Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Effect of abatacept treatment on serum osteoclast-related biomarkers in patients with rheumatoid arthritis (RA): A multicenter RA ultrasound prospective cohort in Japan.

ABSTRACT: We evaluated the effect of abatacept treatment on osteoclast-related biomarkers and explored whether the biomarkers are associated with the therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.We enrolled 44 RA patients treated with abatacept from a multicenter prospective ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug therapy. We evaluated the disease activity score (DAS) 28-CRP (C-reactive protein), musculoskeletal ultrasound scores including the total grayscale score (GS)/power Doppler (PD) score and the serum concentrations of isoform 5b of tartrate-resistant acid phosphate (TRACP-5b) and soluble receptor activator of nuclear factor-κB ligand (sRANKL) at baseline and at 3 and 6 months of treatment. "PD responder" was defined as a patient whose Δtotal PD score over 6 months was greater than the median change of that.Abatacept significantly improved DAS28-CRP as well as the total GS/PD score over 6 months. Serum TRACP-5b was significantly elevated and serum sRANKL was significantly decreased at 6 months (P < .0001 and P < .01, respectively). At 6 months, serum sRANKL was significantly decreased in the patients who achieved DAS28-CRP remission and the PD responders but not in those who did not. However, serum TRACP-5b rose regardless of the therapeutic response.Among RA patients treated with abatacept, serum sRANKL decreased in the patients with a good therapeutic response, but serum TRACP-5b elevated paradoxically regardless of the therapeutic response.

Association between serum bone biomarker levels and therapeutic response to abatacept in patients with rheumatoid arthritis (RA): a multicenter, prospective, and observational RA ultrasound cohort study in Japan.

BACKGROUND: To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. METHODS: We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change. RESULTS: Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status. CONCLUSION: Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept. TRIAL REGISTRATION: Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657.

Utility of a simplified ultrasonography scoring system among patients with rheumatoid arthritis: A multicenter cohort study.

ABSTRACT: We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs.

Non-TNF inhibitor switchers versus TNF inhibitor cyclers from multicentre rheumatoid arthritis ultrasonography prospective cohort in Japan.

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers (p < .05). Although there was no significant difference, non-TNFi switchers tended to have a larger decrease than TNFi cyclers in efficacy indicators based on clinical disease activity index and PDUS. Multivariate logistic regression analysis identified a following independent factor associated with both EULAR good response and retention of a biologic agent: non-TNFi switch (p < .05 for both). Non-TNFi switchers were shown to have significantly higher percentage of EULAR good response and higher retention than TNFi cyclers. A non-TNFi biologic agent may hence be a preferential next-line treatment for TNF-IR patients.

Ultrasonographic Efficacy of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drug Therapy in Rheumatoid Arthritis From a Multicenter Rheumatoid Arthritis Ultrasound Prospective Cohort in Japan.

OBJECTIVE: To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA). METHODS: We have been prospectively investigating the course of active RA patients using US after the introduction of b/tsDMARDs in the Kyushu region of Japan since June 2013. A total of 150 patients have completed the first 6 months of observation at present and have been evaluated. US was assessed in 22 joints of bilateral hands using gray-scale and PD images on a scale from 0-3. The sum of these scores was used as the indicator of US disease activity. We defined PD remission as attaining a total PD score of 0 at 6 months and investigated the associated variables by multivariate logistic regression analysis. RESULTS: The total PD and gray-scale scores and the clinical composite measures significantly improved at 6 months, whereas these reductions were less in bDMARD switchers as compared with bDMARD-naive patients. Multivariate logistic regression analysis showed that short disease duration, the absence of any previous use of bDMARDs, and low total PD scores at baseline were independent predictors of PD remission at 6 months. CONCLUSION: This present prospective US cohort has for the first time shown the variables that are associated with initial PD response to b/tsDMARDs.

An investigation of the correlation between blood concentration of mizoribine and its efficacy in treatment of rheumatoid arthritis based on indices of drug survival and improvement in DAS28-CRP.

OBJECTIVES: The efficacy of mizoribine (MZR) in treatment of rheumatoid arthritis (RA) was retrospectively investigated in terms of drug survival, improvement in Disease Activity Score-28 (DAS28)-C-reactive protein (CRP), and blood MZR concentration obtained 3 h after dosing (MZR-C3). METHODS: To compare the efficacy of MZR administered via different regimens, the subjects were divided into 2 groups: those receiving a single dose of MZR at 100-150 mg every other day (group A) and those receiving 2 or 3 divided doses of the drug on consecutive days, which is the usual dosing method of the drug (group B). RESULTS: Group A had significantly higher MZR-C3 levels compared with group B, as well as significantly greater improvement in DAS28-CRP. Moreover, drug survival was significantly longer in group A. The primary regression equation suggested that the effective blood MZR concentration in RA treatment is MZR-C3 of 1.47 µg/mL or more. CONCLUSIONS: The results of the present study indicate that it is possible to increase the efficacy of MZR in a blood concentration-dependent manner, and also to control RA over a prolonged period, using single administration of MZR on alternate days at an increased dose.

A case of mixed connective tissue disease complicated with thymic carcinoma and Hashimoto's thyroiditis.

We report the case of a 63-year-old woman who suffered from mixed connective tissue disease (MCTD) complicated with thymic carcinoma and Hashimoto's thyroiditis. Although many systemic syndromes associated with thymoma and thymic carcinoma, i.e., myasthenia gravis, pure red cell aplasia, hypogammaglobulinemia, and Hashimoto's thyroiditis, are known, this is the first report of MCTD complicated with thymic carcinoma. It was suggested that MCTD may be a paraneoplastic syndrome associated with thymic carcinoma.

Evidence of immunostimulating lipoprotein existing in the natural lipoteichoic acid fraction.

Lipoteichoic acid (LTA) is a cell surface glycoconjugate of gram-positive bacteria and is reported to activate the innate immune system. We previously reported that purified LTA obtained from Enterococcus hirae has no immunostimulating activity, but a subfraction (Eh-AF) in an LTA fraction possesses activity. In this study, we established a mouse monoclonal antibody neutralizing the activity of Eh-AF and investigated its inhibitory effects. Monoclonal antibody (MAbEh1) was established by the immunization of BALB/c mice with Eh-AF, followed by hybridoma screening based on its inhibitory effect for the production of interleukin-6 (IL-6) induced by Eh-AF. MAbEh1 neutralized the production of IL-6 by LTA fraction from not only E. hirae but also Staphylococcus aureus, while it failed to block that of lipopolysaccharide, suggesting that the antibody recognized a common active structure(s) in LTA fractions. Synthetic glycolipids in these LTAs did not induce cytokine production, at least in our system. Interestingly, the antibody was found to inhibit the activity of immunostimulating synthetic lipopeptides, Pam(3)CSK(4) and FSL-1. These results suggest that MAbEh1 neutralizes the activity of lipoprotein-like compounds which is responsible for the activity of the LTA fraction of E. hirae and S. aureus.

Clinical symptoms and the odds of human T-cell lymphotropic virus type 1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) in healthy virus carriers: application of best-fit logistic regression equation based on host genotype, age, and provirus load.

The authors have previously developed a logistic regression equation to predict the odds that a human T-cell lymphotropic virus type 1 (HTLV-1)-infected individual of specified genotype, age, and provirus load has HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in southern Japan. This study evaluated whether this equation is useful predictor for monitoring asymptomatic HTLV-1-seropositive carriers (HCs) in the same population. The authors genotyped 181 HCs for each HAM/TSP-associated gene (tumor necrosis factor [TNF]-alpha-863A/C, stromal cell-derived factor 1 (SDF-1) +801G/A, human leukocyte antigen [HLA]-A*02, HLA-Cw*08, HTLV-1 tax subgroup) and measured HTLV-1 provirus load in peripheral blood mononuclear cells using real-time polymerase chain reaction (PCR). Finally, the odds of HAM/TSP for each subject were calculated by using the equation and compared the results with clinical symptoms and laboratory findings. Although no clear difference was seen between the odds of HAM/TSP and either sex, family history of HAM/TSP or adult T-cell lenkemia (ATL), history of blood transfusion, it was found that brisk patellar deep tendon reflexes, which suggest latent central nervous system compromise, and flower cell-like abnormal lymphocytes, which is the morphological characteristic of ATL cells, were associated with a higher odds of HAM/TSP. The best-fit logistic regression equation may be useful for detecting subclinical abnormalities in HCs in southern Japan.

Association of AKT1 haplotype with the risk of schizophrenia in Iranian population.

AKT-glycogen synthase kinase 3beta (GSK3beta) signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders and schizophrenia. AKT1 protein level is decreased in the peripheral lymphocytes and brains of schizophrenic patients. The SNP2/3/4 TCG haplotype of AKT1 was associated with schizophrenia in patients with Northern European origin. In the present study, we genotyped five single nucleotide polymorphisms (SNP1-5) of AKT1 gene according to the original study in Iranians comprising of 321 schizophrenic patients and 383 controls, all residing in Mashhad city, Northeastern Iran. Haplotype analysis showed that the frequency of a five-SNP haplotype (AGCAG) was significantly higher in schizophrenic patients (0.068) than that of controls (0.034) (P = 0.03 after Bonferroni correction, OR = 2.04, CI = 1.2-3.4). In stratified analysis by schizophrenia subtypes, the frequency of the same haplotype was significantly higher in disorganized subtype (n = 78, frequency of haplotype=0.081) when compared with normal controls (P = 0.04 after Bonferroni correction, OR = 2.59, CI = 1.3-5.2). Our findings did not confirm the association of AKT1 SNP2/3/4 TCG haplotype with the risk of schizophrenia as reported in the original study but showed the evidence of association with a different haplotype, AKT1 five-SNP AGCAG haplotype, with the risk of schizophrenia in Iranian population.

Chronic progressive sensory ataxic neuropathy associated with limited systemic sclerosis.

We report the case of a 33-year-old woman with limited systemic sclerosis and chronic progressive sensory ataxic neuropathy. Sural nerve biopsy showed loss of myelinated fibers mostly those of large diameter, axonal degeneration and infiltration of macrophages, but no signs of vasculitis. Physical examination, laboratory testing, neurophysiological and neuroradiological examinations suggested that the dorsal root was primarily affected in this patient. Cytokine analysis by multiplex bead array assay revealed that IL-1beta and GM-CSF were increased both in serum and CSF. Although her symptoms did not respond to corticosteroid therapy, intravenous immunoglobulin (IVIg) therapy resulted in marked improvement. IVIg could be effective in case of immune-mediated reversible neuronal dysfunction associated with collagen disease without vasculitis.

ApaI polymorphism of vitamin D receptor gene is associated with susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis in HTLV-1 infected individuals.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is one outcome of human T-cell lymphotropic virus type-1 (HTLV-1) infection. It remains unknown why the majority of infected people remain healthy, whereas only approximately 2-3% of infected individuals develop the disease. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor (VDR) appear to be associated with differential susceptibility to several infectious diseases. To investigate whether VDR single nucleotide polymorphisms (SNPs) are associated with the development of HAM/TSP, we studied four VDR SNPs in a group of 207 HAM/TSP patients and 224 asymptomatic HTLV-1 seropositive carriers (HCs) in Kagoshima, Japan, by using PCR-RFLP analysis. We found that ApaI polymorphism of VDR is associated with the risk of HAM/TSP, although this polymorphism did not affect the provirus load of HTLV-1 in either HAM/TSP patients or HCs.

Pleural cryptococcosis with idiopathic CD4 positive T-lymphocytopenia.

A 19-year-old man was admitted to our hospital because of chest pain. He was diagnosed as having pleural cryptococcosis by pleural biopsy. His CD4 positive T-lymphocyte count was low (< 300 microl) and there was no evidence of human immunodeficiency virus infection. He was successfully treated with fluconazole. However, his CD4 positive lymphocyte counts remained low after the recovery and he was diagnosed as idiopathic CD4 positive T-lymphocytopenia. Pleural cryptococcosis is rare and its predisposing condition is still controversial. To our knowledge, this is the first case of pleural cryptococcosis associated with idiopathic CD4 positive T lymphocytopenia.

TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus.

Neutropenia is a common laboratory finding in systemic lupus erythematosus (SLE). However, the molecular mechanism of SLE neutropenia has not been fully explained. In this study, we examined whether TNF-related apoptosis-inducing ligand (TRAIL) is involved in the pathogenesis of SLE neutropenia using samples from SLE patients. Serum TRAIL levels in SLE patients with neutropenia were significantly higher than those of SLE patients without neutropenia and healthy volunteers. Serum TRAIL levels showed a significant negative correlation with neutrophil counts in SLE patients. The expression of TRAIL receptor 3 was significantly lower in SLE patients with neutropenia than in patients without neutropenia or in healthy volunteers. Treatment with glucocorticoids negated the decrease of TRAIL receptor 3 expression on neutrophils of SLE patients. TRAIL may accelerate neutrophil apoptosis of neutrophils from SLE patients, and autologous T cells of SLE patients, which express TRAIL on surface, may kill autologous neutrophils. Interferon gamma and glucocorticoid modulated the expression of TRAIL on T cells of SLE patients and also modulated the expression of cellular Fas-associating protein with death domain-like interleukin-1 beta-converting enzyme (FLICE)-inhibitory protein (cFLIP), an inhibitor of death receptor signaling, in neutrophils. Thus, our results provide a novel insight into the molecular pathogenesis of SLE neutropenia.

Decreased human T lymphotropic virus type I (HTLV-I) provirus load and alteration in T cell phenotype after interferon-alpha therapy for HTLV-I-associated myelopathy/tropical spastic paraparesis.

To analyze the mechanism by which interferon (IFN)-alpha is effective against human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), we investigated the T cell phenotype and HTLV-I provirus load in peripheral blood mononuclear cells from 25 patients with HAM/TSP that were obtained before and after administration of IFN-alpha. The frequency of memory (CD45RA(-)CD27(+)) T cells that were CD8(high+), CXCR3(+) cell populations, and HTLV-I provirus loads were significantly decreased after treatment. The proportion of memory T cells in the CD8(high+) cell population correlated well with HTLV-I provirus load, whereas the proportion of effector (CD45RA(+)CD27(-)) cells in the CD8(high+) cell population was inversely correlated with provirus load. Interestingly, the frequency of perforin expression in CD8(high+) cells was significantly decreased after treatment in patients who experienced clinical improvement, whereas patients who did not experience clinical improvement showed an increased frequency of perforin expression. Our data suggest that fluctuations in these cell subsets are associated with both the immunomodulatory effect of IFN-alpha and the observed clinical benefit of IFN-alpha treatment in patients with HAM/TSP.

Human T-cell lymphotropic virus type I (HTLV-I)-related clinical and laboratory findings for HTLV-I-infected blood donors.

Clinical and laboratory findings were examined for 111 human T-cell lymphotropic virus type I (HTLV-I)-infected blood donors. HTLV-I provirus loads in subjects with a family history of adult T-cell leukemia (ATL) or HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) tended to be higher than those in subjects without a family history of these conditions. There were 3 asymptomatic patients with ATL, 4 with a history of uveitis, 7 with hyperreflexia in the lower limbs, and 3 with urinary frequency in the night. The mean CD4 cell/CD8 cell ratio +/- SD was significantly lower (p<.0001) in subjects with hyperreflexia in the lower limbs (1.3 +/- 0.2) than in subjects without any clinical abnormalities (1.7 +/- 0.6), suggesting that subjects with hyperreflexia in the lower limbs already have some immunologic abnormalities. The concordance of HTLV-I infection between husband and wife was lower in this study than in a previous study. HTLV-I-related inflammatory symptoms were more frequent (p =.021, Fisher exact test; OR = 9.5; 95% CI, 1.7-53.5) in HTLV-I tax A-infected donors (3 [50%] of 6 donors) than in HTLV-I tax B-infected donors (10 [9.5%] of 105 donors), suggesting different risks of HTLV-I-related symptoms according to the virus genotype.