Kazuhiro Furuya

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.

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.

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.

Therapeutic effects of sunitinib, one of the anti-angiogenetic drugs, in a murine arthritis

Abstract Objectives. The purpose of this study was to confirm the inhibitory effects of sunitinib, an angiogenesis inhibitor that targets tyrosine kinases of vascular endothelial growth factor receptor (VEGFR) family and platelet-derived growth factor receptor (PDGFR) family, on arthritis in mice with type II collagen-induced arthritis (CIA). Methods. Sunitinib at a concentration of 30 or 60 mg/kg/day was intraperitoneally administered to mice with CIA. We compared the changes in arthritis score over time, pathological score, bone density, and microvascular density in synovial membrane between the vehicle and treatment groups. Results. In the sunitinib-treated groups, the arthritis score decreased in a dose-dependent manner in comparison with that in the vehicle group. Furthermore, improvement in the pathological score, inhibitory tendency of loss in the bone density, and a decrease in the synovial microvascular density were also observed in the sunitinib-treated groups. Conclusions. Sunitinib remarkably inhibited arthritis, particularly synovial angiogenesis in a murine CIA model. This compound may be useful for treating arthritis.

Dual energy CT iodine map for delineating inflammation of inflammatory arthritis

Iodine mapping is an image-processing technique used with dual-energy computed tomography (DECT) to improve iodine contrast resolution. CT, because of its high spatial resolution and thin slice reconstruction, is well suited to the evaluation of the peripheral joints. Recent developments in the treatment of inflammatory arthritis that require early diagnosis and precise therapeutic assessment encourage radiological evaluation. To facilitate such assessment, we describe DECT iodine mapping as a novel modality for evaluating rheumatoid arthritis and psoriatic arthritis of the hands and feet.Key Points• Dual-energy CT iodine mapping can delineate inflammation of peripheral inflammatory arthritis.• DECT iodine mapping has high spatial resolution compared with MRI.• DECT iodine mapping has a high iodine contrast resolution.• DECT iodine mapping may reflect therapeutic effects.

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.

Angiogenesis and VEGF-expressing cells are identified predominantly in the fascia rather than in the muscle during the early phase of dermatomyositis

BackgroundWe previously demonstrated that fasciitis is a common lesion in dermatomyositis (DM) and that DM-associated fasciitis is detectable, as the result of the increased vascularity in the fascia, by power Doppler ultrasonography. We aimed to investigate whether angiogenesis and vascular endothelial growth factor (VEGF)-expressing cells in the fascia are histologically demonstrated during the early phase of DM, and whether inflammation is involved in angiogenesis and an increased number of VEGF-expressing cells.MethodsWe prospectively evaluated 22 patients with DM and 11 patients with polymyositis (PM). Immunohistochemical staining for CD31, VEGF, and tumor necrosis factor-α (TNF-α) were performed on paraffin-embedded sections. The total vascular inflammation score (TVIS), angiogenesis score (AS), and numbers of VEGF-expressing and TNF-α-expressing cells were analyzed in the fascia and muscle.ResultsSignificant fasciitis was detected in most of the patients DM with or without myositis-specific/associated antibodies, while mild fasciitis was detected in four patients with PM, two of whom were positive for anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies. The AS and the number of VEGF-expressing cells in the fascia of patients with DM were significantly greater than those of patients with PM; no significant difference was observed in muscle in patients with DM and PM. The number of VEGF-expressing cells in the fascia correlated with the AS of DM patients. In early-phase DM, the AS, the number of VEGF-expressing cells, and the TVIS in the fascia were significantly higher than in muscle. However, no significant differences were observed in these scores excluding the TVIS between muscle and the fascia in late-phase DM. In DM patients, the TVIS correlated with the AS in the fascia, while the number of TNF-α-expressing cells correlated with the TVIS and the number of VEGF-expressing cells in the fascia.ConclusionAngiogenesis, the number of VEGF-expressing cells, and the degree of inflammation were higher in the fascia in DM than in PM, and were increased predominantly in the fascia rather than in the muscle in early-phase DM. The degree of inflammation correlated with that of angiogenesis in the fascia of DM. The fascia can therefore be a primary site of inflammation and angiogenesis in the pathogenesis of DM.

Fasciitis as a disease manifestation in immune-mediated necrotizing myopathy with anti-signal recognition particle antibodies: a case report of two cases

SIR, Immune-mediated necrotizing myopathy (IMNM) is now classified as part of the group of idiopathic inflammatory myopathies, which are divided into DM, PM, inclusion body myositis and IMNM [1]. IMNM patients present with subacute or insidious onset of muscle weakness and highly elevated creatine kinase (CK) concentrations. The characteristic pathological features of IMNM comprise a lack of significant inflammatory infiltrates in muscle tissue despite the presence of muscle fibre necrosis, degeneration and regeneration [1, 2]. The pathogenesis of IMNM remains incompletely understood. We describe two cases of anti-signal recognition particle (SRP) antibody-positive IMNM patients with fasciitis. Patient 1 was a 68-year-old man who presented with muscle weakness of the lower extremities, dysphagia and an elevated CK concentration (5948 U/l). ANAs (speckled, discrete speckled and cytoplasmic pattern) were present at a titre of 1:640. Anti-SRP antibodies were detected by the commercial assay EUROLINE Myositis Profile 3 (immunoblots), and the positivity of anti-SRP antibodies was confirmed with an in-house ELISA [3]. The patient had combined pulmonary fibrosis and emphysema, but neither skin sclerosis nor RP. Short tau inversion recovery and gadolinium-enhanced fat-suppressed T1-weighted MRI revealed abnormal high signal intensity and enhancement, respectively, along the fasciae of the anterior tibial (Fig. 1A), gastrocnemius and soleus muscles and within these muscles. En bloc biopsy specimens including skin, subcutaneous tissue, fascia and muscle obtained from the anterior tibial muscle before treatment showed muscle fibre necrosis and regeneration with a few CD68þ macrophages and CD8þ T lymphocytes and no B lymphocytic infiltrates around the endomysium within the fascicles, whereas CD4þ T, CD8þ T and CD20/CD79aþ B lymphocytic infiltrates were distributed at perivascular sites in the fascia. The patient was treated with prednisolone 60 mg/day and improved, with normalization of his CK concentration after 3 months of treatment. Prednisolone was gradually tapered; however, 7 months later, the patient relapsed with muscle weakness and an increased CK concentration (812 U/l). We increased the prednisolone dose from 17 to 30 mg/day and used high-dose IVIG 0.4 g/kg/day for 5 days. At 2 months after IVIG, his muscle weakness and increased CK concentration improved. Patient 2 was a 29-year-old woman who presented with proximal muscle weakness and an elevated CK concentration (8880 U/l). The patient was positive for ANAs (cytoplasmic pattern) at a titre of 1:80, and antiSRP antibodies were detected by both EUROLINE Myositis Profile 3 and the in-house ELISA. Short tau inversion recovery and gadolinium-enhanced fatsuppressed T1-weighted MRI showed abnormal high signal intensity and enhancement, respectively, along the fasciae of the biceps brachii (Fig. 1B) and quadriceps femoris muscles and within these muscles. Chest CT scans revealed the presence of mild ground-glass opacity in the lower lungs. En bloc biopsy specimens obtained from the biceps brachii muscle before treatment showed muscle fibre necrosis and regeneration, with small numbers of CD68þ macrophages, T and B lymphocytes around the endomysium within the fascicles (Fig. 1C). In the fascia, massive lymphocytic infiltrates, mainly consisting of CD20/CD79aþ B cells with a few CD4þ T and CD8þ T cells, were distributed in lymphoid follicle-like aggregates and at perivascular sites (Fig. 1C and D). The patient was given prednisolone at an initial dose of 40 mg daily in combination with tacrolimus 6 mg/day. After 5 months, the muscle weakness disappeared, and her CK concentration had decreased to 160 U/l. In the present cases, fasciitis was found in addition to necrotizing myopathy. To date, fasciitis has not been recognized as a disease manifestation in IMNM because a muscle biopsy including the fascia (en bloc biopsy) is not usually performed for diagnosis of idiopathic inflammatory myopathies. We previously demonstrated that fasciitis was a common disease manifestation in patients with DM and anti-aminoacyl-tRNA synthetase antibody-positive patients (anti-synthetase syndrome) diagnosed with DM or PM by the Bohan and Peter criteria [4–7]. Fasciitis may also be a disease manifestation in patients with IMNM. Regarding the inflammatory infiltrates in our cases, scant presence of macrophages and lymphocytes was noted around the endomysium within the fascicles, whereas significant B lymphocytic infiltrates were found at perivascular sites and in lymphoid follicle-like aggregates in the fascia. Many reports have described a few or no lymphocytic infiltrates in the muscle, whereas significant B lymphocytic infiltrates have not Key message • Fasciitis is a potential disease manifestation in patients with immune-mediated necrotizing myopathy.