to and lysing oncogenic cells. 70 More recently, CAR technology has been applied to the treatment of systemic autoimmune diseases such as SLE. 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 CD19‐targeting CAR‐T cells, which deplete B cells, have shown promising efficacy in lupus nephritis. 71 , 72 Similarly, BCMA CAR‐T cells, designed to eliminate plasma cells, are used in multiple myeloma. 70 Given the central roles of B cells and plasma cells in SjD, both CD19 and BCMA CAR‐T cell therapies warrant further investigation as potential treatments. Beyond depleting pathogenic cells, CAR technology is also being explored to develop regulatory cell products that suppress autoreactive cells, presenting a novel strategy for treating autoimmune diseases.
Monoclonal antibodies that recognize single antigens, like a cytokine or cytokine receptor, have been used for the treatment of rheumatic diseases for over 20 years and have revolutionized patient care. This advancement has paved the way for more sophisticated antibody‐based therapies, such as bispecific T cell engagers (BiTEs). BiTEs are bispecific antibodies that recognize an antigen on a target cell and endogenous T cells to direct T cells toward target cells for precise T cell–mediated destruction. 80 , 81 Blinatumomab (CD3/CD19) and teclistamab (CD3/BCMA) are BiTEs that target B cells and plasma cells, respectively. 80 , 81 Akin to CAR‐T cells, BiTEs were initially developed for the treatment of hematologic malignancies, but there is emerging evidence for efficacy in autoimmune diseases. For example, blinatumomab has been used in six patients with rheumatoid arthritis (RA), and teclistamab has been used in five patients with systemic autoimmunity (RA, myositis, SjD, systemic sclerosis, and SLE), with disease improvement in all patients. 82 , 83 , 84 Bispecific and BiTE antibody engineering offers a flexible platform for the treatment of systemic autoimmune diseases such as SjD. B cell–targeted CAR‐T, bispecific, and BiTE therapies have a more potent and sustained effect on B cell depletion than CD20‐targeted monoclonal antibodies like rituximab. These agents target plasmablasts, early plasma cells, and memory B cell populations, 85 both in the periphery and end organs.
Conclusions
The patient returned nine years later. Since her last visit with a rheumatologist, she had been observed regularly by a ears, nose, and throat specialist for recurrent left parotid swelling. Her ultrasound showed diffuse anechoic and hypoechoic foci comprising most of the gland tissue and now showed one dominant cystic lesion. This cystic lesion was very hypoechoic/anechoic, was oval, and had well‐defined margins without septa or posterior acoustic enhancement (Figure 1F ). She underwent drainage of a left parotid cyst every six months until she was ultimately referred for a parotidectomy. Pathology revealed MALT lymphoma (Figure 1G–J ).
This patient presented with an endotype most consistent with a B cell active phenotype, which is associated with a higher risk of lymphoma. She had several clinical risk factors for lymphoma development in her history and laboratory tests. She had recurrent parotid swelling, a history of leukocytoclastic vasculitis, and her serologies were notable for a high‐titer RF, all of which have been linked to an increased likelihood of lymphoma. Her initial parotid biopsy also demonstrated GCs, indicative of chronic B cell activation and a heightened risk of lymphomatous transformation.
This case underscores the critical need for vigilant surveillance in patients with SjD with known risk factors because early detection of lymphomas can be crucial for timely intervention and optimal outcomes. Such considerations are particularly important given the complex relationship between SjD and lymphoma, which may have implications for both oncologic and autoimmune disease management. Although the treatment of SjD‐associated lymphoma is an area of controversy, actively under investigation and largely under the purview of hematology, there are data that indicate treatment of SjD‐associated lymphoma might also improve disease activity in SjD. 86
Despite being nearly as common as RA, SjD still lacks US Food and Drug Administration (FDA)‐approved disease‐modifying therapies. SjD heterogeneity is a major contributor to the lack of FDA‐approved disease‐modifying therapies. Endotyping is an approach that is closing this gap, creating pathobiologically similar subtypes to reduce heterogeneity and identifying B cell–driven disease endotypes. Patients with these B cell endotypes seem to have greater risks for lymphoma and are one of the populations that might benefit from the aforementioned burgeoning therapies. The therapeutic landscape in SjD is rapidly expanding, ushering in a new era of innovation and long‐overdue breakthroughs for this overlooked disease.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr McCoy confirms that all authors have provided the final approval of the version to be published, and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
Supporting information
Disclosure Form :
References
1 Shiboski CH , Shiboski SC , Seror R , et al. 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjogren's syndrome: a consensus and data‐driven methodology involving three international patient cohorts . Arthritis Rheumatol 2017 ; 69 ( 1 ): 35 – 45 . 27785888 10.1002/art.39859 PMC5650478
2 Lee AYS , Wang JJ , Gordon TP , et al. Phases and natural history of Sjögren's disease: a new model for an old disease? Arthritis Care Res (Hoboken) 2023 ; 75 ( 7 ): 1580 – 1587 . 36063396 10.1002/acr.25011 PMC10953327
3 Shiboski CH , Baer AN , Shiboski SC , et al. Natural history and predictors of progression to Sjögren's syndrome among participants of the Sjögren's International Collaborative Clinical Alliance Registry . Arthritis Care Res (Hoboken) 2018 ; 70 ( 2 ): 284 – 294 . 28437595 10.1002/acr.23264 PMC5654699
4 Pisetsky DS , Clowse MEB , Criscione‐Schreiber LG , et al. A novel system to categorize the symptoms of systemic lupus erythematosus . Arthritis Care Res (Hoboken) 2019 ; 71 ( 6 ): 735 – 741 . 30354033 10.1002/acr.23794
5 Gandolfo S , Bombardieri M , Pers JO , et al. Precision medicine in Sjögren's disease . Lancet Rheumatol 2024 ; 6 ( 9 ): e636 – e647 . 38723653 10.1016/S2665-9913(24)00039-0
6 Tarn JR , Howard‐Tripp N , Lendrem DW , et al; Leeds CTRU; French ASSESS Cohort; UK Primary Sjögren's Syndrome Registry . Symptom‐based stratification of patients with primary Sjögren's syndrome: multi‐dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials . Lancet Rheumatol 2019 ; 1 ( 2 ): e85 – e94 . 38229348 10.1016/S2665-9913(19)30042-6 PMC7134527
7 McCoy SS , Woodham M , Bartels CM , et al. Symptom‐based cluster analysis categorizes Sjögren's disease subtypes: an international cohort study highlighting disease severity and treatment discordance . Arthritis Rheumatol 2022 ; 74 ( 9 ): 1569 – 1579 . 35594474 10.1002/art.42238 PMC9427679
8 Soret P , Le Dantec C , Desvaux E , et al; PRECISESADS Clinical Consortium ; PRECEISESADS Flow Cytometry Consortium. A new molecular classification to drive precision treatment strategies in primary Sjögren's syndrome . Nat Commun 2021 ; 12 ( 1 ): 3523 . 34112769 10.1038/s41467-021-23472-7 PMC8192578
9 Pucino V , Turner JD , Nayar S , et al. Sjögren's and non‐Sjögren's sicca share a similar symptom burden but with a distinct symptom‐associated proteomic signature . RMD Open 2022 ; 8 ( 1 ): e002119 . 35589331 10.1136/rmdopen-2021-002119 PMC9121491
10 Verstappen GM , Gao L , Pringle S , et al. The transcriptome of paired major and minor salivary gland tissue in patients with primary Sjögren's syndrome . Front Immunol 2021 ; 12 : 681941 . 34295332 10.3389/fimmu.2021.681941 PMC8291032
11 Nguyen Y , Beydon M , Gottenberg JE , et al. Distinct pathophysiologic pathways support stratification of Sjögren's disease based on symptoms, clinical, and routine biological data . Arthritis Rheumatol 2025 ; 77 : 876 – 883 . 39721742 10.1002/art.43096
12 Nocturne G , Mariette X . B cells in the pathogenesis of primary Sjögren syndrome . Nat Rev Rheumatol 2018 ; 14 ( 3 ): 133 – 145 . 29416129 10.1038/nrrheum.2018.1
13 Thorlacius GE , Björk A , Wahren‐Herlenius M . Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies . Nat Rev Rheumatol 2023 ; 19 ( 5 ): 288 – 306 . 36914790 10.1038/s41584-023-00932-6 PMC10010657
14 Mingueneau M , Boudaoud S , Haskett S , et al. Cytometry by time‐of‐flight immunophenotyping identifies a blood Sjögren's signature correlating with disease activity and glandular inflammation . J Allergy Clin Immunol 2016 ; 137 ( 6 ): 1809 – 1821.e12 . 27045581 10.1016/j.jaci.2016.01.024
15 Hansen A , Odendahl M , Reiter K , et al. Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sjögren's syndrome . Arthritis Rheum 2002 ; 46 ( 8 ): 2160 – 2171 . 12209521 10.1002/art.10445
16 Bohnhorst JØ , Bjørgan MB , Thoen JE , et al. Bm1‐Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sjögren's syndrome . J Immunol 2001 ; 167 ( 7 ): 3610 – 3618 . 11564773 10.4049/jimmunol.167.7.3610
17 Hansen A , Gosemann M , Pruss A , et al. Abnormalities in peripheral B cell memory of patients with primary Sjögren's syndrome . Arthritis Rheum 2004 ; 50 ( 6 ): 1897 – 1908 . 15188366 10.1002/art.20276
18 Roberts MEP , Kaminski D , Jenks SA , et al. Primary Sjögren's syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells . Arthritis Rheumatol 2014 ; 66 ( 9 ): 2558 – 2569 . 24909310 10.1002/art.38734 PMC4160119
19 Szabó K , Papp G , Szántó A , et al. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren's syndrome and systemic lupus erythematosus . Clin Exp Immunol 2016 ; 183 ( 1 ): 76 – 89 . 26358223 10.1111/cei.12703 PMC4687513
20 Tengnér P , Halse AK , Haga HJ , et al. Detection of anti‐Ro/SSA and anti‐La/SSB autoantibody‐producing cells in salivary glands from patients with Sjögren's syndrome . Arthritis Rheum 1998 ; 41 ( 12 ): 2238 – 2248 . 9870881 10.1002/1529-0131(199812)41:12<2238::AID-ART20>3.0.CO;2-V
21 Risselada AP , Looije MF , Kruize AA , et al. The role of ectopic germinal centers in the immunopathology of primary Sjögren's syndrome: a systematic review . Semin Arthritis Rheum 2013 ; 42 ( 4 ): 368 – 376 . 22995442 10.1016/j.semarthrit.2012.07.003
22 Le Pottier L , Devauchelle V , Fautrel A , et al. Ectopic germinal centers are rare in Sjögren's syndrome salivary glands and do not exclude autoreactive B cells . J Immunol 2009 ; 182 ( 6 ): 3540 – 3547 . 19265132 10.4049/jimmunol.0803588
23 Szyszko EA , Brokstad KA , Oijordsbakken G , et al. Salivary glands of primary Sjögren's syndrome patients express factors vital for plasma cell survival . Arthritis Res Ther 2011 ; 13 ( 1 ): R2 . 21214903 10.1186/ar3220 PMC3241347
24 Bodeutsch C , de Wilde PC , Kater L , et al. Quantitative immunohistologic criteria are superior to the lymphocytic focus score criterion for the diagnosis of Sjögren's syndrome . Arthritis Rheum 1992 ; 35 ( 9 ): 1075 – 1087 . 1418024 10.1002/art.1780350913
25 Visser A , Verstappen GM , van der Vegt B , et al. Repertoire analysis of B‐cells located in striated ducts of salivary glands of patients with Sjögren's syndrome . Front Immunol 2020 ; 11 : 1486 . 32760405 10.3389/fimmu.2020.01486 PMC7372116
26 Punnanitinont A , Kasperek EM , Zhu C , et al. TLR7 activation of age‐associated B cells mediates disease in a mouse model of primary Sjögren's disease . J Leukoc Biol 2024 ; 115 ( 3 ): 497 – 510 . 37930711 10.1093/jleuko/qiad135 PMC10990110
27 Bagavant H , Durslewicz J , Pyclik M , et al. Age‐associated B cell infiltration in salivary glands represents a hallmark of Sjögren's‐like disease in aging mice . Geroscience 2024 ; 46 ( 6 ): 6085 – 6099 . 38656650 10.1007/s11357-024-01159-3 PMC11493885
28 Cancro MP . Age‐associated B cells . Annu Rev Immunol 2020 ; 38 : 315 – 340 . 31986068 10.1146/annurev-immunol-092419-031130
29 Xu T , Zhu HX , You X , et al. Single‐cell profiling reveals pathogenic role and differentiation trajectory of granzyme K+CD8+ T cells in primary Sjögren's syndrome . JCI Insight 2023 ; 8 ( 8 ): e167490 . 36881472 10.1172/jci.insight.167490 PMC10243796
30 Saadoun D , Terrier B , Bannock J , et al. Expansion of autoreactive unresponsive CD21−/low B cells in Sjögren's syndrome‐associated lymphoproliferation . Arthritis Rheum 2013 ; 65 ( 4 ): 1085 – 1096 . 23279883 10.1002/art.37828 PMC4479193
31 Corneth OBJ , Verstappen GMP , Paulissen SMJ , et al. Enhanced Bruton's tyrosine kinase activity in peripheral blood B lymphocytes from patients with autoimmune disease . Arthritis Rheumatol 2017 ; 69 ( 6 ): 1313 – 1324 . 28141917 10.1002/art.40059
32 Groom J , Kalled SL , Cutler AH , et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome . J Clin Invest 2002 ; 109 ( 1 ): 59 – 68 . 11781351 10.1172/JCI14121 PMC150825
33 Mariette X , Roux S , Zhang J , et al. The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sjögren's syndrome . Ann Rheum Dis 2003 ; 62 ( 2 ): 168 – 171 . 12525388 10.1136/ard.62.2.168 PMC1754442
34 Lavie F , Miceli‐Richard C , Quillard J , et al. Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjögren's syndrome . J Pathol 2004 ; 202 ( 4 ): 496 – 502 . 15095277 10.1002/path.1533
35 Daridon C , Devauchelle V , Hutin P , et al. Aberrant expression of BAFF by B lymphocytes infiltrating the salivary glands of patients with primary Sjögren's syndrome . Arthritis Rheum 2007 ; 56 ( 4 ): 1134 – 1144 . 17393395 10.1002/art.22458
36 Mackay F , Woodcock SA , Lawton P , et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations . J Exp Med 1999 ; 190 ( 11 ): 1697 – 1710 . 10587360 10.1084/jem.190.11.1697 PMC2195729
37 Ittah M , Miceli‐Richard C , Eric Gottenberg J , et al. B cell‐activating factor of the tumor necrosis factor family (BAFF) is expressed under stimulation by interferon in salivary gland epithelial cells in primary Sjögren's syndrome . Arthritis Res Ther 2006 ; 8 ( 2 ): R51 . 16507175 10.1186/ar1912 PMC1526588
38 Beydon M , McCoy S , Nguyen Y , et al. Epidemiology of Sjögren syndrome . Nat Rev Rheumatol 2024 ; 20 ( 3 ): 158 – 169 . 38110617 10.1038/s41584-023-01057-6
39 Theander E , Manthorpe R , Jacobsson LTH . Mortality and causes of death in primary Sjögren's syndrome: a prospective cohort study . Arthritis Rheum 2004 ; 50 ( 4 ): 1262 – 1269 . 15077310 10.1002/art.20176
40 Zintzaras E , Voulgarelis M , Moutsopoulos HM . The risk of lymphoma development in autoimmune diseases: a meta‐analysis . Arch Intern Med 2005 ; 165 ( 20 ): 2337 – 2344 . 16287762 10.1001/archinte.165.20.2337
41 Johnsen SJ , Brun JG , Gøransson LG , et al. Risk of non‐Hodgkin's lymphoma in primary Sjögren's syndrome: a population‐based study . Arthritis Care Res 2013 ; 65 ( 5 ): 816 – 821 . 10.1002/acr.21887 23139233
42 Retamozo S , Brito‐Zerón P , Ramos‐Casals M . Prognostic markers of lymphoma development in primary Sjögren syndrome . Lupus 2019 ; 28 ( 8 ): 923 – 936 . 31215845 10.1177/0961203319857132
43 Hernández‐Molina G , Kostov B , Brito‐Zerón P , et al; Sjögren Big Data Consortium. Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies . Rheumatology (Oxford) 2022 ; 62 ( 1 ): 243 – 255 . 35385104 10.1093/rheumatology/keac205
44 Singh M , Jackson KJL , Wang JJ , et al. Lymphoma driver mutations in the pathogenic evolution of an iconic human autoantibody . Cell 2020 ; 180 ( 5 ): 878 – 894.e19 . 32059783 10.1016/j.cell.2020.01.029
45 Nocturne G , Boudaoud S , Miceli‐Richard C , et al. Germline and somatic genetic variations of TNFAIP3 in lymphoma complicating primary Sjogren's syndrome . Blood 2013 ; 122 ( 25 ): 4068 – 4076 . 24159176 10.1182/blood-2013-05-503383 PMC3862283
46 Nocturne G , Tarn J , Boudaoud S , et al. Germline variation of TNFAIP3 in primary Sjögren's syndrome‐associated lymphoma . Ann Rheum Dis 2016 ; 75 ( 4 ): 780 – 783 . 26338037 10.1136/annrheumdis-2015-207731
47 Ioannidis JPA , Vassiliou VA , Moutsopoulos HM . Long‐term risk of mortality and lymphoproliferative disease and predictive classification of primary Sjögren's syndrome . Arthritis Rheum 2002 ; 46 ( 3 ): 741 – 747 . 11920410 10.1002/art.10221
48 Baimpa E , Dahabreh IJ , Voulgarelis M , et al. Hematologic manifestations and predictors of lymphoma development in primary Sjögren syndrome: clinical and pathophysiologic aspects . Medicine (Baltimore) 2009 ; 88 ( 5 ): 284 – 293 . 19745687 10.1097/MD.0b013e3181b76ab5
49 Quartuccio L , Isola M , Baldini C , et al. Biomarkers of lymphoma in Sjögren's syndrome and evaluation of the lymphoma risk in prelymphomatous conditions: results of a multicenter study . J Autoimmun 2014 ; 51 : 75 – 80 . 24231556 10.1016/j.jaut.2013.10.002
50 Fragkioudaki S , Mavragani CP , Moutsopoulos HM . Predicting the risk for lymphoma development in Sjogren syndrome: an easy tool for clinical use . Medicine (Baltimore) 2016 ; 95 ( 25 ): e3766 . 27336863 10.1097/MD.0000000000003766 PMC4998301
51 Theander E , Vasaitis L , Baecklund E , et al. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome . Ann Rheum Dis 2011 ; 70 ( 8 ): 1363 – 1368 . 21715359 10.1136/ard.2010.144782 PMC3128323
52 Sène D , Ismael S , Forien M , et al. Ectopic germinal center‐like structures in minor salivary gland biopsy tissue predict lymphoma occurrence in patients with primary Sjögren's syndrome . Arthritis Rheumatol 2018 ; 70 ( 9 ): 1481 – 1488 . 29669392 10.1002/art.40528
53 Nocturne G , Virone A , Ng WF , et al. Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjögren's syndrome . Arthritis Rheumatol 2016 ; 68 ( 4 ): 977 – 985 . 26606524 10.1002/art.39518
54 van Ginkel MS , Arends S , van der Vegt B , et al. FDG‐PET/CT discriminates between patients with and without lymphomas in primary Sjögren's syndrome . Rheumatology 2023 ; 62 ( 10 ): 3323 – 3331 . 36759907 10.1093/rheumatology/kead071 PMC10547509
55 Lorenzon M , Tulipano Di Franco F , Zabotti A , et al. Sonographic features of lymphoma of the major salivary glands diagnosed with ultrasound‐guided core needle biopsy in Sjögren's syndrome . Clin Exp Rheumatol 2021 ;39 Suppl 133 ( 6 ): 175 – 183 . 10.55563/clinexprheumatol/4c36nr 34665707
56 Keraen J , Blanc E , Besson FL , et al. Usefulness of 18 F‐labeled fluorodeoxyglucose‐positron emission tomography for the diagnosis of lymphoma in primary Sjögren's syndrome . Arthritis Rheumatol 2019 ; 71 ( 7 ): 1147 – 1157 . 30615273 10.1002/art.40829
57 Jousse‐Joulin S , D'Agostino MA , Nicolas C , et al. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren's syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise . Ann Rheum Dis 2019 ; 78 ( 7 ): 967 – 973 . 31036626 10.1136/annrheumdis-2019-215024
58 Devauchelle‐Pensec V , Mariette X , Jousse‐Joulin S , et al. Tolerance and efficacy of rituximab in primary Sjogren syndrome (tears): results of a randomized controlled trial . Ann Rheum Dis 2012 ; 71 : 75 .21953334
59 Brown S , Navarro Coy N , Pitzalis C , et al; TRACTISS trial team. The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti‐B‐cell therapy in patients with primary Sjögren's syndrome . BMC Musculoskelet Disord 2014 ; 15 : 21 . 24438039 10.1186/1471-2474-15-21 PMC3937118
60 Ramwadhdoebe TH , van Baarsen LGM , Boumans MJH , et al. Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis . Rheumatology (Oxford) 2019 ; 58 ( 6 ): 1075 – 1085 . 30649469 10.1093/rheumatology/key428 PMC6532448
61 Dörner T , Bowman SJ , Fox R , et al. Safety and efficacy of ianalumab in patients with Sjögren's disease: 52‐week results from a randomized, placebo‐controlled, phase 2b dose‐ranging study . Arthritis Rheumatol 2025 ; 77 : 560 – 570 . 39557617 10.1002/art.43059
62 Seror R , Bowman SJ , Brito‐Zeron P , et al. EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI): a user guide . RMD Open 2015 ; 1 ( 1 ): e000022 . 26509054 10.1136/rmdopen-2014-000022 PMC4613159
63 Bowman SJ , Fox R , Dörner T , et al. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's syndrome: a randomised, double‐blind, placebo‐controlled, phase 2b dose‐finding trial . Lancet 2022 ; 399 ( 10320 ): 161 – 171 . Erratum in: Lancet 2025;405:1056. 34861168 10.1016/S0140-6736(21)02251-0
64 Noaiseh, G., Sivils, K. L., Campbell, K., Idokogi, J., Lo, K. H., Liva, S. G., Leu, J. H., Dhatt, H., Ma, K., Leonardo, S., Li, H., Hubbard, J. J., & Gottenberg, J.‐E. ( 2025 ). Efficacy and safety of nipocalimab in patients with moderate‐to‐severe Sjögren’s disease (DAHLIAS): a randomised, phase 2, placebo‐controlled, double‐blind trial . The Lancet , 406 ( 10518 ), 2435 – 2448 . 10.1016/s0140-6736(25)01430-8 41284548
65 Dörner T , Kaul M , Szántó A , et al. Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double‐blind, placebo‐controlled phase 2 trial . Ann Rheum Dis 2024 ; 83 ( 3 ): 360 – 371 . 37932009 10.1136/ard-2023-224691 PMC10894844
66 Xu D , Fang J , Zhang S , et al. Efficacy and safety of telitacicept in primary Sjögren's syndrome: a randomized, double‐blind, placebo‐controlled, phase 2 trial . Rheumatology (Oxford) 2024 ; 63 ( 3 ): 698 – 705 . 37399108 10.1093/rheumatology/kead265
67 Fisher BA , Szanto A , Ng WF , et al. Assessment of the anti‐CD40 antibody iscalimab in patients with primary Sjögren's syndrome: a multicentre, randomised, double‐blind, placebo‐controlled, proof‐of‐concept study . Lancet Rheumatol 2020 ; 2 ( 3 ): e142 – e152 . 38263652 10.1016/S2665-9913(19)30135-3
68 Fisher BA , Mariette X , Papas A , et al; TWINSS study group . Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double‐blind, placebo‐controlled, phase 2b dose‐ranging study . Lancet 2024 ; 404 ( 10452 ): 540 – 53 . 39096929 10.1016/S0140-6736(24)01211-X
69 St Clair EW , Baer AN , Ng WF , et al. CD40 ligand antagonist dazodalibep in Sjögren's disease: a randomized, double‐blinded, placebo‐controlled, phase 2 trial . Nat Med 2024 ; 30 ( 6 ): 1583 – 1592 . 38839899 10.1038/s41591-024-03009-3 PMC11186761
70 Schett G , Müller F , Taubmann J , et al. Advancements and challenges in CAR T cell therapy in autoimmune diseases . Nat Rev Rheumatol 2024 ; 20 ( 9 ): 531 – 544 . 39107407 10.1038/s41584-024-01139-z
71 Mackensen A , Müller F , Mougiakakos D , et al. Anti‐CD19 CAR T cell therapy for refractory systemic lupus erythematosus . Nat Med 2022 ; 28 ( 10 ): 2124 – 2132 . Erratum in: Nat Med 2023;29:2956. 36109639 10.1038/s41591-022-02017-5
72 Mougiakakos D , Krönke G , Völkl S , et al. CD19‐targeted CAR T cells in refractory systemic lupus erythematosus . N Engl J Med 2021 ; 385 ( 6 ): 567 – 569 . 34347960 10.1056/NEJMc2107725
73 Taubmann J , Knitza J , Müller F , et al. Rescue therapy of antisynthetase syndrome with CD19‐targeted CAR‐T cells after failure of several B‐cell depleting antibodies . Rheumatology (Oxford) 2024 ; 63 ( 1 ): e12 – e14 . 37432378 10.1093/rheumatology/kead330 PMC10765150
74 Pecher AC , Hensen L , Klein R , et al. CD19‐targeting CAR T cells for myositis and interstitial lung disease associated with antisynthetase syndrome . JAMA 2023 ; 329 ( 24 ): 2154 – 2162 . 37367976 10.1001/jama.2023.8753 PMC10300719
75 Merkt W , Freitag M , Claus M , et al. Third‐generation CD19.CAR‐T cell‐containing combination therapy in Scl70+ systemic sclerosis . Ann Rheum Dis 2024 ; 83 ( 4 ): 543 – 546 . 38135464 10.1136/ard-2023-225174 PMC10958299
76 Haghikia A , Hegelmaier T , Wolleschak D , et al. Anti‐CD19 CAR T cells for refractory myasthenia gravis . Lancet Neurol 2023 ; 22 ( 12 ): 1104 – 1105 . 37977704 10.1016/S1474-4422(23)00375-7
77 Müller F , Taubmann J , Bucci L , et al. CD19 CAR T‐cell therapy in autoimmune disease ‐ a case series with follow‐up . N Engl J Med 2024 ; 390 ( 8 ): 687 – 700 . 38381673 10.1056/NEJMoa2308917
78 Wang W , He S , Zhang W , et al. BCMA‐CD19 compound CAR T cells for systemic lupus erythematosus: a phase 1 open‐label clinical trial . Ann Rheum Dis 2024 ; 83 ( 10 ): 1304 – 1314 . 38777376 10.1136/ard-2024-225785
79 Granit V , Benatar M , Kurtoglu M , et al; MG‐001 Study Team. Safety and clinical activity of autologous RNA chimeric antigen receptor T‐cell therapy in myasthenia gravis (MG‐001): a prospective, multicentre, open‐label, non‐randomised phase 1b/2a study . Lancet Neurol 2023 ; 22 ( 7 ): 578 – 590 . Erratum in: Lancet Neurol 2023;22:e10. 37353278 10.1016/S1474-4422(23)00194-1 PMC10416207
80 Shouse G. Bispecific antibodies for the treatment of hematologic malignancies: the magic is T‐cell redirection . Blood Rev 2025 ; 69 : 101251 . 39617677 10.1016/j.blre.2024.101251
81 Klein C , Brinkmann U , Reichert JM , et al. The present and future of bispecific antibodies for cancer therapy . Nat Rev Drug Discov 2024 ; 23 ( 4 ): 301 – 319 . 38448606 10.1038/s41573-024-00896-6
82 Bucci L , Hagen M , Rothe T , et al. Bispecific T cell engager therapy for refractory rheumatoid arthritis . Nat Med 2024 ; 30 ( 6 ): 1593 – 1601 . 38671240 10.1038/s41591-024-02964-1
83 Alexander T , Krönke J , Cheng Q , et al. Teclistamab‐induced remission in refractory systemic lupus erythematosus . N Engl J Med 2024 ; 391 ( 9 ): 864 – 866 . 39231352 10.1056/NEJMc2407150
84 Hagen M , Bucci L , Böltz S , et al. BCMA‐targeted T‐cell‐engager therapy for autoimmune disease . N Engl J Med 2024 ; 391 ( 9 ): 867 – 869 . 39231353 10.1056/NEJMc2408786
85 Schett G , Nagy G , Krönke G , et al. B‐cell depletion in autoimmune diseases . Ann Rheum Dis 2024 ; 83 ( 11 ): 1409 – 1420 . 38777374 10.1136/ard-2024-225727
86 Rocca J , Beydon M , Le Guern V , et al. Treatment modalities of marginal zone lymphoma and overall survival, haematological response, and underlying Sjögren's disease activity: a multicentre, retrospective, observational study . Lancet Rheumatol 2024 ; 6 ( 10 ): e703 – e712 . 39182508 10.1016/S2665-9913(24)00198-X