Isamu Kingetsu

Clinical Significance of Serum Levels of Vascular Endothelial Growth Factor, Angiopoietin-1, and Angiopoietin-2 in Patients with Rheumatoid Arthritis

Objective. To evaluate the clinical significance of serum levels of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), and angiopoietin-2 (Ang-2) in patients with rheumatoid arthritis (RA). Methods. The subjects were 70 patients with RA. Serum VEGF, Ang-1, and Ang-2 levels were determined by ELISA. As indices of disease activity, serum levels of C-reactive protein (CRP) and matrix metalloprotease (MMP)-3 were examined, and the 28-joint count Disease Activity Score (DAS28)-CRP was calculated. Power Doppler ultrasonography was performed in the bilateral wrists, elbows, shoulders, knees and ankles. The synovial blood flow signals were scored using a 3-grade scale (0–2), and the total of the scores in the 10 joints was regarded as the total signal score (TSS). Results. Serum VEGF level showed significant correlations with serum CRP and MMP-3 levels, DAS28-CRP, and TSS. Serum Ang-1 level showed significant correlations with serum MMP-3 level and DAS28-CRP. Serum Ang-2 level showed significant correlations with serum CRP level and TSS. Conclusion. The serum VEGF level is important as an index of the activity of RA based on angiogenesis and a prognostic factor regarding joint destruction. Serum Ang-1 level may be useful as an index of sustained arthritis based on the maintenance of newly formed vessels. Serum Ang-2 level may reflect a state of marked angiogenesis.

Fasciitis as a common lesion of dermatomyositis, demonstrated early after disease onset by en bloc biopsy combined with magnetic resonance imaging.

OBJECTIVE To investigate whether fasciitis is histopathologically demonstrable in patients with dermatomyositis (DM), and to analyze the process of inflammatory progression in myopathy accompanying DM. METHODS STIR or fat-suppressed T2-weighted magnetic resonance imaging (MRI) and en bloc biopsy were performed in 14 patients with newly diagnosed adult-onset DM. The severity of inflammatory cell infiltration around the fascial and intramuscular small blood vessels was evaluated using the total vascular inflammation score (TVIS). RESULTS In all patients, MRI revealed abnormal hyperintensity in the fascia and in marginal sites of the muscle, predominantly over central sites. En bloc biopsy revealed the presence of fasciitis in most of the patients, as shown by inflammatory infiltrates around the fascial small blood vessels. In those patients who underwent en bloc biopsy earlier than 2 months after the appearance of muscle symptoms, the TVIS of the fascia was significantly higher than the TVIS of the muscle. In contrast, in those patients who underwent en bloc biopsy >2 months after muscle symptom onset, the TVIS of the fascia did not differ significantly from the TVIS of the muscle. CONCLUSION Fasciitis was histopathologically demonstrated in patients with newly diagnosed adult-onset DM as early as 2 months after the onset of muscle symptoms. These results indicate that fasciitis is a common lesion of DM and suggest that the fascial microvasculature is the primary site of inflammatory cell infiltration in DM. Fasciitis may contribute to muscle symptoms in patients with DM without myositis.

Inhibition of arthritis by systemic administration of endostatin in passive murine collagen induced arthritis

Objective: To investigate the arthritis inhibiting effect of endostatin, known to have potent antiangiogenic activity, systemically given to animal models of rheumatoid arthritis (RA). Methods: Four kinds of monoclonal anti-type II collagen antibody followed by lipopolysaccharide (LPS) three days later were given to 6 week old, female Balb/c mice to induce arthritis. Three groups of mice received 0.2 mg/kg/day, 2 mg/kg/day, and 10 mg/kg/day of endostatin, respectively, whereas a control group received phosphate buffered saline (PBS). Endostatin or PBS was given for 13 days, starting before the development of arthritis. Arthritis was evaluated by arthritis scores and hind paw thicknesses. Mice were killed for histological examination on the 22nd day after the administration of monoclonal anti-type II collagen antibody. Results: Arthritis developed within three days after LPS administration in both the control and endostatin treatment groups. No difference in the development rate of arthritis was noted between the control and endostatin treatment groups. Arthritis scores remained significantly lower in the endostatin 10 mg/kg/day group than in the control group. Hind paw thicknesses also remained significantly smaller in the endostatin 10 mg/kg/day group than in the control group. Histopathological examination showed that synovial thickening and subchondral bone erosion improved more in the endostatin treatment groups than in the control group. Conclusion: The systemic administration of endostatin had an arthritis inhibiting effect in RA animal models. Endostatin inhibited, in particular, pannus formation and bone destruction.

Telomerase activity and telomere length of peripheral blood mononuclear cells in SLE patients.

We evaluated the clinical significance of the telomerase activity and telomere length of peripheral blood mononuclearcells (PBMC) in systemic lupus erythematosus (SLE). PBMC were isolated from 55 patients with SLE and the telomerase activity was measured by TRAP assay. The telomere length of PBMC was also measured in 30 of these subjects. As a control group, 45 healthy adults with no particular clinical history were studied. The results were compared with clinical data. In patients with active SLE, the telomerase activity of PBMC was significantly increased compared with the control group. In patients with inactive SLE, the PBMC telomerase activity was not different compared with the controls in their 20s, 30s and 40s, but it was significantly increased compared with the controls in their 50s. In SLE patients, the telomerase activity of PBMC was significantly correlatedwith modified SLEDAI. The telomere length of PBMC in younger SLE patients tended to be shorter than that in the controls, but no difference was observed in older patients. The correlation coefficient between the telomerase activity and telomere length of PBMC in SLE patients was not significant. Abnormalities in the telomeraseactivity and telomere length observedin SLE patients are consideredto be important findings for evaluation of the pathology of SLE.

The effect of endostatin evaluated in an experimental animal model of collagen-induced arthritis.

Objective: To investigate the arthritis‐inhibiting effect of endostatin, a potent angiogenesis inhibitor, on type II collagen‐induced arthritis (CIA). Methods: In an experimental system of prophylactic administration, endostatin was administered once daily at 1 mg/kg/day or 10 mg/kg/day for 2 weeks from before the onset of arthritis. In the experimental system of therapeutic administration, mice with an arthritis score of 1 to 3 were administered endostatin once daily at 10 mg/kg. In the experimental system of continuous administration, endostatin was administered using an osmotic pump capable of continuously administering a calculated dose of 1 mg/kg/day for 2 weeks. Results: Arthritis scores were lower in a dose‐dependent manner in the prophylactic administration group than in the control group. Arthritis scores were lower in the therapeutic administration group than in the control group. Compared with the once‐daily dosage regimen, the administration of endostatin by an osmotic pump achieved a similar arthritis‐inhibiting effect at one‐tenth of the dose. Conclusion: Both prophylactic and therapeutic administration of endostatin inhibited type II CIA in mice. The administration method using an osmotic pump is useful.

Pneumomediastinum in dermatomyositis itself is not a poor prognostic factor: report of a case and review of the literature

We describe a 38-year-old man who presented with proximal muscle weakness, myalgia, polyarthralgia, and skin rash and was diagnosed as having dermatomyositis (DM). The patient’s symptoms improved with prednisolone therapy. However, myopathy relapsed and pneumomediastinum with subcutaneous emphysema developed. Pneumomediastinum with subcutaneous emphysema rapidly disappeared by the administration of ciclosporin. We reviewed the present case and previously reported cases regarding the clinical characteristics. All of the reported death cases were accompanied by interstitial lung disease (ILD). Although it has been reported that pneumomediastinum in DM can be fatal, the direct cause of patient’s death was due to respiratory failure resulting from progressive ILD. Pneumomediastinum without ILD shows a good prognosis.

Brief Report: Power Doppler Ultrasonography for Detection of Increased Vascularity in the Fascia: A Potential Early Diagnostic Tool in Fasciitis of Dermatomyositis

We previously demonstrated that fasciitis is a common lesion of dermatomyositis (DM) that is detectable early after disease onset by en bloc muscle biopsy combined with magnetic resonance imaging (MRI). Power Doppler ultrasonography (PDUS) is a useful method for detection of inflammation and vascularity in rheumatic diseases. We undertook this study to determine whether fasciitis was detectable by PDUS in patients with DM.

Myalgia in Patients with Dermatomyositis and Polymyositis Is Attributable to Fasciitis Rather Than Myositis: A Retrospective Study of 32 Patients who Underwent Histopathological Examinations

Objective. To determine the association between fasciitis and the clinical variables in patients with dermatomyositis (DM) and polymyositis (PM). Methods. We retrospectively reviewed the medical records of 32 patients (24 DM, 8 PM) with newly diagnosed DM and PM and in whom fascia and muscle specimens were histopathologically examined. The relationship between fasciitis and the clinical variables was statistically analyzed. These included age, sex, myalgia, muscle weakness, creatine kinase (CK) and aldolase activities, anti-Jo1 antibody, interstitial lung disease, and malignancy. Results. Twenty (62.5%) of the 32 patients who underwent the histopathological examination of a fascia specimen had fasciitis, including 18 (75%) of 24 patients with DM and 2 (25%) of 8 patients with PM. The frequency of fasciitis was significantly higher among the patients with DM than among the patients with PM (p < 0.05). Histopathologically, fasciitis in PM was very mild in comparison to that in DM. The frequency of myalgia in patients with fasciitis was significantly higher than that in patients without fasciitis (p < 0.05). However, myalgia was not associated with myositis. There were no significant differences in the patients with and without fasciitis in age, sex, manual muscle test 8 scores, CK or aldolase activities, or the presence of anti-Jo1 antibodies and malignancy. Conclusion. The frequency of fasciitis was significantly higher among patients with DM than among those with PM. Fasciitis, rather than myositis, was associated with myalgia.

Elevation of Bombina variegata peptide 8 in mice with collagen-induced arthritis

BackgroundBombina variegate peptide 8 (Bv8) is a small protein secreted by frog skin. Recently it has been shown to contribute to tumor angiogenesis in mouse model. The purpose of this study was to investigate Bv8 in mice with type II collagen-induced arthritis (CIA).MethodsWe induced CIA in male DBA/1J mice. The severity of arthritis was evaluated based on an arthritis score. RNA was extracted from the joint, and examined for Bv8 mRNA expression by RT-PCR and real-time RT-PCR. Synovial tissue and bone marrow were immunohistochemically examined using anti-Bv8 antibody.ResultsThe level of Bv8 mRNA expression in the joint was below the detection limit in the control group, but was elevated in the CIA group, and was correlated with the arthritis score. In addition, an increase in Bv8-positive cells was observed in the synovium and bone marrow in the CIA group.ConclusionBv8 was elevated in the synovium and bone marrow of CIA mice, suggesting that Bv8 plays an important role in the pathogenesis of arthritis.

AB0522 Clinical Characteristics of Muscular Symptoms in Patients with Systemic Lupus Erythematosus

Background It is well known that myalgia occurs in 40% to 80% of patients with systemic lupus erythematosus (SLE). However, the clinical charasteristics of muscular symptoms associated SLE has not been studied enough. Objectives The aim of this study is to analyze the clinical characteristics of muscular symptoms associated SLE. Methods We retrospectively reviewed the medical record of SLE patient who presented muscular symptoms (muscle weakness or myalgia) between January 2010 and December 2012. We identified 7 SLE patients who developed muscular symptoms. The clinical characteristics, muscle enzymes, laboratory data, MRI fingings, and pathological findings were analyzed. Results At the time of muscle symptom onset, the mean patient age was 32.7±11.1 years, with a male-female ratio of 1:6. All cases showed low complement levels, and showed elevated levels of ds-DNA antibodies. The mean SLE Disease Activity Index (SLEDAI) was 16±6.22. Serum creatine kinase was elevated in 1 of the 7 cases. Meanwhile, all cases showed increased aldolase and the STIR MRI of the muscles revealed a high intensity signal showing myofascial dominance over muscle. Moreover, en bloc biopsy was performed in 4 cases and like the MRI findings, myofascial-dominant mononuclear cell infiltrates were observed. In all cases, a moderate to high dose of prednisolone was administered and muscle symptoms improved. This was accompanied by an improvement in muscle symptoms, decreases in aldolase, ds-DNA antibodies and SLEDAI, and an increase in complement levels. Conclusions In SLE patients with muscular symptoms, fasciitis was demonstrated by MRI or pathological findings. Fasciitis may contribute to muscular symptoms in patients with SLE. References Tsokos GC, Moutsopoulos HM, Steinberg AD. Muscle involvement in systemic lupus erythematosus. JAMA 1981;246:766-8. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1910