Multivariable index for assessing the activity and predicting all-cause mortality in antineutrophil cytoplasmic antibody-associated vasculitis

BACKGROUND: So far, there has been no tool to estimate activity at diagnosis and predict all-cause mortality in patients with ANCA-associated vasculitis (AAV). Hence, we determined the initial predictors of them in patients with AAV. METHODS: We retrospectively reviewed the medical records of 182 patients with AAV. Severe AAV was defined as Birmingham Vasculitis Activity Score (BVAS) ≥ 16. The cutoffs were extrapolated by the receiver operator characteristic (ROC) curve. The odds ratio (OR) and the relative risk (RR) were assessed using the multivariable logistic regression analysis and the chi-square test, respectively. RESULTS: In the comparison analysis, patients with severe AAV exhibited the higher neutrophil and platelet counts, creatinine, erythrocyte sedimentation rate and C-reactive protein, and the lower lymphocyte count, hemoglobin, and serum albumin than those without. In the multivariable logistic regression analysis, creatinine ≥ 0.9 mg/dL (OR 2.264), lymphocyte count ≤ 1430.0/mm3 (OR 1.856), and hemoglobin ≤ 10.8 g/dL (OR 2.085) were associated with severe AAV. We developed a new equation of a multivariable index for AAV (MVIA) = 0.6 × (Lymphocyte count ≤ 1430.0/mm3 ) + 0.7 × (Hemoglobin ≤ 10.8 g/dL) + 0.8 × (Creatinine ≥ 0.9 mg/dL). The optimal cutoff of MVIA for severe AAV was set as 1.35. Severe AAV was identified more frequently in patients with MVIA at diagnosis ≥1.35 than those without (RR 4.432). Patients with MVIA at diagnosis ≥1.35 exhibited the lower cumulative patient survival rate than those without. CONCLUSION: Multivariable index for AAV could assess the cross-sectional activity and predict all-cause mortality in patients with AAV.ope

IM156, a new AMPK activator, protects against polymicrobial sepsis

IM156, a novel biguanide with higher potency of AMP-activated protein kinase activation than metformin, has inhibitory activity against angiogenesis and cancer. In this study, we investigated effects of IM156 against polymicrobial sepsis. Administration of IM156 significantly increased survival rate against caecal ligation and puncture (CLP)-induced sepsis. Mechanistically, IM156 markedly reduced viable bacterial burden in the peritoneal fluid and peripheral blood and attenuated organ damage in a CLP-induced sepsis model. IM156 also inhibited the apoptosis of splenocytes and the production of inflammatory cytokines including IL-1β, IL-6 and IL-10 in CLP mice. Moreover, IM156 strongly inhibited the generation of reactive oxygen species and subsequent formation of neutrophil extracellular traps in response to lipopolysaccharide in neutrophils. Taken together, these results show that IM156 can inhibit inflammatory response and protect against polymicrobial sepsis, suggesting that IM156 might be a new treatment for sepsis.ope

Controlling Nutritional Status Score is Associated with All-Cause Mortality in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

PURPOSE: The controlling nutritional status (CONUT) score was developed to detect undernutrition in patients. Here, we investigated whether the CONUT score estimated at diagnosis could help predict poor outcomes [all-cause mortality, relapse, and end-stage renal disease (ESRD)] of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). MATERIALS AND METHODS: We retrospectively reviewed and collated data, including baseline characteristics, clinical manifestations (to calculate AAV-specific indices), and laboratory results, from 196 newly diagnosed AAV patients. Serum albumin, peripheral lymphocyte, and total cholesterol levels (at diagnosis) were used to calculate CONUT scores. RESULTS: In total, 111 patients had high CONUT scores (≥3), which showed higher frequency of myeloperoxidase-ANCA and ANCA positivity, and demonstrated higher AAV-specific indices. The optimal cut-offs of CONUT score (at diagnosis) for predicting all-cause mortality and ESRD were ≥3.5 and ≥2.5, respectively. Patients with CONUT scores higher than the cut-off at diagnosis exhibited lower cumulative and ESRD-free survival rates compared to those with lower scores than the cut-off. In multivariable analyses, diabetes mellitus [hazard ratio (HR): 4.394], five-factor score (HR: 3.051), and CONUT score ≥3.5 (HR: 4.307) at diagnosis were independent predictors of all-cause mortality, while only serum creatinine (HR: 1.714) was an independent predictor of ESRD occurrence.ope

Extracellular histones aggravate autoimmune arthritis by lytic cell death

Although recent studies have demonstrated a proinflammatory effect of extracellular histones in sepsis via endothelial cytotoxicity, little is known about their contribution to autoimmune arthritis. Therefore, we investigated the role of extracellular histones in autoimmune arthritis and their cytotoxic effect on synoviocytes and macrophages. We measured histones in the synovial fluid of patients with rheumatoid arthritis (RA) and evaluated arthritis severity in a serum-transfer arthritis (STA) mouse model with intraperitoneal histone injection. Histone-induced cytotoxicity was measured using SYTOX green staining in the synoviocyte cell line MH7A and macrophages differentiated from the monocytic cell line THP-1, and the production of damage-associated molecular patterns (DAMPs) was measured by HMGB1 and ATP. Furthermore, we performed RNA-seq analysis of THP-1 cells stimulated with H2B-α1 peptide or with its citrullinated form. The levels of histones were elevated in RA synovial fluid, and histones aggravated arthritis in the STA model. Histones induced cytotoxicity and DAMP production in synoviocytes and macrophages. Chondroitin sulfate reduced histone-induced cytotoxicity, while lipopolysaccharides aggravated cytotoxicity. Moreover, the cytotoxicity decreased when the arginines in H2B-α1 were replaced with citrullines, which demonstrated its electrostatic nature. In transcriptome analysis, H2B-α1 changed the gene expression pattern of THP-1 cells involving chemokines, interleukin-1, -4, -10, -13, and toll-like receptor (TLR) signaling pathways. Extracellular histones were increased in RA synovial fluid and aggravated synovitis in STA. They induced lytic cell death through electrostatic interaction with synoviocytes and macrophages, leading to the secretion of DAMPs. These findings suggest that histones play a central role in autoimmune arthritis.ope

Total Haemolytic Complement Activity at Diagnosis as an Indicator of the Baseline Activity of Antineutrophil Cytoplasmic Antibody-associated Vasculitis

Objective. The total haemolytic complement activity (CH50) assay evaluates the functioning of the complement system. Accumulating evidence indicates that the activation of the complement system plays a critical role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Therefore, this study aimed to investigate whether CH50 levels at diagnosis could reflect the baseline activity of AAV. Methods. This retrospective study included 101 immunosuppressive drug-naïve patients with AAV. At diagnosis, all patients underwent clinical assessments for disease activity, including measurement of the Birmingham Vasculitis Activity Score (BVAS) and Five Factor Score (FFS), and laboratory evaluations, such as tests for CH50, C3, and C4 levels. The association between CH50 levels and disease activity was determined. Results. The median BVAS and FFS at diagnosis were 12.0 and 1.0, respectively, whereas the median CH50 level was 60.4 U/mL. There was a negative correlation between the CH50 level and BVAS (r=−0.241; p=0.015). A CH50 cut-off value of 62.1 U/mL was used to classify the patients into two groups: patients with CH50 levels ＜62.1 U/mL (low-CH50 group) and those with CH50 levels ≥ 62.1 U/mL (high-CH50 group). The low-CH50 group had a higher proportion of patients with high disease activity, based on the BVAS, than the high-CH50 group (52.5% vs. 23.8%, p=0.004). Additionally, the low-CH50 group exhibited a lower relapse- free survival rate than the high-CH50 group; however, this difference was not statistically significant (p=0.082). Conclusion. Low CH50 levels at diagnosis may reflect high baseline activity of AAV.ope

Novel mortality-predicting index at diagnosis can effectively predict all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis

Background: This study investigated whether the inflammation prognostic index (IPI) and the mortality predicting index (MPI) at diagnosis could predict all-cause mortality in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: We included 223 AAV patients and reviewed their medical records. Clinical and laboratory data and AAV-specific indices at diagnosis were assessed. The IPI was calculated as neutrophil-to-lymphocyte ratio (NLR) × C-reactive protein to albumin ratio (CAR). Here, we newly developed an MPI (NLR × CAR × monocyte counts). Results: The mean age of 223 patients (122 MPA, 57 GPA and 44 EGPA patients) was 59 years. The rate of mortality was 11.2%. Using the receiver operator characteristic curve for all-cause mortality, the cut-offs were calculated as NLR: 3.22, CAR: 3.25, IPI: 18.53 and MPI: 8367.82. In the univariable Cox hazard analysis, age, gender, smoking history, BVAS, FFS and over the cut-off of each index showed statistical significance. As the indices share at least two mutual variables, the multivariable analysis was conducted four times based on each index. An IPI ≥18.53 (HR 3.162) and MPI ≥8367.82 (HR 3.356) were significantly associated with all-cause mortality. Conclusions: This study developed a novel indicator, MPI, that uses the existing NLR and CAR indices and proved that it could predict all-cause mortality in AAV patients.ope

Treat-to-Target Strategy for Asian Patients with Early Rheumatoid Arthritis: Result of a Multicenter Trial in Korea

Background: To evaluate the therapeutic benefits of the treat-to-target (T2T) strategy for Asian patients with early rheumatoid arthritis (RA) in Korea. Methods: In a 1-year, multicenter, open-label strategy trial, 346 patients with early RA were recruited from 20 institutions across Korea and stratified into 2 groups, depending on whether they were recruited by rheumatologists who have adopted the T2T strategy (T2T group) or by rheumatologists who provided usual care (non-T2T group). Data regarding demographics, rheumatoid factor titer, anti-cyclic citrullinated peptide antibody titer, disease activity score of 28 joints (DAS28), and Korean Health Assessment Questionnaire (KHAQ) score were obtained at baseline and after 1 year of treatment. In the T2T group, the prescription for disease-modifying antirheumatic drugs was tailored to the predefined treatment target in each patient, namely remission (DAS28 < 2.6) or low disease activity (LDA) (2.6 ≤ DAS28 < 3.2). Results: Data were available for 163 T2T patients and 162 non-T2T patients. At the end of the study period, clinical outcomes were better in the T2T group than in the non-T2T group (LDA or remission, 59.5% vs. 35.8%; P < 0.001; remission, 43.6% vs. 19.8%; P < 0.001). Compared with non-T2T, T2T was also associated with higher rate of good European League Against Rheumatism response (63.0% vs. 39.8%; P < 0.001), improved KHAQ scores (-0.38 vs. -0.13; P = 0.008), and higher frequency of follow-up visits (5.0 vs. 2.0 visits/year; P < 0.001). Conclusion: In Asian patients with early RA, T2T improves disease activity and physical function. Setting a pre-defined treatment target in terms of DAS28 is recommended.ope

Association between follistatin-related protein 1 and the functional status of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

Background: Follistatin-like 1 (FSTL1) plays both pro-inflammatory and anti-inflammatory roles in the inflammatory processes. We investigated whether serum FSTL1 could predict the current anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)-specific indices. Methods: We randomly selected 74 patients with AAV from a prospective and observational cohort of Korean patients with AAV. Clinical and laboratory data and AAV-specific indices were recorded. FSTL1 concentration was determined using the stored sera. The lowest tertile of the short-form 36-item health survey (SF-36) was defined as the current low SF-36. The cutoffs of serum FSTL1 for the current low SF-36 physical component summary (PCS) and SF-36 mental component summary (MCS) were extrapolated by the receiver operator characteristic curve. Results: The median age was 62.5 years (55.4% were women). Serum FSTL1 was significantly correlated with SF-36 PCS (r = - 0.374), SF-36 MCS (r = -0.377), and C-reactive protein (CRP) (r = 0.307), but not with Birmingham vasculitis activity score (BVAS). In the multivariable linear regression analyses, BVAS, CRP, and serum FSTL1 were independently associated with the current SF-36 PCS (β = -0.255, β = -0.430, and β = -0.266, respectively) and the current SF-36 MCS (β = -0.234, β =-0.229, and β = -0.296, respectively). Patients with serum FSTL1 ≥779.8 pg/mL and those with serum FSTL1 ≥841.6 pg/mL exhibited a significantly higher risk of having the current low SF-36 PCS and SF-36 MCS than those without (relative risk 7.583 and 6.200, respectively). Conclusion: Serum FSTL1 could predict the current functional status in AAV patients.ope

Metabolic Reprogramming by the Excessive AMPK Activation Exacerbates Antigen-Specific Memory CD8+ T Cell Differentiation after Acute Lymphocytic Choriomeningitis Virus Infection

During virus infection, T cells must be adapted to activation and lineage differentiation states via metabolic reprogramming. Whereas effector CD8+ T cells preferentially use glycolysis for their rapid proliferation, memory CD8+ T cells utilize oxidative phosphorylation for their homeostatic maintenance. Particularly, enhanced AMP-activated protein kinase (AMPK) activity promotes the memory T cell response through different pathways. However, the level of AMPK activation required for optimal memory T cell differentiation remains unclear. A new metformin derivative, IM156, formerly known as HL156A, has been reported to ameliorate various types of fibrosis and inhibit in vitro and in vivo tumors by inducing AMPK activation more potently than metformin. Here, we evaluated the in vivo effects of IM156 on antigen-specific CD8+ T cells during their effector and memory differentiation after acute lymphocytic choriomeningitis virus infection. Unexpectedly, our results showed that in vivo treatment of IM156 exacerbated the memory differentiation of virus-specific CD8+ T cells, resulting in an increase in short-lived effector cells but decrease in memory precursor effector cells. Thus, IM156 treatment impaired the function of virus-specific memory CD8+ T cells, indicating that excessive AMPK activation weakens memory T cell differentiation, thereby suppressing recall immune responses. This study suggests that metabolic reprogramming of antigen-specific CD8+ T cells by regulating the AMPK pathway should be carefully performed and managed to improve the efficacy of T cell vaccine.ope

The significance of cytoplasmic antinuclear antibody patterns in autoimmune liver disease

We aimed to determine the significance of cytoplasmic antinuclear antibody (ANA) patterns using computer-aided immunofluorescence microscopy in patients with autoimmune liver diseases (AILD). ANA staining pattern was identified by treating cultured human epithelial type 2 (HEp-2) cells with the sera of the patients. Medical records of patients with suspected AILD who had positive cytoplasmic ANA patterns between February 2017 and November 2019 were retrospectively reviewed for clinical, laboratory, and immunological data. Cytoplasmic ANA patterns of AILD and non-AILD groups were compared. Further subgroup analysis of patients with AILD who had reticular or speckled cytoplasmic ANA patterns was conducted. We found that among the 196 patients with positive cytoplasmic ANA patterns, 113 (57.6%) were diagnosed with AILD. The percentage of reticular cytoplasmic pattern was higher in the AILD group than that in the non-AILD group (64.0% vs. 21.9%, p < 0.001). Furthermore, patients with AILD who exhibited a reticular ANA pattern demonstrated a higher positive rate for anti-mitochondrial antibodies (66.7% vs. 2.6%, p < 0.001) than those who exhibited the speckled ANA pattern. Moreover, AILD patients with the reticular ANA pattern displayed a lower positive rate for anti-smooth muscle antibodies (0% vs. 45%, p < 0.001) and nuclear ANA pattern (73.2% vs. 97.5%, p = 0.003) than those with the speckled ANA pattern. Therefore, cytoplasmic ANA patterns could be used to guide AILD characterization in suspected AILD cases, especially as the reticular ANA pattern is strongly associated with AILD. Thus, it is important to check cytoplasmic ANA patterns for AILD evaluation, even when nuclear ANA patterns are negative.ope