Efficacy of Adalimumab in a Girl with Refractory Intestinal Behcet's Disease.

We describe our experience with a juvenile patient who had refractory intestinal Behcet's disease that responded to adalimumab, a fully humanized antibody against soluble TNF-α and its receptor. The patient, a 13-year-old girl, presented with oral aphthous ulcers, vulvar pain, and rashes on the lower extremities. She gradually developed a low-grade fever, abdominal pain, diarrhea, and hematochezia. Lower gastrointestinal endoscopy revealed ulcers in the terminal ileum, consistent with intestinal Behcet's disease. Methylprednisolone pulse therapy was initiated, after which the symptoms transiently improved, but, during the corticosteroid taper, the abdominal pain recurred. The symptoms resolved soon after the administration of adalimumab. Of importance, the dose of corticosteroids was successfully reduced without exacerbation during 8 months of observation. This is the first reported case in which adalimumab was used for pediatric gastrointestinal Behcet's disease. Adalimumab is a good choice for intestinal Behcet's disease refractory to conventional treatment.

Long-term outcome of 114 adult JIA patients in a non-pediatric rheumatology institute in Japan.

OBJECTIVE: To evaluate the long-term outcome of patients with juvenile idiopathic arthritis (JIA) using data from a large cohort database, Institute of Rheumatology, Rheumatoid Arthritis, managed by the Tokyo Women's Medical University. METHODS: Of 182 patients identified from the database from 2000 to 2013, 114 were verified as having JIA. The transition of medical care and the contributions of biological DMARDs were evaluated. RESULTS: The mean age of the patients (93 females, 81.6%) at the latest examination was 36.6 ± 13.3 years. The mean age at disease onset and mean disease duration were 11.6 ± 3.4 and 25.0 ± 13.3 years, respectively. Of the 114 patients, 106 (93.0%) had poly- or oligoarthritis. Only one-fourth transferred from general pediatricians or pediatric rheumatologists. More patients with recent disease onset were treated with biological DMARDs (16.7% in the 1970s, vs. 80.0% in the 2000s). Disease activity assessed with DAS28 was significantly lower when disease onset was more recent (3.9 ± 1.3 for onset in the 1960s vs. 2.2 ± 1.1 for onset in the 2000s, p = 0.04). The percentage of patients requiring orthopedic surgery has decreased (53.8% before the 1970s vs. 10.0% in the 2000s). CONCLUSION: Patients with more recent disease onset showed an improved outcome. Establishing and sharing a transition program among pediatric and non-pediatric rheumatologists is desirable.

A nationwide survey of Aicardi-Goutières syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study.

OBJECTIVES: Aicardi-Goutières syndrome (AGS) is a rare, genetically determined, early onset progressive encephalopathy associated with autoimmune manifestations. AGS is usually inherited in an autosomal recessive manner. The disease is rare, therefore the clinical manifestations and genotype-phenotype correlations, particularly with regard to autoimmune diseases, are still unclear. Here we performed a nationwide survey of AGS patients in Japan and analysed the genetic and clinical data. METHODS: Patients were recruited via questionnaires sent to paediatric or adult neurologists in Japanese hospitals and institutions. Genetic analysis was performed and clinical data were collected. RESULTS: Fourteen AGS patients were identified from 13 families; 10 harboured genetic mutations. Three patients harboured dominant-type TREX1 mutations. These included two de novo cases: one caused by a novel heterozygous p.His195Tyr mutation and the other by a novel somatic mosaicism resulting in a p.Asp200Asn mutation. Chilblain lesions were observed in all patients harbouring dominant-type TREX1 mutations. All three patients harbouring SAMHD1 mutations were diagnosed with autoimmune diseases, two with SLE and one with SS. The latter is the first reported case. CONCLUSION: This study is the first to report a nationwide AGS survey, which identified more patients with sporadic AGS carrying de novo dominant-type TREX1 mutations than expected. There was a strong association between the dominant-type TREX1 mutations and chilblain lesions, and between SAMHD1 mutations and autoimmunity. These findings suggest that rheumatologists should pay attention to possible sporadic AGS cases presenting with neurological disorders and autoimmune manifestations.

Guidance on the use of adalimumab for juvenile idiopathic arthritis in Japan.

Adalimumab is a monoclonal antibody produced by DNA recombination technology, and is the first human monoclonal antibody against human tumor necrosis factor (TNF)-α in the world. Adalimumab binds with high affinity and specificity to soluble TNF-α and normalizes its biological action. The clinical development of adalimumab started in Europe. Adalimumab was approved for the treatment of rheumatoid arthritis (RA) in December 2002 in the United States and in September 2003 in the European Union. Since then, adalimumab has been approved for the expanded indications of psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis (Ps), and juvenile idiopathic arthritis (JIA) in the United States and the European Union, and it is now used widely for the treatment of these diseases. In Japan, adalimumab was approved for the treatment of RA in April 2008, and its use was approved for the indications of Ps and PsA in January 2010, and for CD and AS in October 2010. In Japan, children who have been diagnosed and treated according to the "Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007)" (published in this journal in 2007; see reference 1 in the main text), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adherence to the indications and exclusion criteria and should be used, for the time being, only by physicians trained in how to use them. In Japan, adalimumab was approved for the treatment of JIA in July 2011. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidance presented here define the indications, exclusion criteria, usage, and evaluation criteria of adalimumab for the treatment of polyarticular JIA.

Guidance on using tocilizumab for juvenile idiopathic arthritis.

Medical care for rheumatic disease in children has been supported by advances in rheumatology. In the past few years and based on knowledge about cytokines, particularly marked advances have been made in treatments using biological products. The fact that patients showed a marked response to treatment with biological products also provided uniform direction to treatment choice, which had previously been chaotic. On the other hand, biological products inhibit the action of physiologically essential substances, such as inflammatory cytokines or their receptors. This led to concerns about the risk of fatal or life-threatening adverse reactions, and rheumatologists are now required to take a disciplined approach to the use of these products. Thus, we sincerely hope that this guidance on using tocilizumab for juvenile idiopathic arthritis serves as a desk reference for pediatric rheumatologists and other healthcare professionals treating children with rheumatic diseases by biological drugs.

Guidelines on the use of etanercept for juvenile idiopathic arthritis in Japan.

Etanercept is a dimeric fusion protein consisting of the extracellular domain of human tumor necrosis factor receptor II (TNFR II, molecular weight 75 kDa) coupled to the Fc region of human immunoglobulin (IgG1). It is produced by recombinant DNA technology by first introducing the gene into Chinese hamster ovarian cells and then purifying the protein from the culture supernatant. The mechanism of action of etanercept consists of binding to serum TNF-alpha and lymphotoxin (LT)-alpha (TNF-beta), which prevents TNF-alpha and LT-alpha from binding to the TNF-alpha receptor on the plasma membrane of the target cell. Etanercept is currently approved for treating adult rheumatoid arthritis (RA) in more than 70 countries worldwide. In Japan, it was approved for this target group in January 2005. The USA and Europe were the first to approve entanercept for use in treating juvenile idiopathic arthritis (JIA), initially for the treatment of active polyarticular JIA in patients not responding to disease-modifying antirheumatic drugs (USA in May 1999, followed by the EU in February 2000). Thereafter, the drug received approval for the treatment of JIA in many other countries. In Japan, children who have been diagnosed and treated according to Yokota et al. (Mod Rheumatol 17:353-363, 2007), but who have responded poorly to treatment must move onto the next stage of treatment. Such treatments include biological drugs, which, however, should be used with strict adhesion to the indications and exclusion criteria and should be used, for the time being, only by physicians trained on how to use them. In Japan, etanercept was approved in July 2009 for use in children. Although this drug has brought about a revolutionary advance in the treatment of JIA, it is our task to maximize its therapeutic effects and minimize its toxic effects. The guidelines presented here define the indications, exclusion criteria, usage, and evaluation criteria of etanercept for the treatment of polyarticular JIA.

Methotrexate for the treatment of juvenile idiopathic arthritis: process to approval for JIA indication in Japan.

Methotrexate (MTX), the primary treatment for the articular-type juvenile idiopathic arthritis (JIA), is effective and brings about radiological improvement. Patient compliance is good, and it is recognized that its known side effects, namely, disruption of liver function and induction of pulmonary lesions, are unlikely to be severe at the low MTX doses that are administered. In Japan, MTX was granted approval in 1999 by the then Ministry of Health and Welfare specifically for treating rheumatoid arthritis in adult patients, allowing it be generally used in medical institutions for patients having National Health Insurance. However, in the pediatric field, its use outside the indications has so far been unavoidable, and has been left to the discretion of the physician. Finally, at the present conference, expansion of the indications of MTX for JIA was approved in Japan. It is noteworthy that this expansion of indications was achieved without requiring clinical trials on children sponsored by the pharmaceutical company: it was achieved rather by collecting necessary information through ongoing efforts (including collection and analysis of information about approval status in foreign countries, adequate evidence from the literature, implementation of a clinical use survey in Japan, etc.). It also merits attention that the maximum dose (10 mg/m2) was set on the basis of pharmacokinetic data from children, rather than relying on the dosing method and dose for adults.

Proposal for juvenile idiopathic arthritis guidance on diagnosis and treatment for primary care pediatricians and nonpediatric rheumatologists (2007).

The Pediatric Standing Committee of the Japan College of Rheumatology, in collaboration with the Pediatric Rheumatology Association of Japan, produced guidance on the diagnosis and treatment for juvenile idiopathic arthritis (JIA) for primary care pediatricians and nonpediatric rheumatologists in Japan. This guidance aims to achieve early diagnosis and treatment for JIA, which is similar to adult rheumatoid arthritis (RA), based on recent progress in rheumatology, and to resolve arthritis at an early stage and improve the prognosis of the affected inflammatory joints. It describes clinical symptoms and laboratory findings characteristic to JIA in order to make early diagnosis and treatment possible, and also serves as a triage of patients who are refractory to the treatment protocol described here and need more aggressive interventions. However, because JIA is a complicated and heterogeneous disease and the optimal treatment approach can be diverse and different patient by patient, these guidelines should be viewed as recommendations and be individualized according to the condition of the patient. Finally, we hope that this guidance will trigger exploration for further information by referring to the textbooks and literature listed at the end of these guidelines.

Antiagalactosyl IgG antibodies in juvenile idiopathic arthritis, juvenile onset Sjögren's syndrome, and healthy children.

OBJECTIVE: To determine the normal range of antiagalactosyl IgG antibodies in healthy children, and to investigate the utility of determination of antiagalactosyl IgG antibodies in patients with juvenile idiopathic arthritis (JIA) and juvenile onset Sjögren's syndrome (SS). METHODS: Serum concentrations of antiagalactosyl IgG antibodies were measured in 225 healthy children, 68 patients with JIA (systemic arthritis in 21, polyarthritis in 29, oligoarthritis in 18), and 15 patients with juvenile onset SS, using a lectin-enzyme immunoassay employing prepared human agalactosyl IgG as antigen. A comparison was made between the prevalence and utility of antiagalactosyl IgG antibodies in patients and those of conventional rheumatoid factors (RF) determined by laser nephelometry. RESULTS: The average serum concentration of antiagalactosyl IgG antibodies for healthy controls was 2.41 +/- 0.93 arbitrary units (AU)/ml, and the cutoff value of the normal range was set at 4.3 AU/ml (mean + 2 SD). As a result, antiagalactosyl IgG antibodies were positive in 25 (37%) of 68 patients with JIA, and 14 (93%) of 15 patients with juvenile onset SS, in whom values were much higher than the frequencies of RF positivity. The serum concentrations of antiagalactosyl IgG antibodies in patients were closely correlated with those of RF. Thirteen patients with JIA and 6 patients with juvenile onset SS were positive for antiagalactosyl IgG antibodies despite being negative for RF. With regard to prognosis during followup periods of at least 5 years, JIA patients positive for antiagalactosyl IgG antibodies, even if negative for RF, were resistant to treatment. However, positivity for antiagalactosyl IgG antibodies had no relation to joint destruction. CONCLUSION: Our data suggest that antiagalactosyl IgG antibodies, compared with RF, show higher sensitivity to detect immunological disorders in JIA and juvenile onset SS.

Sendai virus vector-mediated gene transfer of glial cell line-derived neurotrophic factor prevents delayed neuronal death after transient global ischemia in gerbils.

We have developed a cytoplasmic replicating virus vector of Sendai virus (SeV) that infects and replicates in most mammalian cells, including neurons, and directs high-level gene expression. To investigate the protective effect of SeV vector-mediated gene transfer of glial cell line-derived neurotrophic factor (GDNF) on the delayed neuronal death caused by transient global ischemia in gerbils, SeV vectors carrying either GDNF (SeV/GDNF) or enhanced green fluorescent protein gene (SeV/GFP) were stereotaxically microinjected into the lateral ventricle. Four days after injection, occlusion of the bilateral common carotid arteries for 5 min produced transient global forebrain ischemia. Treatment with SeV/GDNF significantly decreased the delayed neuronal death of the hippocampal CA1 pyramidal neurons observed 6 days after the operation. TUNEL staining demonstrated that SeV/GDNF treatment markedly reduced the number of apoptotic cells in the hippocampal CA1 neurons, indicating that SeV/GDNF treatment prevented apoptosis. Furthermore, delayed neuronal death on the contralateral side of the hippocampal CA1 was also prevented to a similar extent as that on the ipsilateral side. These results suggest that SeV/GDNF prevents the delayed neuronal death induced by ischemia and is potentially useful for gene therapy for stroke.

Hyperzincemia with systemic inflammation: a heritable disorder of calprotectin metabolism with rheumatic manifestations?

A boy had infantile-onset systemic inflammation, growth failure, hepatosplenomegaly, anemia, leukocytopenia, progressive muscular dystrophy, and hypercalprotectinemia, resulting in marked hyperzincemia. His mother had a history of chronic arthritis since childhood and also showed hypercalprotectinemia/hyperzincemia. We postulate an inherent defect in calprotectin metabolism.