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-randomized 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 mortality, and the secondary outcomes were composite all-cause mortality 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 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) 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 mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. CONCLUSION: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

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.

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.

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.

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.

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.

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.

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.

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).

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.

Low pre-pregnant body mass index is a risk factor for the decrease of postpartum bone mineral density in systemic lupus erythematosus patients received glucocorticoid therapy.

OBJECTIVES: This study investigated postpartum bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE) receiving long-term glucocorticoid (GC) therapy, assessed risk factors for decreased postpartum BMD, and evaluated change of BMD after postpartum initiation or restarting of osteoporosis drugs. METHODS: We retrospectively examined 30 SLE patients who gave birth and 31 non-pregnant SLE patients. In the postpartum SLE patients, BMD was measured after delivery and 1 year later. Multivariate analyses were performed to assess risk factors for decreased BMD in postpartum SLE patients. RESULTS: Patient age at pregnancy was 34.5 ± 4.5 years, and SLE duration was 9.7 ± 6.0 years. The mean prednisolone dose was 9.7 ± 3.2 mg/day. Body mass index (BMI) was 21.6 ± 2.2 kg/m2, with 13 women (43%) experiencing their first delivery. Postpartum BMD was 1.080 ± 0.120 g/cm2 in the lumbar spine and 0.834 ± 0.109 g/cm2 in the total hip. Bone loss occurred in six patients (21%) in the lumbar spine and 11 patients (37%) in the total hip. Postpartum lumbar spine BMD was significantly reduced compared to that in the non-pregnant group (1.143 ± 0.120 g/cm2, p = 0.048). Multivariate analysis identified gestational age and low BMI before pregnancy as risk factors for hip bone loss. CONCLUSION: Postpartum BMD significantly decrease in SLE patients receiving long-term GC, and low BMI before pregnancy was a risk factor for the decrease. Preconception care to prevent osteoporosis and that regularly monitors BMD after delivery are needed.

Congenital cytomegalovirus infection after maternal primary infection in a patient with systemic lupus erythematosus: A case report and literature review.

BACKGROUND: Management of infectious complications in pregnant women receiving immunosuppressive therapy for systemic lupus erythematosus (SLE) is important. Maternal infection with cytomegalovirus (CMV) often causes congenital CMV infection in the foetus. Thus far, there are only few reports on congenital CMV infection after maternal reactivation in patients with SLE. We report the first case of congenital CMV infection after maternal primary infection in a patient with SLE. CASE PRESENTATION: A 19-year-old Japanese primigravida with SLE received treatment with prednisolone 3 mg/day and azathioprine 75 mg/day at conception. At 7 weeks of gestation, she suddenly developed fever and had decreased white blood cell and platelet counts and elevated aspartate aminotransferase and alanine aminotransferase levels. These clinical findings led to a diagnosis of SLE exacerbation. The prednisolone dose was increased to 15 mg/day, and hydroxychloroquine (200 mg/day) was administered. Consequently, all clinical findings normalised at 12 weeks. At 19 weeks, foetal ultrasound findings revealed oligohydramnios, brain hypoplasia, ventriculomegaly and hyperechogenic bowel. Maternal serological test results indicated increased CMV-specific IgG and IgM levels, low IgG avidity (26%), and positive CMV antigenemia. The foetus was diagnosed with symptomatic congenital CMV infection transmitted from the maternal primary infection. After counselling about the severe prognosis of the foetus, the mother decided to terminate her pregnancy and underwent artificial abortion at 21 weeks. DISCUSSION: The foetus of a mother with SLE who is receiving immunosuppressive therapy may be at increased risk of transmission and aggravation of congenital CMV infection; thus, preventive management and screening for congenital CMV infection during pregnancy are recommended for such patients. Maternal CMV infection shows clinical findings similar to those of SLE exacerbation, and careful differential diagnosis by maternal serological evaluation and foetal ultrasound scans is required.

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.

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.

The addition of iguratimod can reduce methotrexate dose in rheumatoid arthritis with clinical remission.

OBJECTIVES: We prospectively evaluated whether the addition of iguratimod (IGU) could sustain clinical remission in rheumatoid arthritis (RA) patients after tapering of methotrexate (MTX). METHODS: The study included 47 patients; 25 patients in the MTX maintenance group, and 22 patients in the IGU addition group who were treated with additional IGU and tapering of MTX dose. Clinical efficacy and safety were evaluated at 12, 24, and 36 weeks. RESULTS: In the IGU addition group, the dose of MTX could be reduced from 8.6 ± 2.4 mg/week at baseline to 4.7 ± 2.2 mg/week at 36 weeks (p < .001). Clinical remission was maintained (disease activity score [DAS]28-ESR 1.48 ± 0.63 at baseline and 1.69 ± 0.76 at 36 weeks, p = .911), and disease activity remained low (clinical disease activity index [CDAI] 2.4 ± 1.5 at baseline and 3.1 ± 3.4 at 36 weeks, p = .825). The US-GLOSS score significantly decreased from 9.2 ± 5.3 at baseline to 6.4 ± 4.3 at 36 weeks (p = .034). In the IGU addition group, two patients discontinued IGU because of stomatitis and three patients relapsed during the follow-up period (flare rate: 15.0%). There was no significant difference in RA disease activity at 36 weeks between the two groups. CONCLUSION: Additional use of IGU can effectively reduce the MTX dose required by patients during clinical remission without inducing a flare.

Comparison of therapeutic effects of combination therapy with prednisolone and tacrolimus or azathioprine on progressive interstitial pneumonia with systemic sclerosis.

OBJECTIVES: We retrospectively compared the therapeutic effects of combination therapy with prednisolone (PSL) and oral tacrolimus (TAC) or azathioprine (AZA) on progressive interstitial pneumonia with systemic sclerosis (SSc-PIP). METHODS: The effects of PSL (0.2-0.5 mg/kg/day) and TAC (3 mg/day) or AZA (1-2 mg/kg/day) therapies (n = 18) were evaluated for short (12 months) and long (36 months or more) periods. RESULTS: In the short period, IP improved in 6 and 5 patients and was stable in 12 and 13 patients in the TAC and AZA groups, respectively. In the long period, 11 patients were followed up in the TAC group and 12 in the AZA group. IP improved in 4 and 2 patients and was stable in seven and nine in the TAC and AZA groups, respectively. The rates of evolution of total fibrosis score, and those corrected by disease duration for the long period, in the TAC group were significantly lower than those in the AZA group (p = .017 and .025, respectively). CONCLUSION: The inhibitory effect of PSL and TAC combination therapy on the progression of fibrosis in SSc-PIP may be superior to that of PSL and AZA in the long period.

CCL2 produced by CD68+/CD163+ macrophages as a promising clinical biomarker of microscopic polyangiitis-interstitial lung disease.

OBJECTIVES: Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance. METHODS: We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining. RESULTS: Initial serum C-C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs. CONCLUSION: CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD.

Simplified disease activity index and clinical disease activity index before and during pregnancy correlate with those at postpartum in patients with rheumatoid arthritis.

OBJECTIVES: We explored rheumatoid arthritis (RA) disease activity before, during, and after pregnancy in patients treated with tight control and investigated the association between disease activity in the postpartum period and those before and during pregnancy. METHODS: We retrospectively reviewed disease activity and medications of 27 patients before pregnancy, at every trimester, and in the postpartum period. RESULTS: Prednisolone was administered to 33% of patients with a median dose of 0 (0-2.5) mg/day and biologic agents was 78% in the third trimester. The median remission rates during all periods were the Disease Activity Score-28-C-reactive Protein assessed with three variables (DAS28-CRP-3) 85%, Simplified Disease Activity Index (SDAI) 55%, and Clinical Disease Activity Index (CDAI) 54%. Although SDAI and CDAI decreased significantly from before pregnancy to the first trimester and increased from the third trimester to the postpartum period, DAS28-CRP-3 did not change during all periods. Although SDAI and CDAI before and during pregnancy were significantly correlated with those in the postpartum period, DAS28-CRP-3 was not. CONCLUSIONS: Tight control before pregnancy suppressed RA disease activity during pregnancy and in the postpartum period. SDAI/CDAI before and during pregnancy were predictive for disease activity in the postpartum period.

Exploration of pathomechanism using comprehensive analysis of serum cytokines in polymyositis/dermatomyositis-interstitial lung disease.

OBJECTIVES: To elucidate the serum cytokine profile and address the pathomechanism of interstitial lung disease (ILD) complicated with PM/DM. METHODS: Forty patients with PM/DM-ILD were enrolled, and principal components analysis and cluster analysis were performed to classify patients into subgroups. Additionally, we compared cytokine profiles between the survivors and dead patients and between anti-melanoma differentiation-associated gene 5 antibody- and anti-aminoacyl tRNA synthetase antibody-positive ILD patients. We also examined the association of various cytokines with disease activity indicators and prognosis of ILD. RESULTS: The principal components analysis data allowed classification of the cytokine profile into three groups: group 1, neutrophilic and M1-macrophage-driven cytokines; group 2, type 1 Th cell-driven and M2-macrophage-induced cytokines; and group 3, M2-macrophage-driven cytokines. Cluster analysis showed the presence of PM/DM-ILD patient groups with high or low levels of total cytokines. Ninety percent of patients who died of ILD were included in clusters with high cytokine levels. Serum cytokine levels of all groups were significantly higher in the anti-melanoma differentiation-associated gene 5 antibody-positive patients than in the anti-aminoacyl tRNA synthetase antibody-positive patients. Groups 1 and 2 significantly correlated with known factors for poor prognosis, such as serum ferritin levels and alveolar-arterial oxygen difference. Serum cytokine levels of patients in group 1 were significantly higher initially and at 2 and 4 weeks in those who died. CONCLUSION: These findings suggested that the activation of monocytes, macrophages and type 1 Th cells, and neutrophils play roles in the pathomechanism of PM/DM-ILD, and group 1 cytokines could be useful biomarkers for predicting prognosis of PM/DM-ILD.

Comparison of the efficacy and safety of biologic agents between elderly-onset and young-onset RA patients: the ANSWER cohort study.

The objective of the study was to compare the efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) between elderly-onset rheumatoid arthritis (EORA) and young-onset rheumatoid arthritis (YORA) patients. Patients with rheumatoid arthritis (RA) aged ≧18 years enrolled in a Japanese multicenter observational registry between 2009 and 2018 who had moderate or high disease activity when initiating bDMARDs were included. EORA was defined as RA with onset at 60 or over. After propensity score weighting for differences in confounding factors, generalized estimating equations were used to assess the relationship between the age of RA onset and bDMARD clinical effectiveness at 48 weeks after starting a bDMARD. Among a total of 7183 patients in the registry, 2815 (39.2%) were identified as EORA. The proportion of patients on bDMARDs was lower in the EORA as compared to the YORA (18.3% vs 28.0%, p < 0.001). Of the 989 bDMARD initiators, 364 (36.8%) were identified as EORA. The median follow-up duration was 48 weeks both in the EORA and in the YORA. After adjusting for differences in baseline characteristics between the two age groups, there was no significant difference in Clinical Disease Activity Index scores at 48 weeks (mean difference 1.01, 95% CI = - 0.62 to 2.64, p = 0.22). There was a non-significant trend toward lower remission in EORA (OR = 0.52, 95% CI = 0.24-1.14, p = 0.10), and low disease activity/remission was similar (OR = 0.86, 95% CI = 0.29-2.52, p = 0.77). Drug retention (HR = 0.95, 95% CI = 0.55-1.35, p = 0.78) and discontinuations due to adverse events (HR = 0.78, 95% CI = 0.38-1.18, p = 0.22) were similar between the two age groups after adjustment for confounders. In RA patients initiating bDMARDs, improvements in clinical disease at 48 weeks were similar between EORA and YORA. Drug retention and adverse events discontinuation were similar between the two age groups.