Utako Kaneko

Safety and response to influenza vaccine in patients with systemic-onset juvenile idiopathic arthritis receiving tocilizumab

ObjectiveWe investigated the safety and efficacy of administering influenza vaccines to patients with systemic-onset juvenile idiopathic arthritis (sJIA) treated with tocilizumab.Patients and methodsThe subjects were 27 sJIA patients treated with tocilizumab and 17 healthy age- and sex-matched volunteers. Serum samples were collected prior to and 4–7 weeks after vaccination. Hemagglutination inhibition values of the vaccine were taken as the antibody titers. The duration of tocilizumab administration and the daily doses of prednisolone per unit body weight were analyzed to identify factors affecting the responses of the sJIA patients to influenza vaccination. We questioned all the subjects about whether they had contracted influenza and whether they had had adverse reactions to the influenza vaccination. We compared steroid doses in sJIA patients before and after vaccination to document any worsening of the underlying disease.ResultsThe efficacy of influenza vaccination did not differ significantly between the sJIA group and the healthy controls. The duration of tocilizumab administration did not affect the response of the sJIA patients to the influenza vaccination. None of the sJIA patients experienced either severe adverse reactions or disease exacerbation after the influenza vaccination.ConclusionWe found that sJIA patients treated with tocilizumab could be effectively and safely immunized with the influenza vaccine.

Effect of anakinra on arthropathy in CINCA/NOMID syndrome

CINCA/NOMID is an autoinflammatory disorder characterized by the triad of neonatal onset of cutaneous symptoms, chronic meningitis, and recurrent fever and it presents with distinctive osteoarthropathy, synovitis mainly of the large joints and overgrowth of epimetaphyseal cartilage, particularly of the long bones. The cartilage overgrowth eventually causes osseous overgrowth and deformity that persists beyond skeletal maturity and leads to limb length discrepancy, joint contracture, and early degenerative arthropathy. Autoinflammation in CAPS/NOMID has been proven to derive from excessive release of interleukin-1 (IL-1). It has been well documented that the IL-1 receptor antagonist anakinra (Kineret(R)) helps mitigate systemic inflammation in the disorder. However, a general consensus has not been reached on its beneficial effect on osteoarthropathy. The case of a girl with CINCA/NOMID syndrome who showed dramatic improvement of osteoarthropathy after anakinra treatment is reported. A 4-year-old girl suffered at the age of 10 months from a generalized urticarial skin lesion with recurrent episodes of fever and growth disorder. Blood examination revealed persistent massive neutrophilia, anemia and intense acute phase response. She manifested knee joint swelling with limited ROM when she was 20 months old and was diagnosed as being CINCA/NOMID based on characteristic findings of radiograph despite negative CIAS1 mutation. Radiological examination demonstrated metaphyseal fraying and cupping and widening of the growth plate in the distal femur. MR imaging showed mottled gadolinium enhancement at the chondrosseous junction. Neither significant joint effusion nor synovitis was identified. At 2 years and 7 months of age, anakinra, 2 mg/kg/day given by regular daily subcutaneous injections, was started. A few days after the initiation of the treatment, her clinical symptoms and laboratory findings of active inflammation were promptly alleviated. She was not able to walk unaided prior to the treatment, but she walked independently 1 month after the treatment. Follow-up radiographs and MR imaging showed that growth plate widening and gadolinium enhancement at the chondrosseous junction were less conspicuous. Furthermore, longitudinal growth of the femur and tibia was identified during 20 months of observation.

Increased mutations of CD72 transcript in B-lymphocytes from adolescent patients with systemic lupus erythematosus

Recent studies have shown that B cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE). Abnormal expression of molecules engaging in B‐cell receptor (BCR) signaling and resultant hyperactivity of B cells has been reported in both mouse models of lupus and patients with SLE. CD72 on B cells is unique in that it regulates BCR signaling both positively and negatively. We analyzed the expression of CD72 protein and mRNA in peripheral blood B cells from adolescent patients with SLE. The expression level of CD72 on B cells of the patients was decreased compared with that on B cells of controls. Sequence analysis of CD72 mRNA showed significantly increased nucleotide mutations, including both nucleotide substitutions and deletions. Almost all (95.6%) of the CD72 transcripts from the patients had different nucleotide sequences from those of the wild type. About half (41.3%) of the mutations were point mutations located close to the sequence of the immunoreceptor tyrosine‐based inhibitory motif (ITIM), which negatively regulates BCR signaling. These results indicate that increased nucleotide mutation of CD72 mRNA accounts for the decreased expression level of CD72 in B cells, and it might be related to hyperactivity of B cells in patients with SLE.

De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis.

Systemic-onset juvenile idiopathic arthritis (s-JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s-JIA remains poorly understood. To detect disease-related copy number variations (CNVs), we performed single-nucleotide polymorphism array analysis in 50 patients with s-JIA. We detected many CNVs, but most of them were inherited from either of normal-phenotype parents. However, in one patient, we could identify two de novo microduplications at 19q13.42 with the size of 77 and 622 kb, separated by a 109-kb segment of normal copy number. The duplications encompass NLRP family (NLRP2, NLRP9 and NLRP11) as well as IL11 and HSPBP1, all of which have an important role in inflammatory pathways. These genes may significantly contribute to the pathogenesis of s-JIA.

Discrepancy Between Clinical and Radiological Responses to Tocilizumab Treatment in Patients with Systemic-onset Juvenile Idiopathic Arthritis

Objective. Tocilizumab (TCZ), an antiinterleukin-6 receptor monoclonal antibody, is clinically beneficial in patients with systemic-onset juvenile idiopathic arthritis (sJIA). We investigated the clinical and radiological outcomes of TCZ therapy in patients with sJIA. Methods. We retrospectively evaluated 2 clinical trials (NCT00144599 and NCT00144612) involving 40 patients with sJIA who received intravenous TCZ (8 mg/kg) every 2 weeks. Clinical data and radiographs of the hands and large joints were assessed before and during TCZ treatment. The Poznanski score, modified Larsen scores of the hands and large joints, and Childhood Arthritis Radiographic Score of the Hip (CARSH) were recorded. Results. After a mean duration of 4.5 years of TCZ treatment, clinical data had improved significantly, the mean Poznanski score improved from −1.5 to −1.1, the mean Larsen score of the hands deteriorated from 7.0 to 10.0, the mean Larsen score for the large joints deteriorated from 5.9 to 6.8, and the CARSH worsened from 3.9 to 6.2. The Larsen score for the large joints improved in 11 cases (28%), remained unchanged in 8 cases (20%), and worsened in 21 cases (52%). Matrix metalloproteinase 3 (MMP-3) levels remained significantly higher (278 mg/dl) in patients with worsened Larsen scores than in patients with improved or unchanged scores (65 mg/dl). Logistic regression analysis showed that older age at disease onset was a significant risk factor for radiographic progression. Conclusion. The modified Larsen score of the large joints deteriorated in half the patients who had high MMP-3 levels during TCZ treatment and who were significantly older at disease onset.

EFFECT OF CHARCOAL HEMOPERFUSION FOR REMOVAL OF PLASMA METHOTREXATE IN A PATIENT WITH ACUTE RENAL FAILURE

Strategies effective for accelerating methotrexate removal in delayed methotrexate excretion have not been universally accepted. The authors report a case of a 12-year-old girl with osteosarcoma who developed acute renal failure immediately after the first administration of high-dose methotrexate. Plasma methotrexate was effectively removed with repeated charcoal hemoperfusion in addition to plasma exchange and leucovorin rescue. Charcoal hemoperfusion was most effective for reducing plasma methotrexate with approximately 50% of methotrexate being reduced during each of the procedures. No rebound increase in MTX levels was observed. The patient received further therapy with other cancer drugs and has been well for 3.5 years.

Expression of immunoglobulin E‐dependent histamine‐releasing factor in idiopathic nephrotic syndrome of childhood

Concanavarin‐A (conA)‐stimulated peripheral blood mononuclear cells (PBMNC) from patients with idiopathic nephrotic syndrome (INS) produce putative factors that increase vascular permeability. These factors are expressed in the nephrotic phase but are reduced in the convalescent phase. To identify the genes that are expressed only in the nephrotic phase, we performed cDNA subtraction using conA‐stimulated PBMNC from three patients with INS. We isolated several gene transcripts in all three subtracted cDNA libraries. Among these genes, IgE‐dependent histamine‐releasing factor (HRF) was overexpressed in the nephrotic phase not only at the mRNA level but also at the protein level in another 10 patients with INS. Moreover, we found increased secretion of HRF from conA‐stimulated PBMNC in the nephrotic phase. The results suggest that HRF is involved in the pathogenesis of idiopathic nephrotic syndrome.

Exonic deletion of CASP10 in a patient presenting with systemic juvenile idiopathic arthritis, but not with autoimmune lymphoproliferative syndrome type IIa.

Systemic juvenile idiopathic arthritis (s‐JIA) is a rare inflammatory disease classified as a subtype of chronic childhood arthritis, manifested by spiking fever, erythematous skin rash, pericarditis and hepatosplenomegaly. The genetic background underlying s‐JIA remains poorly defined. To detect copy number variations, we performed single nucleotide polymorphism (SNP) array analysis in 50 patients with s‐JIA. We found a 13‐kb intragenic deletion of CASP10 in one patient. RT‐PCR of the mRNA extracted from the patient’s lymphoblastoid cells revealed that CASP10 mRNA was truncated. Sequencing the mRNA revealed that this deletion resulted in a frame shift with an early stop codon. CASP10 is known as a causative gene for autoimmune lymphoproliferative syndrome (ALPS) type IIa, another childhood syndrome of lymphadenopathy and splenomegaly associated with autoimmune haemolytic anaemia and thrombocytopenia. TCR αβ+ CD4/CD8 double‐negative T cells in the peripheral blood as a diagnostic marker of ALPS were not high in this patient and lymphocyte apoptosis induced by anti‐Fas antibody was normal, denying ALPS in the patient. The father and a sister of the patient showing no symptoms of ALPS or s‐JIA, also had the same deletion. Furthermore, we found no other mutations of CASP10 in the other 49 s‐JIA patients. These data suggest that the pathogenic significance of CASP10 mutations should be carefully evaluated in s‐JIA or even ALPS type IIa in further studies.

A case of early onset renal sarcoidosis complecated with multiple enchondromatosis

Methods A five month old boy suffered from skin rash on his whole body after vaccination of BCG. At three years old, he developed fever and painless soft mass on his right ankle. Enhanced abdominal CT scan showed multiple low density lesions in both kidneys. He was initially diagnosed as having acute focal bacterial nephritis. However, antibiotics were not effective and he was referred to our hospital.

Glomerular epithelial cell phenotype in diffuse mesangial sclerosis: a report of 2 cases with markedly increased urinary podocyte excretion☆

We report 2 cases of diffuse mesangial sclerosis (DMS) accompanied by severe podocyte excretion in urine. Patient 1 was a 9-day-old girl with a WT1 mutation who developed Wilms tumor at 6 months of age and was subsequently diagnosed with Denys-Drash syndrome. Patient 2 was a 1-year-old boy without a WT1 abnormality but presenting with heavy proteinuria. In both patients, histological examination showed findings of DMS. Immunohistochemical staining for synaptopodin (a podocyte marker) revealed a reduced number of podocytes in the glomeruli with severe sclerosis; however, podocytes persisted in the relatively intact glomeruli. Some glomeruli were accompanied by sclerotic lesions surrounded by proliferating cells; immunofluorescence staining revealed a majority of these proliferating cells to be positive for claudin-1 (a parietal cell marker) but negative for synaptopodin. These findings suggest that podocyte loss and the consequent proliferation of parietal cells are common processes in the pathogenesis of DMS.