Safety and tolerability of IgPro10 in Japanese primary immunodeficiency patients: a registrational study.

Studies investigating the safety of IgPro10 (Privigen®, CSL Behring, King of Prussia, PA, USA) in Japanese patients with primary immunodeficiency (PID) are lacking. This study evaluated safety and tolerability of IgPro10 in Japanese patients with PID. In this prospective, open-label, single-arm, registrational study for Japan, IgPro10 was administered intravenously at pre-study doses of 138-556 mg/kg body weight per 3-/4-weekly dosing cycle for up to 4 months. Frequency and intensity of adverse events (AEs), their relationship to IgPro10 and AE rate per infusion (AERI) were evaluated. Of 11 enrolled patients, 10 completed the study. The median (range) total duration of exposure was 16.14 (4.1-16.3) weeks. Eight patients reported 19 AEs, none severe (based on maximum severity), giving an AERI of 0.442. One AE was deemed related to IgPro10 treatment. Three patients experienced temporally associated AEs. No serious AEs or deaths were reported. Nine patients (90%) who completed the study tolerated flow rates of ≥ 8 mg/kg/min; 5 tolerated 12 mg/kg/min (7.2 mL/kg/h), translating into a threefold decrease in mean infusion time. IgPro10 was well tolerated at a flow rate of up to 12 mg/kg/min. Safety and tolerability findings were consistent with previously reported studies in non-Japanese patients with PID.

Pediatric intestinal Behçet disease complicated by myeloid malignancies.

Behçet disease (BD) is rarely seen in children. Its clinical manifestations are believed to differ between pediatric and adult patients. The characteristics of BD complicated by myelodysplastic syndrome (MDS) are well established for adult patients; however, because only a few cases of pediatric-onset BD complicated by MDS have been reported, its clinical characteristics remain unknown. We here retrospectively review pediatric-onset BD complicated by myeloid malignancies in Japan, having identified five such patients. All patients were female and had gastrointestinal involvements, but lacked both major features of BD, i.e., uveitis and association with HLA-B51. All patients had advanced MDS or acute myeloid leukemia and received chemotherapy followed by hematopoietic stem cell transplantation. These five cases suggest that intestinal BD and myeloid malignancies have one or more pathophysiological mechanisms in common.

Cellulitis-Like Rash Associated with Kawasaki Disease.

We present the case of a 5-year-old-boy who developed a fever and cellulitis-like groin rash 5 days before developing conjunctivitis and 6 to 7 days before other typical signs of Kawasaki disease (KD) appeared. The cellulitis failed to respond to antibiotics and no pathogens were isolated. His fever and clinical signs resolved with intravenous immunoglobulin and high-dose aspirin after discontinuation of antibiotics. Nonbacterial cellulitis is a rare presenting sign of KD, but in the appropriate clinical setting and population, a diagnosis of KD should be considered when cellulitis and fever fail to respond to an appropriate antibiotic regimen and no pathogen can be isolated.

Immunity against Mycobacterium tuberculosis and the risk of biologic anti-TNF-α reagents.

A third of the world's population is exposed to Mycobacterium tuberculosis in their lifetime. Over eight million people develop a tuberculosis (TB) illness and 1.3 million people die from the disease every year. Acquired immunity (cytotoxic CD8+ T cells (CBT), Th1 CD4+ helper T cells) macrophages, and dendritic cells all play important roles in TB infection. Recently, it is well established that innate immunity as well plays a definitive role in the development of TB immunity under the effects of several cytokines, microbicidal proteins and Toll-like receptors. Meanwhile, the introduction and widespread use of biological disease-modifying anti-rheumatic reagents over the last 15 years worldwide has dramatically advanced and improved the standard care and prognosis of patients with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). However, as clinical experience with these drugs has grown, the risk of granulomatous infections, especially disseminated TB and fungal infections, has become apparent, especially because having RA or JIA may innately increase the risk of infection (bacterial, viral and fungal). The knowledge of basic immunology has also advanced over the past 10 years and adult and pediatric rheumatologists should increase their understanding of this dynamic between arthritis diseases, anti-TNF-α medications, and TB. This review will provide an up-to-date discussion of both the immunology of the TB organism in the human host and the pathophysiologic mechanisms of the TNF-α blockers in the development of secondary (disseminated) tuberculosis.

[Immunity against mycobacterium tuberculosis and risk of biological anti-rheumatic agents].

A third of world's population is invaded with Mycobacterium tuberculosis, about 9.0 million people developed tuberculosis (TB) illness and 1.3 million people died from the disease every year. Acquired immunity (cytotoxic CD8(+) T cell, Th1 CD4(+) helper T cell) and macrophage play important role for TB infection. Recently, natural immunity also play a very attractive role for the development TB immunity, with several cytokines, microbicidal proteins and Toll-like receptors. The introduction and uptake of biological disease-modifying anti-rheumatic drugs has dramatically advanced and improved the standard care and the prognosis of patients with rheumatoid arthritis (RA). However, as clinical experience with these drugs has grown, risk of granulomatous infections - especially disseminated tuberculosis in adult RA - and reactivation of hepatitis B virus (HBV) are focused. This year marks the tenth anniversary of the approvals of the first tumor necrosis factor (TNF)-alpha antagonist for the treatment of rheumatoid arthritis in Japan. Our understanding of this subject and the knowledge of basic immunology has also advanced during ten years. This review especially focuses on the pathologic action of the TNF blockers in the development of secondary (disseminated) tuberculosis.

Thalidomide attenuates excessive inflammation without interrupting lipopolysaccharide-driven inflammatory cytokine production in chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a rare inherited disorder characterized by an inability to produce reactive oxygen species, resulting in recurrent life-threatening infections. Curiously, half of the patients with CGD suffer from aseptic bowel inflammation (CGD colitis) due to dysregulated inflammation induced by TNF-α and IL-1ß. Thus, developing therapies that regulate excessive inflammatory responses without interrupting antimicrobial immunity would benefit CGD colitis patients. Here, we show that thalidomide suppressed TNF-α-induced NF-κB activation and ATP-induced IL-1ß secretion, but did not interrupt the production of IL-1ß, IL-6, IL-8, and TNF-α in response to lipopolysaccharide in CGD monocytes. We report on a CGD colitis patient that showed decreased bowel inflammation characterized by reduced serum levels of inflammatory cytokines without evidence of progression of fungal and bacterial infections present at initiation of thalidomide therapy. Our results suggest that thalidomide could be an efficacious therapeutic option for patients with CGD colitis suffering from serious infections.

Onset of polyarticular juvenile idiopathic arthritis with both anti-cyclic citrullinated peptide antibodies and rheumatoid factor in a 3-year-old girl.

This report describes 3 year old girl with the unusual presentation of polyarticular juvenile idiopathic arthritis (JIA) with anti-cyclic citrullinated peptide (anti-CCP) antibodies and a positive rheumatoid factor (RF). She was initially treated with a nonsteroidal anti-inflammatory drug (NSAID; ibuprofen) followed by methotrexate (MTX, 10 mg/m2/week) and prednisolone (0.25 mg/kg/day), but these treatments were ineffective. Administration of tocilizumab, a humanized antihuman interleukin-6 receptor monoclonal antibody, promptly improved her clinical manifestations, and she has been in complete remission (DAS28 <2.6) without bone erosion and/or destruction. Positivity for both antibodies (anti-CCP and RF) can forecast the severity of JIA (radiographic bone destruction). In such cases the administration of biologic remissive therapy may be prudent early in the disease course.

Tumor necrosis factor-α can induce Langhans-type multinucleated giant cell formation derived from myeloid dendritic cells.

The formation of the rich cellular features of MGCs, where the nuclei are arranged circularly at the periphery of the cell (morphologically epithelioid; Langhans-type), is assumed to be associated with any granulomatous disease. The mechanism by which TNF controls the formation of human MGCs in vitro was investigated, focusing on the effect of the TNF-neutralizing antibody. Peripheral blood monocytes were isolated with mAb-coated immunologic magnetic beads and cultured for 10 days in the presence of 20 ng/mL GM-CSF and 10 ng/mL IL-4. These cells were further incubated in the presence of TNF-α with/without its blockade antibodies for 14 days. Myeloid DCs can be generated from peripheral blood monocytes, and both IL-4 and GM-CSF can provide sufficient stimulus for their differentiation. The formation of MGC can be induced in the presence of TNF-α. This reaction was prohibited by the presence of the TNF-neutralizing antibody but not by the presence of anti-TNF receptor II antibody. The activation of Rho and focal adhesion kinases induced by TNF-α stimulation might be linked to cell assembling and the formation of Langhans-type MGCs. MGCs can produce only small amounts of superoxide anions compared to isolated macrophages such as myeloid DCs.

Increased eosinophilic cationic protein in nasal fluid in hospitalized wheezy infants with RSV infection.

BACKGROUND: Respiratory syncytial virus (RSV) is a major respiratory pathogen which causes bronchiolitis with dyspnea and wheezing in children less than 2 years old. RSV bronchiolitis in infancy severe enough to cause hospitalization might be a risk factor for allergic sensitization and bronchial asthma in future. However, the pathophysiology behind this development has not been clearly characterized. To evaluate the existence of airway inflammation and characteristic of RSV bronchiolitis, we analyzed and compared the concentrations of eosinophilic cationic protein (ECP) in nasal fluid and plasma. METHODS: From 69 infants (aged <2 years) hospitalized for possible lower respiratory tract infections including RSV infection, we collected nasal fluid and plasma and determined the ECP concentrations. RESULTS: ECP concentrations in nasal fluid were significantly higher in patients with wheezing and/or bronchial rales than in patients without them (1733 ± 660 ng/mL vs 680 ± 450 ng/mL, p = 0.018), and those of the respiratory syncitial virus-infected group were significantly higher than those of the uninfected group (p = 0.04). Meanwhile, there was no significant difference in plasma ECP levels between patients with wheezing and patients without wheezing, and no significant difference between RSV-infected and other pathogen-infected patients. There were significant correlations between nasal fluid ECP concentrations and both neutrophil and eosinophil counts in the peripheral blood. CONCLUSIONS: Nasal fluid ECP concentrations are increased in infants with lower respiratory infections including RSV infection accompanied with wheezing. ECP probably originates from neutrophils as well as eosinophils migrated into airways. The monitoring of ECP concentration in nasal fluid may be useful for evaluating leukocyte (including eosinophils and neutrophils)-mediated airway inflammation during infancy and its severity.

[Thalidomide as immunomodulatory drug: pharmacological actions and its indications].

Thalidomide was developed in the 1950s as a sedative drug and withdrawn in 1961 because of its teratogenic effects, but has been rediscovered as an immuno-modulatory drug. It has been administered successfully for the treatment of erythema nodosum leprosum, aphthous ulceration and cachexia in HIV disease, inflammatory bowel diseases, and several malignant diseases. The suppressive effect of thalidomide on the activation of the nuclear transcription factor NF-κB may explain these effects of thalidomide. NF-κB is retained in the cytoplasm with IκBα, and is activated by a wide variety of inflammatory stimuli including TNF, IL-1 and endotoxin followed by its translocation to the nucleus. Angiogenesis and organogenesis also require gene transcription and signal translocation. The findings shed new light on the anti-inflammatory properties of thalidomide and suggest pharmaceutical actions of thalidomide via interference of transcription mechanism. I reviewed the effects of thalidomide on auto-inflammatory diseases of childhood.

The clinical characteristics of vitamin D deficiency in childhood: a systematic literature review of Japanese patients.

To describe the characteristics of children with vitamin D deficiency, we reviewed the reports of vitamin D deficiency among Japanese children that were published between 1989 and 2008. We identified 25 patients with vitamin D deficiency in 9 published studies and evaluated their clinical characteristics together with those of 3 patients we recently treated. The patients were distributed in two distinct age groups at diagnosis: < 1 year old and > or = 1 year old. The main symptom of the < 1 year old age group was hypocalcemic convulsions and that of the > or = 1 year old age group was bowed legs. Serum calcium, intact PTH, and 1,25(OH)2D levels were significantly lower in the < 1 year age group than in the > or = 1 year age group. It would be useful to find and make early interventions in cases of children at a high-risk of vitamin D deficiency.

Increase of tumor necrosis factor-alpha in the blood induces early activation of matrix metalloproteinase-9 in the brain.

Increases of cytokine in the blood play important roles in the pathogenesis of influenza-associated encephalopathy. TNF-alpha was administered intravenously to wild-type mice, after which blood, CSF and brain tissue were obtained, and changes in BBB permeability, the amounts of MMP-9 and TIMP-1, and the localization of activated MMP were assessed. There was a significant increase in BBB permeability after 6 and 12 hr. MMP-9 was increased after 3 hr in the brain and cerebrospinal fluid, which was earlier than in the serum. TIMP-1 protein in the brain increased significantly after MMP-9 had increased. Activation of MMP-9 was observed in neurons in the cerebral cortex and hippocampus, and in vascular endothelial cells. These findings suggest that an increase in blood TNF-alpha promotes activation of MMP-9 in the brain, and may also induce an increase in permeability of the BBB. Early activation of MMP-9 in the brain may contribute to an early onset of neurological disorders and brain edema prior to multiple organ failure in those inflammatory diseases associated with highly increased concentrations of TNF-alpha in the blood, such as sepsis, burns, trauma and influenza-associated encephalopathy.

Thalidomide dramatically improves the symptoms of early-onset sarcoidosis/Blau syndrome: its possible action and mechanism.

OBJECTIVE: Early-onset sarcoidosis (EOS), which occurs in children younger than 5 years of age, is associated with granulomatous lesions and a sporadic genetic mutation of the nucleotide-binding oligomerization domain 2 that causes constitutive NF-kappaB activation. The symptoms of EOS can be uncontrollable, progressive, and associated with profound complications. However, appropriate therapy is still under investigation. The aim of this study was to assess the efficacy of thalidomide in patients with severe EOS, based on etiology supporting an initial role of NF-kappaB in activation of this disease. METHODS: Thalidomide was given to 2 patients with EOS (a 16-year-old girl and an 8-year-old boy) at an initial dosage of 2 mg/kg/day, and the dosage was increased if necessary. To elucidate the mechanism of the drug, peripheral blood monocytes were isolated from the patients and stimulated with cytokines (macrophage colony-stimulating factor, tumor necrosis factor alpha, and interleukin-4), and their ability to form multinucleated giant cells (MGCs) and osteoclasts was measured. RESULTS: Both patients showed dramatic improvement of their clinical symptoms (alleviation of fever and optic nerve papillitis, achievement of a response according to the American College of Rheumatology Pediatric 50 and Pediatric 70 criteria) and laboratory findings. Monocytes from patients with EOS had a greater ability to survive and induce MGCs and osteoclasts than those from healthy control subjects. The formation of MGCs and osteoclasts was inhibited by the presence of thalidomide. CONCLUSION: The ability of thalidomide to improve clinical symptoms and laboratory findings in patients with EOS indicates a central role for NF-kappaB activity in this disorder. Inhibition of IKK might be a pharmacologic action by which thalidomide down-regulates NF-kappaB signaling. Thalidomide may be an effective medication in patients with severe complications of EOS, including ocular involvement.

Adult onset X-linked chronic granulomatous disease in a woman patient caused by a de novo mutation in paternal-origin CYBB gene and skewed inactivation of normal maternal X chromosome.

We report a 28-year-old woman patient suffering from refractory subcutaneous abscess. Stimuli-induced microbicidal reactive oxygen metabolites formation test of the patient's neutrophils revealed that only 9.6% of the neutrophils produced H2O2. DNA analysis of the CYBB that encodes gp91(phox) demonstrated that she was heterozygous for a nonsense mutation, 206Trp(TGG)/stop(TGA) and therefore, a diagnosis of adult onset X-linked chronic granulomatous disease was made. Our molecular biological study revealed that her disease was caused by a de novo mutation in the CYBB gene on the paternal-origin X-chromosome and a skewed inactivation of the normal maternal X-chromosome.

Anakinra improves sensory deafness in a Japanese patient with Muckle-Wells syndrome, possibly by inhibiting the cryopyrin inflammasome.

Muckle-Wells syndrome (MWS) is a dominantly inherited autoinflammatory syndrome. Patients with MWS have a mutation in CIAS1, the gene encoding cryopyrin, a component of the inflammasome that regulates the processing of interleukin-1beta (IL-1beta). In this report we describe an 8-year-old Japanese girl with MWS who had symptoms of periodic fever, urticarial rash, conjunctivitis, arthropathy, and sensory deafness. Laboratory analysis of the patient's serum showed abnormally high concentrations of C-reactive protein, serum amyloid A, and IL-1beta, and she had a heterozygous mutation in the CIAS1 gene, with C-to-T transversion at nucleotide position 778, encoding an arginine-to-tryptophan mutation at position 260 (R260W). Mononuclear cells (MNCs) isolated from the patient secreted large amounts of IL-1beta, without stimulation, and were highly sensitive to muramyldipeptide and lipopolysaccharide. After treatment with anakinra, laboratory results normalized, and clinical symptoms, including sensory deafness, disappeared, while MNCs appeared to remain activated. Thus, our case suggests that anakinra possibly affects the cryopyrin inflammasome and markedly improves the clinical and laboratory manifestations of MWS.

Simultaneous onset of type 1 diabetes in monozygotic twins younger than 1 year.

This report describes type 1 insulin deficient diabetes mellitus (IDDM) arising in identical twins aged under one year. One twin presented with symptoms and was diagnosed with type 1 IDDM; the diagnosis of type 1 IDDM was simultaneously made in the second twin without clinical symptoms. Both twins were positive for anti-GAD (glutamic acid decarboxylase) antibody at first, and then positive for islet cell antibodies. Interestingly, the twins have four susceptible HLA DR and DQ genes together that are usually recognized separately in IDDM patients in Japan.

Thalidomide for treatment of intestinal involvement of juvenile-onset Behçet disease.

BACKGROUND: Thalidomide has been identified and its anti-inflammatory and immunomodulatory properties clarified. This report expands our report of 2 entero-Behçet disease children who developed significant steroid toxicity and improved dramatically with thalidomide. METHODS: We studied the effects of thalidomide in 7 juvenile-onset patients with severe, recurrent intestinal involvement of Behçet disease. Thalidomide was given at an initial dose of 2 mg/kg per day, and the dose was increased to 3 mg/kg per day if necessary (3 of 7 patients) or decreased to 1-0.5 mg/kg per day according to the responses to the drug. RESULTS: All 7 patients showed dramatic improvement in clinical symptoms with thalidomide therapy, and they successfully discontinued steroid therapy. Patients receiving thalidomide were monitored for prolonged neurotoxicity, and the treatment and a few side effects were well tolerated by all patients. CONCLUSIONS: Our results indicate that thalidomide can be an efficacious medication in appropriately selected patients with some inflammatory bowel diseases with many chances of success.

Recent changes in the trends of seasonal influenza outbreaks in the Nagano Prefectural area of Japan: an oseltamivir effect?

We carried out a study to assess the pharmacological role of oseltamivir in the regulation of influenza epidemics in Japan, examining data for the years 1998 to 2006 from Nagano Prefecture. Oseltamivir is effective for the treatment of influenza, and its use in Japan has increased in the 3 years from 2003 to 2006. We found that, in the Nagano Prefectural area, the peak in the number of influenza infections showed a deviation to later periods after the 2003 season. and after 2003, it also took a longer time to reach the end of the seasonal epidemics of influenza infections compared with data from 1998 to 2002. To prevent influenza outbreaks having a long duration, we believe that the period of isolation in patients receiving anti-influenza drugs has to be reconsidered.

Perfluorocarbon suppresses lipopolysaccharide- and alpha-toxin-induced interleukin-8 release from alveolar epithelial cells.

BACKGROUND/AIMS: Human pulmonary alveolar epithelial (A549) cells release interleukin-8 (IL-8) on stimulation by lipopolysaccharide (LPS) and alpha-toxin. We hypothesised that the perfluorocarbons (PFCs), perflubron and FC-84, would block stimulation of A549 cells by these toxins. METHODS: The levels of IL-8 production in A549 cells were measured following exposure to toxins for 24 h with or without PFC. The amount of IL-8 released from A549 cells was measured by enzyme-linked immunosorbent assay, and the level of IL-8 mRNA was measured by real-time RT-PCR. RESULTS: When stimulated with LPS or alpha-toxin, IL-8 release from A549 cells increased. There were no significant differences in level of IL-8 release between cells pre-incubated for 24 h with or without PFC after toxin stimulation for 24 h. When PFC was administered along with LPS stimulation, the level of IL-8 release was decreased (LPS control, 1,398 +/- 110 pg/well; FC-84, 686 +/- 50 pg/well; perflubron, 749 +/- 137 pg/well; p < 0.05). Levels of IL-8 mRNA expression were significantly higher with than without LPS, and those with LPS and perflubron were significantly lower than those with LPS alone. CONCLUSIONS: The results show that PFCs block stimulation of A549 cells by LPS or alpha-toxin. PFC may be useful clinically in treatment of pulmonary inflammation in the alveolar space.