Objective Patients with Sjögren’s disease (SjD) have an increased risk of developing B cell lymphomas, which may express rheumatoid factors (RhF). However, it remains unclear whether RhF-secreting cells undergo malignant transformation. To address this question, we longitudinally tracked the evolution of a RhF clone in a rare SjD case before and after lymphoma diagnosis. Methods Peripheral blood B cells, serum and malignant lymph node biopsy were collected from a 68-year-old male with SjD who developed diffuse large B cell lymphoma (DLBCL). Clonal RhF sequences were identified in serum by mass spectrometry and in B cells by mRNA sequencing. Recombinant IgM were generated from clonal sequences and assessed for RhF activity and cryoaggregation. Results A monoclonal RhF was detected in serum and circulating B cells six months before DLBCL diagnosis. The same clone was expressed by the lymphoma. Clonal analysis demonstrated divergence into two branches: one with seven antibody mutations expressed by blood B cells, and a second with twelve antibody mutations in the serum RhF and lymphoma. Recombinant IgM representing the blood and serum RhF demonstrated RhF activity, whereas the lymphoma clone acquired three additional mutations that impaired RhF binding. Conclusions Our prospective and longitudinal analyses provide direct evidence for a RhF secreting clone evolving into a lymphoma in a SjD patient. This work expands on previous cross-sectional studies of RhF expressing lymphomas in SjD and provides a proof-of-concept case, which potentially supports early therapeutic targeting of expanded RhF clones.

Cryoglobulins are immune complexes of antibodies that precipitate from serum at temperatures less than 37 °C. In the diagnostic laboratories, the usual method for the detection of cryoglobulins is the observation of a serum precipitate when left for several days at 4 °C. Dissolution of the precipitate when warmed at 37 °C is confirmation that the precipitate is cryoglobulin immune complexes. We report a rare case of heat-resistant type II cryoglobulin in an asymptomatic patient with chronic hepatitis C, that effectively solubilised at 42 °C. Mass spectrometric typing revealed this to be a minimally mutated cryoglobulin of the Wa-idiotype. This case emphasises the importance of laboratorians to be aware of rare cases of heat-resistant cryoglobulins to avoid false negative results.

Objectives Autoantibodies directed against Telomerase RNA Ro y-RNAs and Vault RNAs Domain Family Member 2 (TROVE2)/Ro60 and Tripartite Motif 21 (TRIM21)/Ro52 are historically related to distinct SSA/Ro autoantigens. However, despite advances facilitating separate testing, these autoantibodies remain frequently confused resulting in a lack of clarity and precision in the literature. We conducted a systematic literature review to inform a Delphi process to achieve consensus on a clearer, harmonised nomenclature. Methods The systematic review included primary publications in systemic lupus erythematosus (SLE) and Sjögren disease (SjD) published between January 1, 2000 and May 26, 2025 that mentioned testing for anti-TROVE2/Ro60 and/or anti-TRIM21/Ro52 autoantibodies. This analysis contributed to a Delphi consensus exercise proposing preferred nomenclature by a group of 17 international expert physicians and laboratorians. Results Eight hundred ninety-one publications were included (301 SLE, 493 SjD, and 97 mixed SLE/SjD). Only 20.9% of studies tested and reported the autoantibodies separately; 75.0% did neither; and 4.2% tested but did not report them separately. There was considerable nomenclatural heterogeneity with 16 different terms used for anti-TROVE2/Ro60 and 11 terms for anti-TRIM21/Ro52 autoantibodies. After 2 rounds of voting, the Delphi panel reached a unanimous consensus on the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies. Conclusions The distinction of anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies was frequently unclear and imprecise throughout the literature. Their clinical associations also lacked clarity and precision. To clarify and strengthen the understanding of the clinical associations of these 2 important autoantibodies, the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 are recommended for future studies and publications.

Protein electrophoresis (PEP) is a key laboratory technique for identifying and quantifying proteins in body fluids, commonly used for detection of paraproteins in plasma cell disorders like multiple myeloma (MM), amyloidosis, and related conditions. The utility of urine PEP and urine immunofixation electrophoresis (uIFE) has been criticised in recent years due to its poorer sensitivity and precision than the corresponding serum assays. This study, conducted in an Australian cohort, aimed to assess the utility of uIFE when serum immunofixation electrophoresis (sIFE) results are negative and determine the predictors for such cases. We conducted a single-laboratory retrospective cross-sectional study over 18 months (2023-2024) involving 1065 individual patient encounters who had a uIFE test performed. Samples were run on the Sebia HYDRASYS system and were read independently by three experienced readers. We identified 51 discordant cases (5% of cases) where uIFE detected monoclonal proteins absent in paired sIFE. Common diagnoses in these 51 patients included MM (n=1, 22%) and amyloidosis (n=9, 18%). A random selection of 51 age- and gender-matched uIFE patients with positive sIFE results were compared to the discordant cases. Renal function or serum-free light chain status did not influence the presence of discordant results. Discordant uIFE/sIFE results may be seen in clinically relevant syndromes. Our findings highlight the importance of uIFE in detecting low-level monoclonal proteins, particularly in conditions where serum assays fall short, such as in minimal residual disease or light chain amyloidosis.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of monoclonal gammopathy of renal significance (MGRS) in which monoclonal immunoglobulin deposits are found within the glomerulus, without involvement of other renal compartments. This condition can result in kidney dysfunction and ultimately kidney failure. It most commonly presents in the native kidney and has a high risk of recurrence in renal allografts, typically within a few months post-transplantation. PGNMID rarely presents as de novo in a transplanted kidney; if so, it usually manifests within 3 years. Early treatment is required to prevent further deterioration and reduce the risk of allograft loss. We present a case of a patient who presented with progressive kidney function decline 10.5 years after simultaneous pancreas-kidney (SPK) transplantation. The patient had a prior diagnosis of an immune complex-mediated glomerulonephritis on the pre-transplant native renal biopsy. The subsequent allograft biopsy showed electron-dense, glomeruli-limited deposits on electron microscopy, with immunofluorescence showing a nonspecific full-house pattern of staining. Immunofluorescence performed following protease (pronase) digestion on FFPE tissue showed the deposits to be IgG3 lambda light chain restricted, with no plasma cell or lymphoid clone identified in the bone marrow, resulting in a diagnosis of MGRS with a PGNMID pattern in the renal biopsy. This prompted treatment with prednisone and rituximab, with subsequent ongoing improvement in proteinuria and kidney function. To our knowledge, this is the latest presentation of post-transplantation de novo PGNMID with survival reported to date.

OBJECTIVES:Sjögren disease (SjD) is a common systemic autoimmune disease and patients experience a wide range of symptoms with unique emotional, social and physical impacts. Understanding the individual experience of SjD is crucial to providing comprehensive and sensitive care in the clinics. Therefore, the aim of this systematic review was to analyze primary literature that examined the lived experiences of patients with SjD. METHODS:Primary literature qualitatively exploring the lived experiences of SjD patients through interviews and/or focus groups were identified. Papers were included if they were written in English, participants were ≥ 18 years old and they fulfilled a diagnosis of SjD as per the 2002 American-European Consensus or 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology criteria. Thematic analyses were performed using the Thomas and Harden approach. RESULTS:Nine of 1990 screened manuscripts (0.5 %) fulfilled our selection criteria. These comprised a total of 162 participants (154, 95 % female) across 10 countries. Thematic analysis revealed several key themes: the burden of the physical symptoms (such as sicca), social isolation, negative impact on function, unpredictability of the disease, diverse coping strategies, and the challenges of navigating the healthcare system. Few studies addressed any bias in the recruitment of patients or analyses of data. CONCLUSION:SjD patients encounter a large variety of individual experiences in their illness that have important repercussions on quality of life. Understanding these experiences will help create a harmonized set of patient-centered outcomes to inform the generation of Outcome Measurement in Rheumatology (OMERACT) target domains in SjD.

Sjögren disease (SjD) is a prevalent systemic autoimmune condition characterised by exocrine gland dysfunction, systemic inflammation and heterogeneous organ involvement. Current management remains largely symptomatic, with no approved disease-modifying therapies available and substantial unmet clinical need. However, advances in understanding immunopathogenesis have accelerated the development of targeted treatments. Ianalumab, a dual-acting B cell-activating factor receptor (BAFF) receptor inhibitor with B cell-depleting activity, is the first agent to report positive phase 3 results, showing significant improvements in systemic disease activity. Other investigational approaches include BAFF/APRIL pathway inhibition, T-cell-B-cell costimulation inhibition, type I interferon blockade, JAK-STAT, TYK2 and BTK inhibition, neonatal Fc receptor antagonist and endosomal Toll-like receptor inhibition, with exploratory modalities such as RNA-targeted agents and cellular immunotherapy (including Chimeric antigen receptor T therapy) under evaluation for severe or refractory disease. Outcome assessment has also evolved, with European Alliance of Associations for Rheumatology (EULAR) Sjögren Syndrome Disease Activity Index and EULAR Sjögren Syndrome Patient Reported Index providing validated physician- and patient-centred measures. Composite endpoints such as the Composite of Relevant Endpoints for Sjögren Syndromeand the Sjögren Tool for Assessing Response now integrate systemic, symptomatic and functional domains, improving sensitivity and feasibility in trials. Together, these tools support more rigorous evaluation of novel therapies. Overall, therapy in SjD is shifting towards precision, phenotype-informed strategies. Priorities now are confirming long-term safety and durability of response, and demonstrating patient-important benefit. In Australia, the impact of new therapies for SjD will hinge on clear diagnostic pathways, routine use of validated disease activity measures and multidisciplinary care models.

Sjögren's disease (SjD) is a chronic autoimmune disease that is characterised by dryness symptoms, arthralgias, systemic disease and B-cell hyperactivity. Serum autoantibodies are key pathological features of this disease. Anti-Ro52, anti-Ro60 and anti-La immunoglobulin G autoantibodies (sometimes known as antinuclear antibodies) are perhaps the most well-known autoantibodies, are important in the formal classification criteria for SjD and exist in up to 70% of patients. Rheumatoid factors, which are present in approximately 50% of patients, can reveal important prognostic information regarding the development of B-cell lymphomas. Beyond these autoantibodies, there are several emerging and novel autoantibodies associated with SjD that hold promise in identifying clinical features of SjD and facilitating the diagnosis of patients who lack the classic SjD-associated autoantibodies. These include anti-fodrin antibodies, anti-muscarinic acetylcholine receptor 3 antibodies and those autoantibodies traditionally associated with systemic lupus erythematosus. This narrative review article provides an updated review of these autoantibodies, discussing their potential clinical utility and the current limitations. Although many clinical associations have been identified, the routine clinical use of these autoantibodies is hampered by issues such as poor diagnostic sensitivity, contradictory associations, heterogeneous studies and small single-cohort studies. Further research using harmonised testing and large, multicentre cohorts is required to explore and validate the utility of these autoantibodies.

Self-reactive B cells are a hallmark of autoimmune disease and may directly contribute to disease pathogenesis. This Research Highlight article reviews four articles published in 2025 that offer new insights into the origins and drivers of self-reactive B cells. These studies investigate self-reactive B cells in human peripheral blood, murine models, and the role of viral and genetic drivers.

CONTEXT.—:Anti-extractable nuclear antigens (ENAs) are a form of antinuclear antibody test in the diagnostic laboratory that plays a crucial role in the diagnosis of systemic autoimmune diseases. The line immunoassay (LIA) is one of the most popular assays used to measure these autoantibodies. However, LIAs suffer from limited diagnostic specificity, and numerous attempts have been made to improve the cutoffs. OBJECTIVE.—:To readjust LIA autoantibody cutoffs, using the clinical diagnoses of a large and heterogeneous group of patients. DESIGN.—:During a 12-month period, 667 discrete patients received an LIA test that had adequate clinical records to determine a diagnosis. Autoantibodies on the Euroimmun LIA (anti-Ro52, anti-Ro60, anti-dsDNA, anti-La, anti-mitochondrial antibodies, anti-Sm, anti-RNP, anti-histone, anti-nucleosome, anti-ribosomal P, anti-centromere protein B, and anti-Scl70) were evaluated. Two laboratory physicians independently rated whether the LIA density for each autoantibody was consistent or not consistent with the diagnosis. Receiver operating characteristic curves were constructed for each autoantibody and cutoffs were reestablished to maximize diagnostic specificities of 85% to 90%. RESULTS.—:New cutoffs were proposed at the diagnostic specificities of 85% and 90%. Overall, there were similar rates of autoantibody detections, using the new cutoffs, compared to the manufacturer's defined cutoff of 10 units for each autoantibody. CONCLUSIONS.—:We have used a novel approach to redefining anti-ENA LIA cutoffs by using clinical diagnoses across a range of pathologic conditions. This ensures that results are clinically relevant to a general laboratory cohort and, when used as a characterizing assay after an initial anti-ENA screen, maximizes diagnostic specificity. Longitudinal evaluation of the new cutoffs is required after implementation to examine clinical impact.

Sjögren disease (SjD) is a commonly encountered systemic autoimmune disease. We performed a single-centred study of 147 patients with primary SjD and found that SjD patients of Asian and Middle Eastern ancestry had earlier onset disease than Caucasian patients. It is likely that genetic factors dictate disease characteristics and future studies to dissect the biological basis for these differences are warranted.

Systemic lupus erythematosus (SLE) is an extremely heterogenous autoimmune disorder. A key biomarker, the double stranded (ds) DNA autoantibody, provides diagnostic specificity for SLE. We analyzed anti-dsDNA by mass spectrometry (MS) to determine if ascertaining the autoantibody’s heavy chain variable region (IGHV) may hold any clinical relevance. A cross-sectional study of 32 SLE patients (75% female) in a single center was performed. Serum anti-dsDNA was subjected to MS analyses. Obtained IGHV subfamilies were correlated with active clinical features of SLE, as determined by medical record reviews. We established significant associations with the presence of IGHV3-15 and active neuropsychiatric lupus (relative risk [RR] 5.71); IGHV3-21, IGHV3-23 and IGHV4-34 and leukopenia (RR 13.70, 2.14 and 10.29 respectively); and IGHV3-23 and serositis (RR 2.41) and cutaneous lesions (RR 2.82). This study provides the first evidence for the clinical benefits of deep anti-dsDNA profiling through MS, and provides an avenue for improving predictive medicine for SLE patients. Future studies with a greater number of patients, and to determine if these subfamilies have direct pathogenic properties are required.

Background Cluster of differentiation (CD) 5+ B cells comprise approximately 15% of peripheral blood B cells and are commonly encountered in diagnostic flow cytometry. However, their disease associations have not been systematically reviewed before, particularly in non-CD5+ B-cell malignancy cases. The aim of this study was to ascertain the prevalence and clinical associations of nonmalignant-associated peripheral blood CD5+ B cells in the diagnostic flow cytometry laboratory. Methods Over a period of 3 months, we undertook a single-laboratory cross-sectional study to examine disease associations of CD5+ B cells. B cells were assessed by flow cytometry using our standard B-cell panel. Medical records were reviewed to ascertain disease associations. Results In the audit period, there were 426 consecutive B-cell panels excluding duplicate patients, CD5+ B-cell malignancies, and B-cell-depleted samples. The highest percentage of CD5+ B cells were noted in patients with autoimmune diseases and was, in general, higher than patients who had infections or other hematological disorders. Conclusions CD5+ B cells are common in the periphery of patients with a variety of medical conditions and may reflect a degree of B-cell hyperreactivity. It would be important for future studies to examine the functional role and consequences of these B cells, and whether they may hold any prognostic or monitoring value.