Toshitaka Kizawa

Mycophenolate mofetil as maintenance therapy for childhood-onset systemic lupus erythematosus patients with severe lupus nephritis

Abstract Objectives. We evaluated histological changes occurring in renal biopsy specimens, between the time before initial induction therapy and after 12 months’ maintenance therapy, as well as changes in laboratory parameters, SLE disease activity (SLEDAI), and dosage of corticosteroid (CS) in childhood-onset systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Methods. A retrospective analysis was performed on nine patients diagnosed with childhood-onset SLE and lupus nephritis. They were treated with pulsed mPSL and intravenous cyclophosphamide as induction therapy and MMF (500–1500 mg/day) plus CS as maintenance therapy. Renal biopsy was performed before the initial induction therapy and after 12 months’ maintenance therapy. Results. Pathological findings at second biopsy were improved in eight of nine patients (89%). The findings of SLEDAI, urinalysis, and blood tests also showed improvement. CS doses could be tapered satisfactorily. Adverse events were observed in two patients. No patients treated with MMF experienced any disease flares during maintenance therapy. Conclusions. MMF as maintenance therapy might be useful in that not only the histological findings of lupus nephritis were improved, but also CS doses could be beneficially tapered. Nonetheless, this is a retrospective report of only nine cases and further prospective multicenter studies are necessary.

A pediatric patient with myopathy associated with antibodies to a signal recognition particle

We report the case of a 15-year-old Japanese girl with myopathy associated with antibodies to a signal recognition particle (anti-SRP myopathy). The patient presented with progressive symmetrical proximal muscle weakness that caused difficulty in walking within 3 months, and marked elevation of the serum creatine kinase levels. A skeletal muscle biopsy revealed active necrotic and regenerating processes, with mild inflammatory changes. Based on the above findings, the patient was diagnosed as having anti-SRP myopathy. Only a limited number of pediatric patients with anti-SRP myopathy has been reported previously, with usually a poor prognosis. Early diagnosis is important for obtaining a better prognosis in patients with anti-SRP myopathy.

Guidance on the use of canakinumab in patients with cryopyrin-associated periodic syndrome in Japan

Cryopyrin-associated periodic syndrome (CAPS) is an orphan disease with incidence of about one in 1,000,000 persons. This autoinflammatory disease develops in the neonatal period or early childhood, with various inflammatory symptoms occurring repeatedly throughout the patient’s lifetime. It is caused by abnormality of the NLRP3 protein which mediates the intracellular signal transduction mechanism of inflammatory processes, resulting in continuous overproduction of interleukin (IL)-1β, which induces chronic inflammation and progressive tissue damage. Definitive diagnosis of CAPS is difficult, and treatment has also been difficult because of a lack of effective medications in Japan. Clinical studies of human anti-human IL-1β monoclonal antibody (canakinumab) treatment were conducted in Japan, and approval was granted for therapeutic use of canakinumab for CAPS in September 2011. Similar to other biological drugs, canakinumab is clinically highly effective. However, sufficient attention to the method of use and adverse drug reactions is necessary. This guidance describes the use of canakinumab in Japan for CAPS in relation to exclusion criteria, method of use, evaluation criteria, and adverse drug reactions.

A case report of cutaneous polyarteritis nodosa in siblings

Abstract Cutaneous polyarteritis nodosa (CPAN) is characterized by a necrotizing vasculitis of small and medium-sized arteries in the skin, which can be associated with fever, arthralgia, myalgia, and neuropathy, but, unlike polyarteritis nodosa (PAN), there is no visceral involvement. CPAN is rare in childhood. We report two siblings who developed CPAN during childhood. Interestingly, both had Mediterranean fever gene (MEFV) mutation, i.e. heterozygous E148Q. They also shared HLA-A24, -DR15 alleles. Simultaneous occurrence of MEFV mutation and HLA alleles with CPAN has never been reported in Japan. These cases could provide some hereditary clue for the development of CPAN.

Tocilizumab-effects on growth impairment in systemic juvenile idiopathic arthritis

Background The safety and efficasy of anti-IL-6 receptor monoclonal antibody, tocilizumab (TCZ) has been reported in children with systemic juvenile idiopathic arthritis (s-JIA). Objectives Growth analysis during the study was performed. Methods Forty-five s-JIA patients (8.1±4.2 years) who completed phase-III study of TCZ were enrolled. Mean standard deviation score (SDS) for height, changes in SDS from baseline (ΔSDS), correlation between ΔSDS and several factors such as age, disease duration, corticosteroid dose exposure were evaluated. Yearly height velocity analysis was made with 28 patients who had data for 1 year prior to TCZ administration and received TCZ for more than 1 year. Results Thirty-eight of 45 (84%) obtained clinical response at week 144. The baseline SDS-height was -2.7±2.0 with inverse correlation with disease duration. Significant improvement was seen in height velocity SDS changes from 1 year prior to 1 year posterior to baseline (n=28, -6.0±4.0 to-2.5±3.9, p =0.0064). Reduction in corticosteroid exposure was significantly associated with improvement in height velocity SDS ( p =0.0027). Standardized height velocity continued to improve over 3 years of TCZ, whereas average daily prednisolone equivalent dose showed inverse correlation (n=17, Figure). Conclusions Growth impairments evidenced by SDS-height were more prominent in patients with longer standing disease. Catch up growth was observed in patients who required less or no corticosteroid during TCZ treatment. References Yokota S, et al. Lancet. 2008 Mar 22;371(9617):998-1006. Disclosure of Interest None Declared

A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan.

Purpose. To conduct a national survey of systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Based on current information on the use of MMF, we aimed to evaluate its efficacy and safety for childhood-onset (c-) SLE. Target. We evaluated 115 patients by questionnaire on MMF use for c-SLE in medical facilities specializing in pediatric rheumatic and renal diseases. Results. Average age at SLE onset was 10.6 (range, 2–15) years; average age at the time of starting MMF was 12.3 (range, 2–15) years. Average dose per body surface area was 1,059.3 mg/m2/day. Corticosteroid dosing was 20.9 mg/day before treatment but 7.7 mg/day after treatment. Laboratory values before and after MMF treatment were as follows: C3 increased from 67.0 to 84.9 mg/dl (p < 0.001), C4 increased from 10.2 to 15.1 mg/dl (p < 0.001), and anti-DNA antibody decreased from 154.2 to 18.4 IU/ml (p < 0.001). 24 adverse events in 21 cases were reported, but MMF was not discontinued in any. Conclusions. The amount of MMF for c-SLE in Japan is similar to the standard dose in other countries. Reduction of corticosteroid dose and improvement of laboratory values represent efficacy of MMF. The side effects recorded here indicated tolerability of the drug.

OP0178 Tocilizumab-effects on growth impairment in systemic juvenile idiopathic arthritis

Background The safety and efficasy of anti-IL-6 receptor monoclonal antibody, tocilizumab (TCZ) has been reported in children with systemic juvenile idiopathic arthritis (s-JIA). Objectives Growth analysis during the study was performed. Methods Forty-five s-JIA patients (8.1±4.2 years) who completed phase-III study of TCZ were enrolled. Mean standard deviation score (SDS) for height, changes in SDS from baseline (ΔSDS), correlation between ΔSDS and several factors such as age, disease duration, corticosteroid dose exposure were evaluated. Yearly height velocity analysis was made with 28 patients who had data for 1 year prior to TCZ administration and received TCZ for more than 1 year. Results Thirty-eight of 45 (84%) obtained clinical response at week 144. The baseline SDS-height was -2.7±2.0 with inverse correlation with disease duration. Significant improvement was seen in height velocity SDS changes from 1 year prior to 1 year posterior to baseline (n=28, -6.0±4.0 to-2.5±3.9, p=0.0064). Reduction in corticosteroid exposure was significantly associated with improvement in height velocity SDS (p=0.0027). Standardized height velocity continued to improve over 3 years of TCZ, whereas average daily prednisolone equivalent dose showed inverse correlation (n=17, Figure). Conclusions Growth impairments evidenced by SDS-height were more prominent in patients with longer standing disease. Catch up growth was observed in patients who required less or no corticosteroid during TCZ treatment. References Yokota S, et al. Lancet. 2008 Mar 22;371(9617):998-1006. Disclosure of Interest None Declared

SAT0407 Association between the rates of enlarged nailfold capillaries and serum FDP-E levels reflects microvascular injuries in juvenile dermatomyositis

Background One indicator of the active microvascular damages of juvenile dermatomyositis (JDM) is enlarged nailfold capillary (NFC). We have reported that serum FDP–E level is a marker of fibrinogenolysis and reflects maicroangiopathy in JDM patients. Objectives To determine clinical factors associated with the rates of enlarged NFCs. Methods Forty NFC images of fifteen JDM patients (7.3±3.9 years at first visit) were evaluated. NFC findings of 4 fingers of hand, excluding thumb were recorded in maintaining a constant room temperature of range 24–26°C. The rates of enlarged capillaries (>20 μm) to total number of end raw loops per millimeter in 4 digits were evaluated. Correlations between the rates of enlarged NFCs and serum level of CK, aldorase, FDP-E and ESR were examined. Associations between clinical manifestations (skin involvemrnts and muscle weakness) and the rates of enlarged NFCs were also evaluated. The rates of enlarged NFCs were devided into four groups in this study (group 1=0∼25%, group 2=26∼50%, group 3=51∼75%, group 4=76∼100%), and rates of abnormal levels of serum CK, aldolase, FDP-E, and ESR were evaluated, respectively. Results The rates of enlarged NFCs were significantly associated with serum FDP-E levels (r=0.34, P<0.05). Skin involvements were associated with higher rates of enlarged NFCs. Furthermore, abnormal FDP-E levels were found in 33% in group 1, whereas in group 4 abnormal FDP-E levels were found in all patients (p=0.0034). Conclusions Enlarged NFCs may reflect microangiopathy in active disease of JDM. Serum FDP-E levels will indicate microvascular inflammation especially in skin involvements. References Takayuki K, et al. Clinical analysis of juvenile dermatomyositis; a retrospective study of 45 Japanese. Eular congress. 2009 Disclosure of Interest None Declared

FRI0239 Arthritis complicated with kawasaki disease is not TNF-alpha-dependent

Background Around 10% of children with Kawasaki disease are still refractory to IVIG, and infliximab, anti-TNF-alpha monoclonal antibody, will be successfully administered as the second line of the treatment for these cases. We investigate whether or not TNF-alpha is responsible for the induction of arthritis in Kawasaki disease. Objectives To investigate the number of children and the characteristics of arthritis of Kawasaki disease following infliximab treatment. Methods Among 29 children (2005-2011) with Kawasaki disease who were refractory to IVIG (2 g/kg/day), and treated with infliximab (5 mg/kg), five were complicated with arthritis. The number of arthritis in other intractable children to IVIG was 0 out of 21 children treated with additional IVIG, and 1 out of 10 treated with plasma exchange. The clinical characteristics of arthritis treated with infliximab were investigated retrospectively and the arthritis was examined by musculoskeletal ultrasonography. Results Arthritis in one child was found early in Day 4 after the disease onset, and arthritis in other 4 children developed later in Day 18–24. Two children affected more than 5 joints including knee and hip joints, and 3 had arthritis on 4 or less joints. The mean titers of MMP-3 levels were high in those with active arthritis (205.5 ng/mL). The affected joints in all the children treated with TNF-alpha were examined by ultrasonography to demonstrate synovial hypertrophy and power Doppler signal indicating active synovial inflammation. Conclusions Arthritis is sometimes concurrent with Kawasaki disease in the early or convalescent phase of the disease. Our findings indicated that the frequency of concurrent arthritis treated with infliximab, a recommended biologics for juvenile idiopathic arthritis (JIA), was relatively high, and that it was not efficacious against active arthritis in Kawasaki disease suggesting that the synovial inflammation complicated with the disease will be TNF-alpha-independent. We speculated that other proinflammatory cytokines such as IL-6 and IL-1-beta would be responsible for the induction of concurrent arthritis in Kawasaki disease as the same with systemic JIA. Disclosure of Interest None Declared