Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomised into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day, and IVMP 1.0 g/day. The primary outcome was all-cause death, and the secondary outcomes were composite all-cause death and kidney failure, severe relapse, and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (2.8%) died, 4 (2.0%) had kidney failure, 11 (5.3%) had severe relapse, and 40 (19.8%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause death = 0.46 (95% confidence interval [95%CI]: 0.07-2.81) and 0.07 (95%CI: 0.01-0.41); all-cause death/kidney failure = 1.18 (95%CI: 0.26-5.31) and 0.59 (95%CI: 0.08-4.52); subdistribution HRs for severe relapse = 1.26 (95%CI: 0.12-13.70) and 3.36 (95%CI: 0.49-23.29); and serious infection = 1.88 (95%CI: 0.76-4.65) and 0.94 (95%CI: 0.28-3.13). CONCLUSIONS: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Aggressive multi-combination therapy for anti-MDA5 antibody-positive dermatomyositis-rapidly progressive interstitial lung disease.

OBJECTIVES: To elucidate the efficacy and safety of aggressive multi-combination therapy with mycophenolate mofetil, rituximab, and plasma exchange or polymyxin B immobilized fiber column direct hemoperfusion followed by conventional therapy with corticosteroids, calcineurin inhibitors, and intravenous pulse cyclophosphamide in patients with rapidly progressive interstitial lung disease (RPILD) with anti-melanoma differentiation-associated gene 5 (MDA5)-antibody-positive dermatomyositis (DM). METHODS: A total of 23 patients with anti-MDA5 antibody-positive DM-RPILD were enrolled, with nine patients in Group A (treated conventionally before March 2015) and 14 patients in Group B (received aggressive treatment after April 2015). RESULTS: Pretreatment severity of interstitial lung disease (ILD) did not differ between the two groups. However, Group B exhibited a higher cumulative survival rate at 48 weeks than Group A (64.3% vs. 33.3%). The corticosteroid dose, divided by the initial dose at 3 months and 12 months, was significantly lower in Group B than in Group A (p = .046 and .026, respectively). Among the ILD-related deaths in Group B, there was a tendency toward a higher proportion of males and more severe ILD. The incidence of infection did not differ between the groups, but leukopenia was more common in Group B. CONCLUSION: This aggressive multi-combination therapy may improve the survival outcome of patients with anti-MDA5 antibody-positive DM-RPILD. However, careful management of complications, such as opportunistic infections and leukopenia, is essential. Future refinement through longitudinal investigations tracking the long-term efficacy, safety, and cost-effectiveness of this treatment strategy is needed.

A successful plasma exchange in bridging to rituximab for severe neuropsychiatric lupus and lupus nephritis with viral infections and aspiration pneumonia.

Systematic lupus erythematosus (SLE) is a chronic autoimmune disease involving several organs such as the kidneys, skin, vessels, and central nervous system. Neuropsychiatric SLE (NPSLE) is a life-threatening condition that needs treatment with the combination of glucocorticoids and Immunosuppressants (IS). This includes cyclophosphamide and rituximab (RTX) which can lead to several infections. Therapeutic apheresis is an optional treatment for inflammatory diseases and has less risks of infections than IS. Plasma exchange (PE) is one of the most common apheresis, and is recommended for the management of NPSLE. We report a refractory NPSLE case with bacterial pneumonia and cytomegalovirus antigenemia. PE was performed prior to RTX. After the initiation of RTX which was incompatible due to infection such as aspiration pneumonia and cytomegalic virus, PE was scheduled considering the pharmacokinetics of RTX. Her SLE activity was well managed after PE and RTX without flare. PE treatment plan bridging to IS and RTX may effectively work in refractory SLE patients with infections.

Risk prediction model for mortality in microscopic polyangiitis: multicentre REVEAL cohort study.

BACKGROUND: To establish refined risk prediction models for mortality in patients with microscopic polyangiitis (MPA) by using comprehensive clinical characteristics. METHODS: Data from the multicentre Japanese registry of patients with vasculitis (REVEAL cohort) were used in our analysis. In total, 194 patients with newly diagnosed MPA were included, and baseline demographic, clinical, laboratory, and treatment details were collected. Univariate and multivariate analyses were conducted to identify the significant risk factors predictive of mortality. RESULTS: Over a median follow-up of 202.5 (84-352) weeks, 60 (30.9%) of 194 patients died. The causes of death included MPA-related vasculitis (18.3%), infection (50.0%), and others (31.7%). Deceased patients were older (median age 76.2 years) than survivors (72.3 years) (P < 0.0001). The death group had shorter observation periods (median 128.5 [35.3-248] weeks) than the survivor group (229 [112-392] weeks). Compared to survivors, the death group exhibited a higher smoking index, lower serum albumin levels, higher serum C-reactive protein levels, higher Birmingham Vasculitis Activity Score (BVAS), higher Five-Factor Score, and a more severe European Vasculitis Study Group (EUVAS) categorization system. Multivariate analysis revealed that higher BVAS and severe EUVAS independently predicted mortality. Kaplan-Meier survival curves demonstrated lower survival rates for BVAS ≥20 and severe EUVAS, and a risk prediction model (RPM) based on these stratified patients into low, moderate, and high-risk mortality groups. CONCLUSIONS: The developed RPM is promising to predict mortality in patients with MPA and provides clinicians with a valuable tool for risk assessment and informed clinical decision-making.

Serum Complement C4 Levels Are a Useful Biomarker for Predicting End-Stage Renal Disease in Microscopic Polyangiitis.

This study aimed to evaluate the risk factors for end-stage renal disease (ESRD) in microscopic polyangiitis (MPA). In total, 74 patients with MPA were enrolled, and we compared the baseline clinical characteristics and disease activity between MPA patients who have progressed to ESRD and those without ESRD to select predictive factors for ESRD. Out of 74 patients, 12 patients (16.2%) had ESRD during follow-up. Serum C4 levels were significantly higher in MPA patients who have progressed to ESRD than in those without ESRD (p = 0.009). Multivariate analyses revealed that high serum creatinine levels (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.25-15.5) and high serum C4 levels (OR 1.24, 95% CI 1.03-1.49) were risk factors for ESRD. Using receiver operating characteristic analysis, the cut-off value for initial serum C4 levels and serum creatinine levels were 29.6 mg/dL and 3.54 mg/dL, respectively. Patients with MPA with a greater number of risk factors (serum C4 levels > 29.6 mg/dL and serum creatinine levels > 3.54 mg/dL) had a higher ESRD progression rate. Serum C4 levels were significantly positively correlated with serum creatinine levels and kidney Birmingham vasculitis activity score (p = 0.02 and 0.04, respectively). These results suggest that serum C4 levels are useful tools for assessing renal disease activity and prognosis in MPA.

Trends of disease activity in Japanese patients over 75 years with rheumatoid arthritis from 2014 to 2021- the ANSWER cohort study.

OBJECTIVES: To investigate if disease activity among elderly RA patients over 75 years has changed over time in the real-world clinical setting. METHODS: Data from an observational multicentre registry of RA patients in Japan were analyzed. The primary outcome was to evaluate the changes in the proportion of very elderly RA patients (over 75 years) who achieved remission and low disease activity, from 2014 to 2021. The secondary outcome was to identify factors associated with remission and low disease activity by comparing demographic and clinical characteristics among the patients who had a study visit within the study period, using multivariate logistic regression. RESULTS: A total of 32 161 patient visits were identified from 2014 to 2021. The proportion of patients over 75 years increased from 16.5% to 26.9%, with biologics and targeted-synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) usage increasing and glucocorticoids usage decreasing, while conventional-synthetic DMARDs usage remained relatively stable. The proportion of RA patients over 75 years achieving remission and low disease activity significantly increased from 62.2% to 78.2% (p for trend < 0.001). A negative factor associated with achieving remission and low disease activity was glucocorticoid usage, seropositivity, and history of previous b/tsDMARDs use while MTX usage was associated positively, independent of other predictors. CONCLUSIONS: In our cohort, disease activity among very elderly RA patients has improved over time. The study suggests the importance of using a treat-to-target approach in very elderly RA patients to improve clinical outcomes.

Optimal Dose of Intravenous Cyclophosphamide during remission induction therapy in ANCA-associated vasculitis: a retrospective cohort study of J-CANVAS.

OBJECTIVES: To identify the optimal dose of intravenous cyclophosphamide (IVCY) for induction therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: We retrospectively assessed patients with AAV who received IVCY every 2-3 weeks during the remission induction phase. The associations of the IVCY dose with infection-free survival and relapse-free survival were analysed using a Cox regression model. We compared patients in three categories: very low-dose (VLD), low-dose (LD), and conventional dose (CD) (<7.5 mg/kg, 7.5-12.5 mg/kg, and >12.5 mg/kg, respectively). The non-linear association between IVCY dose and the outcomes were also evaluated. RESULTS: Of the 80 patients (median age 72 years), 12, 42, and 26 underwent the VLD, LD, and CD regimens, respectively, of whom 4, 3, and 7 developed infection or died. The adjusted hazard ratios for infection or death were 4.3 (95% confidence interval (CI) 0.94-19.8) for VLD and 5.1 (95% CI 1.21-21.3) for CD, compared with LD. We found the hazard ratio for infection or death increased when the initial IVCY dose exceeded 9 mg/kg. Relapse-free survival did not differ clearly. CONCLUSION: Low-dose IVCY (7.5-12.5 mg/kg) may result in fewer infections and similar relapse rates compared with the conventional regimen (>12.5 mg/kg).

Prediction model for respiratory-related mortality in microscopic polyangiitis with interstitial lung disease: multicenter REVEAL cohort study.

OBJECTIVE: This study aimed to establish prediction models for respiratory-related mortality in microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using clinical characteristics. METHODS: We enrolled patients with MPA with ILD between May 2005 and June 2021 in a multicentre cohort of Japanese patients with MPA (REVEAL cohort). We evaluated the demographic, clinical, laboratory, radiological findings, treatments, and the presence of honeycombing 1 cm above the diaphragm using chest high-resolution computed tomography (HRCT) on admission. We explored the risk factors predictive of respiratory-related mortality. RESULTS: Of 115 patients, 26 cases died of respiratory-related diseases during a median follow-up of 3.8 years. Eighteen patients (69%) died due to respiratory infection, three (12%) had diffuse alveolar hemorrhage (DAH), and five (19%) had exacerbation of ILD. In univariate analysis, older age, lower percent forced vital capacity (%FVC), lower percent diffusing capacity of carbon monoxide (%DLco), and the presence of honeycombing in the right lower lobe were identified as risk factors. Additionally, in multivariate analysis adjusted for age and treatment, %FVC, %DLco, and the presence of honeycombing in the right lower lobe were independently associated with respiratory-related mortality. We created prediction models based on the values of %FVC, %DLco, and presence of honeycombing on chest HRCT (MPF model). The 5-year respiratory-related death-free rate was significantly different between patients with MPA with ILD stratified by the number of risk factors based on the MPF model. CONCLUSIONS: Our study indicates that the MPF model may help predict respiratory-related death in patients with MPA with ILD.

Seasonal Influence on Development of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Retrospective Cohort Study Conducted at Multiple Institutions in Japan (J-CANVAS).

OBJECTIVE: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season. RESULTS: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA (P < 0.001), but not in those with PR3-ANCA (P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis. CONCLUSION: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

The Impact of Early Optimization of Infliximab Blood Concentrations >1 µg/mL on Therapeutic Effectiveness in Rheumatoid Arthritis.

BACKGROUND: Infliximab is a human-murine chimeric monoclonal IgG antibody against tumor necrosis factor that is used in combination with methotrexate for the treatment of moderate to severe rheumatoid arthritis (RA). The trough concentration of serum infliximab required to control disease activity in RA is ≥1 µg/mL, and we investigated whether this trough concentration can predict the effectiveness of RA treatment. METHODS: We retrospectively analyzed the cases of 76 patients with RA. The REMICHECK Q® (REMIQ) is a kit that can check for serum infliximab concentrations. Infliximab concentrations >1 µg/mL at 14 weeks after an initial infliximab induction is considered REMIQ-positive, otherwise considered REMIQ-negative. Here, we determined the retention rates and investigated the clinical and serologic features of REMIQ-positive and REMIQ-negative patients. RESULTS: At 14 weeks, significantly more of the REMIQ-positive patients (n = 46) were responders compared to the non-responders (n = 30). The retention rate at 54 weeks was also significantly higher in the REMIQ-positive group versus the negative group. After 14 weeks, more patients in the REMIQ-negative group were considered inadequate responders, and their infliximab doses were escalated. At baseline, the REMIQ-positive group had significantly lower C-reactive protein (CRP) levels compared to the negative group. Cox regression analysis with multiple variables showed that the positivity of REMIQ (hazard ratio [HR] 2.10 and 95% confidence interval [CI]: 1.55-5.71) at baseline was associated with the achievement of low disease activity. The positivities of rheumatoid factor and anti-CCP antibody at baseline were associated with the achievement of remission with infliximab treatment (HR 0.44, 95% CI: 0.09-0.82 and HR 0.35, 95% CI: 0.04-0.48, respectively). CONCLUSIONS: The results of this study suggest that the control of RA disease activity may be facilitated by using the REMIQ kit at 14 weeks to check whether it is necessary to increase a patient's infliximab dose to ensure a therapeutic blood concentration that will help the patient achieve low disease activity.

Prognostic Factors Affecting Death in Patients with Rheumatoid Arthritis Complicated by Pneumocystis jirovecii Pneumonia and One-Year Clinical Course: The ANSWER Cohort Study.

This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP (median age, 69 years; 73% female), chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention.

Association between hypogammaglobulinaemia and severe infections during induction therapy in ANCA-associated vasculitis: from J-CANVAS study.

OBJECTIVES: To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. METHODS: We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups. RESULTS: Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. CONCLUSION: Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Examination of nailfold videocapillaroscopy findings in ANCA-associated vasculitis.

OBJECTIVE: The objective of this study was to evaluate nailfold videocapillaroscopy (NVC) as a useful tool for assessing the disease activity of ANCA-associated vasculitis (AAV). METHODS: This study enrolled 51 patients with AAV and 21 healthy controls. We scored NVC findings semiquantitatively, and compared them between AAV patients and controls. We examined the association of NVC findings with disease activity indicators, histopathological findings of skin biopsies, and high-resolution CT (HRCT) scores in AAV. Additionally, we repeatedly rated the NVC findings 3 months after immunosuppressive therapy. RESULTS: Of the 51 enrolled patients, 36 (70.6%) showed a microangiopathy pattern and 4 (7.8%) showed a scleroderma pattern in AAV. The scores for microhaemorrhage, capillary loss, neoangiogenesis, and tortuosity were significantly higher in the AAV group than in the control group. NVC abnormalities correlated with the severity of skin, lung and kidney involvement. The scores of giant capillaries significantly correlated with the total BVAS and the chest BVAS; the scores of capillary loss correlated with the chest BVAS and the renal BVAS. The scores of microhaemorrhage significantly correlated with perivascular inflammatory cell infiltrations in the upper dermis of the purpura and tended to correlate with the total ground-glass opacity and consolidation scores on HRCT. In addition, capillary loss scores had a significant positive correlation with serum creatinine levels. Additionally, the microhaemorrhage scores were significantly reduced after 3 months of immunosuppressive therapy. CONCLUSION: In AAV patients, NVC abnormalities are significantly associated with disease severity. This result suggests that NVC is a useful tool for assessing the disease activity and treatment response in AAV.

Prognostic factors affecting respiratory-related death in patients with rheumatoid arthritis complicated by interstitial lung disease: An ANSWER cohort study.

The aim of this multi-centre retrospective study was to clarify the prognostic factors for respiratory-related death in patients with interstitial lung disease (ILD) complicated rheumatoid arthritis (RA). Patient background data, treatment regimen, and disease activity indicators of RA and ILD at baseline, 6 months after the diagnosis of ILD, and at the last follow-up visit were extracted. A total of 312 patients with RA-ILD (17 patients who died from respiratory-related causes and 295 survivors) were included. Patients who died from respiratory-related causes had an older median age, a higher proportion of being male, and a higher anti-cyclic citrullinated peptide antibody positivity rate than survivors (p = .0001, .038, and .016, respectively); they also had significantly higher baseline serum levels of Krebs von den Lungen-6 (KL-6) than survivors (p = .013). Patients who died from respiratory-related causes showed significantly greater changes in serum KL-6 levels between the 6-month time point and the last visit [ΔKL-6 (6 months - last)] than survivors (p = .011). Multivariate analysis showed that the ΔKL-6 (6 months - last) corrected by disease duration was a predictor of respiratory-disease-related death in patients with RA-ILD (p < .0001). Long-term increase in serum KL-6 levels is associated with respiratory-disease related death in patients with RA-ILD.

Association between Serum Biomarkers and Peripheral Neuropathy in Microscopic Polyangiitis.

This study aimed to elucidate the pathomechanism of peripheral neuropathy (PN) in microscopic polyangiitis (MPA) and to identify biomarkers useful for diagnosis and severity assessment. Patients with MPA (n = 37) and other non-inflammatory neurological diseases (ONDs; n = 12) were enrolled, and the peripheral nerves of all patients were evaluated using nerve conduction studies. We compared the clinical characteristics and 14 serum biomarker profiles among patients with MPA and PN, MPA without PN, and ONDs. Patients with MPA had a higher prevalence of motor neuropathy than patients with ONDs. Among the patients with MPA, those with motor neuropathy had significantly higher total Birmingham Vasculitis Activity Scores and serum levels of C-reactive protein (CRP), tissue inhibitor of metalloproteinase-1 (TIMP-1), and interleukin-6 than patients without motor neuropathy. Multivariable analyses adjusted for age, serum CRP level, and diabetes mellitus showed that high serum levels of TIMP-1 were independently related to a diagnosis of motor neuropathy in MPA. Additionally, there were significant negative correlations between the serum levels of TIMP-1 and compound muscle action potential amplitudes. Serum levels of TIMP-1 may be associated with the pathomechanism of motor neuropathy in MPA and could be a useful biomarker for diagnosing and evaluating the severity of motor neuropathy in MPA.

Therapeutic effects of adipose-derived mesenchymal stem/stromal cells with enhanced migration ability and hepatocyte growth factor secretion by low-molecular-weight heparin treatment in bleomycin-induced mouse models of systemic sclerosis.

BACKGROUND: Adipose-derived mesenchymal stem cells (ASCs) have gained attention as a new treatment for systemic sclerosis (SSc). Low-molecular-weight heparin (LMWH) enhances cell function and stimulates the production of hepatocyte growth factor (HGF) in a variety of cells. This study investigated the effects of LMWH on the functions of mouse ASCs (mASCs), and the therapeutic effects of mASCs activated with LMWH (hep-mASCs) in mouse models of SSc. METHODS: The cellular functions of mASCs cultured with different concentrations of LMWH were determined. Mice were divided into four groups: bleomycin (BLM)-induced SSc (BLM-alone), BLM-induced SSc administered with mASCs (BLM-mASC), and BLM-induced SSc administered with mASCs activated with 10 or 100 µg/mL LMWH (BLM-hep-mASC); there were 9 mice per group (n = 9). Skin inflammation and fibrosis were evaluated using histological and biochemical examinations and gene expression levels. RESULTS: In vitro assays showed that migration ability and HGF production were significantly higher in hep-mASCs than in mASCs alone. The mRNA expression levels of cell migration factors were significantly upregulated in hep-mASCs compared to those in mASCs alone. The hep-mASCs accumulated in the skin tissues more than mASCs alone. The thickness of skin and hydroxyproline content in BLM-hep-mASC groups were significantly decreased, and the skin mRNA expression levels of interleukin-2, α-smooth muscle actin, transforming growth factor ß1, collagen type 1 alpha 1, and tissue inhibitor of metalloproteinase 2 were significantly downregulated compared to those in the BLM-alone group. CONCLUSIONS: hep-mASCs showed higher anti-inflammatory and anti-fibrotic effects than mASCs alone and may be a promising candidate for SSc treatment.

Adipose-derived stem/stromal cells with heparin-enhanced anti-inflammatory and antifibrotic effects mitigate induced pulmonary fibrosis in mice.

Interstitial lung disease (ILD) is a life-threatening pathological condition that causes respiratory failure and often presents as pulmonary fibrosis. Although it is treated using immunosuppressive and antifibrotic agents, the beneficial effects of these agents remain limited. Thus, the development of new therapeutic strategies for lung fibrosis is crucial. Mesenchymal stem/stromal cells (MSCs) have multilineage differentiation potential; additionally, they have anti-inflammatory and antifibrotic effects as well as the ability to modulate the immune response and modify the microenvironment at the site of engraftment. Numerous adipose-derived MSCs (ASCs) are present in the adipose tissue. Heparin and low-molecular-weight heparin (LMWH) mediate the secretion of several cytokines and growth factors with cell migratory and antifibrotic effects. This study aimed to confirm the therapeutic effect of LMWH-activated ASCs on ILD. Mouse ASCs (mASCs) were cultured in an LMWH-supplemented medium. LMWH significantly increased the number of mASC and enhanced their migratory, anti-inflammatory, and antifibrotic effects. Furthermore, mice with bleomycin-induced pulmonary fibrosis were intravenously administered LMWH-activated mASCs. The relative mRNA expression of inflammation-related genes in ILD lungs was significantly lower in the treatment group than in the pathological model group. Our findings suggest that LMWH-activated mASC administration reduces lung fibrosis.

Human MIKO-1, a Hybrid Protein That Regulates Macrophage Function, Suppresses Lung Fibrosis in a Mouse Model of Bleomycin-Induced Interstitial Lung Disease.

Although interstitial lung disease (ILD) is a life-threatening pathological condition that causes respiratory failure, the efficiency of current therapies is limited. This study aimed to investigate the effects of human MIKO-1 (hMIKO-1), a hybrid protein that suppresses the abnormal activation of macrophages, on murine macrophage function and its therapeutic effect in a mouse model of bleomycin-induced ILD (BLM-ILD). To this end, the phenotype of thioglycolate-induced murine peritoneal macrophages co-cultured with hMIKO-1 was examined. The mice were assigned to normal, BLM-alone, or BLM + hMIKO-1 groups, and hMIKO-1 (0.1 mg/mouse) was administered intraperitoneally from day 0 to 14. The mice were sacrificed on day 28, and their lungs were evaluated by histological examination, collagen content, and gene expression levels. hMIKO-1 suppressed the polarization of murine macrophages to M2 predominance in vitro. The fibrosis score of lung pathology and lung collagen content of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. The expression levels of TNF-α, IL-6, IL-1ß, F4/80, and TIMP-1 in the lungs of the BLM + hMIKO-1 group were significantly lower than those in the BLM-alone group. These findings indicate that hMIKO-1 reduces lung fibrosis and may be a future therapeutic candidate for ILD treatment.

Hypertrophic pachymeningitis in ANCA-associated vasculitis: a cross-sectional and multi-institutional study in Japan (J-CANVAS).

BACKGROUND: This study investigated the characteristics of hypertrophic pachymeningitis (HP) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), using information from a multicenter study in Japan. METHODS: We analyzed the clinical information of 663 Asian patients with AAV (total AAV), including 558 patients with newly diagnosed AAV and 105 with relapsed AAV. Clinical findings were compared between patients with and without HP. To elucidate the relevant manifestations for HP development, multivariable logistic regression analyses were additionally performed. RESULTS: Of the patients with AAV (mean age, 70.2 ± 13.5 years), HP was noted in 30 (4.52%), including 20 (3.58%) with newly diagnosed AAV and 10 (9.52%) with relapsed AAV. Granulomatosis with polyangiitis (GPA) was classified in 50% of patients with HP. A higher prevalence of GPA was significantly observed in patients with HP than in those without HP in total AAV and newly diagnosed AAV (p < 0.001). In newly diagnosed AAV, serum proteinase 3 (PR3)-ANCA positivity was significantly higher in patients with HP than in those without HP (p = 0.030). Patients with HP significantly had ear, nose, and throat (ENT) (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.03-2.14, p = 0.033) and mucous membrane/eye manifestations (OR 5.99, 95% CI 2.59-13.86, p < 0.0001) in total AAV. Moreover, they significantly had conductive hearing loss (OR 11.6, 95% CI 4.51-29.57, p < 0.0001) and sudden visual loss (OR 20.9, 95% CI 5.24-85.03, p < 0.0001). CONCLUSION: GPA was predominantly observed in patients with HP. Furthermore, in newly diagnosed AAV, patients with HP showed significantly higher PR3-ANCA positivity than those without HP. The ear and eye manifestations may be implicated in HP development.

Association of M2 Macrophages, Th2, and B Cells With Pathomechanism in Microscopic Polyangiitis Complicated by Interstitial Lung Disease.

OBJECTIVE: To address the pathomechanism of microscopic polyangiitis (MPA) complicated by interstitial lung disease (ILD) using serum biomarker profile and pulmonary histopathology. METHODS: Serum biomarkers from patients with MPA-ILD (n = 32), MPA without ILD (n = 17), and healthy controls (n = 10) were examined. Based on the biomarker profiles, principal component analysis (PCA) and cluster analysis were performed to classify patients with MPA-ILD into subgroups. Clinical characteristics and prognosis were assessed for each subgroup. Two lung biopsies were examined following H&E staining and immunostaining. RESULTS: T cell and macrophage polarization was skewed toward the T helper (Th) 2 cells and M2 macrophages in the MPA-ILD group relative to that in MPA without ILD group. The PCA allowed classification of the 19 biomarker profiles into 3 groups: (1) B cell- and neutrophil-related cytokines, vascular angiogenesis-related factors, extracellular matrix-producing factors; (2) Th1-driven cytokines, M1 macrophage-driven cytokines, and Th2-driven cytokines; and (3) M2 macrophage-induced and driven cytokines. The cluster analysis stratified the patients with MPA-ILD into clinically fibrotic-dominant (CFD) and clinically inflammatory-dominant (CID) groups. Notably, severe infections were significantly higher in the CFD group than in the CID group. Immunohistochemical staining demonstrated intense CXC motif chemokine ligand 13 staining in B cells and Th2 cells in the interstitium of the lungs of patients with MPA-ILD. CONCLUSION: The activation of M2 macrophages, Th2 cells, and B cells plays a key role in the pathomechanism of MPA-ILD. Classification of MPA-ILD based on serum biomarker profile would be useful in predicting the disease activity and the complications of severe infection in MPA-ILD.