Correlation of muscle ultrasound with clinical and pathological findings in idiopathic inflammatory myopathies.

INTRODUCTION/AIMS: In idiopathic inflammatory myopathies (IIMs), the change in muscle echogenicity and its histopathological basis are not well understood. We quantitatively measured muscle echogenicity in patients with IIMs and evaluated its correlation with disease activity and histopathological findings. METHODS: This study involved patients with IIMs who underwent both ultrasonography (US) and muscle biopsy, as well as age- and sex-matched rheumatoid arthritis patients as inflammatory disease controls. On US, axial images of the right biceps brachii and vastus medialis were obtained. Standardized histopathological scoring was used to quantitatively measure each pathological domain. RESULTS: Forty-two patients (17 with inclusion body myositis [IBM] and 25 with IIMs other than IBM) and 25 controls were included. The muscle echo intensity (EI) of patients with IIMs was significantly higher than that of controls. Muscle EI showed significant correlations with creatine kinase (r = 0.66, p < .001) and muscle strength (r = -0.73, p < .0001) in patients with non-IBM IIMs. In patients with IBM, moderate correlation was found between muscle EI and quadriceps muscle strength (r = -0.53, p = .028). Histopathologically, the number of infiltrating CD3+ inflammatory cells correlated with muscle EI in the non-IBM group (r = 0.56, p = .017), but not in the IBM group. DISCUSSION: Muscle EI may be useful as a surrogate marker of muscle inflammation in non-IBM IIM. Increased muscle EI may be difficult to interpret in patients with long-standing IBM, which has advanced and complex histopathology.

Influence of concomitant methotrexate use on the clinical effectiveness, retention, and safety of abatacept in biologic-naïve patients with rheumatoid arthritis: Post-hoc subgroup analysis of the ORIGAMI study.

OBJECTIVES: We performed post-hoc analyses of the ORIGAMI study to investigate whether concomitant methotrexate (MTX) influences the clinical outcomes of abatacept in biologic-naïve patients with rheumatoid arthritis. METHODS: Enrolled patients (n = 325) were divided into two groups according to whether abatacept was prescribed without (MTX-) or with (MTX+) concomitant MTX. We compared the changes in Simplified Disease Activity Index (SDAI), Disease Activity Score-28 with C-reactive protein (DAS28-CRP), and Japanese Health Assessment Questionnaire (J-HAQ) through to 52 weeks of treatment, the abatacept retention rate, and safety. RESULTS: At Week 52, the mean SDAI (8.9 vs. 8.8), DAS28-CRP (2.6 vs. 2.6), and J-HAQ (0.92 vs. 0.91) scores were comparable in the MTX- (n = 129) and MTX+ (n = 150) groups. Multivariable logistic regression revealed no significant association between MTX use and SDAI (low disease activity) or J-HAQ (minimum clinically important difference). The abatacept retention rates, estimated using the Kaplan-Meier method, were 73.2% and 66.7% in the MTX- and MTX+ groups, respectively. Adverse events occurred in 47.5% (of 139) and 52.2% (of 159) of patients in the MTX- and MTX+ groups, respectively. CONCLUSION: The effectiveness and safety of abatacept appeared comparable with or without concomitant MTX in this real-world clinical setting.

Ultrasound assessment of sarcopenia in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the efficacy of ultrasound (US) as a diagnostic tool for sarcopenia in patients with rheumatoid arthritis (RA). METHODS: Female RA patients aged >50 years and matched controls were cross-sectionally assessed. Sarcopenia was diagnosed based on the 2019-updated Asian Working Group for Sarcopenia definition. The cross-sectional area (CSA) and echo intensity (EI) of the biceps brachii, rectus femoris, and EI of the vastus lateralis were examined bilaterally. Correction for subcutaneous fat and calculation of the recorrected EI (rcEI) were performed. We performed logistic regression using both muscle rcEI and CSA with receiver operating curve analysis to evaluate the discriminative performance per muscle group. RESULTS: Seventy-eight consecutive RA patients and 15 age-and sex-matched controls were assessed. Sarcopenia was diagnosed in 34 RA patients (43.6%). The rcEI of examined muscles were significantly higher, whereas CSA were significantly lower in sarcopenic RA patients than in non-sarcopenic patients and matched controls. The combined discriminative performance of rcEI and CSA was superior to those of rcEI or CSA alone. CONCLUSIONS: This study suggests the use of US for the diagnosis of sarcopenia in RA patients. The diagnostic performance increases when both echogenicity and CSA are considered together rather than individually.

Detection of nerve enlargement with ultrasound and correlation with skin biopsy findings in painful sensory neuropathy associated with Sjögren's syndrome.

OBJECTIVES: We evaluated usefulness of peripheral nerve ultrasound (US) in detecting abnormality in painful sensory neuropathy (PSN) associated with primary Sjögren's syndrome (pSS), and associations among various clinical factors, US findings, and intraepidermal nerve fiber density (IENFD). METHODS: We conducted a retrospective, single-center, observational study of patients with pSS-PSN. US image was obtained to measure cross sectional area (CSA) of peripheral nerves and compared with matched pSS control. RESULTS: We included 11 patients with pSS-PSN (10 women; age 70.5 ± 5.66) and 17 pSS controls (15 women; age 62.5 ± 16.7). Sural nerve CSA were significantly increased in pSS-PSN group (3.48 ± 1.0 mm2 vs 2.05 ± 0.65 mm2, p = .001). US of sural nerve showed the area under the ROC curve of 0.872 (95% CI, 0.732 - 1). Sural nerve CSA and IENFD of lower leg showed positive correlation. Compared with pSS-PSN patients with abnormal IENFD, those with normal IENFD showed significantly larger sural nerve CSA, and trends toward less systemic disease activity and small fiber impairment with sparing of large fibers. CONCLUSION: US was useful in discriminating pSS patients with PSN from those without. Additionally, US may disclose distinct subsets of pSS-PSN with different clinical findings and IENFD.

Abatacept may be effective and safe in patients with amyloid A amyloidosis secondary to rheumatoid arthritis.

OBJECTIVES: To examine the efficacy and safety of abatacept (ABT) in patients with amyloid A (AA) amyloidosis secondary to rheumatoid arthritis (RA), and to speculate about the immunologic association of ABT with AA amyloid deposit regression. METHODS: We administered ABT to 70- and 65-year-old Japanese women with RA and AA amyloidosis. We quantified serum cytokine concentrations and analysed regulatory T lymphocytes (Treg cells) via flow cytometry. We also studied AA amyloid deposits via histopathology and immunohistochemistry. RESULTS: ABT improved rheumatoid inflammation and AA amyloidosis, one case showing clinical remission and the other demonstrating incomplete recovery of nephrosis but stable kidney function. Serum levels of interleukin-6 and tumour necrosis factor α decreased to baseline in the first 6 months of treatment, but serum interleukin-2 concentrations did not change. CD4+CD25++FoxP3+ Treg cells gated on T lymphocytes and CD4+ T lymphocytes decreased to baseline in the first 3 treatment months. One case showed complete regression of AA amyloid fibrils in serial upper gastrointestinal biopsies, but the other case still had AA amyloid deposits despite ABT-induced normalised rheumatoid inflammation, with polymorphonuclear leukocytes and macrophages infiltrating tissues containing AA amyloid. CONCLUSIONS: ABT demonstrated efficacy and safety in AA amyloidosis secondary to RA and affected Treg cells and inflammatory cytokines. Because the gradual decrease in Treg cells population coincided with AA amyloid deposit regression during ABT therapy, AA amyloid fibril turnover in these patients may involve an immunologic mechanism. Phagocytes seemed to have an important role in AA amyloid fibril regression, which suggests an immunologic interaction.

Positron emission tomography/computed tomography: a clinical tool for evaluation of enthesitis in patients with spondyloarthritides.

OBJECTIVE: To evaluate the accuracy of PET/CT using [(18)F]fluorodeoxyglucose (FDG) in determining the presence of enthesitis in patients with SpAs. METHODS: Results of PET/CT scans of eight patients with SpA and seven patients with RA were retrospectively examined, with specific focus on five joints and three entheses. Volume fixation values are expressed as standardized uptake values (SUVs). Data from 20 patients with non-rheumatic (NR) diseases and 20 healthy subjects were also examined if non-specific, false positive findings were possible. We evaluated the clinical utility of PET/CT examinations in SpA, compared with MRI and Ga scintigraphy. RESULTS: Images of PET/CT scans of the shoulder, hip and knee joints revealed that FDG accumulated at the entheses in SpA and in the synovium in RA patients. The maximum SUVs [mean (s.d.)] were statistically higher in SpA patients compared with RA patients at the entheses of lumbar spinous process [4.83 (1.15) vs 1.42 (0.34); P < 0.05, respectively], pubic symphysis [3.93 (0.87) vs 1.35 (0.31); P < 0.05, respectively] and ischial tuberosity [4.76 (1.5) vs 1.35 (0.42); P < 0.05, respectively]. The positive frequencies of lumbar spinous processes and ischial tuberosity evaluated by PET/CT scan in the SpA group were significantly higher than that evaluated by MRI. CONCLUSION: MRI is now widely used to detect bone marrow oedema and enthesitis in patients with SpA. PET/CT scans offer an alternative method to identify enthesitis, and will likely contribute to the early diagnosis of SpA.

Link between pericardial effusion and attenuation of QRS voltage in patients with hypothyroidism.

OBJECTIVES: To determine the clinical correlates of pericardial effusion (PE) and a low-voltage electrocardiogram (ECG) in patients with primary hypothyroidism. METHODS: ECG, echocardiography and blood tests, including thyroid function tests, were performed in 64 consecutive patients with primary hypothyroidism. RESULTS: Twenty-four patients (38%) had PE and 16 patients (25%) had low voltage. To determine the important variables present in patients with hypothyroidism that may be related to PE, 3 variables (free T4, pulmonary artery systolic pressure and serum albumin) were used in the multivariate analysis. From the analysis, free T4 (odds ratio = 0.032) and pulmonary artery systolic pressure (odds ratio = 1.085) emerged as significant variables related to PE, whereas when 4 variables (free T4, serum albumin, pulmonary artery systolic pressure and PE) were used to determine the important variables related to low voltage, free T4 (odds ratio = 0.029) and serum albumin (odds ratio = 0.255) were the significant variables, but PE had no significant relation with low voltage (p = 0.424). CONCLUSIONS: In addition to its association with more severe thyroid hormone deficiency, the presence of PE was also associated with an increase in pulmonary artery pressure, whereas attenuation of QRS voltage was associated with lower colloid osmotic pressure in patients with hypothyroidism.

Edaravone inhibits collagen-induced arthritis possibly through suppression of nuclear factor-kappa B.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic autoimmune disease which is induced by proinflammatory cytokines or oxidative stress. The activation of nuclear factor-kappa B (NF-kappaB) that contributed to imbalance between apoptosis and proliferation of rheumatoid synovial cells (SC). Edaravone, clinically available free radical scavenger in Japan, is confirmed to be beneficial in the acute stage of stroke. We aimed to investigate the suppressive effect of edaravone on collagen-induced arthritis (CIA) mice and on the activated molecules in SC stimulated by interleukin-1beta (IL-1beta). METHODS: Edaravone was administrated intravenously at a dose of 3mg/kg of body weight to CIA mice. The progression of CIA was evaluated by the macroscopic arthritis scoring system of paws. Interleukin-6 (IL-6) and matrix metalloproteinase-3 (MMP-3) concentrations in culture medium of human SC were measured by enzyme linked immunosorbent assays. Caspase-3/7 activity and nuclear factor-kappa B (NF-kappaB) protein level of cultured human SC were estimated by fluorometric assay and Western blot analysis, respectively. RESULTS: Edaravone significantly decreased macroscopic arthritis score in CIA mice. Acceleration of IL-6 and MMP-3 productions and attenuation of caspase-3/7 activity in IL-1beta-stimulated SC were abated by edaravone. Activated NF-kappaB in IL-1beta-stimulated SC was suppressed by edaravone. CONCLUSION: Edaravone, antioxidants available for clinical use, appears to have therapeutic effect on RA. We suggest that the inhibitory effect of edaravone on RA might be exerted, at least in part, through suppression of activated NF-kappaB. Therefore, we expect therapeutical use of edaravone as an anti-rheumatic agent.

Asymptomatic pericardial effusion in patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study was to determine the frequency and clinical correlates of asymptomatic pericardial effusion (PE) detected by echocardiography in patients with rheumatoid arthritis (RA). METHODS: Echocardiography and electrocardiography were performed in 87 consecutive patients with RA. Asymptomatic PE was correlated with electrocardiographic changes and laboratory findings. RESULTS: Among 87 patients with RA, 20 patients (23%) had PE and 28 patients (32%) had hypoalbuminemia. The patients with PE had significantly lower serum albumin level (p < 0.001), higher rheumatoid factor (RF)titer (p = 0.002) and higher incidence of impaired left ventricular relaxation (55 vs. 28%, p = 0.028) and tended to have a higher incidence of PR-segment depression than those without PE (p = 0.085). When five variables (PR-segment depression, C-reactive protein, serum albumin, RF and impaired left ventricular relaxation) were used in the multivariate analysis, serum albumin (p = 0.003, Odds ratio = 0.131) and RF (p = 0.020, Odds ratio = 3.775) emerged as significant variables related to the presence of asymptomatic PE. CONCLUSIONS: In addition to pericardial inflammation due to more severe RA, hypoalbuminemia was an important factor associated with the presence of asymptomatic PE.

Glucose enhances protein tyrosine phosphatase 1B gene transcription in hepatocytes.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin receptor signal transduction pathway. We investigated the effects of glucose on PTP1B transcription in the human hepatocyte cell line Huh7. Using a reporter gene assay, we found that D-glucose dose-dependently enhanced the PTP1B promoter activity. Real-time PCR demonstrated that D-glucose also increased PTP1B mRNA expression. Protein kinase C (PKC) inhibitors partially but significantly inhibited the transactivation by D-glucose. Mithramycin, a Sp1 inhibitor, completely abrogated this transactivation. The deletion of three possible Sp1 sites in the promoter region of PTP1B significantly reduced the basal promoter activity and transactivation by D-glucose. Sp1 activation by PKC is one of the key mechanisms in the regulation of several gene expressions. Our data suggested that glucose enhanced PTP1B transcription through Sp1 activation by PKC. Increased hepatic PTP1B expression may partly explain glucose toxicity in diabetes.

[Biochemical markers for detection of atherosclerotic vascular complications].

Atherosclerotic vascular complication is considered as a final complication of lifestyle-related disease; however, suitable biochemical markers to detect vascular complications are yet to be determined. To clarify the clinical usefulness of oxidized low-density lipoprotein(oxLDL), high-sensitive C-reactive protein (hsCRP), and serum lysophosphatidylcholine (LPC) for the detection of vascular complications in type 2 diabetics, we evaluated the clinical implications of oxLDL, hsCRP and LPC in relation to clinical backgrounds and vascular complications. OxLDL was measured by ELISA(Mercodia, Sweden), hsCRP by immunonephelometry (Roche Diagnostics, Germany) and LPC by enzymatic methods (Alfresa, Japan), respectively. The oxLDL level did not differentiate any vascular complications; however, hsCRP was significantly higher in patients with ischemic heart disease (IHD), and LPC was significantly lower in patients with IHD and macroangiopathy composed of IHD, cerebral vascular accident and arteriosclerosis obliterans. Interestingly, the plasma LPC level was lower in women than in men. Multivariate regression analysis revealed that IHD potently contributed negatively to the LPC level, and also contributed positively to the hsCRP level, but did not contribute to the oxLDL level. Multivariate regression analysis also revealed that LPC, but not oxLDL nor hsCRP, contributed to the development of IHD and macroangiopathy. Thus, LPC is a better biochemical marker than oxLDL and hsCRP for the detection of vascular complications.

Edaravone inhibits rheumatoid synovial cell proliferation and migration.

Rheumatoid arthritis (RA) is characterized by synovial proliferation and migration which is induced by proinflammatory cytokines or oxidative stress, followed by joint destruction. Edaravone, clinically available free radical scavenger in Japan, is confirmed to be beneficial in the acute stage of cerebral infarction. We aimed to investigate whether edaravone suppressed in vitro proliferation and migration of synovial cells (SC) induced by IL-1beta. SC proliferation and migration induced by IL-1beta were dose-dependently suppressed by edaravone at the clinically available concentration. These data suggest that edaravone has potential effects to suppress SC proliferation and migration, followed by suppression of synovial proliferation in RA. Therefore, edaravone, an antioxidant agent, might be a novel therapeutic agent which develops the new strategy for treatment of RA, and more detailed studies are required to establish the therapeutic effect of edaravone on RA in vivo.

Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene.

Hepatic hydroxymethyl glutary coenzyme A HMG-CoA reductase inhibitors (statins) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction. Human serum paraoxonase 1 (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidative modification of low-density lipoprotein (LDL). We investigated the effects of statins on PON1 gene transcription using a reporter gene assay. Promoter activity of the PON1 gene was estimated by measuring luciferase activity of plasmids with a PON1 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney (HEK) 293 cells. Pitavastatin, simvastatin, and atorvastatin each significantly increased PON1 promoter activity, and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate (FPP), however, not by geranylgeranyl pyrophosphate. Further, PON1 promoter activity was enhanced by farnesyl transferase inhibitor (FTI), but not by geranylgeranyl transferase inhibitor (GGTI). PON1 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin, an inhibitor of Sp1. Our results suggest that pitavastatin activates transcription of the PON1 gene through the FPP pathway, which may play an important role in the anti atherosclerotic effects of statins.

Pioglitazone prevents reactive hypoglycemia in impaired glucose tolerance.

A 42-year-old woman with hypoglycemic symptoms that occurred several hours after a meal visited our hospital. The hypoglycemic symptoms appeared when she was 37 years old, and her plasma glucose level had been assessed as less than 60 mg/dL when she experienced the symptoms. One year before, she had been diagnosed with reactive hypoglycemia by 75 g-oral glucose tolerance test (OGTT), which showed a normal glucose tolerance (NGT) pattern, and had begun taking an alpha-glucosidase inhibitor and nutritional treatment. A 75 g-OGTT on admission showed hypoglycemia at 240 min after glucose loading, excessive insulin secretion and an impaired glucose tolerance (IGT) pattern. A euglycemic-hyperinsulinemic clamp study demonstrated decreased insulin sensitivity. Therefore, we suspected that she had reactive hypoglycemia associated with insulin resistance and treated her with 15 mg/day pioglitazone. Her hypoglycemic symptoms completely disappeared after treatment with pioglitazone; insulin sensitivity in a euglycemic-hyperinsulinemic clamp study improved. Another 75 g-OGTT revealed that the excessive insulin secretion and hypoglycemia at 240 min after glucose loading had disappeared, and glucose tolerance was normalized from an IGT pattern to an NGT pattern. Thus, we believe that pioglitazone is effective for reactive hypoglycemia and aggravated glycemic metabolism associated with insulin resistance.