Shumpei Yokota

Longterm Safety and Effectiveness of the Anti-interleukin 6 Receptor Monoclonal Antibody Tocilizumab in Patients with Systemic Juvenile Idiopathic Arthritis in Japan

Objective. To assess the longterm safety and effectiveness of tocilizumab (TCZ) in systemic-onset juvenile idiopathic arthritis (sJIA). Methods. The longterm extension phase of 2 pivotal studies (phase II with 11 patients and phase III with 56 patients) in patients with active sJIA was analyzed. Patients received open-label TCZ (8 mg/kg, every 2 weeks) without concomitant use of disease-modifying antirheumatic drugs. Results. In total, 67 patients were enrolled. All patients received corticosteroid at baseline. Median duration of exposure to TCZ was 3.4 years. Nine patients withdrew from the study [4 because of adverse events (AE), 4 because of the development of anti-TCZ antibodies, and 1 because of inadequate response]. Rates of AE and serious AE were 803.7/100 patient-years (PY) and 34.7/100 PY, respectively. The most common serious AE were infections (13.2/100 PY). No cases of malignancy or death were reported. Two serious infusion reactions were reported in patients testing negative for anti-TCZ antibodies. One definite macrophage activation syndrome (MAS) case and 1 potential MAS case were identified. American College of Rheumatology (ACR) response rates attained early in the TCZ treatment period were maintained throughout the study: at Week 168, JIA ACR 30, 50, 70, 90, and 100 response rates were 80.3%, 80.3%, 75.4%, 60.7%, and 18.0%, respectively. In total, 22 of 67 patients (32.8%) completely discontinued corticosteroids without flare. Conclusion. TCZ has demonstrated durability of effectiveness in the longterm treatment of children with sJIA and has shown good tolerability and a low discontinuation rate associated with AE, development of anti-TCZ antibodies, or inadequate response. (ClinicalTrials.gov NCT00144599 and NCT00144612). (First Release March 15 2014; J Rheumatol 2014;41:759-67; doi:10.3899/jrheum.130690)

Toxic epidermal necrolysis in a child successfully treated with cyclosporin A and methylprednisolone

© 2007 Japan Pediatric Society Toxic epidermal necrolysis (TEN) is an acute and life-threatening disease that is characterized by severe necrosis of the skin. It also involves visceral organs and manifests systemic symptoms. 1,2 Some medicines and infections are known to be major precipitating factors of the disease. 3 TEN and Stevens – Johnson syndrome (SJS) are now categorized into the same type of disorder. 4 The mortality rate of TEN is 30 – 35% and prompt management including withdrawal of causative drugs with long half-lives is essential for a favorable outcome. 5 Many drugs such as corticosteroids, i.v. immunoglobulin, 3 and thalidomide 6 are used as treatment for TEN, but these drugs are unsatisfactory in effi cacy. In the current report we present a pediatric case of TEN associated with leukopenia successfully treated with i.v. cyclosporin A (CsA), methylprednisolone and granulocyte-colony stimulating factor (G-CSF).

A Report of Two Cases of Kawasaki Disease Treated With Plasma Exchange

Abstract:  Kawasaki disease is a generalized vasculitis of unknown etiology that occurs predominantly in infants and young children. It is very important to prevent its cardiovascular manifestations, especially coronary artery lesions. Early treatment with intravenous immunoglobulin reduces cardiovascular sequelae, but some patients do not respond to this treatment, and they have a high incidence of coronary artery lesions. On the other hand, acute heart failure is rare in Kawasaki disease. We report on the cases of two patients with persistent fever and shock even after intravenous immunoglobulin therapy. In both cases, plasma exchange may have reduced the risk of coronary artery lesions and proved effective against acute heart failure with catecholamine‐refractory shock; yet the mechanism of this improvement remains unclear.

Immune response to Haemophilus influenzae type b conjugate vaccine in preterm infants.

Background:  Haemophilus influenzae type b (Hib) vaccine became available for use in Japan in December 2008. The aim of the present study was to evaluate the immunogenicity of Hib vaccine in Japanese preterm infants.

Superior mesenteric artery syndrome: risk factor for duodenal involvement in Henoch-Schönlein purpura.

Background:  The anatomical location of the third portion of the duodenum is between the superior mesenteric artery (SMA) and the abdominal aorta (AA). When the aorto‐mesenteric angle (AMA) is small and the aorto‐mesenteric distance (AMD) is short, the duodenum becomes tightly compressed between these two blood vessels. Severe compression can obstruct the duodenum, resulting in vomiting and abdominal pain. This clinical condition is termed superior mesenteric artery syndrome (SMA syndrome). The duodenum is frequently affected in Henoch–Schönlein purpura (HSP). The aim of the present study was to verify that duodenal anatomy mimicking SMA syndrome is a risk factor for duodenal involvement and abdominal pain in HSP.

Usefulness of serum fibrinogen degradation product-E in sporadic cases of classical hemolytic uremic syndrome

Abstract Background: Hemolytic uremic syndrome (HUS) associated with Shiga toxin (Stx)‐producing Escherichia coli O157:H7 infection is one of the diseases causing acute renal failure in young children. Although HUS is still a serious disease in children, no reliable predictive markers for HUS nor markers of disease severity are available so far. Recently, we experienced a sporadic case of typical HUS caused by Stx‐producing E. coli O157:H7 and detected, at the prodromal stage, a high level of serum fibrin/fibrinogen degradation product‐E (FDP‐E) fraction.

GI involvement of sigmoid mucosal erosion in a 13-year-old girl with microscopic polyangiitis

endobiliary RFA can completely obviate the need for an SEMS. Until now, photodynamic therapy was the only evidencebased endoscopic treatment other than stenting that improved the quality of life and survival of such patients.5 Endobiliary RFA adds to the endoscopic armamentarium for the treatment of these subjects. However, further randomized controlled trials are needed to establish improved SEMS patency, cost-effectiveness, and survival advantages, if any. In conclusion, endobiliary RFA seems to be a userfriendly and effective palliative treatment modality for paFigure 4. Cholangiogram obtained 2 weeks after the use of endoscopic RFA.

Latent cerebral hypoperfusion in a boy with persistent nephrotic syndrome

Pediatricians are often faced with both bad temper and decreased daily activity in children with persistent nephrotic syndrome. These problems, which might affect both mental and physical development, have been explained as a consequence of general fatigue due to systemic edema and/or long-term hospitalization. However, other factors, such as cerebral hypoperfusion, may be involved. We experienced a case of a boy with steroid-resistant nephrotic syndrome who showed diffuse cerebral hypoperfusion on single photon emission computed tomography. Diffuse cerebral hypoperfusion dramatically resolved as the nephrotic syndrome remitted. His bad temper, decreased daily activity, and delay of speech and motor development also improved. In our patient, cerebral hypoperfusion might have been associated with his mental problems, physical problems, and delayed development of speech.

Anatomical condition mimicking superior mesenteric artery syndrome might cause duodenal involvement in Henoch–Schönlein purpura

The authors thank Dr Fujii for his voluminous contribution to the literature in general and to our article in particular. The excellent and comprehensive discussion in his letter of the anatomical condition similar to superior mesenteric artery syndrome (SMA) and duodenal lesion in Henoch–Schönlein purpura (HSP) provides an illuminating framework on our study. We would like to offer a few comments. Dr Fujii indicated that HSP patients with abdominal pain and duodenal lesion by ultrasound showed hypoperistalsis, which was not consistent with characteristics of SMA syndrome. We have also observed bowel abnormalities (BA) on ultrasound in HSP that were inflammatory, and paralytic findings of the intestine. Thus, in our manuscript, BA were defined as bowel wall thickness of more than 3 mm and signs of paralytic ileus, such as hypoperistalsis of thickened bowel and bowel fluid stagnation in the proximal side, which differ from small bowel series criteria for SMA syndrome. We referred to ultrasound criteria for SMA syndrome, only to emphasize and explain the correlation between the anatomical condition mimicking SMA syndrome and duodenal involvement in HSP, not to diagnose SMA syndrome. Moreover, we are afraid that duodenal BA never develop merely due to the anatomical condition mimicking SMA syndrome, and we think BA develop due to this anatomical condition concomitant with systemic leukocytoclastic vasculitis. As described in our manuscript, ultrasound criteria for SMA are just one set of the required criteria to diagnose SMA syndrome. In one of twelve HSP patients with abdominal pain and duodenal lesions by ultrasound in our study, we measured the aortomesenteric angle (AMA) and the aortomesenteric distance (AMD) both on admission and at the time of discharge. Decrease of AMA (23°→12°) and AMD (5.3 mm→3.3 mm) at the time of discharge compared with those on admission was observed in this patient, because bowel edema resolved after prednisolone therapy. We used the values of AMA and AMD measured on admission in all HSP patients in our study. The difference between patients and controls might have been more significant in AMA and AMD after resolution of intestinal edema, if we had adopted the values at the time of discharge or the asymptomatic state in all HSP patients. Thus, the significant differences in AMA and AMD between the two groups would not be overestimated but rather underestimated. Strictly speaking, we should adopt the values at the asymptomatic state, not the edematous state, because we would research the causality of duodenal lesion in an HSP patient with abdominal pain. However, since the number of HSP patients assessed in our study was small, we are now planning an extended study.

Intravenous gamma globulin for atypical hemolytic uremic syndrome

Sir, We appreciate Dr. Watanabe’s appropriate comment [1] on our article [2]. He pointed out that it is possible that our patient had atypical hemolytic uremic syndrome (HUS) caused by dysregulation of components of the alternative complement pathway, such as complement factor H (CFH), factor I (FI), and membrane cofactor protein (MCP) [3–5]. Our patient did, in fact, have normal levels of factors H, C3, C4, and CH50. However, as Dr. Watanabe pointed out, this is not sufficient to rule out atypical HUS with an abnormality of CFH, because some patients do not exhibit decreased CFH or C3 levels in blood but nonetheless develop atypical HUS [3]. Precise diagnosis thus requires genetic analysis. Plasma exchange (PE) by frozen fresh plasma (FFP) can, in theory, eliminate insufficiency of complement factors and remove autoantibodies to CFH. Notably, though 50– 60 ml/kg FFP was used for our patient at each PE, he was clearly unresponsive to this treatment. Although this might be evidence that our patient had atypical HUS of unknown etiology, we agree that genetic analysis is important for detecting mutations of CFH, FI, and MCP and thus to predict recurrence of atypical HUS in our transplanted patient. However, awaiting the results of genetic analysis may not be possible in clinically urgent situations. We believe that intravenous gamma globulin is worth trying if a patient with atypical HUS is refractory to treatment with PE, steroids, and immunosuppressive agents.