Tadafumi Yokoyama

Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis

OBJECTIVES To compare the pro-inflammatory cytokine profiles and the cytokine kinetics in patients with secondary macrophage activation syndrome (MAS) due to systemic-onset juvenile idiopathic arthritis (s-JIA) and in both active and inactive disease states of s-JIA (but no MAS), with those demonstrated in EBV-induced haemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD), and to investigate the significance of IL-18 in the pathogenesis of s-JIA. METHODS Five patients with MAS complicating s-JIA (MAS/s-JIA), 10 with HLH due to EBV infection (EBV-HLH), 22 with KD and 28 healthy controls were analysed. Cytokine concentrations (IL-18, IL-6, neopterin and TNF-alpha receptor Types I and II) were quantified in serum by ELISA. Results were compared with clinical features of MAS/s-JIA, including ferritin concentrations. RESULTS Serum IL-18 concentrations in MAS/s-JIA patients were significantly higher than those in EBV-HLH or KD patients (P < 0.05). Serum IL-6 concentrations in KD patients were significantly higher than those in EBV-HLH or MAS/s-JIA patients. Serum neopterin concentrations in EBV-HLH patients were significantly higher than those in MAS/s-JIA or KD patients. Serum IL-18 correlated positively with the following measurements of disease activity: CRP, ferritin, lactate dehydrogenase and other cytokines (P < 0.05). Serum concentrations of IL-18 in s-JIA patients remained elevated in the inactive phase of disease, whereas clinical parameters and other cytokines normalized. CONCLUSIONS IL-18 may be an important mediator in s-JIA. Although serum Il-18 concentrations correlated with markers of the disease activity, IL-18 concentrations remained elevated even when other markers of disease activity normalized. Serum IL-18 concentration may be a promising indicator of the disease activity. The cytokine release pattern in MAS/HLH is different among patients with different aetiologies. Monitoring the cytokine profile, including IL-18, may be useful for differentiation of MAS/HLH and evaluation of disease activity in s-JIA.

Cytokine profiles in children with primary Epstein-Barr virus infection

Primary Epstein–Barr virus (EBV) infection causes infectious mononucleosis and hemophagocytic lymphohistiocytosis (HLH) in children, where EBV infects B and CD8+ T cells, respectively. We measured pro‐inflammatory and anti‐inflammatory cytokines in both diseases. Significantly higher concentrations of various mediators, including interferon‐γ, neopterin, interleukin (IL)‐6, IL‐10, IL‐18, and heme oxygenase‐1, were observed in EBV‐HLH. Because of their similarity to the profile of familial HLH, this profile was likely a consequence of HLH, but not ectopic infection. TNF‐α levels were elevated in both diseases. Elevation of those mediators may contribute to the disease pathogenesis of EBV‐HLH by activating and inhibiting host immune responses. Pediatr Blood Cancer 2013; 60: E46–E48.

Colchicine-responsive chronic recurrent multifocal osteomyelitis with MEFV mutations: a variant of familial Mediterranean fever?

*KURAに登録されているコンテンツの利用については,著作権法に規定されている私的使用や引用などの範囲内で行ってください。 *著作権法に規定されている私的使用や引用などの範囲を超える利用を行う場合には,著作権者の許諾を得てください。ただし,著作権者 から著作権等管理事業者(学術著作権協会,日本著作出版権管理システムなど)に権利委託されているコンテンツの利用手続については ,各著作権等管理事業者に確認してください。 Title Colchicine-responsive chronic recurrent multifocal osteomyelitis with MEFV mutations: A variant of familial Mediterranean fever? Author(s) Shimizu, Masaki; Tone, Yumi; Toga, Akiko; Yokoyama, Tadafumi; Wada, Taizo; Toma, Tomoko; Yachie, Akihiro Citation Rheumatology, 49(11): 2221-2223

Distinct cytokine profile in juvenile systemic lupus erythematosus-associated macrophage activation syndrome

Macrophage activation syndrome (MAS) has been observed in patients with systemic lupus erythematosus (SLE). Recognition of MAS in patients with SLE may be particularly challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. Massive hypercytokinemia is strongly associated with the pathogenesis of systemic lupus erythematosus-associated macrophage activation syndrome (SLE-MAS) but the pathogenesis and kinetics of cytokine release in SLE-MAS patients is not well studied. We present a case of SLE-MAS. The patient showed the distinct cytokine profile of SLE-MAS compared to systemic juvenile idiopathic arthritis associated MAS and Epstein-Barr virus-induced hemophagocytic lymphohistiocytosis. The observed TNF-α dominant increase appears to be characteristic of SLE-MAS. IgM type antilymphocyte antibody (ALAB) was detected on the surface of lymphocytes during the acute phase and disappeared when the patient was in remission. The patient had a heterozygous P369S-R408Q mutation in the MEFV gene. Our results suggest that ALAB and a MEFV mutation might play important roles in the pathogenesis of SLE-MAS. Furthermore, the cytokine profile of SLE-MAS differs from that of S-JIA-MAS: the TNF-α dominant increase appears to be characteristic.

Urinary Heme Oxygenase-1 as a Sensitive Indicator of Tubulointerstitial Inflammatory Damage in Various Renal Diseases

Background/Aims: In oxidative stress, heme oxygenase-1 (HO-1) plays a pivotal role in maintaining renal function and protecting renal structure, especially in renal tubular epithelial cells. We examined urinary HO-1 (uHO-1) levels to assess whether uHO-1 acts as a sensitive biomarker for detecting tubulointerstitial inflammatory damage in renal diseases. Methods: Immunohistochemical analyses and enzyme-linked immunosorbent assays for uHO-1 were performed using 61 urine samples (supernatants and sediment lysates) from healthy children and renal disease patients. Results: Proximal and distal epithelial cells showed higher uHO-1 levels than squamous and urothelial cells. Inflammatory renal disease patients had higher uHO-1 levels than noninflammatory renal disease patients and controls. In IgA nephropathy, patients with interstitial cellular infiltration showed higher uHO-1 levels than those without it. Among patients with increased urinary β2-microglobulin or N-acetyl-β-D-glucosaminidase levels, uHO-1 levels increased only in those with renal disease and tubulointerstitial inflammatory damage. uHO-1 levels positively correlated with urinary interleukin-6 in inflammatory renal disease patients. Conclusions: These results indicate that uHO-1 is a potentially useful, novel, and noninvasive biomarker for evaluating the degree of tubulointerstitial inflammatory damage in renal disease.

Effect of pravastatin on cisplatin-induced nephrotoxicity in rats.

We investigated whether pravastatin ameliorates renal damage induced by cisplatin (CP). Forty-three male Wistar rats were divided into four groups: rats treated with a control diet for 19 days and saline injection on day 14 (group1), group 1 with pravastatin treatment with 19 days (group 2), group 1 with CP injection on day 14 (group 3), and group 2 with CP injection (group 4). Renal function and serum lipids, renal malondialdehyde (MDA) and glutathione (GSH) levels, glutathione peroxidase (GPx) mRNA expression and activity, and kidney triglyceride (TG) concentrations were measured. Histology was evaluated by light microscopy with immunohistochemistry for p53, p53-upregulated modulation of apoptosis (PUMA), and terminal deoxynucleotide transferase dUTP nick end-labeling (TUNEL) staining. CP induced renal tubular damage with a higher MDA level, increased PUMA expression, p53- and TUNEL-positive cells counts, elevation of serum lipids, and decreased GSH level, GPx mRNA expression, and activity. Pravastatin partially ameliorated CP-induced renal injury, based on suppression of the renal MDA and TG levels, decreased p53 expression, and apoptosis in CP-treated rats. These findings suggest that pravastatin has a partial protective effect against CP nephrotoxicity via antioxidant activity as well as attenuation of the p53 response, and lipid-lowering effects.

Bicipital Synovial Cyst in Systemic-Onset Juvenile Idiopathic Arthritis

Figure. Contrast CT scan. Sagittal view (left) and transverse view (right) showing a large multiloculated collection of fluid along the margin of the biceps muscle extending from the synovium. A 4-year-old girl with systemic-onset juvenile idiopathic arthritis (s-JIA) relapsed while on prednisolone and ibuprofen therapy. She presented with swelling of upper left arm. The masses were firm and slightly tender, and the skin was slightly warm but not hyperemic. Ultrasonography revealed a large collection of hypoechogenic fluid (30 15 mm) along the margin of the biceps muscle. Contrast computed tomography (CT) scan showed moderate joint effusion with synovial hypertrophy. A large multiloculated collection of fluid was found along the margin of the biceps muscle extending from the synovitis (Figure). Magnetic resonance imaging (MRI) also demonstrated fluid collection with synovial hypertrophy. A large multiloculated cystic mass, hyperintense on T2-weighted MRI and hypointense on T1-weighted MRI, was seen along the margin of the biceps muscle extending from the synovitis. The collected fluid was hyperintense on fat-suppression T1-weighted MRI, suggesting that the cyst had inflammatory contents. A diagnosis of brachial synovial cyst was made. The swelling decreased and then disappeared with control of disease activity. How bicipital synovial cysts arise remains unclear. The findings in this patient demonstrate communication between the shoulder and the cyst. This might suggest that the fluid arises within the shoulder joint and then descends into the contiguous bicipital tendon sheath. The tendon eventually ruptures, leading to collection of fluid in the bicipital area. Another possibility is that the cyst arises as a collection of fluid secreted by the inflamed synovial sheath of the biceps tendon extending from the synovium of the shoulder joint. Even though bicipital synovial cyst is a rare manifestation of s-JIA, synovial cyst should be considered in the differential diagnosis in all children with s-JIA presenting with swelling of the upper arm. n

Successful Treatment with Bosentan for Pulmonary Hypertension and Reduced Peripheral Circulation in Juvenile Systemic Sclerosis

Pulmonary arterial hypertension (PAH) when associated with systemic sclerosis (SSc) (SSc–PAH) is one of the leading causes of mortality and is found in 10–15% of adult patients with SSc. The ET receptor antagonist bosentan has been shown to be effective in the treatment of adult patients with SSc-PAH. Furthermore, it has been shown that bosentan ameliorates decreased skin perfusion and digital ulceration secondary to SSc. However, the effectiveness and safety of bosentan for treatment of juvenile SSc still remains unclear. We describe a case of juvenile SSc–PAH successfully treated with bosentan. The present case shows that bosentan ameliorated PAH and peripheral circulation as evaluated by cold stress thermography. No bosentan-related adverse events such as liver dysfunction were observed. Prospective randomized trials are required to validate the effectiveness of bosentan for patients with juvenile SSc; however, bosentan might be useful for the management of patients with juvenile SSc.

Flow cytometric analysis of skin blister fluid induced by mosquito bites in a patient with chronic active Epstein-Barr virus infection

In chronic active Epstein–Barr virus (EBV) infection (CAEBV), ectopic EBV infection has been described in T or natural killer (NK) cells. NK cell-type infection (NK-CAEBV) is characterized by large granular lymphocytosis, high IgE levels and unusual reactions to mosquito bites, including severe local skin reactions, fever and liver dysfunction. However, the mechanisms underlying these reactions remain undetermined. Herein, we describe a patient with NK-CAEBV whose blister fluid after mosquito bites was analyzed. The patient exhibited significant increases in the percentage of CD56+ NK cells in the fluid compared with a simple mosquito allergy, in which the majority of infiltrated cells were CD203c+ cells, indicating basophils and/or mast cells. His fluid also contained CD203c+ cells, and his circulating basophils were activated by mosquito extracts in vitro. These results suggest that CD203c+ cells as well as NK cells may play pathogenic roles in the severe skin reactions to mosquito bites in NK-CAEBV.

Thomsen-Friedenreich antigen exposure as a cause of Streptococcus pyogenes-associated hemolytic-uremic syndrome.

Infection with Streptococcus pyogenes, a Group A beta-hemolytic streptococcus (GAS), is a rare cause of hemolyticuremic syndrome (HUS). Invasive infections with Streptococcus pneumoniae that produce neuraminidase are a well-recognized cause of HUS without diarrhea. The Thomsen- Friedenreich antigen (T antigen) plays a role in the pathophysiology of pneumococcal HUS. We describe the case of a 3-year-old boy with GAS-associated HUS and show how T-antigen exposure was implicated in this case. He had no diarrhea and cultures for blood, urine, and stool were negative. The urinary pneumococcal antigen was negative; his direct Coombs test was positive. Glomerular capillary loops, tubular epithelium on his renal biopsy specimen, and red blood cells in his blood smear showed positive fluorescence with anti-T lectin. Although the pathogenesis of GAS-associated HUS is not well understood, T-antigen exposure may be implicated in some cases with GAS-associated HUS.