The artificial amino acid change in the sialic acid-binding domain of the hemagglutinin neuraminidase of newcastle disease virus increases its specificity to HCT 116 colorectal cancer cells and tumor suppression effect.

BACKGROUND: Oncolytic viruses are being studied and developed as novel cancer treatments. Using directed evolution technology, structural modification of the viral surface protein increases the specificity of the oncolytic virus for a particular cancer cell. Newcastle disease virus (NDV) does not show specificity for certain types of cancer cells during infection; therefore, it has low cancer cell specificity. Hemagglutinin is an NDV receptor-binding protein on the cell surface that determines host cell tropism. NDV selectivity for specific cancer cells can be increased by artificial amino acid changes in hemagglutinin neuraminidase HN proteins via directed evolution, leading to improved therapeutic effects. METHODS: Sialic acid-binding sites (H domains) of the HN protein mutant library were generated using error-prone PCR. Variants of the H domain protein were screened by enzyme-linked immunosorbent assay using HCT 116 cancer cell surface molecules. The mutant S519G H domain protein showed the highest affinity for the surface protein of HCT 116 cells compared to that of different types of cancer cells. This showed that the S519G mutant H domain protein gene replaced the same part of the original HN protein gene, and S519G mutant recombinant NDV (rNDV) was constructed and recovered. S519G rNDV cancer cell killing effects were tested using the MTT assay with various cancer cell types, and the tumor suppression effect of the S519G mutant rNDV was tested in a xenograft mouse model implanted with cancer cells, including HCT 116 cells. RESULTS: S519G rNDV showed increased specificity and enhanced killing ability of HCT 116 cells among various cancer cells and a stronger suppressive effect on tumor growth than the original recombinant NDV. Directed evolution using an artificial amino acid change in the NDV HN (S519G mutant) protein increased its specificity and oncolytic effect in colorectal cancer without changing its virulence. CONCLUSION: These results provide a new methodology for the use of directed evolution technology for more effective oncolytic virus development.

First-year cumulative myeloperoxidase-ANCA titres are associated with all-cause mortality in patients with microscopic polyangiitis.

OBJECTIVES: We investigated whether first-year cumulative myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and proteinase 3 (PR3)-ANCA titres were associated with all-cause mortality and relapse during follow-up in patients with microscopic polyangiitis (MPA) and granMETHODS: Altogether, 74 patients with MPA and 40 with GPA were included in this study. Their clinical data at diagnosis were collected. First-year cumulative ANCA titres were defined as the area under the curve (AUC) of ANCA titres during the first year after MPA or GPA diagnosis, which was obtained using the trapezoidal rule. All-cause mortality and relapse were considered poor outcomes of MPA and GPA. RESULTS: The median ages of patients with MPA and GPA were 65.5 and 60.5 years, respectively. No significant correlation was observed between ANCA titres at diagnosis and concurrent MPA and GPA activity or the inflammatory burden. First-year cumulative MPO-ANCA titres exhibited a significant AUC for all-cause mortality during follow-up in patients with MPA. The optimal cut-off of first-year cumulative MPO-ANCA titres for all-cause mortality was determined as 720.8 IU/mL using receiver operating characteristic curve analysis. MPA patients with first-year cumulative MPO-ANCA titres ≥720.8 IU/mL exhibited a significantly higher risk for all-cause mortality than those without (relative risk 13.250). Additionally, MPA patients with first-year cumulative MPO-ANCA titres ≥720.8 IU/mL exhibited a significantly lower cumulative patients' survival rate than those without. CONCLUSIONS: This is the first study to demonstrate the association between first-year cumulative MPO-ANCA titres and all-cause mortality during follow-up in patients with MPA.

Earliest total vascular damage index scores independently predict all-cause mortality in patients with ANCA-associated vasculitis.

OBJECTIVES: This study investigated whether the earliest total Vasculitis Damage Index (VDI) score could significantly predict all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: This study included AAV patients who were first diagnosed at this hospital from 2001 to 2022. The earliest total VDI score was defined as the first VID assessed more than 3 months after AAV diagnosis in 93.5% of patients or after the first AAV presentation in 6.5% of patients. The optimal cut-off of the earliest total VDI score for all-cause mortality was obtained using the receiver operating characteristic curve. RESULTS: The median age and earliest VDI score were 60.0 years (35.5% men), and 3.0. The most common damaged system in the earliest VDI was the pulmonary (55.3%) system. Among the AAV patients, 39 (13.3%) died. When the optimal cut-off of the earliest total VDI score for all-cause mortality was set at 3.0 (sensitivity 64.1%, specificity 75.2%), AAV patients with the earliest total VDI score ≥3.0 exhibited a significantly higher risk for all-cause mortality than those without (relative risk 6.090). AAV patients with the earliest total VDI score ≥3.0 exhibited a significantly lower cumulative patients' survival rate than those without. In the multivariable Cox hazards model analyses, not only the earliest total VDI score but also the earliest total VDI score ≥3.0 were independently associated with all-cause mortality. CONCLUSIONS: This study was the first to demonstrate that the earliest total VDI score could predict all-cause mortality during follow-up in AAV patients.

Effect of Corticosteroid Use on the Occurrence and Progression of Osteonecrosis of the Femoral Head: A nationwide Nested Case-Control Study.

BACKGROUND: Although it is very well known that corticosteroids cause osteonecrosis of the femoral head (ONFH), it is unclear as to which patients develop ONFH. Additionally, there are no studies on the association between corticosteroid use and femoral head collapse in ONFH patients. We aimed to investigate the association between corticosteroid use and the risk of ONFH among the general population and what factors affect ONFH occurrence. Additionally, we aimed to demonstrate which factors affect femoral head collapse and total hip arthroplasty (THA) after ONFH occurrence. METHODS: A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort (2002 to 2019) in the Republic of Korea. We defined ONFH (N = 3,500) using diagnosis and treatment codes. Patients who had ONFH were matched 1:5 to form a control group based on the variables of birth year, sex, and follow-up duration. Additionally, in patients who have ONFH, we looked for risk factors for progression to THA. RESULTS: Compared with the control group, ONFH patients had a low household income and had more diabetes, hypertension, dyslipidemia, and heavy alcohol use (drinking more than 3 to 7 drinks per week). Systemic corticosteroid use (≥ 1,800 mg) was significantly associated with an increased risk of ONFH incidence. However, lipid profiles, corticosteroid prescription, and cumulative doses of corticosteroid did not affect the progression to THA. CONCLUSION: The ONFH risk increased rapidly when cumulative prednisolone use was ≥ 1,800 mg. However, oral or high-dose intravenous corticosteroid use and cumulative dose did not affect the prognosis of ONFH. Since the occurrence and prognosis of ONFH are complex and multifactorial processes, further study is needed.

Circulating cold-inducible RNA-binding protein levels in microscopic polyangiitis and granulomatosis with polyangiitis : Correlation with disease activity.

OBJECTIVE: This study investigated whether circulating cold-inducible RNA-binding protein (CIRP) could be a biomarker to reflect the current activity, function, and damage status in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: This study selected 39 MPA and 26 GPA patients. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices include the Birmingham Vasculitis Activity Index (BVAS), five-factor score (FFS), the Korean version of the Short-Form 36-Item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS), and the vasculitis damage index (VDI). The highest tertile of BVAS was defined as high activity of AAV. RESULTS: The median age of the study subjects was 65.0 years and 53.8% were women. The median BVAS, FFS, SF-36 PCS, MCS, and VDI scores were 12.0, 2.0, 47.5, 50.3, and 3.0, respectively. The median circulating CIRP level was 6.4 ng/mL. Among the four AAV-specific indices, circulating CIRP was significantly correlated with BVAS (r = 0.256). Using the receiver operator characteristic curve, the cut-off of circulating CIRP for high activity of AAV was 6.16 ng/mL. High activity of AAV was identified more frequently in patients with circulating CIRP ≥ 6.16 ng/mL than in those with circulating CIRP < 6.16 ng/mL (48.6% vs. 21.4%). In addition, patients with circulating CIRP ≥ 6.16 ng/mL exhibited a significantly higher risk for high activity of AAV than those with circulating CIRP < 6.16 ng/mL (relative risk 3.474). CONCLUSION: This study suggests the clinical potential of circulating CIRP as a biomarker for reflecting the current BVAS and predicting high activity of AAV in patients with MPA and GPA.

Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Index at Diagnosis Is Associated with All-Cause Mortality during Follow-Up in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Background and Objectives: The purpose of this study was to investigate whether a new index related to chronic liver disease, the alcoholic liver disease/nonalcoholic fatty liver disease index (ANI) at diagnosis, is associated with all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: In this study, we included 270 patients with AAV. ANI was calculated using the following equation: ANI = -58.5 + 0.637 (adjusted mean corpuscular volume) + 3.91 (adjusted aspartate transaminase/alanine transaminase) - 0.406 (body mass index) + 6.35 (if male sex). All-cause mortality was defined as death from any cause during follow-up. Results: The median age of the 270 patients with AAV was 61.0 years (34.4% male and 66.6% female). The median ANI was significantly higher in deceased patients than in surviving patients. In the receiver operating characteristic curve analysis, ANI at diagnosis exhibited a statistically significant area under the curve for all-cause mortality during follow-up, and its cut-off was determined to be -0.59. Patients with ANI at diagnosis ≥ -0.59 exhibited a significantly higher risk for all-cause mortality and a significantly lower cumulative patient survival rate than those without. In the multivariable Cox analysis, ANI at diagnosis ≥ -0.59, together with age at diagnosis, was independently associated with all-cause mortality. Conclusions: This study is the first to demonstrate the predictive potential of ANI at diagnosis for all-cause mortality during follow-up in AAV patients without significant chronic liver diseases.

The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus.

Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19+B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity.

Reclassification of previously diagnosed GPA patients using the 2022 ACR/EULAR classification criteria.

OBJECTIVES: This study applied the 2022 criteria for granulomatosis with polyangiitis (GPA) proposed by the ACR and EULAR (the 2022 ACR/EULAR criteria) to Korean patients with previously diagnosed GPA to investigate the number of patients who could be reclassified as having GPA. METHODS: Sixty-five patients with GPA, who met the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides and the 2007 European Medicines Agency algorithm for GPA, were included in this study. They were reclassified based on the 2022 ACR/EULAR criteria. RESULTS: Of the 65 patients, 48 patients (73.8%) were reclassified as having GPA. A patient could not be reclassified as having GPA if the patient did not have a total score of 5 despite granulomas on biopsy or clear GPA surrogate markers. Among the 17 patients unclassified as having GPA, 16 patients were reclassified as having MPA and one as having unclassifiable vasculitis, and furthermore, 94.1% of them harboured MPO-ANCA (or perinuclear (P)-ANCA). CONCLUSION: The concordance rate between the 2022 ACR/EULAR criteria for GPA and the previous criteria in patients with previously diagnosed GPA was 73.8%. Although the 2022 ACR/EULAR criteria are the product of the most advanced methodologic process, it should be noted that there were some consequences of distorting the CHCC definition, and further discussion is required, especially with respect to the weightage of the items.

Application of the 2022 ACR/EULAR criteria for microscopic polyangiitis to patients with previously diagnosed microscopic polyangiitis.

OBJECTIVES: This study applied the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (the 2022 ACR/EULAR) criteria for microscopic polyangiitis (MPA) to patients with previously diagnosed MPA as per the 2007 European Medicines Agency algorithm (the 2007 EMA algorithm) and the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides (the 2012 CHCC definitions) The concordance rate between the new and old criteria was investigated. METHODS: This study included 117 patients with MPA, and the new criteria were applied to these patients. MPA could be classified when the total score is ≥5. RESULTS: The median age was 64.0 years. The concordance rate between the new and old criteria reached 96.6%. Four patients with previously diagnosed MPA were unclassified. Of these, three patients without myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) (or perinuclear [P]-ANCA) were not reclassified as having MPA according to the new criteria, despite histopathological findings that were suggestive of MPA based on both the 2007 EMA algorithm and the 2012 CHCC definitions. Conversely, three of four patients with both MPO-ANCA (or P-ANCA) and proteinase 3 (PR3)- ANCA (or cytoplasmic [C]-ANCA) were reclassified as having both MPA and granulomatosis with polyangiitis (GPA) simultaneously according to the 2022 ACR/EULAR criteria for MPA and GPA. CONCLUSIONS: In the new criteria, excessively high score was assigned to MPO-ANCA (or P-ANCA) and MPA-specific histopathological findings were not considered. Hence, the 2007 EMA algorithm and the 2012 CHCC definitions can be applied as additional criteria to complex cases.

Serum soluble interleukin-7 receptor alpha levels are negatively correlated with the simultaneous activity of antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: This study investigated whether serum soluble interleukin-7 receptor alpha (sIL-7Rα) levels could reflect the simultaneous activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Sixty patients with AAV were included in this study. AAV-related variables and clinical and laboratory data were collected at the two-time points (at early high and late low BVAS) for each patient along with blood sampling. Serum sIL-7Rα levels and the populations of CD3+CD4+ and CD3+CD8+ T cells expressing membranous IL-7Rα (mIL-7Rα) were compared between patients at different time points and between patients and healthy controls. RESULTS: Serum sIL-7Rα levels were significantly lower in AAV patients at early high BVAS than in those at late low BVAS, and the direction of change in serum sIL-7Rα levels increased as BVAS decreased. Serum sIL-7Rα levels were inversely correlated with BVAS, erythrocyte sedimentation rate and C-reactive protein levels. In addition, serum sIL-7Rα levels in AAV patients at early high BVAS exhibited significantly lower levels than those in healthy controls. Particularly, AAV patients at early high BVAS showed significantly increased populations of CD3+ T cells and CD3+CD8+ T cells expressing mIL-7Rα compared to those at late low BVAS. CONCLUSIONS: This study demonstrated that not only serum sIL-7Rα levels but also the populations of CD3+ and CD3+CD8+ T cells expressing m IL-7Rα were negatively correlated with simultaneous BVAS in patients with AAV. Therefore, we suggest that serum sIL-7Rα levels can be an additional and useful biomarker for assessing the simultaneous activity of AAV.

Soluble Tyro-3 and Axl may reflect the current activity and renal involvement in patients with microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: This study investigated whether soluble Tyro-3 (sTyro-3), sAxl, and sMer could reflect the current activity in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: This study retrospectively reviewed the medical records of 76 patients with MPA and GPA, and measure the serum concentrations of sTyro-3, sAxl, and sMer using the stored serum at AAV diagnosis. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices included Birmingham vasculitis activity index (BVAS), five-factor score, the short-form 36-item health survey, and vasculitis damage index. High AAV activity was defined as the highest tertile of BVAS. RESULTS: The median age of the 47 MPA and 29 GPA patients was 66.0 years and 43.4% were men. The serum concentrations of sTyro-3 and sAxl were significantly correlated with BVAS and the total score of renal manifestation. The serum concentrations of sTyro-3 and sAxl were independently correlated with BVAS (ß=0.343 and ß=0.310, respectively). In addition, the serum concentrations of sTyro-3 and sAxl were independently associated with the renal involvement of MPA and GPA (OR 1.003 and OR 1.055, respectively). CONCLUSIONS: This study demonstrated the potential of the serum concentrations of sTyro-3 and sAxl to reflect the current activity and renal involvement in patients with MPA and GPA.

Acute Brain Infarction in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Korean Single-Center Study.

OBJECTIVES: This study investigated the clinical and radiological features of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with acute brain infarction, using a cohort of Korean patients with AAV. METHODS: This study included 263 patients with AAV. Acute brain infarction was defined as infarction that occurred within 7 days or less. The brain territories affected by acute brain infarction were investigated. Active AAV was arbitrarily defined as the highest tertile of Birmingham Vasculitis Activity Score (BVAS). RESULTS: The median age at diagnosis was 59.0 years, and 35.4% were male. Fourteen cases of acute brain infarction occurred in 12 patients (4.6%), which was calculated as 1332.2 per 100,000 patient-years and 10 times higher than the incidence rate in the Korean general population. Patients with AAV with acute brain infarction exhibited significantly older age, increased BVAS at diagnosis, and a more frequent history of prior brain infarction compared with those without. The brain territories affected in AAV patients were middle cerebral artery (50.0%), multiple territories (35.7%), and posterior cerebral artery (14.3%). Lacunar infarction and microhemorrhage were observed in 42.9% and 71.4% of cases, respectively. Prior brain infarction and BVAS at diagnosis were independently associated with acute brain infarction (hazard ratios, 7.037 and 1.089). Patients with AAV with prior brain infarction or BVAS for active AAV exhibited significantly lower cumulative acute brain infarction-free survival rates than those without. CONCLUSION: Acute brain infarction was observed in 4.6% of AAV patients, and both prior brain infarction and BVAS at diagnosis were independently associated with acute brain infarction.

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-1ß, 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.

Clinical characteristics and long-term outcomes in patients with mixed Class III/IV + V and pure proliferative lupus nephritis: A single-center experience.

OBJECTIVES: Proliferative lupus nephritis (LN) is a crucial complication in systemic lupus erythematosus (SLE). This study evaluated the clinical implications of coexistence of membranous LN in proliferative LN in terms of clinical characteristics and long-term outcome. METHODS: We retrospectively reviewed the medical records of patients with SLE who underwent renal biopsy between 2005 and 2018. Patients with proliferative LN based on the 2003 International Society of Nephrology/Renal Pathology Society classification were subclassified into pure (Class III or IV only) and mixed (Class III or IV + Class V) proliferative LN. The clinical features at the time of renal biopsy, incidence of end-stage renal disease (ESRD), and all-cause mortality were compared between patients with mixed or pure proliferative LN. RESULTS: Of the 171 patients, 30 and 141 were classified into mixed and pure proliferative LN groups, respectively. Patients with pure proliferative LN showed higher anti-dsDNA antibody and lower hemoglobin, platelet, and complement 3 levels than patients with mixed proliferative LN. The SLE disease activity index was also higher in patients with pure proliferative LN (p = 0.047). The pure proliferative LN group showed a higher proportion of Class IV and higher histologic activity index scores (p < 0.001 and p = 0.004, respectively). During the follow-up period of 58.3 months, 18 patients developed ESRD and 15 patients died. ESRD was exclusively observed in patients with pure proliferative LN, although the incidence of ESRD was not statistically different (p = 0.055). All-cause mortality was comparable between the two groups. CONCLUSION: Pure proliferative LN was associated with higher clinical and histological activities and modestly increased risk of ESRD. Active immunosuppressive treatment would be required to control the renal inflammation in patients with proliferative LN, regardless of the coexistence of membranous LN.

Effect of numbers of metabolic syndrome components on mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis with metabolic syndrome.

OBJECTIVES: This study investigated the effect of the number of metabolic syndrome (MetS) components on all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) with MetS. METHODS: The medical records of 93 AAV patients with MetS were retrospectively reviewed. MetS was diagnosed when three or more the following MetS components for Asians were met: (i) increased waist circumference; ii) high blood pressure; (iii) hypertriglyceridaemia; (iv) low level of high-density lipoprotein (HDL)-cholesterol; and (v) impaired fasting glucose (IFG) or type 2 diabetes mellitus (T2DM). All-cause mortality was defined as death owing to any aetiology. RESULTS: The median age was 61.4 years and 33 patients were men. Among 93 AAV patients with MetS, as the number of MetS components increased, the cumulative patient survival rate significantly decreased (p = 0.024). Compared to surviving AAV patients with MetS, deceased AAV patients with MetS were older, had higher Birmingham vasculitis activity score (BVAS) and Five-factor score (FFS), a lower frequency of IFG or T2DM, and a higher number of MetS components. In the multivariable Cox analysis, AAV patients with MetS who had all five MetS components were approximately 62 times more susceptible to all-cause mortality than those who had only three components. In terms of IFG or T2DM, patients with only IFG exhibited a significantly lower cumulative patients' survival rate than those without. CONCLUSIONS: The presence of many MetS components at the initial diagnosis of AAV was an independent and significant predictor of all-cause mortality in AAV patients with MetS.

Serum galectin-9 could be a potential biomarker in assessing the disease activity of antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Serum galectin levels have been reported to be associated with the activity in autoimmune diseases. This study investigated whether serum levels of galectin (Gal)-1, Gal-3, and Gal-9 could be used as biomarkers in assessing the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Eighty AAV patients were selected for inclusion in our AAV cohort. AAV-specific indices and clinical and laboratory data were assessed on the same day when blood samples were obtained from the patient and serum levels of Gal-1, Gal-3, and Gal-9 were measured by ELISA from obtained sera. High disease activity was defined as Birmingham vasculitis activity score (BVAS) ≥ 12. The optimal cut-off value of galectins was extrapolated by receiver operator characteristic analysis and linear and logistic regression analyses were performed to evaluate the association between Gal-3, Gal-9, and BVAS. RESULTS: The median values of BVAS, Gal-1, Gal-3, and Gal-9 were 8.0, 38.1 ng/mL, 12.4 ng/mL, and 1017.7 ng/mL, respectively. Serum Gal-3 and Gal-9 levels were correlated with BVAS (r=0.375 and r=0.462), while only serum Gal-9 levels were independently associated with BVAS (ß=0.250) in linear regression analyses. Serum Gal-9 ≥10.28 ng/mL was also associated with high activity of AAV (odds ratio 5.303) in multivariable logistic regression analysis. In addition, serum Gal-1, Gal-3, and Gal-9 levels were found to differ according to ANCA positivity status and the presence of renal manifestations. CONCLUSIONS: These results suggest the potential possibility of serum Gal-9 levels in assessing AAV disease activity.

Serum glycated albumin as a predictive biomarker for renal involvement of antineutrophil cytoplasmic antibody-associated vasculitis in non-diabetic patients.

BACKGROUND: Glycated albumin (GA) is known to reflect the current inflammatory burden in non-diabetes mellitus (DM) patients. In this study, we investigated whether GA at diagnosis could reflect the cross-sectional activity and predict poor outcomes during follow-up in non-DM patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: The medical records of 118 immunosuppressive drug-naïve AAV patients were retrospectively reviewed, and 76 patients who had both GA and glycated haemoglobin (HbA1c) results but not DM were included in this study. Demographic, clinical, and laboratory data at diagnosis were assessed. RESULTS: The median age of AAV patients was 61 years, and 31 patients were male. GA was positively correlated with five-factor score (r = 0.282), Birmingham vasculitis activity score (BVAS) assigned to renal manifestation (r = 0.315), and blood urea nitrogen (r = 0.382), whereas negatively correlated with haemoglobin (r = -0.345). AAV patients with end-stage renal disease (ESRD) exhibited significantly higher GA than those without ESRD (15.8% vs. 13.6%). When the cut-off of GA at diagnosis for ESRD was set at GA ≥ 14.25%, AAV patients with GA ≥ 14.25% had a significantly higher risk for ESRD development than those without (relative risk 12.040). In addition, AAV patients with GA ≥ 14.25% exhibited significantly lower cumulative ESRD-free survival rates than those without (P = 0.020). CONCLUSION: In conclusion, GA at diagnosis can reflect the cross-sectional BVAS assigned to renal manifestation of AAV and predict ESRD development during follow-up better than HbA1c or GA/HbA1c in AAV patients.

Clinical application of low erythrocyte sedimentation rate/high C-reactive protein to antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: This study investigated whether the discordance between erythrocyte sedimentation rate (ESR) and C-reactive protein at diagnosis could estimate the simultaneous clinical and laboratory variables and predict the poor outcomes during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: The medical records of 254 AAV patients were reviewed. Clinical and laboratory and AAV-specific indices at diagnosis and all-cause mortality, relapse and end-stage renal disease during follow-up were obtained. ESR and CRP levels were categorised as high and low based on the median values. Accordingly, the patients were divided into the following four groups: high ESR/low CRP; low ESR/high CRP; low ESR/low CRP; and high ESR/high CRP. RESULTS: Of the 254 AAV patients, 51 patients exhibited discordance between ESR and CRP. Among the 51 AAV patients, the median age was 59.0 years, and 20 patients were men (29 MPA, 13 GPA and 9 EGPA). Cardiovascular and nervous systemic manifestations were observed more frequently in AAV patients with low ESR/high CRP than in those with high ESR/low CRP. Six patients from the low ESR/high CRP group died. AAV patients with low ESR/high CRP exhibited significantly lower cumulative patients' survival rates than both those with high ESR/low CRP and those with low ESR/low CRP. Also, AAV patients with low ESR/high CRP exhibited significantly higher simultaneous BVAS than those with low ESR/low CRP. CONCLUSIONS: Low ESR/high CRP at diagnosis could not only estimate the simultaneous high BVAS but also predict all-cause mortality during follow-up in AAV patients.

Predicting the depressive status using empirical dietary inflammatory index in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: This study investigated whether the empirical dietary inflammatory index (eDII) score is associated with the inflammatory burden as well as the depressive status in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Eighty-four patients with AAV participated in this study. Birmingham vasculitis activity score (BVAS) and short-form 36-item Health Survey mental component summary (SF-36 MCS) were considered as indices assessing the inflammatory burden and depressive status, respectively. The eDII includes 16 food components and consists of three groups: -9 to -2, the low eDII group; -1 to +1, the moderate eDII group; and +2 to +10, the high eDII group. Furthermore, the lower eDII group includes both the low and moderate eDII groups. RESULTS: The median age was 64.5 years (36 men). The eDII scores inversely correlated with SF-36 MCS (r = -0.298, p = 0.006) but not with BVAS. SF-36 MCS significantly differ between the lower and higher eDII groups (69.7 vs. 56.7, p = 0.016), but not among the low, moderate and high eDII groups. Additionally, when patients with AAV were divided into two groups according to the upper limit of the lowest tertile of SF-36 MCS of 55.31, patients in the higher eDII group exhibited a significantly higher risk for the lowest tertile of SF-36 MCS than those in the lower eDII group (RR 3.000). CONCLUSION: We demonstrated for the first time that the eDII could predict the depressive status by estimating SF-36 MCS without utilising K-CESD-R ≥ 16 in patients with AAV.

Nutrition Risk Index Score at Diagnosis Can Effectively Predict Poor Prognosis in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVES: This study investigated whether the nutritional risk index (NRI) score at diagnosis might be useful for anticipating poor prognosis, in particular, all-cause mortality and end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: The medical records of 242 immunosuppressive drug-naïve patients with AAV were retrospectively reviewed. Data at diagnosis and poor prognosis and medications during follow-up were assessed. The NRI score was calculated by 1.519 × serum albumin (g/L) + 41.7 × present (kg)/ideal body weight (kg). RESULTS: The median age at diagnosis of patients with AAV (131 microscopic polyangiitis, 62 granulomatosis with polyangiitis, and 49 eosinophilic granulomatosis with polyangiitis) was 60 years (85 male). During follow-up, twenty-nine patients (12.0%) died after a period of 35.9 months, and 42 patients (17.4%) had ESRD for a period of 30.0 months. Using the receiver operator characteristic curve, the cutoffs of the NRI scores for all-cause mortality and ESRD were calculated as NRI ≤ 101.95 (sensitivity, 46.5%; specificity, 89.7%) and NRI ≤ 99.85 (sensitivity, 57.0%; specificity, 83.3%). In the multivariable Cox hazard model analyses, age (hazard ratio [HR], 1.035), five-factor score (HR, 1.623), and the NRI score ≤ 101.95 (HR, 4.262) were independent predictors of all-cause mortality, whereas, five-factor score (HR, 1.516), hypertension (HR, 1.906), and the NRI score ≤ 99.85 (HR, 3.623) were independent predictors of ESRD occurrence during follow-up in patients with AAV. CONCLUSIONS: The NRI score at diagnosis may be a useful index to anticipate all-cause mortality and ESRD occurrence during follow-up in patients with AAV.