M. Hama

Ultrasonography is a potent tool for the prediction of progressive joint destruction during clinical remission of rheumatoid arthritis

ObjectivesAlthough “clinical remission” has been a realistic goal of treatment in rheumatoid arthritis (RA), there is evidence that subclinical synovitis is associated with ongoing structural damage even after clinical remission is achieved. In the study reported here, we assessed whether ultrasonography (US) can predict progressive joint destruction during clinical remission of RA.MethodsThirty-one patients with RA in clinical remission based on the disease activity score in 28 joints were recruited for this study. Bilateral wrists and all of the metacarpophalangeal and proximal interphalangeal (PIP) joints were examined by power Doppler (PD) ultrasonography (US), and the PD signals were scored semiquantitatively in each joint. The total PD score was calculated as the sum of individual scores for each joint.ResultsAmong 22 RA patients who maintained clinical remission during the 2-year follow-up period, seven showed radiographic progression. Radiographic progression was strongly associated with total PD score at entry, with all patients showing radiographic progression having a total PD score of ≥2 at entry and none of the patients with a total PD score of ≤1 showing any radiographic progression. There was no significant association of therapeutic agents with progressing or non-progressing cases.ConclusionsPD-US detects synovitis causing joint destruction even when the patient is in clinical remission. Thus, remission visible on US is essential to reach “true remission” of RA.

Expression of heme oxygenase‐1 in human leukemic cells and its regulation by transcriptional repressor Bach1

Heme oxygenase (HO)‐1 has anti‐oxidative, anti‐inflammatory, and anti‐apoptotic activities. However, little is known about the regulation of HO‐1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO‐1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid‐derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO‐1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO‐1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or γ‐interferon, they significantly expressed both HO‐1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO‐1 expression in U937 cells but suppressed it in primary monocytes and PMA‐treated U937 cells. In HO‐1‐expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf‐recognition elements, the enhancer regions of the HO‐1 gene. The downregulation of the HO‐1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO‐1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO‐1 gene expression in AML cells and its expression suppresses their survival by downregulating HO‐1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy. (Cancer Sci 2010)

Therapeutic angiogenesis in patients with systemic sclerosis by autologous transplantation of bone-marrow-derived cells

We examined the efficacy and safety of autologous transplantation of bone-marrow-derived cells in patients with intractable ulcers caused by systemic sclerosis. Eight patients with ulcers resistant to treatment were enrolled. Bone marrow cells were gathered from the bilateral iliac crests with multiple repositioning bone marrow needles, and bone-marrow-derived mononuclear cells were isolated and injected into skeletal muscles of the ischemic limb. Visual analog scale (VAS), Sclerosis Health Assessment Questionnaire (SHAQ), modified Rodnan total skin score (mTSS), and the size and depth of the ulcer were examined. Thermography, capillaroscopy, intra-arterial digital subtraction angiography (IA-DSA), and laser Doppler flowmetry were also examined before and after transplantation. In all patients, reduction of ulcer size and improvement of VAS were observed after treatment. Elevation of surface temperature, increase of blood flow volume, and new capillaries of the nail bed were also found after our treatment. There were no major adverse effects of this treatment. Autologous transplantation of bone-marrow-derived cells was shown to be a novel and useful approach to intractable ulcers in systemic sclerosis.

A novel 8-joint ultrasound score is useful in daily practice for rheumatoid arthritis

Abstract Objectives. To investigate the optimal number and combination of joints to be assessed by power Doppler ultrasonography (PDUS) in daily practice for rheumatoid arthritis (RA). Methods. PDUS were performed in 24 joints, including all proximal interphalangeal, metacarpophalangeal (MCP), and bilateral wrist and knee joints in 234 patients with RA. PD signals were scored semiquantitatively from 0 to 3 in each joint, and total PD score-24 was calculated by summing them up as comprehensive assessment. Results. Positive PD signals were more frequently found in bilateral wrist, knee, and the second and third MCP joints than the other joints. The individual PD scores of these 8 joints also showed higher correlation coefficients with total PD score-24 (rs ≥ 0.4). Among the sum PD scores of various selected joint combinations, the score of the combination of 8 joints (total PD score-8), including bilateral second and third MCP, wrist, and knee joints, showed the highest sensitivity and negative predictive value (98.1% and 96.2%, respectively). Total PD score-8 showed high correlation with the total PD score-24 (rs = 0.97, p < 0.01). Conclusions. Total PD score-8 is simple and efficient enough for monitoring disease activity and judging imaging remission of RA in daily practice.

Bach1 regulates osteoclastogenesis in a mouse model via both heme oxygenase 1–dependent and heme oxygenase 1–independent pathways

OBJECTIVE Reducing inflammation and osteoclastogenesis by heme oxygenase 1 (HO-1) induction could be beneficial in the treatment of rheumatoid arthritis (RA). However, the function of HO-1 in bone metabolism remains unclear. This study was undertaken to clarify the effects of HO-1 and its repressor Bach1 in osteoclastogenesis. METHODS In vitro osteoclastogenesis was compared in Bach1-deficient and wild-type mice. Osteoclasts (OCs) were generated from bone marrow-derived macrophages by stimulation with macrophage colony-stimulating factor and RANKL. Osteoclastogenesis was assessed by tartrate-resistant acid phosphatase staining and expression of OC-related genes. Intracellular signal pathways in OC precursors were also assessed. HO-1 short hairpin RNA (shRNA) was transduced into Bach1(-/-) mouse bone marrow-derived macrophages to examine the role of HO-1 in osteoclastogenesis. In vivo inflammatory bone loss was evaluated by local injection of tumor necrosis factor α (TNFα) into calvaria. RESULTS Transcription of HO-1 was down-regulated by stimulation with RANKL in the early stage of OC differentiation. Bach1(-/-) mouse bone marrow-derived macrophages were partially resistant to the RANKL-dependent HO-1 reduction and showed impaired osteoclastogenesis, which was associated with reduced expression of RANK and components of the downstream TNF receptor-associated factor 6/c-Fos/NF-ATc1 pathway as well as reduced expression of Blimp1. Treatment with HO-1 shRNA increased the number of OCs and expression of OC-related genes except for the Blimp1 gene during in vitro osteoclastogenesis from Bach1(-/-) mouse bone marrow-derived macrophages. TNFα-induced bone destruction was reduced in Bach1(-/-) mice in vivo. CONCLUSION The present findings demonstrate that Bach1 regulates osteoclastogenesis under inflammatory conditions, via both HO-1-dependent and HO-1-independent mechanisms. Bach1 may be worthy of consideration as a target for treatment of inflammatory bone loss in diseases including RA.

(18)F-FDG and (18)F-NaF PET/CT demonstrate coupling of inflammation and accelerated bone turnover in rheumatoid arthritis.

Objective. To compare the findings in rheumatoid arthritis (RA)-affected joints between 18F-fluorodeoxyglucose (FDG) and 18F-fluoride (NaF) positron emission tomography (PET)/computed tomography (CT). Methods. We enrolled twelve RA patients who started a new biologic agent (naïve 9 and switch 3). At entry, both hands were examined by 18F-FDG PET/CT, 18F-NaF PET/CT, and X-ray. Intensity of PET signals was determined by standardized uptake value max (SUVmax) in metacarpophalangeal (MCP), proximal interphalangeal (PIP), and ulnar, medial, and radial regions of the wrists. Hand X-rays were evaluated according to the Genant-modified Sharp score at baseline and 6 months. Results. Both 18F-FDG and 18F-NaF accumulated in RA-affected joints. The SUVmax of 18F-FDG correlated with that of 18F-NaF in individual joints (r = 0.65), though detail distribution was different between two tracers. 18F-NaF and 18F-FDG signals were mainly located in the bone and the surrounding soft tissues, respectively. The sum of SUVmax of 18F-NaF correlated with disease activity score in 28 joint (DAS28), modified health assessment questionnaire (MHAQ), and radiographic progression. 18F-FDG and 18F-NaF signals were associated with the presence of erosions, particularly progressive ones. Conclusion. Our data show that both 18F-FDG and 18F-NaF PET signals were associated with RA-affected joints, especially those with ongoing erosive changes.

Ultrasonography predicts achievement of Boolean remission after DAS28-based clinical remission of rheumatoid arthritis

Abstract Objectives. To determine whether ultrasonography (US) predicts Boolean remission in rheumatoid arthritis (RA) patients who had achieved disease activity score in 28 joints (DAS28)-based remission criteria. Methods. Thirty-one RA patients in DAS28-based clinical remission were recruited. US semiquantitatively determined Gray scale (GS) and power Doppler (PD) signal scores in the bilateral wrists and all metacarpophalangeals and proximal interphalangeals. Total GS score and total PD score were calculated as the sum of individual scores for each joint. Results. Among 22 RA patients, who maintained DAS28 remission for 2 years, 16 met Boolean remission criteria at the end of study. Both total GS and total PD scores at baseline were significantly lower in Boolean remission group than non-remission group. There was no significant difference in other baseline parameters, including duration of disease, duration of remission, mTSS, and disease activity composite parameters between the two groups. Among the factors for Boolean remission criteria at 2 years, patient global assessment score was associated with total GS score at the entry, while swollen joint count was related to total PD score. Conclusions. Null or low grade of GS and PD findings in US are associated with achieving Boolean remission. Thus, US is essential for assessment and prediction of “deeper remission” of RA.

Predicting joint destruction in rheumatoid arthritis with power Doppler, anti-citrullinated peptide antibody, and joint swelling

Objective. To determine combined evaluation of musculoskeletal ultrasonography (MSUS) and power Doppler (PD) signals, anti-citrullinated peptide antibody (ACPA), and other clinical findings improve the prediction of joint destruction in rheumatoid arthritis (RA). Methods. We performed a retrospective study of 331 RA patients (female n = 280 and male n = 51, mean age: 57.9 ± 13.2 years) who underwent MSUS from 2002 to 2012. Correlations with progression of joint destructions in 1,308 2nd and 3rd metacarpophalangeal (MCP) joints and various factors including PD signals of the same joints, clinical findings, age, disease duration at the study entry, gender, observation period, radiographic bone scores according to modified Sharp–van der Heijde methods, ACPA, and rheumatoid factor (RF) were analyzed in patient- and joint-based fashions, using univariate and multivariate logistic regression analyses and generalized linear mixed model. Results. Patients’ characteristics were as follows: mean disease duration: 5.7 ± 7.5 years, observation period: 4.6 ± 2.6 years, RF positivity: 79.9%, and ACPA positivity: 77.5%. PD-positive 2nd and 3rd joints showed higher rate of joint destruction, especially in ACPA-positive patients. Moreover, PD-positive joints in ACPA-positive patients showed joint destruction even in joints without swelling. Multivariate analysis determined PD, swollen joint (SJ), observation period, basal radiographic bone scores, and ACPA as independent risks for joint destruction. Conclusion. PD, SJ, basal radiographic bone scores, and ACPA are independent predictors for the joint destruction of 2nd and 3rd MCPs in RA; thus, considering these factors would be useful in daily practice.

Multiple extra-articular synovial cysts complicated with rheumatoid arthritis.

Multiple extra-articular synovial cysts (MESC) are rarely complicated with various rheumatic diseases. We here first report a rheumatoid arthritis (RA) patient with MESC, which were extensively analyzed by a series of imaging techniques including fluorine-18-2-fluoro-d-glucose positron emission tomography (18F-FDG-PET), magnetic resonance imaging (MRI), and ultrasonography. FDG uptakes in joint lesions with MESC were much higher than those reported in typical lesions of RA, suggesting that marked joint inflammation is implicated in the development of MESC.

Deep-inspiration breath-hold 18F-FDG-PET/CT is useful for assessment of connective tissue disease associated interstitial pneumonia

Abstract Objective: To examine clinical utility of 18F-flurodeoxyglucose (FDG)-positron emission tomography (PET)/CT for assessment of interstitial lung disease (ILD) in patients with connective tissue diseases (CTDs). Methods: A total of 69 18F-FDG PET/CT scans were conducted under deep inspiratory breath hold (DIBH) conditions in 45 CTD patients with ILD, including 16 dermatomyositis/polymyositis, nine systemic scleroderma and seven rheumatoid arthritis. Intensity and distribution of 18F-FDG signals in PET/CT were determined by standardized uptake value (SUVmax) and visual score in 18 regions, respectively. ILD was defined as active when immunosuppressive therapy was initiated or intensified. Results: Both SUVmax and visual score were higher in active phase (n = 32) than inactive phase (n = 37) (both p < 0.05), regardless of the underlying CTD and plain CT findings. The both parameters reduced after initiating or intensifying treatment in the follow-up study of 17 active patients except two died patients who showed increased visual score. Another two died patients showed high visual score (15 and 6/18, respectively). Changing ratio of visual score, but not SUVmax was correlated with KL-6 (r2 = 0.38, p < 0.05) and CRP (r2 = 0.52, p < 0.05). Conclusion: The DIBH 18F-FDG PET/CT procedure sensitively illustrates active ILD lesions in CTD and the extended signal distribution is associated with unfavorable clinical outcome.