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PD-1/PD-L1 inhibitors have increasingly been associated with the occurrence of subacute cutaneous lupus erythematosus (SCLE), but the clinical characteristics and outcomes remain under-explored. Literature on PD-1/PD-L1 inhibitors induced SCLE was retrieved from Chinese and English databases until June 31, 2024, and clinical data of patients were extracted for retrospective analysis. Twenty-nine patients participated, with a median age of 63 years (range 43, 80). The most frequently reported drugs were Nivolumab (51.7%) and pembrolizumab (31.0%). The median time from treatment initiation to SCLE onset was 3 months (range 0.5, 47). Cutaneous manifestations presented primarily as papulosquamous lesions (65.5%) and erythema annulare (31.0%), predominantly occurring on the trunk (51.7%) and arms (51.7%). Serological analysis revealed positive anti-Ro antibodies in 91.7% of patients, positive antinuclear antibodies in 75.0%, and positive anti-La antibodies in 50.0%. Skin biopsies showed interface dermatitis in 65.5% of cases and lymphocyte infiltration in 82.8%. Treatment with topical corticosteroids, systemic corticosteroids, and hydroxychloroquine led to gradual improvement or resolution of the rash, with a median recovery time of 1 month (range 0.5, 11). As the use of PD-1/PD-L1 inhibitors in oncology increases, SCLE should be recognized as a rare cutaneous adverse effect. Histological and serological evaluations play a critical role in diagnosing SCLE. Typically, SCLE resolves on its own with appropriate local and systemic treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Anti-Sjögren's syndrome type A (anti-SSA) antibodies are non-organ-specific autoantibodies highly prevalent in various autoimmune diseases. This study primarily investigated the prevalence of anti-SSA antibodies in the health screening population. Additionally, we explored the clinical features of the anti-SSA antibody-positive population and evaluated the development of connective tissue diseases (CTD) over the years in individuals with anti-SSA antibodies for whom follow-up was available. A total of, 64 045 individuals without a history of CTD from 2013 to 2022 who visited Peking Union Medical College Hospital for health screening were screened for autoimmune antibodies: 1.7% (1091/64 045) of the Chinese health screening population were positive for anti-SSA antibodies, with a prevalence of 0.9% (290/33 829) in men and 2.7% (801/30 216) in women. Compared with matched autoantibody-negative controls, anti-SSA antibody-positive individuals had higher levels of serological abnormalities, including erythrocyte sedimentation rate (ESR) [10 (6-15) mm/h vs. 7 (4-12) mm/h, P < 0.0001], rheumatoid factor (RF) [7.15 (4.30-16.90) IU/ml vs. 5.00 (3.20-7.90) IU/ml, P < 0.0001], and immunoglobulin G [13.09 (11.20-15.45) g/L vs. 11.34 (9.85-13.18) g/L, P < 0.0001], and lower levels of white blood cells (WBC; 5.49 ± 1.50 × 109/L vs. 5.82 ± 1.49 × 109/L, P < 0.0001). Additionally, they had a higher proportion of coexisting thyroid autoantibodies, including anti-thyroid peroxidase antibodies (TPO-Ab) (17.1% vs. 11.3%, P < 0.0001) and anti-thyroglobulin antibodies (Tg-Ab) (17.8% vs. 11.0%, P < 0.0001). Among the 381 subjects who were anti-SSA positive and followed up for a median of 4.6 years, 146 (38.3%) individuals developed CTD, including 68 (17.8%) cases of primary Sjögren's syndrome (pSS), 10 (2.6%) cases of rheumatoid arthritis (RA), 5 (1.3%) cases of systemic lupus erythematosus (SLE), 4 (1.0%) cases of secondary Sjögren's syndrome (sSS), and 59 (15.5%) cases of undifferentiated connective tissue disease (UCTD). In all, 235 (61.7%) individuals did not develop CTD over a median time of 5.9 (2.9-8.1) years after the earliest autoantibody detection. Elevated ESR (>20 mm/h), RF positivity (>20 IU/ml), and female gender were identified as independent risk factors for CTD among the anti-SSA antibody-positive individuals. Anti-SSA antibodies were found in 17 among approximately 1000 individuals without a history of autoimmune diseases. Anti-SSA antibody-positive individuals are advised to periodically monitor thyroid function. Elevated ESR (>20 mm/h), female gender, and RF positivity may delineate a high-risk cohort for CTDs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.

Introduction: The global SARS-CoV-2 pandemic significantly altered lifestyles, access to healthcare, and social interactions, introducing unprecedented physical and psychological stress all over the world. This study explores the relationship between psychological stress, vitamin D (Vit-D) levels, and autoimmune connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, and rheumatoid arthritis., Methods: The analysis was based on over one million patient data points derived from anti-nuclear antibody (ANA) testing conducted both before and during the COVID-19 pandemic 2017-2021. In a subset of patients, longitudinal data were collected bi-yearly to yearly over 5-8 years using the same three-month criteria. The dataset was analyzed using GraphPad Prism9 using paired t-tests or ordinary one-way ANOVA with a significance threshold of p < 0.05 to ensure robust correlations between the variables., Results: Data indicated that Vit-D levels peaked between 2017 and 2019 before declining, while ANA data demonstrated a rise in autoimmune connective tissue disease cases during the pandemic, reaching a peak in 2021. A clear correlation was observed, with autoimmune disease incidence increasing as Vit-D levels decreased. In-depth case analysis revealed that declining Vit-D levels preceded higher ANA titers and increased autoimmune disease severity, whereas improvements in Vit-D levels were associated with reduced ANA titers and less severe disease manifestations., Conclusions: The findings suggest that maintaining mental health and ensuring adequate Vit-D supplementation could be essential strategies for mitigating autoimmune disease risks and maintaining immune stability, particularly in pandemic scenarios. Clinically, these results underscore the need for early interventions targeting both psychological well-being and Vit-D levels to reduce the burden of autoimmune diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alobaid and Alqabandi.)

Objective: To investigate the prevalence of Sjögren's syndrome (SS) and the associated factors in a sample of the Egyptian population., Methods: This cross-sectional study obtained data by screening subjects from several hospitals in different governorates across Egypt. Demographic and health data were collected including symptoms and type of Sjögren's syndrome, associated autoimmune diseases, the presence of specific autoantibodies and associated malignancies., Results: The study analysed 7960 participants and 64 (0.80%) had SS. Of these, 22 (34.38%) had primary SS and 42 patients (65.63%) had secondary SS. For the total study cohort, the prevalence of primary and secondary SS was 0.28% and 0.53%, respectively. There was a higher prevalence of SS in females compared with males and SS was more common in the fifth and sixth decades. All patients with SS complained of oral and ocular dryness. The most common concomitant autoimmune disease was rheumatoid arthritis. Anti-SSA (Ro) and anti-SSB (La) antibodies were the most frequently associated autoantibodies. Only two patients had non-Hodgkin's lymphoma., Conclusion: This was the first study to describe the prevalence of SS in Egypt. SS is not a rare disease in Egypt, so raising awareness of SS in both patients and healthcare professionals is very important., Competing Interests: Declaration of conflicting interestThe authors declare that there are no conflicts of interest.

Objectives: To identify and characterize undescribed systemic sclerosis (SSc)-specific autoantibodies targeting nucleolar antigens and to assess their clinical significance., Methods: We conducted proteome-wide autoantibody screening (PWAS) against serum samples from SSc patients with nucleolar patterned anti-nuclear antibodies (NUC-ANAs) of specific antibodies (Abs) unknown, utilizing wet protein arrays fabricated from in vitro human proteome. Controls included SSc patients with already-known SSc-specific autoantibodies, patients with other connective tissue diseases and healthy subjects. The selection of nucleolar antigens was performed by database search in the Human Protein Atlas. The presence of autoantibodies was certified by immunoblots and immunoprecipitations. Indirect immunofluorescence assays on HEp-2 cells were also conducted. Clinical assessment was conducted by retrospective review of electronic medical records., Results: PWAS identified three candidate autoantibodies, including anti-nuclear valosin-containing protein-like (NVL) Ab. Additional measurements in disease controls revealed that only anti-NVL Abs are exclusively detected in SSc. Detection of anti-NVL Abs was reproduced by conventional assays such as immunoblotting and immunoprecipitation. Indirect immunofluorescence assays demonstrated homogeneous nucleolar patterns. Anti-NVL Ab-positive cases were characterized by significantly low prevalence of diffuse skin sclerosis and interstitial lung disease, compared with SSc cases with NUC-ANAs other than anti-NVL Abs, such as anti-U3-RNP and anti-Th/To Abs., Conclusion: Anti-NVL Ab is an SSc-specific autoantibody associated with a unique combination of clinical features, including limited skin sclerosis and lack of lung involvement., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Primary Sjögren's Syndrome (pSS) is a complex autoimmune disorder characterized by diverse clinical manifestations yet lacking effective therapeutic strategies currently. This study aims to gain a thorough understanding of the clinical landscape of pSS and further delineate its clinical subtypes, thereby enabling the efficient management for pSS., Methods: We conducted a cross-sectional observational study of 1318 pSS patients. The pSS patients were categorized and compared based on gender, anti-SSA antibodies, and labial salivary gland biopsies (LGSB). Unsupervised clustering analysis was employed to identify pSS subtypes using systemic involvement among patients. Furthermore, we assessed clinical and biological variances among these subtypes., Results: Through group comparisons, we observed more pronounced extraglandular manifestations among male patients, SSA-negative group, and those with positive LGSB results. Based on systemic involvement, pSS patients were categorized into four groups. C1 exhibited minimal systemic involvement, lacking hematologic or serologic manifestations, with the lowest ESSDAI scores. C2 presented with serologic changes in all patients, partial joint involvement, and no hematologic systemic manifestations. C3 lacked joint involvement but all members displayed hematologic systemic involvement, with higher rates of renal, cutaneous, and systemic manifestations. C4 encompassed patients with joint and hematologic involvement, displaying the highest ESSDAI scores. The positivity rates of antibodies, immunological parameters, and inflammatory markers exhibited significant differences among the groups. Furthermore, notable variances were observed in the expression of peripheral blood transcriptomic modules among these groups., Conclusion: In this cohort study, we summarized the clinical characteristics of Chinese patients with pSS and identified four distinct subgroups of pSS based on systemic involvement, revealing clinical and molecular disparities that unveil distinct pathobiological endotypes. Our findings hold significant implications for clinical management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Different human leukocyte antigen (HLA) genotypes have been known to be associated with the risk of development of Sjögren's syndrome in different populations, but this association has never been reported in Taiwan. We enrolled 1044 subjects (673 patients, 371 controls) and tested their HLA-DR genotypes. We found an increased risk of Sjögren's syndrome in patients carrying HLA-DR8. DR1 and DR14 were associated with increased risk of eye involvement (uveitis, scleritis or optic neuritis), while DR15 was associated with increased risk of interstitial lung disease. DR8 was associated with increased risk of formation of multiple antibodies: anti-Ro, rheumatoid factor and antinuclear antibodies (ANA) reaching titer 1:80 or above. DR9 was associated with decreased risk of formation of anti-La antibodies and increased risk of formation of antithyroglobulin antibodies. DR10 was associated with risk of formation of anticyclic citrullinated peptide (anti-CCP) antibodies, and DR11 was associated with increased risk of formation of anti-La antibodies. Oral ulcer was found to be negatively associated with anti-Ro antibodies and with anti-ENA antibodies. Skin lesions were associated with ANA antibody titer elevation to 1:80 or above. Malignancies of any kind were associated with the presence of cryoglobulin. Females were more likely to be diagnosed at a younger age than males. There was no statistically significant relationship between HLA-DR genotype and age at disease diagnosis. In patients with Sjögren's syndrome in Taiwan, the presence of HLA-DR8 appeared to be a risk factor. In addition, we found several associations between HLA-DR genotype, clinical presentation, and autoantibody status among them., (© 2024 The Author(s). The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Objective: Mechanisms underpinning clinical evolution to systemic lupus erythematosus (SLE) from preceding antinuclear antibodies (ANA) positivity are poorly understood. This study aimed to understand blood immune cell transcriptional signatures associated with subclinical ANA positivity, and progression or non-progression to SLE., Methods: Bulk RNA-sequencing of peripheral blood mononuclear cells isolated at baseline from 35 ANA positive (ANA+) subjects with non-diagnostic symptoms was analysed using differential gene expression, weighted gene co-expression network analysis, deconvolution of cell subsets and functional enrichment analyses. ANA+ subjects, including those progressing to classifiable SLE at 12 months (n=15) and those with stable subclinical ANA positivity (n=20), were compared with 15 healthy subjects and 18 patients with SLE., Results: ANA+ subjects demonstrated extensive transcriptomic dysregulation compared with healthy controls with reduced CD4+naïve T-cells and resting NK cells, but higher activated dendritic cells. B-cell lymphopenia was evident in SLE but not ANA+ subjects. Two-thirds of dysregulated genes were common to ANA+ progressors and non-progressors. ANA+ progressors showed elevated modular interferon signature in which constituent genes were inducible by both type I interferon (IFN-I) and type II interferon (IFN-II) in vitro. Baseline downregulation of mitochondrial oxidative phosphorylation complex I components significantly associated with progression to SLE but did not directly correlate with IFN modular activity. Non-progressors demonstrated more diverse cytokine profiles., Conclusions: ANA positivity, irrespective of clinical trajectory, is profoundly dysregulated and transcriptomically closer to SLE than to healthy immune function. Metabolic derangements and IFN-I activation occur early in the ANA+ preclinical phase and associated with diverging transcriptomic profiles which distinguish subsequent clinical evolution., Competing Interests: Competing interests: LMC has received consultancy fees from UCB and Alumis. MYMY has received consultancy fees from Aurinia Pharmaceuticals and UCB and speaker fees from Alumis, Roche and Novartis. EMV has received consultancy fees from Roche, GSK, AstraZeneca, Aurinia Pharmaceuticals, Lilly and Novartis. He has also received research grants paid to his employer from Roche, AstraZeneca and Sandoz. All other authors have declared no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Background: Systemic lupus erythematosus (SLE) is the quintessential autoimmune disease, as it is characterized by hyperactivity of CD4 + T cells and subsequently drives lupus pathology. Follicular helper T (TFH) cells play an important role in B cell maturation and antibody production. However, which specific subset of cTFH cells drives B cell function and contributes to the development of anti-dsDNA antibodies and SLE pathogenesis remains unclear., Methods: Peripheral blood mononuclear cells from SLE patients with inactive (n = 11) and active (n = 21) were used to determine and detect frequencies and phenotypes of circulating TFH cells (cTFH), memory cTFH, and B cell subsets. The correlations among cTFH cell subsets and phenotypes, B cell subsets, anti-dsDNA autoantibodies, and clinical parameters were analyzed., Results: In subjects with active SLE, cTFH1 and cTFH17 cells were significantly expanded and activated. These expanded cTFH cells expressed memory phenotypes; cTFH1 cells were predominantly central memory (CM) type, while cTFH17 cells were largely effector memory (EM) type. Phenotyping B cell subsets in these patients showed increased frequencies of aNAV and DN2 B cells. Clinically, ICOS + cTFH1, ICOS + cTFH17 cells, and SLEDAI-2k scores were found to be correlated. Analysis of cTFH-B cell relationship revealed positive correlations among ICOS + cTFH1 cells, aNAV B cells, and anti-dsDNA antibodies. Activation of ICOS + cTFH17 cells was significantly related to the expansion of aNAV and DN2 B cells. The presence of CM cells in cTFH1 and cTFH17 subsets was correlated with aNAV and DN2 B cell frequencies., Conclusion: SLE cTFH cells were found to be polarized toward cTFH1 and cTFH17 cells; activation of these cTFH subsets was significantly associated with disease activity score, aNAV, DN2 B cell expansion, and anti-dsDNA antibody level. Thus, the interactions among cTFH1, cTFH17, and B cells likely contribute to the development of autoantibodies and the pathogenesis in SLE., (© 2024. The Author(s).)

Elevated numbers of antibody-secreting cells (ASCs) and anti-double-stranded DNA (anti-dsDNA) antibodies are found in nasal polyp (NP) tissue. The presence of anti-dsDNA IgG in tissue prospectively predicts recurrent NP but the characteristics of the source ASCs are unknown. Here, we investigated whether NP B cells expressing the extrafollicular marker EBI2 have increased propensity for autoantibody production and evaluated the molecular characteristics of NP ASCs. NPs showed increased frequencies of anti-dsDNA IgG and total IgG ASCs compared with tonsils, with more pronounced differences among EBI2+ cells. In NPs, EBI2+ cells were frequently double negative (IgD-CD27-) and ASCs. Single-cell RNA-Seq analysis of tonsils and NPs revealed substantial differences in B lineage composition, including differences in percentages of ASCs, germinal centers, proliferative cells, and non-ASCs. NPs exhibited higher expression of specific isotypes (IGHE, IGHA1, IGHA2, and IGHG4) and mature plasma genes, including SDC1 and XBP1, than tonsils. Gene Ontology biological processes indicated upregulated NF-κB and downregulated apoptosis pathways in NP ASCs. Together, these data indicate that NP EBI2+ ASCs secret increased total and anti-dsDNA IgG compared with those from tonsils and had molecular features of mature plasma cell differentiation.

Background: Systemic Lupus Erythematosus (SLE) has a strong genetic susceptibility, but little is known about the impact of diet on disease severity. The Western diet is typically deficient in magnesium (Mg), and given the immunomodulatory effects of Mg, we hypothesized that the low Mg intake increases disease risk and that increasing Mg intake would reduce severity of murine lupus. Here, we placed 12-week old MRL/lpr female lupus mice on a normal (Mg500) or a high (Mg2800) Mg diet for 9 weeks. Urine and blood were collected during the study for quantification of urinary albumin, BUN, anti-dsDNA antibodies, and immune phenotyping., Results: MRL/lpr lupus mice on high Mg2800 diet had significantly fewer skin lesions and less severe skin histology score, and reduced levels of pathogenic anti-dsDNA antibodies, compared with the Mg500 group (143.8±75.0 vs. 47.4±36.2 × 10 6 U/ml; P < 0.05). The high Mg2800 group had a nearly two-fold increase in the percentage of CD4 + FOXP3 + Treg cells compared to controls (19.9±5.4 vs. 11.4±5.5%; P < 0.05). Treg percentages inversely correlated with the concentration of anti-dsDNA. None of the mice developed arthritis during the observation period and there were no significant differences in weight, proteinuria, BUN or kidney histology., Conclusion: In conclusion, oral supplementation of Mg has a protective effect in a murine lupus model and may represent an inexpensive and safe adjuvant in the treatment of SLsE., (© 2024. The Author(s).)

Introduction: Connective tissue diseases (CTDs) are autoimmune diseases with multiorgan involvement. CTDs present with a heterogeneous clinical manifestation, especially in the cutaneous system. This study aimed to describe the common cutaneous manifestations of CTDs, to determine the association with antinuclear antibody (ANA) and other associated antibodies, and to assess the impact of CTDs on patient's quality of life (QOL)., Material and Methods: This was a cross-sectional study conducted among patients 18 years and above, with a confirmed diagnosis of systemic lupus erythematosus (SLE), systemic sclerosis, dermatomyositis, mixed connective tissue disease (MCTD) or overlap syndrome, who attended the rheumatology clinic at Hospital Sultan Ismail Johor Bahru between March 2023 to June 2023. The assessment instrument used was the Dermatology Quality Life Index (DLQI)., Results: Among 79 patients recruited, the majority were females with a mean age of 39 ± 14.5 years. Malay was the predominant ethnic group. SLE was the most common CTD (64 patients, 81%), followed by systemic sclerosis (six patients, 7.6%), overlap syndrome (four patients, 5.1%), dermatomyositis (four patients, 5.1%) and MCTD (one patient, 1.3%). All patients had cutaneous involvement with photodermatitis being the commonest cutaneous manifestation (65 patients, 82.3%). ANA and anti-double stranded DNA (dsDNA) positivity were significantly associated with SLE while anti-scl70 and anti-centromere antibodies (ACA) were strongly associated with systemic sclerosis (p < 0.05). The presence of anti-dsDNA and antiscl70 were significantly associated with renal involvement and interstitial lung disease (ILD) respectively (p < 0.05). CTD had a moderate effect on patient's QOL., Conclusion: Photosensitivity was the commonest cutaneous manifestation among CTD patients. ANA was positive in the majority of SLE patients. The presence of anti-dsDNA was significantly associated with lupus nephritis, while anti-scl70 and ACA were strongly associated with systemic sclerosis and ILD. CTD had a moderate effect on patient's QOL.

Background: There have been only few reports on Rhupus syndrome with severe visceral involvement. Moreover, there was little consensus regarding its treatment. Belimumab is one of the options for treating this disease. For patients with clinical symptoms and elevated levels of anti CCP antibodies and anti-double stranded DNA antibodies, and it suggests Rhupus syndrome. After effective treatment, the decrease in levels of anti CCP antibodies and anti-double stranded DNA (ds-DNA) antibodies can effectively delay the progression of the disease and protect target organs., Methods: We used a chemiluminescence instrument, (Yahuilong; Shenzhen, China), to measure the changes in CCP and dsDNA before and after treatment., Results: Prior to treatment, the patient presented with symptoms of rheumatoid arthritis and systemic lupus erythematosus. Her laboratory tests showed dsDNA (214 IU/mL) and CCP level of ˃ 3,000 U/mL. After treatment with belimumab, the clinical symptoms were significantly relieved, and the patient's CCP IgG level decreased to 263.5 U/mL. A blood test found that her anti-dsDNA was negative., Conclusions: CCP and dsDNA can serve as indicators for the diagnosis and treatment of Rhupus syndrome.

Objective: Autoantibodies and autoimmune diseases after SARS-CoV-2 infection are widely reported. Given evolving variants, milder infections, and increasing population vaccination, we hypothesized that SARS-CoV-2 infection earlier in the pandemic would be associated with more autoimmune connective tissue disease (CTD) symptoms and immunologic abnormalities., Methods: Patients ≥18 years old with COVID-19 3/1/2020-8/15/2022 completed the CTD Screening Questionnaire and were tested for 27 autoimmune serologies, SARS-CoV-2 serologies, cell-bound complement activation products (CB-CAPs), and T and B lymphocyte immunophenotypes by flow cytometry. We assessed relationships between symptoms, serologies, and immunophenotypes in earlier (3/1/2020-1/31/2021) vs. later (2/1/2021-8/15/2022) periods, with different predominating SARS-CoV-2 viruses., Results: 57 subjects had earlier and 23 had later pandemic COVID-19. 35 % of earlier vs. 17 % of later pandemic patients had CTD symptoms (p 0.18). More patients were antinuclear antibody (ANA) positive (44 % vs. 13 %, p 0.01) and had lupus anticoagulant (11 % vs. 4 %, p 0.67). After adjustment for age, race, and sex, earlier (vs. later) COVID-19 was associated with increased ANA positivity (OR 4.60, 95%CI 1.17, 18.15). No subjects had positive CB-CAPs. T and B cell immunophenotypes and SARS-CoV-2 serologies did not differ by group. In heatmap analyses, higher autoantibody variety was seen among those with infection in the early pandemic., Conclusion: In this sample, having COVID-19 infection in the earlier (pre-2/1/2021) vs. later pandemic was associated with more CTD symptoms, ANA positivity, and autoantibody reactivities. Earlier SARS-CoV-2 variants circulating in a less vaccinated population with less natural immunity may have been more immunogenic., Competing Interests: Declaration of competing interest Roberta Alexander is a former employee and shareholder of Exagen Inc. May Choi is the Associate Director of MitogenDx. Dr. Sparks has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB unrelated to this work. Dr. Solomon receives salary support through unrelated research contracts to Brigham and Women's Hospital from CorEvitas, Janssen, and Novartis. Dr. Costenbader acknowledges the following: Amgen (Consultant, Grant/Research Support); AstraZeneca (Grant/Research Support); Bristol-Myers Squibb (BMS) (Consultant); Cabaletta Bio (Consultant); Eli Lilly (Consultant); Exagen Inc. (Grant/Research Support); Gilead (Grant/Research Support); GlaxoSmithKline (GSK) (Consultant, Grant/Research Support); Janssen (Consultant, Grant/Research Support). The funders had no role in the decision to publish or preparation of this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Autoantibodies directed against the intracellular protein bicaudal D2 (BICD2) have been identified as a specific marker of systemic sclerosis (SSc). Since autoantibodies are of value in predicting disease onset and identifying meaningful clinical subsets, as well as having prognostic value, this study aimed to establish the prevalence of BICD2 autoantibodies (anti-BICD2) in a cohort of patients with connective tissue disease and healthy controls., Method: In this cross-sectional study, 363 patients with connective tissue disease (121 SSc, 141 systemic lupus erythematosus, 101 myositis, and 100 blood donors) were tested for the presence of anti-BICD2. All SSc patients were tested for specific anti-nuclear antibodies (ANAs), and clinical and laboratory associations were evaluated in the SSc patients, stratified by anti-BICD2 status., Results: In the SSc cohort, 35 patients had autoantibodies directed against BICD2. The specificity of anti-BICD2 in SSc patients was 96.5%; however, the sensitivity was only 28.9%. Anti-BICD2 and centromere autoantibodies were present together in 91% of the anti-BICD2-positive SSc patients, and in none of the cases was anti-BICD2 the only antibody present. Anti-BICD2-positive patients had lower forced expiratory volume in 1 s (FEV 1 ) (p = 0.01) and lower carbon monoxide transfer coefficient (K CO ) (p = 0.01) than anti-BICD2-negative SSc patients, but they had higher forced vital capacity (p = 0.03)., Conclusion: Autoantibodies against BICD2 were highly specific for SSc patients. Reduced FEV 1 and K CO in anti-BICD2-positive patients may indicate that the presence of anti-BICD2 is associated with altered lung function in an unknown pathophysiological manner, which awaits further elucidation.

Background: Guillain-Barré syndrome (GBS), an acquired immune-mediated autoimmune disorder affecting the peripheral nervous system (PNS), is associated with autoimmunity. The presence of autoantibodies in the blood is an important feature of autoimmune diseases. Herein, we explored the distribution characteristics of the antinuclear antibodies (ANAs) in GBS and the correlation between ANAs and disease severity., Materials and Methods: We retrospectively analyzed the clinical data of 170 GBS patients. According to ANAs, GBS patients were divided into ANAs positive and negative groups. The clinical characteristics of these two groups were compared. The distribution difference was also compared between male and female GBS patients. In addition, all enrolled patients were divided into more severe group and milder group according to whether the Hughes score at nadir ≥ 3 or not. Gender, age, and ANAs were compared between the two groups., Results: In this study, the positive rate of ANAs was 27.1 % in 170 GBS patients, among which anti-SSA-52/Ro52 antibody and antimitochondrial antibody M2 made up the largest proportion. In the ANAs positive group, GBS patients had longer days of hospitalization, more respiratory function involvement, and higher level of CSF IgG than the ANAs negative group. Compared to the ANAs negative group, Medical Research Council (MRC) scores on admission and at nadir were lower, and Hughes functional Grading Scale (HFGS) scores on admission and at nadir were higher in GBS patients with ANAs positive group. Erasmus GBS Respiratory Insufficiency Score (EGRIS) in ANAs positive GBS patients group was significantly higher than ANAs negative group. Gender had no effects on the distribution of ANAs in GBS patients. Moreover, we found that the anti-SSA-60 antibodies and age were positively correlated with GBS severity. In addition, in the anti-SSA-60 antibody positive group, GBS patients had longer days of hospitalization, more respiratory function involvement, higher HFGS scores on admission/at nadir, and lower MRC scores at nadir compared with the anti-SSA-60 antibody negative group., Conclusion: Anti-SSA-52/Ro52 antibody and antimitochondrial antibody M2 were the most common ANAs in GBS patients. Anti-SSA-60 antibodies and age positively correlated with GBS severity. Positive anti-SSA-60 antibodies and age were independent predictors of GBS patient severity., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Whole-exome sequencing of two unrelated kindreds with systemic autoimmune disease featuring antinuclear antibodies with IgG4 elevation uncovered an identical ultrarare heterozygous TNIP1 Q333P variant segregating with disease. Mice with the orthologous Q346P variant developed antinuclear autoantibodies, salivary gland inflammation, elevated IgG2c, spontaneous germinal centers and expansion of age-associated B cells, plasma cells and follicular and extrafollicular helper T cells. B cell phenotypes were cell-autonomous and rescued by ablation of Toll-like receptor 7 (TLR7) or MyD88. The variant increased interferon-β without altering nuclear factor kappa-light-chain-enhancer of activated B cells signaling, and impaired MyD88 and IRAK1 recruitment to autophagosomes. Additionally, the Q333P variant impaired TNIP1 localization to damaged mitochondria and mitophagosome formation. Damaged mitochondria were abundant in the salivary epithelial cells of Tnip1 Q346P mice. These findings suggest that TNIP1-mediated autoimmunity may be a consequence of increased TLR7 signaling due to impaired recruitment of downstream signaling molecules and damaged mitochondria to autophagosomes and may thus respond to TLR7-targeted therapeutics., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that primarily affects young women and causes a wide range of inflammatory manifestations. The hallmark of SLE is the production of antibodies to components of the cell nucleus (antinuclear antibodies [ANAs]). These antibodies can bind to DNA, RNA, and protein complexes with nucleic acids. Among ANAs, antibodies to DNA (anti-DNA) are markers for classification and disease activity, waxing and waning disease activity in many patients. In the blood, anti-DNA antibodies can bind to DNA to form immune complexes with two distinct roles in pathogenesis: (1) renal deposition to provoke nephritis and (2) stimulation of cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors. These sensors are part of an internal host defense system in the cell cytoplasm that can respond to DNA from infecting organisms; during cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors. The formation of immune complexes requires a source of extracellular DNA in an immunologically accessible form. As shown in in vivo and in vitro systems, extracellular DNA can emerge from dead and dying cells in both a free and a particulate form. Neutrophils undergoing the process of NETosis can release DNA in mesh-like structures called neutrophil extracellular traps. In SLE, therefore, the combination of ANAs and immunologically active DNA can create new structures that can promote inflammation throughout the body as well as drive organ inflammation and damage., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Maternal autoimmune disease is the most common cause of congenital heart block (CHB), a rare illness characterized by fibrosis and calcification of the fetal atrioventricular (AV) node due to maternal autoantibodies anti-SSA/Ro and anti-SSB/La. We report the full autopsy and clinical information on a female neonate with high degree AV block and calcification in the AV node, atrial approaches to the AV node, and both right and left bundle branches, born to a 27-year-old female with subclinical autoimmune disease., Competing Interests: Declaration of competing interest All authors have declared there are no conflicts of interest. There are no relationships with industry. This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Sjögren disease (SjD) diagnosis often requires either positive anti-SSA antibodies or a labial salivary gland biopsy with a positive focus score (FS). One-third of patients with SjD lack anti-SSA antibodies (SSA-), requiring a positive FS for diagnosis. Our objective was to identify novel autoantibodies to diagnose 'seronegative' SjD., Methods: IgG binding to a high-density whole human peptidome array was quantified using sera from SSA- SjD cases and matched non-autoimmune controls. We identified the highest bound peptides using empirical Bayesian statistical filters, which we confirmed in an independent cohort comprising SSA- SjD (n=76), sicca-controls without autoimmunity (n=75) and autoimmune-feature controls (SjD features but not meeting SjD criteria; n=41). In this external validation, we used non-parametric methods for binding abundance and controlled false discovery rate in group comparisons. For predictive modelling, we used logistic regression, model selection methods and cross-validation to identify clinical and peptide variables that predict SSA- SjD and FS positivity., Results: IgG against a peptide from D-aminoacyl-tRNA deacylase (DTD2) bound more in SSA- SjD than sicca-controls (p=0.004) and combined controls (sicca-controls and autoimmune-feature controls combined; p=0.003). IgG against peptides from retroelement silencing factor-1 and DTD2 were bound more in FS-positive than FS-negative participants (p=0.010; p=0.012). A predictive model incorporating clinical variables showed good discrimination between SjD versus control (area under the curve (AUC) 74%) and between FS-positive versus FS-negative (AUC 72%)., Conclusion: We present novel autoantibodies in SSA- SjD that have good predictive value for SSA- SjD and FS positivity., Competing Interests: Competing interests: SMcC declares consulting for Novartis, Horizon, Target RWE, Otsuka/Visterra, Kiniksa, BMS and iCELL., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Anti-Ro-52 antibodies have been associated with interstitial lung disease (ILD) in various autoimmune diseases. However, their role in ILD among patients with idiopathic inflammatory myopathies (IIMs) is relatively underexplored. This study aimed to investigate the association between anti-Ro-52 antibodies and the occurrence of ILD in individuals with IIMs., Methods: This retrospective observational study included 604 patients who underwent myositis autoantibody testing between July 2018 and January 2021 at our hospital and were diagnosed with either IIMs or IIM-mimics. Comparative analyses were conducted between IIMs and IIM-mimics, as well as within the IIM group between cases with and without ILD. Logistic regression or Firth's logistic regression analyses were employed to assess the risk of ILD development in different IIM subgroups and myositis antibody categories., Results: This study included 190 patients with IIM and 414 patients with IIM-mimics. Patients with IIM demonstrated higher incidence of ILD, concurrent autoimmune disease, and a greater likelihood of various myositis autoantibodies when compared to the IIM-mimics group. Within the IIM patient cohort, those with ILD exhibited a later age of onset of IIM, an increased mortality rate, and a more frequent presence of anti-aminoacyl-tRNA synthetase (ARS) antibodies compared to those without ILD. The presence of any myositis-specific antibody (MSA) was associated with a six-fold increased risk of ILD, while dual positivity for MSA and anti-Ro-52 antibodies conferred a twenty-fold risk. Anti-ARS antibodies carried a 14-fold increased risk of ILD, which escalated to 38-fold in cases of dual positivity for anti-ARS and anti-Ro-52 antibodies. Anti-Ro-52 antibodies alone increased the risk eight-fold., Conclusions: Among patients with IIM, the presence of ILD was linked to higher mortality. Certain autoantibodies, notably anti-ARS and anti-Ro-52 antibodies, were associated with an increased risk of ILD. The greatest risk of ILD was observed in cases of dual positivity for anti-ARS and anti-Ro-52 antibodies., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) is recognized as a prevalent autoimmune disorder characterized by a multifaceted pathogenesis potentially influenced by a combination of environmental factors, genetic predisposition, and hormonal regulation. The continuous study of immune system activation is especially intriguing. Analysis of blood samples from individuals with SLE reveals an abnormal increase in interferon levels, along with the existence of anti-double-stranded DNA antibodies. This evidence suggests that the development of SLE may be initiated by innate immunity. The presence of abnormal dsDNA fragments can activate DNA sensors within cells, particularly immune cells, leading to the initiation of downstream signaling cascades that result in the upregulation of relevant cytokines and the subsequent initiation of adaptive immune responses, such as B cell differentiation and T cell activation. The intricate pathogenesis of SLE results in DNA sensors exhibiting a wide range of functions in innate immune responses that are subject to variation based on cell types, developmental processes, downstream effector signaling pathways and other factors. The review aims to reorganize how DNA sensors influence signaling pathways and contribute to the development of SLE according to current studies, with the aspiration of furnishing valuable insights for future investigations into the pathological mechanisms of SLE and potential treatment approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background/aims: Autoimmune hepatitis (AIH) is characterized by the presence of auto-antibodies and high blood immunoglobulin G (IgG) levels. In this study, the line immunoassay (LIA) was designed to assess various autoantibodies., Methods: In total, 1371 patients who underwent autoimmune liver disease antibody testing between July 2019 and November 2022 were enrolled. Autoantibodies including antinuclear antibody (ANA) and anti-mitochondrial antibody (AMA) were tested, and clinical data were collected. Statistical analyses were performed by categorizing the data based on diagnosis and IgG quantification separately. A scoring system was applied to identify individuals with AIH. Patients were also classified into the AIH and non-AIH groups., Results: The positivity rate for ANA was 80.2% in the AIH group. The IgG-high group had a high likelihood of the presence of detectable autoantibodies, with anti-Ro-52 being the most frequently detected antibody using LIA. The "Consider AIH" and "AMA" groups had 3-4 times more patients in the IgG-high group than in the "Not Considered" group., Conclusions: Among autoantibodies, the prevalence of ANA was the highest. As per LIA results, anti-Ro-52 was the most prevalent. AIH cannot be diagnosed based on IgG levels alone and must be distinguished via autoantibody testing. Therefore, extensive testing, including autoantibodies, IgG, ANA, and liver enzyme levels, will help accurately diagnose AIH., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Yellow nail syndrome (YNS) is a rare, acquired condition, characterised by at least two of the three clinical criteria: nail changes, respiratory tract disease and lymphoedema. Currently, the aetiology of YNS remains unknown; however, it is believed to be caused by impaired lymphatic drainage. Currently, there remain no definitive treatment options available and no prospective trials evaluating this. Management includes supportive care and symptomatic treatment. The presence of YNS has been described alongside various conditions, including autoimmune diseases, malignancies and drug exposures. To strengthen the literature on this topic, we present the case of a female patient with a history of anti-SSA and anti-SSB positive primary Sjögren's syndrome, who developed YNS in the immediate postpartum period., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by a variety of both signs and symptoms; it mainly affects women of childbearing age, with an estimated prevalence of 24/100,000 people in Europe and North America. SLE is often described as an antibodies-driven disease as its clinical manifestations are usually associated with the presence or the absence of specific antibodies., Objectives: To evaluate clinical manifestations in patients with SLE and to assess the relationship with the presence of specific antibodies by using real-world data., Methods: A retrospective study was performed; the 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus were used to classify patients with SLE. Data concerning serological profiles (which included Antinuclear antibodies - ANA, anti dsDNA, anti-Ro/SS-A, anti-La/SS-B, anti-Smith) were gathered along with medical records of clinical manifestations. Complement levels were also tested for possible clinical correlations. χ² or Fisher's exact tests were utilized to establish associations between autoantibodies and symptoms. The odds ratios (OR) and their 95% confidence intervals (CI) were computed. No correction was made for multiple testing; only a p-value 0.01 ≤ was considered significant., Results: One-hundred and twenty-seven patients (n=127, mean age 53.43 ± 14.02) were enrolled in this study. Anti-dsDNA antibodies were found to be statistically significant for both malar rash and proteinuria; anti-Ro/SSA antibodies showed an association with photosensitivity and pericarditis; furthermore, a strong association was found between anti-Ro antibodies and proteinuria, but only if anti-dsDNA antibodies were present as well. Patients who tested positive for anti-La/SSB antibodies correlated with a threefold increase in the risk of developing pericarditis. Lastly, anti-Smith appeared to be associated with NPSLE as well as an increased risk for both autoimmune hemolytic anemia and thrombocytopenia., Conclusions: In our study, many associations confirmed those found in previous studies; however, new relationships between antibodies and clinical manifestations were found thus indicating the need for additional evaluations to assess these correlations further., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nicola, Borrelli, Corradi, Lo Sardo, Badiu, Romito, Rashidy, Quinternetto, Mazzola, Meli, Saracco, Vitali, Cosseddu and Brussino.)

Objectives: To study the correlation of anti-C1q antibodies with active systemic lupus erythematosus (SLE) and lupus nephritis (LN) in children, as well as their diagnostic value for active SLE and LN., Methods: A retrospective selection of 90 hospitalized children with SLE at the Children's Medical Center of Second Xiangya Hospital, Central South University from January 2016 to March 2019 as the SLE group, all of whom were tested for anti-C1q antibodies. A control group was formed by collecting 70 hospitalized children with other autoimmune diseases (OAD) during the same period. The differences in anti-C1q antibody levels were compared between two groups.The correlation of anti-C1q antibodies with various indicators of SLE and LN was analyzed, and the diagnostic value of anti-C1q in SLE and LN was evaluated., Results: The serum levels of anti-C1q antibodies in the SLE group were higher than those in the OAD group ( P <0.05). The SLE disease activity index score was positively correlated with anti-C1q antibodies ( r s =0.371, P <0.001) and positively correlated with anti-double-stranded DNA antibodies ( r s =0.370, P <0.001). The sensitivity and specificity of anti-C1q antibodies for diagnosing active SLE were 89.90% and 53.90%, respectively, with an area under the curve of 0.720 ( P <0.05) and a critical value of 5.45 U/mL. The sensitivity and specificity of anti-C1q antibody levels for diagnosing active LN were 58.50% and 85.00%, respectively, with an area under the curve of 0.675 ( P <0.05) and a critical value of 22.05 U/mL., Conclusions: Anti-C1q antibodies can serve as non-invasive biomarkers for evaluating the activity of SLE or predicting the activity of LN in children.

Objectives: Antinuclear antibodies (ANA) of the IgE-type have been described in several connective tissue disorders (CTD) but not yet in systemic sclerosis (SSc). Aim of the study was, therefore, to establish an ELISA for the demonstration of IgE-autoantibodies to topoisomerase-I (topo-I) and the centromeric proteins A and B (CENP-A/B), to assess their prevalence and reactivity in SSc and to analyse their clinical relevance., Methods: One hundred fifty-one patients with SSc and 88 with CREST-syndrome, 291 patients with other CTD, and 23 patients with fibromyalgia syndrome (FM) as a control collective were included into the study. Patients' sera were analysed by an in-house-ELISA for IgE autoantibodies against topo-I and CENP-A/B using recombinant antigens. Patients were assessed for median Rodnan skin score(mRSS), different organ and cutaneous manifestations., Results: Of the patients with CREST syndrome, 67% had IgE-anti-CENP-A- and 77% IgE-anti-CENP-B-antibodies. IgE-anti-topo-I antibodies were found in 56% of patients with SSc. Prevalence and reactivity were significantly higher in CREST and SSc, respectively, than in other CTD or FM. IgE-reactivity strongly correlated with IgG-antibody reactivity. In CRESTsyndrome, IgE-anti-CENP-A (but not CENP-B)-antibodies were significantly higher and more prevalent in patients with skin ulcers, high mRSS, and more than four organ manifestations. They did not correlate with blood eosinophil counts. In contrast, for IgE-anti-topo-I antibodies no correlation with clinical manifestations was observed., Conclusions: IgE-autoantibodies against CENP-A/B and topo-I occur in SSc underlining the concept that SSc may be a T helper cell type 2 mediated disease. IgE-anti-CENP-A-antibodies correlated with disease activity, but this has to be confirmed in larger studies.

The relevance of the problem of immunoinflammatory rheumatic diseases (IIRD) for modern medicine is determined by their high prevalence in the population, the difficulty of early diagnosis, the rapid development of disability and poor life prognosis. Recent data on the significance of anti-DFS70 have opened up new possibilities for optimizing the step-by-step diagnosis of IIRD. The detection of these antibodies can help in the interpretation of a positive result for antinuclear antibodies (ANA) by indirect immunofluorescence assay on HEp-2 cells (IIFA-HEp-2) in the absence of autoantibodies specific for IIRD. Detection of anti-DFS70 in antinuclear factor (ANF) seropositive patients without clinical and/or serological markers characteristic of a certain disease from the IIRD group can be considered as a potential marker that excludes this group of diseases., (© 2024. Pleiades Publishing, Ltd.)

Background: The examination of anti-double stranded DNA (ds-DNA) IgG antibody is of great significance for the diagnosis, differential diagnosis, assessment of disease activity, and prognosis of disease recurrence in SLE., Methods: We used a chemiluminescence method to detect ds-DNA IgG and found that the levels of ds-DNA IgG antibody in the patient's serum were significantly increased and the indirect immunofluorescence (IIF) test result was negative. Laboratory tests show that the patient's RF level far exceeds the upper limit of their reference range., Results: RF 110.6 IU/mL, ds-DNA IgG 753 IU/mL; After PEG6000 treatment, the RF was 108.7 IU/mL, and then the ds-DNA IgG was measured at 23.5 IU/mL., Conclusions: The RF IgM subtype is the main cause of RF interference in IgG antibody detection, mainly due to the binding of the Fc region of RF to the Fab segment of IgG. Combining with capture antibodies and labeled antibodies leads to the formation of non-specific detection signals, or directly reacting with the detected substance, resulting in false positive test results.

Objectives: The predominant determinant of an unfavorable prognosis among Systemic Lupus Erythematosus (SLE) patients resides in the irreversible organ damage. This prospective cohort study aimed to identify the additional value of anti-nucleosome antibodies on organ damage accumulation in SLE patients., Methods: Based on the Chinese SLE Treatment and Research group (CSTAR) registry, demographic characteristics, autoantibodies profiles, and clinical manifestations were collected at baseline. Follow-up data were collected by reviewing clinical records., Results: Of 2481 SLE patients with full follow-up data, 663 (26.7%) were anti-nucleosome antibodies positive and 1668 (68.0%) were anti-dsDNA antibodies positive. 764 (30.8%) patients developed new organ damage during a mean follow-up of 4.31 ± 2.60 years. At baseline, patients with positive anti-nucleosome antibodies have a higher rate of lupus nephritis (50.7% vs 36.2%, p < .001). According to the multivariable Cox regression analysis, both anti-nucleosome (HR = 1.30, 95% CI, 1.09-1.54, p < .001) and anti-dsDNA antibodies (HR=1.68, 95% CI, 1.38-2.05, p < .001) were associated with organ damage accumulation. Anti-nucleosome (HR = 2.51, 95% CI, 1.81-3.46, p < .001) and anti-dsDNA antibodies (HR = 1.69, 95% CI, 1.39-2.06, p < .001) were independent predictors for renal damage. Furthermore, the combination of the two antibodies can provide more accurate information about renal damage in overall SLE patients (HR = 3.19, 95% CI, 2.49-4.10, p < .001) and patients with lupus nephritis at baseline (HR = 2.86, 95% CI, 2.29-3.57, p < .001)., Conclusion: Besides anti-dsDNA antibodies, anti-nucleosome antibodies can also provide information about organ damage accrual during follow-up. The ability of co-positivity of anti-nucleosome and anti-dsDNA antibodies in predicting renal damage may lead to additional benefits in the follow-up of these patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: We aimed to investigate the prevalence of skin disease among patients with systemic lupus erythematosus (SLE) and determine whether LE skin disease had clinical or serologic correlates with SLE., Methods: We reviewed records of 335 patients with SLE (seen at Mayo Clinic, Rochester, Minnesota, USA) and abstracted skin manifestations, fulfilled mucocutaneous SLE criteria, and clinical and serologic parameters., Results: Of the 231 patients with skin manifestations, 57 (24.7%) had LE-specific conditions, 102 (44.2%) had LE-nonspecific conditions, and 72 (31.2%) had both. LE skin disease was associated with photosensitivity, anti-Smith antibodies, and anti-U1RNP antibodies (all P < 0.001). Patients without LE skin disease more commonly had elevated C-reactive protein levels (P = 0.01). Patients meeting 2-4 mucocutaneous American College of Rheumatology criteria less commonly had cytopenia (P = 0.004) or anti-double-stranded DNA antibodies (P = 0.004). No significant associations were observed for systemic involvement (renal, hematologic, neurologic, and arthritis) when comparing patients with or without LE skin involvement. LE skin involvement was not significantly associated with internal SLE disease flare, number of medications, or overall survival., Conclusions: LE skin disease commonly occurs in patients with SLE. The presence of LE skin disease had no mitigating impact on the severity of SLE sequelae, disease flares, number of medications, or overall survival., (© 2024 Mayo Foundation for Medical Education and Research. International Journal of Dermatology published by Wiley Periodicals LLC on behalf of the International Society of Dermatology.)

Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti-OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti-OX40L on immunosuppression in keyhole limpet hemocyanin-immunized C57BL/6J mice. In vitro treatment of anti-OX40L in CD4 + T and B220 + B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti-OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti-dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T-follicular helper cells (Tfh). In keyhole limpet hemocyanin-immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti-OX40L group. Anti-OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti-OX40L downregulated CD4 + T-cell differentiation into Th1 and Tfh cells and upregulated CD4 + T-cell differentiation into regulatory T cells in vitro. Furthermore, anti-OX40L inhibited toll-like receptor 7-mediated differentiation of antibody-secreting cells and antibody production through the regulation of the SPIB-BLIMP1-XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE., (© 2024 Wiley‐VCH GmbH.)

Objectives: Systemic sclerosis (SSc)-specific autoantibodies allow the diagnosis and predict the prognosis of SSc patients with different clinical characteristics. The aim of this study was to describe new SSc-related autoantibodies by a novel protein immunoprecipitation (IP) assay., Methods: Serum samples and clinical data were collected from 307 SSc patients. Antinuclear autoantibodies were tested in all patients by indirect immunofluorescence (IIF) on HEp-2 cells. SSc-specific autoantibodies were evaluated with a commercial immunoblot and chemiluminescence immunoassay, and traditional RNA-IP. Patients negative for all these autoantibodies (n = 51) were further tested with a non-radioactive protein IP assay. Protein bands detected on SDS-PAGE were then analysed by mass spectrometry (MS) and confirmed by western blot (WB). Additional 56 patients with nucleolar pattern by IIF were tested by protein IP-WB., Results: Five patients who underwent protein IP testing showed a 110-115kDa molecular weight band on SDS-PAGE and a homogeneous nucleolar pattern by IIF. MS identified the bands as nuclear valosin-containing protein-like (NVL). An additional positive patient was detected by IP-WB. As compared with the remaining 101 negative patients, anti-NVL positive patients showed a greater prevalence of calcinosis (100% vs 18.9%, P < 0.001), and cancer (66.7% vs 8.9%, P = 0.002), with a particular association with synchronous cancer (OR = 16.3; P = 0.024)., Conclusion: We identified NVL as a new autoantibody target by a novel protein IP assay in SSc patients with a homogeneous nucleolar IIF pattern, testing negative for all known SSc-specific autoantibodies by commercial assays and RNA IP. Anti-NVL identifies a new clinical phenotype, characterized by calcinosis and cancer., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Systemic sclerosis (SSc) often overlaps with other autoimmune diseases. More complex autoantibody profiles may be observed in SSc overlap syndrome (SSc OS). To determine the clinical significance of autoantibodies in SSc OS and classify the patients more accurately for better disease assessments, we analysed the correlation between serological profiles, organ involvements and outcomes., Methods: A retrospective cohort study was conducted in Peking University People's Hospital. Chi-square tests and analysis of variance were used to analyse univariate comparisons of clinical symptoms, organ involvement and laboratory indicators. Survival was evaluated using Cox proportional hazards model., Results: Among 141 cases, anti-Ro-52 was the most common antibody, followed by anti-centromere antibody and anti-Scl-70 antibody. We analysed the correlation between autoantibodies and vital organ damage in SSc OS patients, and compared the differences across four SSc OS subgroups (SSc SLE, SSc RA, SSc PM/DM and SSc SS) to demonstrate the correlation between autoantibodies and clinical characteristics and organ damage. Cox regression analysis showed that scleroderma renal crisis (SRC) ( p  = .004) and pulmonary arterial hypertension (PH) ( p  = .010) were independent risk factors for survival., Conclusions: Autoantibodies are associated with clinical features, organ involvement and prognosis in SSc OS patients. Anti-Scl-70 antibody is associated with interstitial lung disease (ILD) and SRC, while ACA is a protective factor of ILD. SRC and PH are risk factors associated with death.

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that causes a breakdown of immune tolerance. Current treatments mainly involve general immunosuppression, increasing the risk of infections. On the other hand, Bacillus Calmette-Guérin (BCG) has been investigated as a potential therapy for autoimmune diseases in recent years, prompting an ongoing investigation. This study aimed to evaluate the effect of BCG vaccination on early and late clinical presentation of SLE in a murine disease model. MRL/MPJ-Fas lpr mice were immunized with BCG or treated with PBS as a control. The progress of the disease was evaluated at 27 days post-immunization (dpi) (early) and 56 dpi (late). Clinical parameters and proteinuria were monitored. Blood samples were collected for measurement of antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), and cytokine determination was performed using ELISA. Samples collected from mice were analyzed by flow cytometry and histopathology. We observed a clinical improvement in BCG-treated mice, reduced proteinuria in the latter stages of the disease, and decreased TNF-α. However, BCG did not elicit significant changes in ANAs, anti-dsDNA, histopathological scores, or immune cell infiltration. BCG was only partially beneficial in an SLE mouse model, and further research is needed to determine whether the immunity induced by this vaccine can counteract lupus's autoimmune response.

Fetal autoimmune atrioventricular block (AVB) is a rare but potentially life-threatening condition. It results from the passage of maternal anti-SSA/Ro or Anti SSB/La auto-antibodies into the fetal circulation, leading to inflammation and fibrosis of the AV node and often to irreversible damage. Besides AVB, these antibodies can also cause cardiomyopathies, but there is no evidence linking them to tachyarrhythmias. We present the case of a patient with significant risk factors for fetal AVB: a prior history of hydrops fetalis , high anti-SSA/Ro antibody levels and hypothyroidism. In this case, the use of dexamethasone and intravenous immunoglobulin may have contributed to reversing the first-degree atrioventricular block detected at 19 weeks of gestation. Additionally, at 21 weeks, the fetus developed a tachyarrhythmia that needed treatment with flecainide. Soon after the birth, the newborn underwent ECG Holter and Wolff-Parkinson-White Syndrome (WPWS) was diagnosed. To our knowledge, the coexistence of fetal AVB and WPWS has never been described., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chícharo, Rebelo, Lopes, Saavedra, Paramés, Araújo, Cruz-Machado, Pinto and Capela.)

Objective: To clarify the impact of intravenous infusion of gamma globulin (IVIg) on antinuclear antibodies (ANAs) in children., Methods: A retrospective analysis was performed on the data of children with nonspecific autoantibody-related diseases whose antinuclear antibody (ANA) and autoantibody profiles were detected in our hospital from January to March 2022. A total of 108 patients with a clear history of IVIg infusion within 28 days composed the IVIg group, and 1201 patients without a history of IVIg infusion composed the non-IVIg group., Results: All patients in the IVIg group had either positive ANAs or positive autoantibodies. Anti-SSA, anti-Ro52 and anti-AMA Mi2 were the top three autoantibodies in the IVIg group. The proportions of patients who were positive for either of these three autoantibodies in the IVIg group were significantly greater than those in the non-IVIg group (all P<0.5). Spearman correlation analysis revealed that the signal intensities of anti-SSA and anti-Ro52 were negatively correlated with the number of days of ANA detection after IVIg infusion (P<0.05). Multiple logistic analyses revealed that a greater total dosage of IVIg, greater IVIg per kilogram of body weight, and fewer ANA detection days after IVIg infusion were independent risk factors for positive anti-SSA and anti-Ro52 results., Conclusions: It is recommended that if rheumatic diseases are suspected, ANA detection should be carried out beforeIVIg infusion. But for patients who are positive for at least one of these three autoantibodies after IVIg infusion, doctors should first consider adoptive antibodies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Zhou, Zhang, Wang, Yan, Wang, Tang and Luo.)

This study aims to analyze the clinical and immunologic features of SLE in Jordan, while also investigating the impact of age and gender on disease presentation. The study included 275 patients diagnosed with SLE. Data were collected through meticulous patient interviews and thorough examination of patient hospital records. The cohort exhibited a mean age of 36.8 ± 12.9 years, with an average disease duration of 7.0 ± 7.8 years. The mean age at diagnosis was 29.9 ± 12.1 years, and the female to male ratio was 7.8:1. The most frequently observed symptoms were arthralgia (90.2%), fatigue (80.7%), hematologic manifestations (62%), photosensitivity (60.7%), Raynaud's phenomenon (53.5%), and malar rash (50.9%). The frequencies of various autoantibodies were as follows: ANA (96.7%), anti-dsDNA (39.6%), anti-SSA/Ro (32.8%), anti-Sm (21.8%), anti-U1-RNP (20.6%), and anti-SSB/La (15.5%). Male patients tended to receive a diagnosis at a younger age and exhibited a higher likelihood of experiencing severe manifestations compared to females. Additionally, juvenile onset patients demonstrated an increased likelihood of fever, photosensitivity, myositis, and anti-dsDNA autoantibodies, while adult onset patients were more predisposed to having anti-Ro, anti-La, and RF autoantibodies. This study reveals that the most prevalent manifestations of SLE in the Jordanian cohort encompassed arthralgia, fatigue, and hematologic manifestations. The prevalence of alopecia and Raynaud's phenomenon exceeded that observed in other published cohorts, while arthritis and discoid rash were less frequently encountered. The study highlights that males are more susceptible to developing severe manifestations of SLE compared to females., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Interleukin-23 (IL-23) is a crucial cytokine implicated in chronic inflammation and autoimmunity, associated with various diseases such as psoriasis, psoriatic arthritis, and systemic lupus erythematosus (SLE). This study aimed to create and characterize a transgenic mouse model overexpressing human IL-23A (TghIL-23A), providing a valuable tool for investigating the pathogenic role of human IL-23A and evaluating the efficacy of anti-human IL-23A therapeutics., Methods: TghIL-23A mice were generated via microinjection of CBA × C57BL/6 zygotes with a fragment of the human IL23A gene, flanked by its 5'-regulatory sequences and the 3' untranslated region of human β-globin. The TghIL-23A pathology was assessed through hematologic and biochemic analyses, cytokine and antinuclear antibody detection, and histopathologic examination of skin and renal tissues. The response to the anti-human IL-23A therapeutic agent guselkumab was evaluated in groups of eight mixed-sex mice receiving subcutaneous treatment twice weekly for 10 weeks using clinical, biomarker, and histopathologic readouts., Results: TghIL-23A mice exhibited interactions between human IL-23A and mouse IL-23/IL-12p40 and developed a chronic multiorgan autoimmune disease marked by proteinuria, anti-double-stranded DNA antibodies, severe inflammatory lesions in the skin, and milder phenotypes in the kidneys and lungs. The TghIL-23A pathologic features exhibited significant similarities to those observed in human patients with SLE, and they were reversed following guselkumab treatment., Conclusion: We have generated and characterized a novel genetic mouse model of SLE, providing proof-of-concept for the etiopathogenic role of human IL-23A. This new model has a normal life span and integrates several characteristics of the human disease's complexity and chronicity, making it an attractive preclinical tool for studying IL-23-dependent pathogenic mechanisms and assessing the efficacy of anti-human IL-23A or modeled disease-related therapeutics., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a hyperactive immune system with multiple abnormalities in B-cell proliferation, antibody production, T-cell regulation, and immune complex (IC) formation. In humans, Immunoglobulin (Ig) G is found in four subclasses. IgG1-IgG4, which are distinguished by both structural and biological differences. Fab-arm Exchange (FAE), specific biases in the IgG4 response repertoire, and a decreased capacity to induce effector functions mediated by interactions in the fragment crystallizable (Fc) region are just a few of the distinctive characteristics of IgG4. The recent finding of the presence of double-stranded DNA (dsDNA) and antinuclear antibody (ANA)-IgG4 has raised attention to this IgG subclass and its possible role in SLE. IgG4 was previously believed to just have anti-inflammatory effects by inhibiting immune responses, but recent studies have shown that these antibodies can also play a role in the onset and development of some clinical disorders. To consider the clinical effects of IgG4 presence, it is necessary to discuss its characteristics, which could underlie the potential role it can play in SLE. Therefore, this study aimed to comprehensively review the role of IgG4 in SLE to elucidate the collective incidence of high IgG4 levels reported in some SLE patients., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objectives: Anti-SSA autoantibodies can be differentiated according to their antigenic target proteins as anti-Ro60 (60 kDa) or anti-Ro52 (52 kDa). Anti-SSA(Ro60) antibodies are clearly associated with connective tissue diseases (CTD), but the clinical significance of anti-SSA(Ro52) antibodies remains unclear. The aim of the present study was to analyse the disease phenotype of patients with anti-Ro52 and/or anti-Ro60 antibodies., Methods: A multicentre, cross-sectional study was carried out of positive anti-Ro52 and/or Ro60 antibodies patients followed at 10 Rheumatology centres from January 2018 until December 2021. Patients were categorised into 3 groups: group 1 (Ro52+/Ro60-); group 2 (Ro52-/Ro60+); group 3 (Ro52+/Ro60+). Antinuclear antibodies were evaluated by indirect immunofluorescence assay and further screened for anti-extractable nuclear antigen (ENA) antibodies. Demographicsand clinical data were compared between the 3 groups, by patients' medical chart review. Univariate analysis was performed and subsequently logistic regression was used to identify intergroup differences and calculate the odds ratio with a 95% confidence interval (95% CI)., Results: We included 776 patients [female: 83.1%; median age: 59 (46-71) years]. Groups 1, 2, and 3 comprised 31.1%, 32.6%, and 36.3% of the patients, respectively. Anti-Ro52 antibody alone was more frequently associated with non-rheumatic diseases, older age, and men (p<0.05). Among patients with CTD, the diagnosis of systemic lupus erythematosus is 3 and 2 times more prevalent in groups 2 and 3, respectively, than in group 1 [OR 2.8 (95% CI 1.60, 4.97), p<0.001; OR 2.2 (95% CI 1.28, 3.86), p<0.01]. In group 2, the diagnosis of undifferentiated CTD is more frequent than in the other groups. Group 1 was more frequently associated with inflammatory myositis than group 2 [OR 0.09 (95% CI 0.01, 0.33), p<0.001] or group 3 [OR 0.08 (95% CI 0.01, 0.29), p<0.001]. Group 1 was also more frequently associated with arthritis (p<0.01), interstitial lung disease (p<0.01), and myositis (p<0.01)., Conclusions: Anti-Ro52+ antibody alone is frequently found in patients with non-rheumatic diseases. In addition, anti-Ro52+ antibody is also prevalent in patients with CTD and associated with clinical phenotypes that are different from anti-Ro60+ antibody.

Anti-Golgi antibodies are uncommon antibodies that exhibit specific, polarized cytoplasmic staining on the Hep-2 substrate. The objective of our study was to identify the clinical and laboratory features associated with anti-Golgi antibodies. We examined 4.5 years of data from a Turkish tertiary hospital in this retrospective cohort analysis. The indirect immunofluorescence staining patterns, antinuclear antibody (ANA) titres and clinical data of all patients were obtained from the hospital record system. A total of 146,055 ANAs were detected, of which 224 patients (0.15%) exhibited anti-Golgi antibody staining. In total, 39.4% of diagnosed patients had autoimmune diseases (AIDs). Of the AIDs, 26 (46.4%) were rheumatoid arthritis (RA). This is a very high rate and another remarkable point is that 17 (65.3%) of these patients had seronegative RA. High-titre results (1 ≥ 1/320) were more common in patients with AID. Anti-Ro52 was prevalent in 50% of extractable nuclear antigen (ENA)-positive patients, making it a remarkable finding. The majority of individuals with high-titre anti-Golgi antibodies had AID, particularly RA. The majority of these patients also tested negative for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF). Finally, high-titre anti-Golgi antibodies may be an important serologic marker for seronegative RA in the Turkish population., (© 2024 The Scandinavian Foundation for Immunology.)

Background: Advanced atrioventricular block (AVB), that is, higher than second-degree Mobitz-1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti-Ro/Sjögren syndrome-related antigen A (SSA) antibodies cross-reacting with L-type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti-Ro/SSA-associated advanced AVBs in a large sample of young athletes., Methods and Results: A total of 2536 consecutive athletes aged <40 years without a history of cardiac diseases/interventions were enrolled in a cross-sectional study. Resting and exercise electrocardiography was performed, and those presenting any AVB were further evaluated by 24-hour Holter ECG. Athletes with second-degree AVBs and their mothers underwent anti-Ro/SSA testing. Moreover, purified immunoglobulin G from subjects with anti-Ro/SSA-positive and anti-Ro/SSA-negative advanced AVB were tested on L-type calcium current and L-type-calcium channel expression using tSA201 cells. The global prevalence of advanced AVB in the overall sample was ≈0.1%, but the risk considerably increased (2%) when intensely trained postpubertal male subjects were selectively considered. While none of the athletes with advanced AVB showed heart abnormalities, in 100% of cases anti-Ro/SSA antibodies were detected. Ex vivo experiments showed that immunoglobulin G from anti-Ro/SSA-positive but not -negative subjects with advanced AVB acutely inhibit L-type calcium current and chronically downregulate L-type-calcium channel expression., Conclusions: Our study provides evidence that advanced AVB occurs in young athletes, in most cases associated with anti-Ro/SSA antibodies blocking L-type calcium channels. These findings may open new avenues for immunomodulating therapies to reduce the risk of life-threatening events in athletes, avoiding or delaying pacemaker implantation.