Interstitial fibrosis increases the risk of end-stage kidney disease in patients with lupus nephritis.

OBJECTIVE: To evaluate the risk of end-stage kidney disease (ESKD) in lupus nephritis (LN) patients using tubulointerstitial lesion scores. METHODS: Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions (e.g. interstitial inflammation [II], tubular atrophy [TA], and interstitial fibrosis [IF]) were analyzed. RESULTS: The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n = 3, 2%), class III/IV (n = 119, 78.8%), class V (n = 23, 15.2%), and class VI (n = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, 9 (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine (hazard ratio [HR]: 1.7, 95% confidence interval [CI]: 1.42-2.03, p < 0.001) and IF (HR: 3.2, 95% CI: 1.58-6.49, p = 0.001) as independent risk factors of ESKD. Kaplan-Meier analysis further confirmed a heightened risk of ESKD associated with IF. CONCLUSION: Tubulointerstitial involvement is commonly observed in histopathological presentation of LN. However, IF, rather than II, or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, degree of IF should be reviewed.

Risk Factors and Incidence of Serious Infections in Patients With Systemic Lupus Erythematosus Undergoing Rituximab Therapy.

OBJECTIVE: To evaluate the risk and protective factors of serious infection (SI) in patients with systemic lupus erythematosus (SLE) within 180 days of rituximab (RTX) treatment. METHODS: Patients with SLE treated with RTX were analyzed. SI was defined as any infectious disease requiring hospitalization. The clinical characteristics, laboratory profiles, medications, and incidence rate (IR) are presented. Multivariate Cox proportional hazards models and Kaplan-Meier analysis for risk factors of SI were performed. RESULTS: A total of 174 patients with SLE receiving RTX treatment were enrolled. The overall IR of SIs was 51.0/100 patient-years (PYs). Pneumonia (30.4/100 PYs), followed by soft tissue infections, intra-abdominal infections, and Pneumocystis jiroveci pneumonia (all 6.1/100 PYs) were the leading types of SIs. Twelve patients died during the 180-day follow-up (crude mortality rate: 14.6/100 PYs). Chronic kidney disease (CKD), defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 (hazard ratio [HR] 2.88, 95% CI 1.30-6.38), and a background prednisolone (PSL) equivalent dosage ≥ 15 mg/day (HR 3.50, 95% CI 1.57-7.78) were risk factors for SIs among all patients with SLE. Kaplan-Meier analysis confirmed the risk of SI for patients with SLE with CKD and a background PSL equivalent dosage ≥ 15 mg/day (log-rank P = 0.001 and 0.02, respectively). Hydroxychloroquine (HCQ) reduced the risk of SIs in patients with SLE (HR 0.35, 95% CI 0.15-0.82; log-rank P = 0.003). CONCLUSION: SI was prevalent in patients with SLE after RTX treatment. Patients with SLE with CKD and high-dose glucocorticoid use required constant vigilance. HCQ may reduce the risk of SI among patients with SLE administered RTX.

Increased risk of malignancy in HLA-B27-positive patients with ankylosing spondylitis requiring biologics for sustained inflammation: A long-term, single-center retrospective study.

OBJECTIVES: To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. METHODS: Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. RESULTS: During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. CONCLUSIONS: HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment.

The Taiwanese Map of Axial Spondyloarthritis: Living with the Condition.

Background and Objective: The International Map of Axial Spondyloarthritis (IMAS) explores the physical, psychological, and social experiences of patients with axial spondyloarthritis (axSpA). This initiative is now being expanded to Taiwan as the Taiwanese Map of Axial Spondyloarthritis (TMAS). We aim to provide rheumatologists with insights into the perspectives of Taiwanese patients, enabling physicians to better understand the unmet needs of these patients and optimize their management. Materials and Methods: The TMAS is a cross-sectional study gathering data through an online survey of axSpA patients, promoted by the Ankylosing Spondylitis Caring Society of R.O.C. (ASCARES), conducted from July 2017 to March 2018 by Ipsos, and analyzed by the Health & Territory Research (HTR) group of the University of Seville. The questionnaire includes 99 questions that cover domains such as patient profile, diagnosis, habits/lifestyle, employment status, physical/psychological health status, social support, use of healthcare services, and treatments. Results: A total of 112 axSpA patients were included in this survey. The mean age was 38.6 years and 75.0% were male. The average diagnostic delay was 3 years, and 19.6% reported extra-articular manifestations. Out of the 49 respondents who reported HLA-B27 information, 35 were HLA-B27-positive. The disease burden was high, with a mean BASDAI score of 4.9 and 75.9% having a mild to moderate degree of spinal stiffness. Furthermore, they were socially and psychologically burdened, with 88.4% experiencing work-related issues and 25.9% suffering from anxiety. Conclusions: The TMAS sheds light on the overall perspective of axSpA patients in Taiwan. The TMAS shows shorter diagnostic delay compared to patients from the EMAS. However, high disease activity and significant psychological distress still trouble the patients, causing functional impairments and even leading to career failures. Understanding the perspective of axSpA patients can help rheumatologists adjust treatment strategies to their unmet needs and improve their disease outcomes.

Immune-mediated diseases after vaccinations with AZD1222, BNT-162b2, &/or mRNA-1273: An observational investigation of 78 patients.

BACKGROUND: Immune-mediated diseases (IMDs) after nucleic acid-based vaccines have been sporadically reported since their introduction during the worldwide COVID-19 crisis. Confirming their cause-effect association remains challenging. We analysed the effects of AZD1222 (ChAdOx1 nCoV-19), BNT-162b2, and/or mRNA-1273 on the development &/or deterioration of IMDs in terms of the time of clinical onsets of IMDs after exposure to these vaccines. METHODS: We retrospectively reviewed 78 in-patients in Taipei Veterans General Hospital, who presented with IMDs within 120 days after receiving AZD1222, BNT-162b2, &/or mRNA-1273 vaccinations in Taiwan from May 2021 to April 2022. The duration from inoculation to development of IMD was analysed by two-tailed Kolmogorov-Smirnov (K-S) test for goodness of fit. RESULTS: The average time to new IMDs or flare-up of the diseases following vaccinations was 36 ± 26 days for all 91 events in these 78 patients. The onset time of IMDs after vaccinations was not haphazard as analysed by two-tailed K-S test for overall 91 events (40 new and 51 deteriorating episodes, p < 0.001). The IMDs presenting as non-connective tissue diseases (non-CTDs) have a shorter duration of incubation after vaccinations than those of CTDs (<14.7 days, 95 % confidence interval [CI], 3.0 to 26.4, p = 0.014). Furthermore, systemic vasculitis and type 2 inflammatory diseases were observed exclusively in those receiving AZD1222. CONCLUSION: AZD1222, BNT-162b2, or mRNA-1273 influence the activities of IMDs in ways yet to be explored. High index of suspicion to IMDs after nucleic acid-based vaccine inoculation against COVID-19 may be important for primary care physicians.

Antibodies against Small Ubiquitin-like Modifier Activating Enzyme May Be a Protective Factor from Rapid Progressive Interstitial Lung Disease in Patients Bearing Antibodies against Melanoma Differentiation Associated Gene 5.

Background: Anti-MDA5 antibody-bearing (anti-MDA5+)-dermatomyositis (DM) or polymyositis (PM) is notorious for causing rapidly progressive interstitial lung disease (RPILD) and/or cancers with high mortality rate. However, anti-MDA5 antibodies (Abs) are also found in other connective tissue diseases and their link with RPILD, especially with regard to the mortality rate, are unknown. Methods: We retrospectively recruited 71 patients bearing anti-MDA5-Abs in serum, stratified them in terms of a presence or absence of RPILD, and evaluated their clinical features, laboratory findings, associated myositis antibodies, concurrent connective tissue disease (CTD) as well as newly developed malignancies. Results: In total, 39 (55%) patients presented with DM/PM, but 32 (45%) did not. In total, 22 of the former and 11 of the latter developed RPILD eventually, accounting for a total of 46% of all MDA-5 bearing patients. On the other hand, 15 of all 71 (21.1%) patients had cancers. Among the 32 patients who did not have DM/PM, 27 (38.0% of all 71) had other CTDs, indicating that only 5 (7.0% of 71) patients did not have CTDs. Senility (odds ratio (OR) = 1.816, p = 0.032), presence of anti-Ro-52 antibody (OR = 1.676, p = 0.018), elevated C-reactive protein (CRP, OR = 4.354, p < 0.001) and carcinoembryonic antigen (CEA, OR = 2.625, p = 0.005) posed risks for RPILD. High lactose dehydrogenase (LDH, p = 0.009), CRP (p = 0.001) and CEA (p = 0.001), ferritin (p ≤ 0.001) and low albumin (p ≤ 0.001) were significantly associated with mortality. Anti-SAE antibodies were negatively correlated with RPILD as analyzed by univariate (OR = 0.245, p = 0.017) and multivariate (OR = 0.058, p = 0.036) regressions, indicating that they may be a protective factor in relation to RPILD (OR = 0.543, p = 0.008) or fatality (OR = 0.707, p = 0.012), which was also demonstrated in subgroup analyses. Conclusions: In contrast to various risk factors for RPILD or mortality, anti-SAE antibodies might conversely be a protective factor in anti-MDA5+ patients.

Risk factors for mortality in systemic lupus erythematosus patients: Analysis of adult and pediatric cohorts in Taiwan.

BACKGROUND: Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models. RESULTS: A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to >10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients. CONCLUSION: SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality.

Significance of high serum IgG4 in complete or non-full-fledged IgG4-related disease-a retrospective investigation of 845 patients and its clinical relevance.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a recently recognized heterogeneous, subacute, and usually silent autoimmune disease involving many organs with protean manifestations. However, high IgG4 in serum is not necessarily indicating an IgG4-RD. The aims of this study were to investigate the clinical relevance of high serum IgG4 level in IgG4-RD or non IgG4-RD patients, and to see if IgG4-RD in Taiwan differs from that in other parts of the world. METHODS: Eight hundred forty-five patients with high IgG4 were retrospectively reviewed from January 2002 to May 2020 in Taipei Veteran General Hospital. Two hundred sixty-seven patients fulfilled IgG4-RD criteria and were categorized into pancreato-hepato-biliary disease, retroperitoneal fibrosis and/or aortitis, head/neck-limited disease, classic Mikulicz syndrome with systemic involvement, CNS-limited disease, sclerosing vasculitis, skin-limited disease, and sensorineural hearing disease. These manifestations were correlated to smoking, atopy, hyper-IgE/eosinophilia, aging, malignancies, and hypocomplementemia. Five hundred seventy-eight patients were not fulfilling the criteria but were also analyzed for the prevalence of allergy, malignancy, connective tissue diseases, lung diseases, and infections. RESULTS: In IgG4-RD patients, 124 (46.4%) smoked. Top 4 clinical subtypes included Mikulicz syndrome with systemic involvement (33.3%), pancreato-hepatobiliary disease (31.4%), head/neck disease (19.4%), and retroperitoneal fibrosis/aortitis (12.7%). Top 4 co-morbid conditions included high serum IgE/eosinophilia (46.2%), hypocomplementemia (34%), malignancies (13.4%), and allergy (13.4%). Pancreato-biliary disease was associated with high IgE/eosinophilia (r2 = 0.380, P = 0.025) and malignancy (r2 = 0.211, P = 0.027), Miculicz syndrome with allergy (r2 = 0.396, P < 0.01) and high IgE/eosinophil (r2 = 0.396, P < 0.01), CNS diseases (r2 = 0.973, P = 0.035) and sclerosing vasculitis (r2 = 1, P < 0.01) with advanced age respectively, with the latter being also related to atopy and high IgE/eosinophilia (r2 = 1, p < 0.01). CONCLUSION: Smoking may precipitate IgG4-RD. IgG4-RD with pancreato-hepatobiliary disease is closely related to allergy and neoplasm, and those with Mikulicz syndrome may result from atopy. Elderly IgG4-RD patients tend to develop CNS pathology parallel to advancing of age. The disease may probably be originated from an unknown mechanism that may sporadically evolve into malignancies.

Real-world effectiveness and safety of golimumab in rheumatoid arthritis treatment: A two-center study in Taiwan.

BACKGROUND: The real-world outcomes of golimumab (GLM) use have been rarely studied in Asian patients with rheumatoid arthritis (RA). This study assessed the real-world effectiveness and safety of GLM in a Taiwanese cohort. METHODS: One hundred and eight GLM-treated RA patients were enrolled. Predictors of a good European League Against Rheumatism (EULAR) response at 24 months and drug retention were identified through multivariate analyses. RESULTS: After 24 months of GLM treatment, the mean Disease Activity Score using 28 joint counts with the erythrocyte sedimentation rate (DAS28-ESR) decreased from 6.7 to 3.1 (p < 0.001). Up to 58.9% of patients achieved a good EULAR response at 24 months. Multivariate logistic regression analysis revealed that after adjustment for other variables, a higher baseline C-reactive protein was an independent negative predictor of good EULAR responses (odds ratio, 0.82; 95% confidence interval [CI], 0.67-0.99; p = 0.043). During the mean follow-up period of 38.3 months, 15 (13.9%) patients discontinued GLM due to treatment failure. In multivariate analysis, high baseline ESR level, high DAS28-ESR, and the experience of biologic therapy were independent risk factors for GLM discontinuation (adjusted hazard ratio [HR], 1.03; 95% CI, 1.01-1.05; p = 0.003; adjusted HR, 2.93; 95% CI, 1.42-6.08; p = 0.004; and adjusted HR, 5.00; 95% CI, 1.75-14.26; p = 0.003, respectively). In receiver operator characteristic curve analysis, the optimal cutoff values of baseline ESR and DAS28-ESR for predicting drug survival were 52 mm/h (sensitivity: 60.0% and specificity: 77.4%) and 7.7 (sensitivity: 46.7% and specificity: 94.3%), respectively. During the follow-up period, 22 patients (20.4%) developed adverse events. The safety profile of GLM in this study was comparable with that in previous clinical trials. CONCLUSION: GLM was effective and safe for the real-life management of Taiwanese RA patients and showed a high retention rate in biologic-naive patients compared with biologic-experienced patients.

Bronchoalveolar lavage fluid analysis and mortality risk in systemic lupus erythematosus patients with pneumonia and respiratory failure.

BACKGROUND: Our aim was to characterize etiologic diagnoses obtained from bronchoalveolar lavage fluid (BALF) and blood specimens, and to identify risk factors for mortality in systemic lupus erythematosus (SLE) patients with pneumonia and respiratory failure. METHODS: We conducted a retrospective analysis of SLE patients with pneumonia and respiratory failure. Clinical characteristics, laboratory profiles, and microbiology in BALF and blood samples were evaluated. We performed univariable analyses to identify mortality risk factors. RESULTS: All 24 patients (F:M = 21:3, median age 46.5 years; disease duration 11 years) received mechanical ventilation (median duration: 11 days). Pathogens identified in BALF included Pneumocystis jiroveci (12 patients [50%]), cytomegalovirus (CMV, 7 patients [29.2%]), and bacteria (11 patients [45.8%]). Thirteen patients (54.2%) yielded pathogens in blood (CMV in 8 patients [33.3%] and Escherichia coli in 5 patients [20.8%]). Eight developed septic shock, and 9 died within 30 days. Univariable analysis identified thrombocytopenia (odds ratio [OR]: 8.0, 95% confidence interval [CI]: 1.23-52.25), bacteremia within 30 days before or after endotracheal intubation (OR: 8.0, 95% CI: 1.23-52.5), and P. jiroveci pneumonia (PJP, OR: 7.0, 95% CI: 1.04-46.95) as risk factors for 30-day mortality. Kaplan-Meier analysis confirmed an increased risk of 30-day mortality with thrombocytopenia and bacteremia. CONCLUSION: There are high prevalence rates of PJP and CMV infections as evidenced by BALF analyses in SLE patients with pneumonia and respiratory failure. BALF analysis can facilitate rescue therapy per pathogen. Thrombocytopenia, bacteremia, and PJP in SLE patients can increase their 30-day mortality, so warrant early and aggressive treatments.

The Potential Role of Genetics, Environmental Factors, and Gut Dysbiosis in the Aberrant Non-Coding RNA Expression to Mediate Inflammation and Osteoclastogenic/Osteogenic Differentiation in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) or radiographic axial spondyloarthritis is a chronic immune-mediated rheumatic disorder characterized by the inflammation in the axial skeleton, peripheral joints, and soft tissues (enthesis, fascia, and ligament). In addition, the extra-skeletal complications including anterior uveitis, interstitial lung diseases and aortitis are found. The pathogenesis of AS implicates an intricate interaction among HLA (HLA-B27) and non-HLA loci [endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin-23 receptor (IL23R), gut dysbiosis, immune plasticity, and numerous environmental factors (infections, heavy metals, stress, cigarette smoking, etc.) The latter multiple non-genetic factors may exert a powerful stress on epigenetic regulations. These epigenetic regulations of gene expression contain DNA methylation/demethylation, histone modifications and aberrant non-coding RNAs (ncRNAs) expression, leading to inflammation and immune dysfunctions. In the present review, we shall discuss these contributory factors that are involved in AS pathogenesis, especially the aberrant ncRNA expression and its effects on the proinflammatory cytokine productions (TNF-α, IL-17 and IL-23), T cell skewing to Th1/Th17, and osteoclastogenic/osteogenic differentiation. Finally, some potential investigatory approaches are raised for solving the puzzles in AS pathogenesis.

Cytomegaloviral or Pneumocystis Jiroveci Pneumonia Increases Mortality in Systemic Lupus Erythematosus Patients with Pulmonary Hemorrhage: Evidence from Bronchoalveolar Lavage Fluid.

OBJECTIVE: To evaluate the role of cytomegaloviral or Pneumocystis jiroveci pneumonia (CMV/PJP) in systemic lupus erythematosus (SLE) patients with pulmonary hemorrhage (PH). METHODS: We retrospectively examined hospital records for 27 SLE patients with PH who received bronchoalveolar lavage fluid (BALF) analyses. Clinical profile and mortality rates were compared between groups with and without CMV/PJP. Risk factors for PH-related mortality were analyzed. RESULTS: Among 27 SLE patients with PH, 15 had pathogens from BALF samples, and 8 had CMV/PJP. Although CMV/PJP was treated, the RR for 90- and 180-day mortality rates of SLE patients with CMV/PJP were higher than those without these infections (5.94, 95% CI 1.44-24.48; 7.13, 95% CI 1.81-28.06, respectively). Risk factors for 90- and 180-day mortality were presence of CMV/PJP (OR 14.2, 95% CI 1.83-109.9; OR 25.5, 95% CI 2.91-223.3, respectively) and use of pulse methylprednisolone for PH treatment (OR 12.0, 95% CI 1.48-97.2; OR 8.5, 95% CI 1.13-63.9, respectively). Factors increasing the 90-day mortality rate were duration of mechanical ventilation exceeding 14 days (OR 11.1, 95% CI 1.11-112.0) and use of aggressive immunosuppression close to PH onset (OR 7.56, 95% CI 1.09-52.4). Three of the 7 patients receiving aggressive immunosuppression died with the presence of CMV/PJP. CONCLUSION: Owing to the high prevalence of CMV/PJP and its association with mortality, routine BALF analysis is recommended for all suitable SLE patients with PH. Use of aggressive immunosuppression does not benefit SLE patients with opportunistic infections during PH attack.