The diagnosis and misdiagnosis of Sjögren disease.

Although one of the most common systemic autoimmune disorders, Sjögren disease (SjD) may be overlooked in patients presenting with non-specific symptoms or no complaints of sicca symptoms. SjD is not a condition to be missed as patients could present with serious extra-glandular manifestations, including lymphomas. In this article, we discuss the diagnostic pitfalls of this disorder and encourage physicians to consider carefully the 'non-textbook' presentations.

The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generation.

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.

Seronegative Sjögren Syndrome: A Forgotten Entity?

As a highly varied disease, Sjögren syndrome (SS; also termed Sjögren disease) is estimated to affect 0.01% to 0.72% of the population, with an overwhelming bias toward the female gender.1 SS causes a significant burden to the quality of life of patients and inhibits their function.

Serological intermolecular epitope spreading in a patient with primary Sjögren's syndrome.

Sjögren's syndrome (SS) is one of the prototypic systemic autoimmune diseases characterised by autoreactive T and B cells, sicca symptoms and various extraglandular manifestations. SS is characterised by autoantibodies (anti-Ro52/tripartite motif containing-21 [TRIM21], anti-Ro60 and anti-La) that are important diagnostic biomarkers. Patients have typically stable serostatus; that is, patients who are positive for one or more of these autoantibodies tend to remain thus and vice versa. We describe a rare instance where a woman in her 50s was diagnosed with primary SS and developed new autoantibodies subsequently through serological epitope spreading. She demonstrated primarily glandular features only and clinical stability despite serological evolution. In this case report, we discuss the significance of this molecular feature and the clinical implications for our understanding of autoimmunity.

Isolated anti-Ro52 identifies a severe subset of Sjögren's syndrome patients.

Introduction: Serum autoantibodies targeting the SSA/Ro proteins are a key component of the classification criteria for the diagnosis of Sjögren's syndrome (SS). Most patients' serum reacts with both Ro60 and Ro52 proteins. Here we compare the molecular and clinical characteristics of patients diagnosed with SS with anti-Ro52 in the presence or absence of anti-Ro60/La autoantibodies. Methods: A cross-sectional study was performed. Patients in the SS biobank at Westmead Hospital (Sydney, Australia) that were positive for anti-Ro52 were included and stratified based on the absence (isolated) or presence (combined) of anti-Ro60/La, measured by line immunoassay. We examined clinical associations and the serological and molecular characteristics of anti-Ro52 using ELISA and mass spectrometry in serological groups. Results: A total of 123 SS patients were included for study. SS patients with isolated anti-Ro52 (12%) identified a severe serological subset characterised by higher disease activity, vasculitis, pulmonary involvement, rheumatoid factor (RhF) and cryoglobulinaemia. Serum antibodies reacting with Ro52 in the isolated anti-Ro52 subset displayed less isotype switching, less immunoglobulin variable region subfamily usage and a lower degree of somatic hypermutation than the combined anti-Ro52 subset. Conclusions: In our cohort of SS patients, isolated anti-Ro52 represents a severe subset of SS, and is associated with the presence of cryoglobulinaemia. We therefore provide clinical relevance to the stratification of SS patients by their sero-reactivities. It is possible that the autoantibody patterns may be immunological epiphenomena of the underlying disease process, and further work is required to unearth the mechanisms of the differential clinical phenotypes.

Hyper-IgM and acquired C1q complement deficiency in a patient with de novo ATM mutation.

Hyper-IgM syndrome (HIGM) is a rare immunodeficiency phenotype that is usually accompanied by serious infections. We present a curious case of the incidental detection of HIGM in a 45-year-old male with complement C1q deficiency. He had relatively mild sinopulmonary infections, recurrent skin infections and lipomas in his adulthood. Investigations revealed normal enumeration of total peripheral blood B cells and reduced expression of CD40L on his CD4+ T cells. C1q was noted to be absent, due to a peripheral inhibitor such as an autoantibody. Genomic sequencing of the patient and his parents revealed a novel, de novo heterozygous mutation in the ATM (ataxia telangiectasia mutated) gene although he displayed no clinical evidence of ataxia telangiectasia. This is a rare case of HIGM and acquired C1q deficiency. We present full phenotyping data that contributes to the growing understanding to these interesting immunodeficiencies.

Comparison of two anti-histones antibodies commercial assays in an immunology laboratory and systemic lupus erythematosus.

BACKGROUND: Anti-histones antibodies (AHAs) are antibodies directed against histone proteins - structural proteins that provides scaffolding for DNA to be wrapped around. AHAs, measured in the serum, are diagnostically helpful in cases of systemic lupus erythematosus (SLE) and drug-induced lupus erythematosus (DILE). In the diagnostic laboratory, they may be measured by enzyme-linked immune-sorbent assay (ELISA) or line immunoassays (LIA); however, the performance of these have never been directly compared in the literature. METHODS: We evaluated a commonly used commercial ELISA and LIA to compare the performance in our immunology laboratory. Retrospective and prospective analyses were undertaken over a 5.5-year period. We also examined their performance in the model disease of SLE and compared their performance to disease activity and the main clinical features. RESULTS: One hundred and thirty-five patients were evaluated including 65 SLE patients. Based on the quantitative cut-offs, there was only moderate agreement between the two assays (κ = 0.444). Both assays only had modest agreement with the clinical situation of the evaluated patients. When considered within the SLE context, both assays were moderately correlated with disease activity. Positive AHAs by ELISA were associated with SLE cytopaenias, and both ELISA and LIA correlated with positive anti-double stranded DNA. CONCLUSIONS: Moderate agreement analytically were seen between ELISA and LIA methods in a general laboratory cohort. Both assays were comparable in their diagnostic performance. ELISA detection of AHAs appears to have some clinical use in our cohort of SLE patients. Future studies are required to explore the clinical utility of AHAs in SLE and other disorders.

Phases and Natural History of Sjögren's Disease: A New Model for an Old Disease?

Sjögren's disease (SjD) is an archetypal and heterogenous autoimmune disorder that is characterized by exocrine glandular dysfunction. A proportion of patients develop severe extraglandular manifestations, such as cryoglobulinemia, and have an increased risk of lymphoma, both of which can adversely affect quality of life and occasionally mortality. As with most autoimmune disorders, the pathogenesis is poorly understood and difficult to predict, and, frustratingly, there is a lack of targeted therapies to cure this disease. We review the disease manifestations of SjD and propose a staged model for understanding the evolution of pathology. In longitudinal studies, most patients remain relatively stable in terms of their laboratory and clinical parameters. However, in the setting of various risk factors, a proportion of patients develop severe symptoms and/or lymphoma. We discuss potential underlying mechanisms for disease progression and the strengths and limitations of using a staged model to correlate the pathogenesis and spectrum of manifestations in SjD. Ultimately, understanding how and why some patients remain relatively stable, whereas others progress and develop florid systemic disease and a fraction develop lymphoma, is key to developing preventative and therapeutic treatments.

Validation of a commercial line blot for the detection of serum anti-Ro60 autoantibodies.

Serum anti-Ro60 is one the most frequently encountered autoantibodies in the diagnostic immunopathology laboratory and in clinical practice. A large variety of assays are available to detect this including the popular multiplex line immunoblot (IB) assay. We evaluated the analytical performance of the IB for anti-Ro60 detection, using the counterimmunoelectrophoresis (CIEP) method as the 'gold standard'. We also undertook a survey of international laboratories, who use the IB, about their reporting practices for anti-Ro60. Using the manufacturer's reported cut-off of 15 units, the IB has an analytical sensitivity of 90.9% and specificity of 99.3% for anti-Ro60 detection. The optimal cut-off to balance sensitivity and specificity was determined to be 5 units with a sensitivity of 100% and specificity of 97.4%. Most laboratories use the manufacturer's specified cut-off (15 units) when determining a positive anti-Ro60 result. Whilst the commercial IB generally performs well, laboratorians need to be mindful of the limitations of IB in detecting antibodies that recognise conformational epitopes and what cut-offs they use. A vast majority of laboratories could potentially miss detection of this clinically important autoantibody.

CD20+ T cells: an emerging T cell subset in human pathology.

INTRODUCTION: Although CD20 is classically a B cell marker, in the last three decades, dim expression has been noted on a subset of T cells as well that has been independently verified by a number of groups. Our understanding of these cells and their function is not well established. METHODS: A thorough review of original articles on CD20+ T cells was undertaken of Pubmed by using combination of phrases including "CD20+", "CD20-positive" and "T cells". Articles in English were considered, and there was no time restriction. RESULTS: CD20+ T cells express the standard T cell markers and, in comparison to CD20¯ T cells, appear to express greater inflammatory cytokines and markers of effector function. Although the ontogeny of these cells is still being established, the current theory is that CD20 may be acquired by trogocytosis from B cells. CD20+ T cells may be found in healthy controls and in a wide range of pathologies including autoimmune diseases, haematological and non-haematological malignancies and human immunodeficiency virus (HIV) infections. One of the best studied diseases where these cells are found is multiple sclerosis (MS) where a number of therapeutic interventions, including anti-CD20 depletion, have been shown to effectively deplete these cells. CONCLUSION: This review summarises the latest understanding of CD20+ T cells, their presence in various diseases, their putative function and how they may be an ongoing target of CD20-depleting agents. Unfortunately, our understanding of these cells is still at its infancy and ongoing study in a wider range of pathologies is required.

Anti-Ro52/TRIM21 serological subsets identify differential clinical and laboratory parameters.

INTRODUCTION: Anti-Ro52/tripartite motif-containing protein 21 (TRIM21) IgG is one of the most common autoantibodies found in systemic autoimmune diseases and is typically found in conjunction with anti-Ro60 and/or anti-La. A retrospective, cross-sectional study was undertaken to examine the clinical and laboratory features of two serological subsets: patients with anti-Ro52/TRIM21 autoantibodies in the absence of anti-Ro60 and anti-La (isolated anti-Ro52/TRIM21) and patients with anti-Ro52/TRIM21 in the presence of anti-Ro60 and/or anti-La. METHODS: Over a 12-month period, patients tested positive for anti-Ro52/TRIM21 via line immunoassay (LIA) at the Westmead Hospital (Australia) immunopathology laboratory were included. The presence of anti-Ro60 and/or anti-La via same LIA was noted. Associated laboratory and medical records were perused to extract demographic, laboratory, and clinical information. RESULTS: There were 346 patients within the study period, and 39.9% of the patients positive for anti-Ro52/TRIM21 lacked anti-Ro60/anti-La autoantibodies. Isolated anti-Ro52/TRIM21 patients tend to be older, have lower anti-Ro52/TRIM21 titres, have lower rheumatoid factors, and have lower proportions of neutropaenia compared to patients who were positive for anti-Ro52/TRIM21 and anti-Ro60/La. This occurred independent to diagnoses of Sjögren's syndrome or systemic lupus erythematosus. Coexisting neurological syndromes, pulmonary pathologies, and malignancies were more prevalent in the isolated anti-Ro52/TRIM21 subset. CONCLUSIONS: Patients with isolated anti-Ro52/TRIM21 tend to have distinct and important clinical and laboratory associations. It is unclear if these patients evolve or remain a stable subset and how they originate immunologically. Longitudinal and prospective studies are required to ascertain the overall predictive and prognostic value of this stratification. Key Points • Anti-Ro52/TRIM21 is an autoantibody found in autoimmunity and non-immunological conditions. • Sixty percent of anti-Ro52/TRIM21 patients are positive for anti-Ro60. • Isolated anti-Ro52/TRIM21 has reduced anti-Ro52/TRIM21 and rheumatoid factor titres. • Isolated anti-Ro52/TRIM21 is associated with anaemia and malignancies.

Clinical use of anti-histone antibodies in idiopathic and drug-induced lupus.

Anti-histone antibodies (AHAs) make their appearance in a number of systemic autoimmune diseases including systemic lupus erythematosus (SLE) and drug-induced lupus erythematosus (DILE). Although being known for over 50 years, they are poorly studied and understood. There is emerging evidence for their use in predicting clinical features of SLE, diversifying their clinical use. AHAs, however, are probably less prevalent in DILE than once thought owing to a move away from older DILE drugs to modern biological agents which do not appear to elicit AHAs. This review examines the historical studies that have defined AHAs and looks at some of the recent work with these autoantibodies.

IgA anti-dsDNA antibodies: A neglected serological parameter in systemic lupus erythematosus.

Anti-double-stranded DNA (anti-dsDNA) autoantibodies are archetypal biomarkers found in systemic lupus erythematosus (SLE). Although they can exist in any isotype, very little is understood about the IgA isotype for which most of our knowledge is derived from observational studies. This review article summarises our knowledge of this autoantibody isotype to date. Attention will be spent on clinical associations as well as its potential links with lupus nephritis for which there is still some controversy. Further understanding of this serological parameter may facilitate diagnosis, prognosis and treatments of systemic lupus erythematosus patients.