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Proteomics among Immune Infertility and Miscarriage Patients: Identification of Biomarkers by Mass Spectrometry-based Protein Quantification Analysis

Objective: This study aimed to explore and compare the plasma proteomic profiles of women with immune infertility and miscarriage, with the goal of identifying differentially expressed biomarkers related to immune and metabolic regulation. Methods: Plasma samples were collected from 11 female participants, including 8 patients with immune infertility or miscarriage, and 3 healthy controls. mass spectrometry-based quantitative proteomics was performed to profile protein expression. Differentially expressed proteins were identified using predefined cut-offs (abundance ratio >1.5 or <0.67, p-value < 0.05, CV < 30%) and further analyzed by subgroup comparison. Results: A distinct proteomic imbalance was observed across groups. Endoplasmic reticulum aminopeptidase 2 (ERAP2) was markedly upregulated in patients with reproductive disorders, suggesting its involvement in immune dysregulation and its potential as a risk biomarker. Conversely, β-arrestin-1 was consistently downregulated in miscarriage cases, indicating a possible protective role in maintaining pregnancy. Other proteins related to immune regulation, metabolic and complement pathways, such as Nicotinamide phosphoribosyltransferase (NAMPT), All-trans-retinol dehydrogenase (ADH4), Complement factor H-related protein 2 (CFHR2), Translin, and Peptidyl-prolyl cis-trans isomerase FKBP1A, also showed differential expression, supporting the multifactorial nature of reproductive failure. Conclusions: This study demonstrates that specific plasma proteins-particularly ERAP2 and β-arrestin-1-may serve as biomarkers for reproductive failure. While limited by a small sample size and variation in treatment timing, these preliminary findings provide valuable insights into the proteomics of immune infertility and miscarriage. Future large-scale studies with functional validation are warranted to confirm these findings and explore their clinical applicability.

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Incidence of Common and Opportunistic Infections in Patients with Rheumatoid Arthritis and Psoriatic Arthritis Treated with Tofacitinib: A Retrospective Cohort Study in Taiwan

Objective: To investigate the incidence and clinical characteristics of common and opportunistic infections, particularly cryptococcal infection, in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) receiving tofacitinib therapy in Taiwan. Methods: This retrospective cohort study included patients treated with tofacitinib at a regional hospital in southern Taiwan between December 1, 2013 and November 30, 2023. Patients diagnosed with RA or PsA who had received tofacitinib for more than three months were eligible. Infection events were identified through systematic medical record review, and IRs were calculated per 100 person-years. Results: A total of 154 patients were enrolled, with a mean follow-up of 3.45 years. The most common infection was herpes zoster (HZ) (IR 3.58 ± 0.82 per 100 person-years), followed by UTI (IR 1.32 ± 0.50 per 100 person-years) and soft tissue infections (IR 1.13 ± 0.46 per 100 person-years). Cryptococcal infections were identified in three patients (IR 0.56 ± 0.33 per 100 person-years), which is higher than rates previously reported with other immunosuppressive agents. All cryptococcal cases occurred in older women concurrently receiving corticosteroids. Conclusion: HZ was the most common opportunistic infection among patients undergoing tofacitinib therapy. Although cryptococcosis was infrequent, its incidence rate was elevated relative to prior reports on other immunosuppressants. These findings demonstrate the importance of close monitoring for opportunistic infections, particularly in older female patients receiving concomitant corticosteroids.

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Epidemiology and Outcomes of Hospitalised Patients With Macrophage Activation Syndrome: A Nationwide Retrospective Study in Taiwan

Background: Macrophage activation syndrome (MAS), a secondary form of hemophagocytic lymphohistiocytosis (HLH), is a rare but life-threatening hyperinflammatory condition frequently associated with autoimmune diseases such as systemic lupus erythematosus and adult-onset Still's disease. Notably, population-based data on adult MAS remain limited, particularly in Asian populations. Objective: To describe the clinical characteristics, epidemiology, mortality, and treatment patterns of HLH/MAS in Taiwan by using a nationwide health database. Methods: We conducted a retrospective cohort study by using data from Taiwan's National Health Insurance Research Database from 2016 to 2018. Patients with HLH/MAS were identified using International Classification of Diseases, Tenth Revision, Clinical Modification codes. Demographic characteristics, comorbidities, treatments, and outcomes were analysed. Mortality and incidence rates were estimated using descriptive statistics and survival analyses. Results: A total of 651 patients with HLH/MAS were included. The median age was 48 years, and 51.8% of the patients were women. The annual prevalence rates of HLH/MAS were 0.99, 0.92, and 0.96 per 100,000 persons in 2016, 2017, and 2018, respectively. The overall mortality rate was 31.03% (95% confidence interval [CI], 27.5%-34.6%), with mortality increasing with age. Intensive care was required in 34.9% of cases. Corticosteroids were administered in 78.5% of patients, whereas intravenous immunoglobulin (IVIG) was used in only 14%. IVIG use was associated with higher all-cause and in-hospital mortality. Conclusion: This study highlights the substantial mortality burden of HLH/MAS in adults and suggests that IVIG treatment correlated with an increased rate of death, however, this finding likely reflects and indication bias. These findings underscore the need for early recognition, standardised treatment protocols, and further prospective studies in adult MAS populations. Limitations: ICD-based coding precluded HLH-2004 or HScore application, preventing reliable distinction of MAS from other secondary HLH, while absence of key data, incomplete drug capture, and observational design further limited causal interpretation.

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Temporal Trends in Fracture Risk Among Patients with Rheumatoid Arthritis A Retrospective Analysis of the Taiwan National Health Insurance Research Database

Objective: To evaluate long-term trends in osteoporotic fracture incidence and post-fracture mortality among rheumatoid arthritis (RA) patients compared with the general population. Methods: We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database (2003-2021). RA patients aged ≥50 years were followed for incident hip, vertebral, and radius/ ulna fractures. Standardized incidence ratios (SIRs) were calculated using general population rates. Post-fracture survival was assessed via Kaplan-Meier and Cox models, matching each RA patient with ten non-RA individuals by age, sex, fracture type, and calendar year. Results: Among 10,874 RA patients with fractures (85.3% female; mean age, 71.3 years), SIRs declined over time for hip (2.36 to 1.83) and vertebral (1.77 to 1.33) fractures but rose for radius/ulna (1.18 to 1.40). Female patients showed greater improvements. RA patients had significantly higher post-fracture mortality (HRs: vertebra 2.29; radius/ulna 1.60; hip 1.35). Conclusion: Despite declining fracture rates, RA patients remain at elevated fracture risk and mortality. Enhanced prevention and post-fracture care remain critical.

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Optimizing the Clinical Utility of a Myositis Line Blot Immunoassay: An Integrated Approach Combining Pre-test Clinical Assessment and Higher Titer Cut-offs in a Taiwanese Tertiary Center Cohort

Objectives: To evaluate the real-world diagnostic performance of a commercial myositis-specific (MSA) and myositis-associated (MAA) autoantibody line blot immunoassay (LIA) in a large Taiwanese cohort. We aimed to assess the association between the number of pre-test clinical domains prompting testing and the likelihood of an idiopathic inflammatory myopathies (IIM) diagnosis, and to determine the impact of applying higher titer cut-offs on the assay's diagnostic performance. Methods: This retrospective, single-center study included 486 patients who underwent MSA/MAA LIA testing at National Taiwan University Hospital in 2024. Patients were categorized as IIM, autoimmune diseases other than IIM, or controls based on clinical diagnosis. We performed a multivariable logistic regression analysis to assess the association between the number of testing indications (clinical domains) and an IIM diagnosis. The diagnostic performance of individual and pooled MSAs was evaluated using both the manufacturer's standard cut-off and a higher cut-off (titer ≥2+). Results: Of the 486 patients, 78 (16.0%) were diagnosed with IIM, 223 (45.9%) had other autoimmune diseases, and 185 (38.1%) were controls. After adjusting for age and sex, an increasing number of clinical domains was associated with a progressively higher likelihood of an IIM diagnosis (adjusted OR: 1 domain = 8.20; 2 domains = 11.75; ≥3 domains = 20.06, all p < 0.05) compared to an autoimmune screening reference group. Applying a higher titer cut-off (titer ≥2+) was associated with an increase in pooled specificity (from 0.826 to 0.931) and positive predictive value (from 0.441 to 0.632), alongside a decrease in sensitivity. Conclusions: For optimal use of the MSA/MAA LIA in our cohort, these results support careful patient selection guided by clinical suspicion and a semi-quantitative interpretation of titers, as higher titer cut-offs strengthened the diagnostic association for myositis specific autoantibodies.

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Cancer risk in patient with systemic lupus erythematosus and the impact on mortality: A single center cohort study

Background: Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by persistent inflammation, which can result in organ damage and various comorbidities, including cardiovascular disease and cancer. Due to inconsistent findings in previous studies on the link between SLE and cancer incidence, an updated analysis is necessary, especially with advancements in treatment and increased patient longevity. Methods: We conducted a retrospective, single-center cohort study involving 1,820 SLE patients at National Taiwan University Hospital. We evaluated cancer incidence and mortality rates from 2006 to 2022 and compared these with data from the general Taiwanese population. Results: Among the 1,820 SLE patients included in the study, 75 individuals (4.1%) were diagnosed with at least one malignancy. Compared to the general population, thyroid cancer showed a potentially increased risk (p = 0.09127), while breast cancer, despite being the most common malignancy in our cohort, had an incidence rate that was approximately half. However, neither of these differences reached statistical significance. A Poisson regression model, adjusting for age, revealed that a cancer diagnosis was independently associated with a significantly increased risk of mortality. Conclusion: Our findings indicate that the occurrence of different cancer types in SLE patients differs from that in the general population. The higher mortality rates among SLE patients with cancer emphasize the importance of prompt cancer screening and managing comorbidities.

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A Retrospective Study on the efficiency of SARS-CoV-2 Vaccination in Rheumatoid Arthritis patients receiving long-term rituximab

Background: Rituximab, an anti-CD20 monoclonal antibody that selectively depletes B cells, has been widely used in the treatment of rheumatoid arthritis (RA) over the past decade. However, immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination may be attenuated in patients receiving long-term rituximab therapy. This study aimed to evaluate the effectiveness of SARS-CoV-2 vaccination in RA patients treated with long-term rituximab. Methods: A retrospective analysis was conducted at the rheumatology clinics of Taipei Veterans General Hospital, Taiwan. RA patients who had received rituximab for more than five years between May 2022 and July 2023 were included. The incidence and outcomes of Coronavirus disease 2019 (COVID-19) infection were compared between vaccinated and unvaccinated patients. Results: A total of 51 patients were enrolled. Despite prolonged B-cell depletion, vaccinated patients had a significantly lower incidence of COVID-19 infection compared to unvaccinated patients (p = 0.041). Although hospitalization and mortality rates associated with COVID-19 infection were lower in the vaccinated cohort compared to the unvaccinated cohort, these differences did not achieve statistical significance (p = 0.157 and p = 0.095, respectively). Conclusion: SARS-CoV-2 vaccination is beneficial in RA patients receiving long-term rituximab therapy, as it significantly reduces infection rates and may also lower the risk of severe outcomes, including hospitalization and death.

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Intestinal Pseudo-obstruction in Patients with Systemic Lupus Erythematosus: A Systematic Review

Objective: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which gastrointestinal manifestations are uncommon but can be clinically significant. Intestinal pseudo-obstruction (IPO) is a rare, underrecognized complication. Delayed diagnosis often results in unnecessary surgical intervention, underscoring the need for greater awareness and clearer treatment strategies. We performed a systematic review to characterize the clinical spectrum, concomitant visceral smooth-muscle involvement, treatments, outcomes, and prognostic factors of SLE-related IPO. Methods: We systematically searched PubMed (January 1974-May 2024) for "intestinal pseudo-obstruction" AND "systemic lupus erythematosus," applying ACR-1997 or SLICC-2012 criteria plus clinical/radiologic IPO diagnosis, and pooled 149 patients (56 case reports; 61 PUMC; 32 SMU). Outcome categories were defined as: good = complete clinical response with durable stability; bad = recurrence or death. Mann-Whitney U and Fisher's exact tests assessed prognostic factors (p <0.05). Results: Patients were predominantly young women (median age 31.5 years; 92.9% female), with a median symptom duration of 30 days before diagnosis. IPO frequently co-occurred with other smooth muscle dysmotility syndromes, including uretero-hydronephrosis and biliary tract dilatation. High-dose glucocorticoids were the mainstay of induction therapy, but early use of cyclophosphamide was significantly associated with favorable outcomes (30.8% in good vs. 0% in bad outcome group, p=0.03). In contrast, maintenance azathioprine was associated with worse outcomes (11.5% in good vs. 42.9% in bad outcome, p=0.04). No demographic or serologic markers predicted prognosis. Conclusion: SLE-related IPO often clusters with other smooth muscle involvement and carries a high risk of relapse or death without aggressive treatment. Early recognition and prompt initiation of high-dose corticosteroids with cyclophosphamide may improve long-term outcomes and prevent surgical complications. These findings support a more intensive immunosuppressive approach in managing SLE-IPO.

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Epstein-Barr Virus-Positive Methotrexate-Associated Lymphoproliferative Disorders in Rheumatoid Arthritis: A Case Series and Literature Review

Objective: To investigate the clinical characteristics, risk factors, histological subtypes, and outcomes of Epstein-Barr Virus-Positive methotrexate-associated lymphoproliferative disorders (EBV positive MTX-LPDs) in rheumatoid arthritis (RA) patients using the fifth edition of the Classification of Hematolymphoid Tumors (WHO-HAEM5), revised in 2022, framework. Methods: A retrospective review of pathology records from January 2009 to March 2025 was conducted at Shuang-Ho Hospital. Clinical data, laboratory findings, treatment histories, and outcomes were analyzed and compared with existing literature. Results: Nine RA patients with EBV-positive MTX-LPD were identified, with a mean exposure of 8.7 years. Most patients exhibited elevated lactate dehydrogenase (LDH), and lymphopenia. Histological subtypes included polymorphic LPD, lymphoma, EBV mucocutaneous ulcer and reactive hyperplasia. Three patients achieved remission after MTX withdrawal, while others required further treatment or had poor outcomes. Conclusions: EBV-positive MTX-LPDs in RA patients may regress after MTX withdrawal. The WHO-HAEM5 classification aids in subtype identification and prognostication. Careful monitoring of high-risk patients and timely MTX discontinuation are critical for favorable outcomes.

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Distribution of Antinuclear Antibody Patterns in Patients With and Without Systemic Lupus Erythematosus: A Multi-Center Study from Taiwan

Objectives: The International Consensus on Antinuclear Antibody Patterns (ICAP) provides a standardized classification of 29 ANA patterns, facilitating more precise interpretation of indirect immunofluorescence (IIF) results. Although ANA testing is widely used in the diagnosis of systemic lupus erythematosus (SLE), the distribution of ICAP-defined ANA patterns in Taiwanese populations remains poorly characterized. This study aims to analyze the distribution of ANA patterns among ANA-positive SLE patients and to compare ANA pattern frequencies between SLE and non-SLE individuals. Methods: This retrospective study included 38,572 individuals who underwent ANA testing using the IIF HEp-2 assay at Chang Gung Memorial Hospital from January 2019 to September 2021. ANA patterns were classified according to the ICAP system. In the primary analysis, only individuals with a single ANA pattern were included; those with mixed or inconsistently classified patterns were excluded. A secondary analysis compared all patients diagnosed with SLE-including those who were ANA-negative-with non-SLE individuals. Results: Among 4,603 ANA-positive individuals, 383 were diagnosed with SLE. The most common ANA pattern was AC-5 (34.5%), followed by AC-1 (20.9%) and AC-4 (15.1%). In the broader comparison, patterns AC-1 through AC-5 and nucleolar patterns (AC-8/9/10) were more frequently observed in SLE than in non-SLE individuals. Conclusion: This is the first study to characterize ANA pattern distributions in Taiwanese SLE patients using ICAP classification. The findings provide insight into regional ANA pattern features and support the clinical relevance of standardized pattern interpretation in autoimmune disease evaluation.