Yoshitaka Miyakawa

Clinical guides for atypical hemolytic uremic syndrome in Japan

Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In 2013, we developed diagnostic criteria to enable early diagnosis and timely initiation of appropriate treatment for aHUS. Recent clinical and molecular findings have resulted in several proposed classifications and definitions of thrombotic microangiopathy and aHUS. Based on recent advances in this field and the emerging international consensus to exclude secondary TMAs from the definition of aHUS, we have redefined aHUS and proposed diagnostic algorithms, differential diagnosis, and therapeutic strategies for aHUS.

Cost-effectiveness of adding rituximab to splenectomy and romiplostim for treating steroid-resistant idiopathic thrombocytopenic purpura in adults

BackgroundIdiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which the platelet count falls to <100u2009×u2009109/L. Corticosteroids are recommended as the first-line treatment, splenectomy is recommended as the second-line treatment, and thrombopoietin receptor agonists (TPO-RAs) and rituximab are recommended as the third-line treatments for ITP in Japanese ITP treatment guidelines. However, in Japan, rituximab is not eligible for reimbursement for the treatment of ITP. The cost-effectiveness of ITP treatment has not been investigated in Japan. Therefore, in this study, the cost-effectiveness of adding rituximab treatment to the existing treatments indicated for ITP in Japan, namely splenectomy and the TPO-RA romiplostim, was investigated based on the scenario that rituximab is eligible for reimbursement in Japan as a treatment for ITP.MethodsThe efficacy endpoint was set as the number of years with a platelet count ≥30u2009×u2009109/L. The analysis was conducted from the healthcare payer’s perspective. If the first treatment is ineffective or relapse occurs, then the patient is given the following treatment. The analyzed treatment order consisted of three patterns: splenectomy-romiplostim (sequence 1), splenectomy-romiplostim-rituximab (sequence 2), and splenectomy-rituximab-romiplostim (sequence 3). A Markov model was built for ITP, and the analysis period was set as 2xa0years. The discount rate was an annual rate of 2%.Sensitivity analyses of the efficacy of splenectomy, romiplostim, and rituximab; treatment cost; and romiplostim dose were performed.ResultsThe expected costs per patient over a 2-year period for sequences 1, 2, and 3 were USD 40,980, USD 39,822, and USD 33,551, respectively. The expected years with a platelet count ≥30u2009×u2009109/L for the three sequences were 1.75, 1.79, and 1.78xa0years, respectively. The sensitivity analyses illustrated that the results of the base case analysis were robust.ConclusionsAdding rituximab to standard treatment for ITP (sequences 2–3) is less costly and marginally more effective than standard therapy in adults. According to the study results, if rituximab is reimbursed for the treatment of ITP in Japan, medical expenses are expected to decline.

Efficacy and safety of rituximab in Japanese patients with acquired thrombotic thrombocytopenic purpura refractory to conventional therapy

AbstractThrombotic thrombocytopenic purpura (TTP), while rare, is a potentially life-threatening disorder. Plasma exchange (PE) is considered the primary treatment for TTP. In Western countries, rituximab, an anti-CD20 antibody, is recommended with PE for the treatment of refractory/relapsed TTP, and as up-front therapy in newly diagnosed TTP with neurological/cardiac pathology. The present open-label, single-arm, multicenter study evaluated the efficacy and safety of rituximab in Japanese patients with refractory/relapsed TTP. Patients received rituximab 375xa0mg/m2 intravenously, once weekly for a total of four treatments, with PE and steroids. Of six evaluable patients in the full analysis set, two met the primary efficacy endpoint (platelet countxa0>150xa0×xa0109/L at week 4), yielding a 33.3xa0% response rate (95xa0% confidence interval: 4.3–77.7). While the lower confidence limit of the primary efficacy endpoint failed to reach the pre-specified threshold of 30xa0%, clinically significant recovery of platelet count with discontinuation of PE, increase of ADAMTS13 activity, disappearance of ADAMTS13 inhibitor, and improvement of TTP-associated clinical manifestations were observed after rituximab therapy in all patients. No safety concerns were identified in this study; therefore, rituximab is considered a useful treatment option in Japanese TTP patients who are refractory to conventional therapy.n Trial registration JMA-IIA00160.

Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) 2017 in Japan

Thrombotic thrombocytopenic purpura (TTP) can rapidly progress into a life-threatening condition, thus the importance of appropriate diagnosis and treatment cannot be overstated. Until recently, TTP has mainly been diagnosed by clinical findings such as thrombocytopenia and non-immune hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has been accepted internationally as a diagnostic criterion for TTP. In the present guidelines, we have taken all of these criteria into consideration. TTP is classified as acquired if the patient is positive for anti-ADAMTS13 autoantibodies, and as congenital if ADAMTS13 gene abnormalities are detected. Fresh-frozen plasma (FFP) transfusion is performed in patients with congenital TTP to supplement ADAMTS13. Plasma exchange therapy using FFP is conducted in patients with acquired TTP to supplement ADAMTS13 and remove anti-ADAMTS13 autoantibodies. To suppress autoantibody production, corticosteroid therapy may be administered in conjunction with plasma exchange. Recent reports show that the monoclonal anti-CD-20 antibody rituximab is effective in patients with refractory or relapsed TTP.

Malignant Hypertension with Thrombotic Microangiopathy.

A 49-year-old man with malignant hypertension, acute kidney injury and mental deterioration was referred to our hospital. We initially observed microangiopathic hemolytic anemia, thrombocytopenia and kidney damage, indicating he had thrombotic microangiopathy (TMA). We considered TMA was caused by malignant hypertension and therefore did not start plasma therapy. The French TMA reference center reported that platelet counts and serum creatine levels have high values for predicting severe ADAMTS13 deficiency. The patient fully recovered from his illness after treatment with antihypertensive drugs and intermittent hemodialysis. This case might thus be useful to understand the proper differential diagnosis and treatment of TMA.

Efficacy and safety of rituximab in Japanese patients with relapsed chronic immune thrombocytopenia refractory to conventional therapy.

Primary immune thrombocytopenia (ITP) is an autoimmune disease mediated by the production of auto-antibody against platelets. Rituximab, an anti-CD20 antibody, is reported to be useful for treatment of ITP. In Japan, however, robust evidence on this treatment has not been accumulated. Hence, we conducted this open-label phase III clinical trial to confirm the efficacy and safety of rituximab, administered at 375xa0mg/m2 once per week at weekly intervals for 4 consecutive weeks in Japanese patients with chronic ITP, who had relapsed and were refractory to conventional therapy. The primary endpoint was defined as the percentage of patients with a platelet count above 50xa0×xa0109/L at week 24 after the first dose of rituximab, which was 30.8xa0% of 26 patients (95xa0% confidence interval 14.3–51.8xa0%). Although the lower confidence limit of primary endpoint failed to meet the pre-specified threshold of 20xa0%, the clinical efficacy of rituximab is substantial in consideration of the 2xa0% response rate in the placebo arm in other clinical studies in patients with chronic ITP. We conclude that rituximab is clinically useful and safe in the treatment of Japanese patients with chronic ITP, achieving the goal of maintaining platelet count and reducing risk of bleeding while minimizing treatment-related toxicity.

Therapy in Pregnancy

Glucocorticoids and intravenous immunoglobulins are widely accepted and recommended in guidelines for the treatment in pregnancy. On the other hand, the safety profile of the other options during pregnancy is not well known. Since ITP affects not only pregnant women but also neonates, the effective communication among hematologists, obstetricians, and pediatricians should be established for efficient management.

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic–uremic syndrome in Japan: interim analysis of post-marketing surveillance

BackgroundEculizumab has been available for the treatment of atypical hemolytic–uremic syndrome (aHUS) in Japan since 2013. To assess safety and effectiveness of eculizumab in adult aHUS patients in the real-life setting, we performed interim analysis of a post-marketing surveillance mandated by Japanese regulations.MethodsThis study enrolled any patient who was diagnosed with TMA excluding Shiga toxin-producing Escherichia coli-HUS or thrombotic thrombocytopenic purpura based on Japanese clinical guide published in 2013 as inclusion criteria and treated with eculizumab. Although the term aHUS was redefined to denote only complement-mediated HUS in the guide revised in 2016, the patients with TMA caused by other causes (secondary TMA) were included. Patient outcomes and safety were evaluated at 6 months, 12 months, and annually thereafter.ResultsThirty-three patients with aHUS and 27 patients with secondary TMA were enrolled. Median treatment duration of aHUS was 24weeks. Complement genes variants were detected in 11 of 18 patients with aHUS (61.1%). Among the 29 aHUS patients with available baseline data, platelet count (PLT), lactic dehydrogenase and serum creatinine (SCr) improved within 1-month after eculizumab initiation. TMA event-free status, complete TMA response, PLT normalization, and SCr decrease were achieved in 67.9% (19/28), 27.8% (5/18), 56.5% (13/23), and 57.1% (16/28) of patients, respectively. Thirty-three and 11 adverse reactions were observed in patients with aHUS (13/33 patients) and secondary TMA (6/27 patients), respectively.ConclusionsThis interim analysis confirmed the acceptable safety profile and effectiveness of eculizumab for Japanese adult aHUS patients in real-world settings.

Long-term Eculizumab Treatment Contributes to Recovery from End-stage Renal Disease Caused by Atypical Hemolytic Uremic Syndrome

We experienced a favorable outcome in an adult case of atypical hemolytic uremic syndrome (aHUS) after long-term eculizumab treatment. A 38-year-old Japanese man with a history of central retinal vein occlusion was admitted to our hospital with progressive dyspnea. He was found to have non-immune hemolytic anemia, thrombocytopenia, and acute renal failure two weeks after an episode of the common cold. Plasma exchange was ineffective; therefore, we initiated eculizumab after we excluded other thrombotic microangiopathies. Although long-term peritoneal dialysis was required, we successfully discontinued dialysis 18 months after the onset of aHUS with eculizumab.