Cyclosporin A in the treatment of refractory immune thrombocytopenia purpura in children

Patients with refractory autoimmune thrombocytopenia do not respond to standard therapy with high-dose corticosteroids, intravenous immunoglobulin, and splenectomy. We describe the cases of two patients with refractory autoimmune thrombocytopenia treated with oral cyclosporin A (CsA) to evaluate the efficacy of this alternative therapy. Blood pressure and hepatic and renal function were in the normal range before initiation of treatment. Induction therapy with pulses of high-dose methylprednisolone was used for 3 consecutive days to improve the initial immune suppression. Gradual dose reduction of CsA, according the platelet count, minimized the long-term adverse effects of CsA. Oral CsA with pulses of high-dose methylprednisolone induced remission of the thrombocytopenia. Gradual weaning of CsA over months, according the platelet count, produced no observable adverse effects of the CsA. Rapid dose reduction caused thrombocytopenia, which resolved with higher dosages of CsA. Our cases show the efficacy of CsA for refractory immune thrombocytopenia. This therapeutic option with oral CsA as an additional salvage option may avoid splenectomy and the adverse effects of long-term corticosteroids. Larger clinical investigations are necessary to establish the indications and therapeutic regimen for CsA in immune thrombocytopenia.     

Refractory immune thrombocytopenia in systemic lupus erythematosus: response to mycophenolate mofetil

Immune thrombocytopenia (IT) is a common manifestation of systemic lupus erythematosus (SLE). Although severe IT (<20 x 10(9)/L) occurs in about 5-10% of patients, usually in the context of active disease, the absence of randomized controlled trials has not allowed the development of evidence-based guidelines for managing this condition. Conventionally, high-dose glucocorticoids are considered first-line therapy. Adjunctive medical and surgical treatments for patients with an absent or partial response to glucocorticoids have met with varying degrees of success. We describe an SLE patient with IT refractory to high-dose corticosteroids, pulse methylprednisolone and intravenous immunoglobulin therapy, whose platelet counts normalized during therapy with mycophenolate mofetil (MMF). Pending further controlled studies to confirm this observation, we suggest that MMF may be considered as a therapeutic option in the treatment of glucocorticoid-refractory immune thrombocytopenia in SLE.     

Successful treatment of type B insulin resistance with mixed connective tissue disease by pulse glucocorticoids and cyclophosphamide

Type B insulin resistance syndrome is a very rare condition caused by autoantibodies against the insulin receptor. We report the successful treatment of a patient with refractory type B insulin resistance with pulse glucocorticoids and cyclophosphamide. The medical record of a patient with type B insulin resistance was reviewed. A 36‐year‐old Chinese woman presented with menopause, weight loss and refractory hyperglycemia for 3 months, which could not be controlled by up to 972 of insulin units per day. Mixed connective tissue disease was diagnosed with high titers of antinuclear antibody, ribonucleoprotein antibody and interstitial lung disease. Type B insulin resistance was diagnosed with positive immunoprecipitation assay of anti‐insulin‐receptor antibodies in serum. We started one cycle of pulse methylprednisolone (1,000 mg/day for 3 days) then tapered to prednisone 1 mg/kg/day, and cyclophosphamide 0.4 g/week was added on. Three weeks after pulse glucocorticoid therapy, fasting glucose returned to 4.4 mmol/L. Fasting insulin decreased from 647.27 to 12.95 uIU/mL 6 weeks later. The patient had gained 15 kg during 20 months of uneventful following up, and glycated hemoglobin decreased from 10.1 to 5.1%.In this patient with type B insulin resistance, a combination of pulse glucocorticoids and cyclophosphamide was successful in inducing a complete remission. Close cooperation between endocrinologists and rheumatologists will ensure an individualized regimen for this rare condition.     

Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP)

Patients with severe immune thrombocytopenic purpura (ITP) may require an acute increase in the platelet count for surgery or ongoing hemorrhage as well as long-term maintenance treatment. Certain of these patients may be refractory to steroids, intravenous anti-D, intravenous immunoglobulin (IVIG), and splenectomy. Therefore, acute platelet increases were studied in 35 patients completely unresponsive to IVIG or high-dose steroid treatment. Because of their lack of response to either or both single agents, these patients were administered a 3- or 4-drug combination including IVIG 1 g/kg, intravenous methylprednisolone 30 mg/kg, Vinca alkaloids (VCR 0.03 mg/kg), and/or intravenous anti-D (50-75 microg/kg). Subsequent maintenance therapy with the oral combination of danazol (10-15 mg/kg) and azathioprine (2 mg/kg) was given to 18 of the 35 patients. Seventy-one percent of the patients responded to the intravenous combination treatment with acute platelet increases of at least 20 x 10(9)/L to a level greater than 30 x 10(9)/L. Two thirds of the patients given maintenance therapy achieved stable platelet counts greater than 50 x 10(9)/L without other treatments. One patient developed an ileus, but otherwise there was little toxicity of combination treatment. Combination chemotherapy is a useful approach for patients with ITP refractory to conventional treatments both for acute induction and for long-term maintenance therapy.     

Mycophenolate mofetil therapy for juvenile dermatomyositis with immune thrombocytopenic purpura

A 6-year-old girl, who had received corticosteroid and cyclosporine on the diagnosis of interstitial pneumonitis related to juvenile dermatomyositis, developed severe thrombocytopenia. Her thrombocytopenia was resistant to repeated intravenous immunoglobulin administration and methylprednisolone pulse therapy. After additional treatment with mycophenolate mofetil (MMF), instead of cyclosporine, the thrombocytopenia improved, facilitating a reduction in the dose of corticosteroid without exacerbation of the interstitial pneumonitis. We propose MMF as effective option in the treatment of immune thrombocytopenic purpura with autoimmune disease.     

Mycophenolate mofetil therapy for juvenile dermatomyositis with immune thrombocytopenic purpura

Abstract

A 6-year-old girl, who had received corticosteroid and cyclosporine on the diagnosis of interstitial pneumonitis related to juvenile dermatomyositis, developed severe thrombocytopenia. Her thrombocytopenia was resistant to repeated intravenous immunoglobulin administration and methylprednisolone pulse therapy. After additional treatment with mycophenolate mofetil (MMF), instead of cyclosporine, the thrombocytopenia improved, facilitating a reduction in the dose of corticosteroid without exacerbation of the interstitial pneumonitis. We propose MMF as effective option in the treatment of immune thrombocytopenic purpura with autoimmune disease.     

Unrelated partially matched peripheral blood stem cell transplantation with highly purified CD34+ cells in a child with Wiskott-Aldrich syndrome

Stem cell transplantation is the only curative approach to the treatment of Wiskott-Aldrich syndrome. However, using grafts from partially matched unrelated donors is associated with increased risk of graft rejection and graft-versus-host disease. In an attempt to prevent these problems, a 6-year-old boy with Wiskott-Aldrich syndrome lacking a suitable family donor, was transplanted with large numbers of unrelated highly purified CD34+ peripheral blood stem cells mismatched at one C locus. Conditioning consisted of busulfan 16 mg/kg body weight, cyclophosphamide 200 mg/kg body weight and antithymocyte globulin 20 mg/kg body weight x 3 days. The boy had a rapid hematopoietic engraftment and showed immunologic reconstitution by day +92. Although he did not receive prophylactic immunosuppression he did not develop any graft-versus-host disease and is well and alive up to now, 25 months after transplantation.     

Experiences with recombinant FVIIa in the emergency treatment of patients with autoimmune thrombocytopenia: a review of the literature

Patients with severe and refractory autoimmune thrombocytopenia (ITP) have significant morbidity and mortality rates. Currently, high-dose methylprednisolone and/or high-dose IVIgG are recommended for the emergency treatment of such patients with uncontrolled bleeding. However, some patients do not immediately respond to these therapeutic regimes and may require additional treatment. Recombinant activated FVIIa (rFVIIa) is a prothrombotic agent that appears to be useful in the treatment of patients with life-threatening bleeding. It has also been used in the treatment of several patients with thrombocytopenia. We administered rFVIIa into a patient with refractory ITP and performed a systemic review of all published reports to assess the available evidence on the efficacy and safety of this drug in patients with ITP. The results indicate that rFVIIa may help in the emergency treatment of patients with ITP who do not respond to other therapies.     

Intermittent cyclophosphamide for the treatment of autoimmune thrombocytopenia in systemic lupus erythematosus

STUDY OBJECTIVE: To determine the effect of monthly intravenous cyclophosphamide therapy in patients with systemic lupus erythematosus and autoimmune thrombocytopenia. DESIGN: Uncontrolled, retrospective clinical study. SETTING: Government referral-based research hospital. PATIENTS: Seven patients with systemic lupus erythematosus and 2 or more months of thrombocytopenia refractory to or requiring excessive doses of corticosteroids. Two patients had also failed to respond to splenectomy and repeated intravenous methylprednisolone infusions. Six patients had severe active renal disease at the time of treatment. INTERVENTIONS: Cyclophosphamide, 0.75 to 1.0 g/m2 body surface area, was given intravenously every month for at least 4 months. Prednisone dose ranged between 0.5 to 1.0 mg/kg.d. MEASUREMENTS AND MAIN RESULTS: All seven patients had normal platelet counts within 2 to 18 weeks after cyclophosphamide treatment (one to four doses). Prednisone was tapered to 0.25 mg/kg on alternate days in all patients. All six patients had significant improvement in their renal disease and lupus serologies. Cyclophosphamide was discontinued after four to six doses in five patients. Four patients maintained normal platelet counts on low dose, alternate-day prednisone for a mean of 5.6 years of follow-up. Two patients had recurrence of thrombocytopenia 1 to 3 years after discontinuing cyclophosphamide. CONCLUSIONS: Monthly intravenous cyclophosphamide is potentially useful for the management of autoimmune thrombocytopenia in patients with systemic lupus erythematosus who are refractory to or dependent on unacceptably high doses of corticosteroids, or are experiencing side effects of conventional medical or surgical treatment.     

Acute respiratory distress syndrome associated with macrophage activation syndrome in systemic lupus erythematosus: A case report and literature review

Rationale:Previous treatment for macrophage activation syndrome (MAS) includes high-dose intravenous methylprednisolone along with intravenous immunoglobulin G. If MAS worsened, second-line therapy consisted of anakinra; if the disease remained refractory, third-line therapy with etoposide was considered. In addition, cyclosporine A plays a role in early MAS and in preventing recurrence. Some studies have reported the use of cytokine-targeting agents other than anakinra, such as canakinumab, tocilizumab, abatacept, and tofacitinib.Patient concerns:The patient with systemic lupus erythematosus (SLE) had an uncommon combination of intermittent fever, hyperferritinemia, hypertriglyceridemia, jaundice, and significantly abnormal liver function test results. The patient reported a history of daily fever of 38 to 39°C, painful oral ulcer, anorexia, abdominal bloating, diarrhea, and malar rash progression for 2 weeks, and jaundice, tea-colored urine, and clay-colored stool for 1 week preceding hospital admission.Diagnosis:SLE flareups in the patient were initially suspected. However, the final diagnosis was acute respiratory distress syndrome (ARDS) associated with MAS.Interventions:The treatment included disease-modifying antirheumatic drugs (DMARDs), such as azathioprine, and titrated steroid doses of methylprednisolone (40 mg q8 h) and dexamethasone (15 mg q8 h), after the patient had ARDS and was intubated.Dose-adjusted monotherapy with dexamethasone was found to be effective; this may be attributed to some DMARDs being unsuitable for cytokine storms, that is, some DMARDs may cause complications in cytokine storms.Outcomes:After dexamethasone 15 mg q8 h treatment, the patient''s fever subsided within 2 days, and liver function became normal within 3 weeks. The patient regularly attended scheduled outpatient follow-up visits after discharge. After 2 years, the patient reported no symptoms or signs of SLE with 2 mg/d oral dexamethasone.Lessons:Early diagnosis of MAS and dexamethasone treatment for MAS with ARDS appear to be crucial for these patients.     

Combination therapy with low-dose cyclosporin A, azathiopurine, and prednisolone for a child with refractory chronic idiopathic thrombocytopenic purpura

We report on a boy with refractory chronic idiopathic thrombocytopenic purpura (ITP) successfully treated with combination therapy composed of low-dose cyclosporin A (CsA), azathiopurine, and prednisolone. The patient was diagnosed as having ITP at 5 years of age, and received high-dose intravenous immunoglobulin (IVIG), followed by oral prednisolone, intravenous pulsed dexamethasone, oral cepharantin, and intermittent IVIG therapies. Because there were no or only transient responses to these medical therapies over 2 years, he was splenectomized. However, 3 months after the splenectomy, his platelet counts fell to below 10 x 10(3)/microl accompanied by wet purpura. We resumed low-dose intermittent IVIG treatment for 1 year without sustained efficacy. We then started combination therapy with CsA (2.5 mg/kg/day), azathiopurine (1.7 mg/kg/day), and prednisolone (0.8 mg/kg/day). Complete remission was achieved within 2 weeks and the platelet counts remained > 50 x 10(3)/microl even after tapering off the prednisolone and azathiopurine at 6 and 12 months, respectively and have moreover remained normal for more than 10 months after completion of 2 years of CsA treatment. There were no adverse events during the therapeutic course. This is the first pediatric case of ITP treated with CsA in Japan. Such combination therapy may be promising and tolerable for childhood ITP with splenectomy failure.     

Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies

HCT is currently the treatment of choice for children with severe primary immunodeficiencies (PIDs). Frequently, these patients lack an HLA-identical sibling donor, and umbilical cord blood (UCB) transplantation may be an option; however, experience in this field remains scant. Fifteen children with PID (SCID 11, X-linked lymphoproliferative syndrome 2, Omenn's syndrome 1, Wiskott-Aldrich syndrome 1) received a UCB transplant. The donor was unrelated in 14 cases and related in 1. Median age at transplant was 11.6 months (range, 2.9-68.0) and median weight 7 kg (range, 4-21). Thirteen patients were conditioned with busulphan and cyclophosphamide and 2 with fludarabine and melphalan. Nine patients received antithymocyte globulin. Median NC x 10(7)/kg infused was 7.9 (range, 2.9-25.0) and median CD34 x 10(5)/kg 2.9 (range, 1.0-7.9). All patients engrafted. Median days to >0.5 x 10(9)/l neutrophils was 31. Eight patients developed acute graft-versus-host disease (GvHD) grades II-IV and one chronic GvHD. Viral and fungal infections were frequent. Four patients died: three from GvHD grade IV complicated by infection and one from progressive interstitial lung disease. Five-year survival was 0.73+/-0.12. All surviving patients presented complete immunologic reconstitution. No patient is intravenous immunoglobulin (IVIg) replacement therapy-dependent. UCB transplantation is a valid option for children with PID who lack an HLA-identical sibling donor.     

A prospective, randomized trial of conventional, dose-accelerated corticosteroids and intravenous immunoglobulin in children with newly diagnosed idiopathic thrombocytopenic purpura

To determine the minimal essential treatment for childhood acute idiopathic thrombocytopenic purpura (ITP), a prospective, randomized trial was conducted focusing on hemorrhagic manifestation as well as platelet count. Subjects with a platelet count of <10 x 10(3)/microL or 10 to 29 x 10(3)/microL and mucosal bleeding (group 1) were randomly assigned to receive intravenous immunoglobulin (IVIg) at 1 to 2 g/kg, conventional oral prednisolone (o-PSL) (2 mg/kg for 2 weeks). parenteral methylprednisolone (mPSL) (5 mg/kg for 5 days), or pulsed parenteral methylprednisolone (PmPSL) (30 mg/kg for 3 days). Subjects with a platelet count of 10 to 29 x 10(3)/microL without mucosal bleeding (group 2) were randomized to receive either o-PSL or no treatment. In subjects with a platelet count of 30 x 10(3)/microL or higher (group 3), patients undergoing no specific treatment were monitored. In group 1, IVIg offered faster platelet enhancement compared with o-PSL and mPSL, although neither mPSL no PmPSL showed any advantage, even over o-PSL. Platelet response was uniformly excellent when pretreatment platelet coun was > or = 10 x 10(3)/microL. Furthermore, the presence or absence of mucosal bleeding in subjects with a platelet count <10 x 10(3)/microL had no effect on the response to treatment. In group 2, platelet increase was indifferently attained with or without o-PSL. These data suggest that childhood acute ITP with a platelet count > or = 10 x 10(3)/microL may be left untreated or may be treated with o-PSL when mucosal bleeding is evident, whereas for those with a platelet count <10 x 10(3)/microL, IVIg is the most predictable platelet enhancer. Thus, a platelet count of 10 x 10(3)/microL seems to be informative enough to decide whether to treat childhood acute ITP.     

Profound thrombocytopenia related to G-CSF

Severe thrombocytopenia in association with G-CSF therapy is extremely rare. Here we report a case of profound thrombocytopenia in a 57-year-old male with refractory cardiac ischemia, who received G-CSF during an angiogenesis trial. After 5 days of G-CSF therapy (10 microg/kg/day) the platelet count fell progressively to a nadir of 5x10(9)/L. The patient received steroid, immunoglobulin and platelet support and recovered without sequelae. Subsequent investigations suggested an underlying immune-mediated thrombocytopenia, which we hypothesize was exacerbated by G-CSF therapy.     

Successful treatment with vincristine for an elderly patient with idiopathic thrombocytopenic purpura]

A 77-year-old female was referred to our hospital in March 1991 because of a severe bleeding tendency. Her blood count on admission was as follows: Hb 7.5 g/dl, WBC 4.6 x 10(9)/l with normal differentiation and platelet 2 x 10(9)/l. One month prior to admission, her blood count was normal. Initially, acute idiopathic thrombocytopenic purpura (ITP) was suspected, because of the acute onset of the bleeding tendency and thrombocytopenia. High dose intravenous immunoglobulin (400 mg/kg/day for 5 days) and bolus methylprednisolone (1 g/day for 3 days then tapered) were administered, starting March 13. Her platelet count had increased immediately on March 20 to 40 x 10(9)/l. However, platelet count decreased to 4 x 10(9)/l in the following two weeks. Her clinical course differed from that of typical acute ITP. Because the treatment with prednisolone was not effective, it was changed to intravenous infusion of vincristine (VCR) at a weekly dose of 1 mg for 6 weeks. The treatment was extremely effective, and her platelet count reached over 200 x 10(9)/l. The treatment was discontinued. Three weeks later, her platelet count decreased to 15 x 10(9)/l, the administration of VCR was resumed, and her platelet count recovered again. Throughout her clinical course, no side effect of VCR was noticed except for mild hypesthesia of the fingertips. VCR therapy was considered to be an useful treatment in elderly patients with ITP.     

Structure and function of the Wiskott-Aldrich syndrome protein

PURPOSE OF REVIEW: Mutations of the Wiskott-Aldrich syndrome protein can result in highly variable clinical symptoms that affect the hematopoietic/immunologic system. The responsible gene, WASP, has multiple domains, each with unique functions that were only recently fully recognized. RECENT FINDINGS: Two new comprehensive studies of patients with mutations of the Wiskott-Aldrich syndrome protein unequivocally demonstrated a strong phenotype-genotype correlation; the most predictive variable was the presence or absence of the Wiskott-Aldrich syndrome protein in the lymphoid cells from patients with X-linked thrombocytopenia or Wiskott-Aldrich syndrome, respectively. A third clinical study revealed a high rate (>70%) of autoimmune disorders in patients with classic Wiskott-Aldrich syndrome, possibly caused by immune dysregulation involving both T and B cell defects. In addition, the Wiskott-Aldrich syndrome protein is required for natural killer cell function by participating in the formation of immunologic synapses and facilitating the nuclear translocation of nuclear factor for activated T cell and nuclear factor-kappaB. Finally, the Wiskott-Aldrich syndrome protein was shown to play an important role in lymphoid development and in the maturation and function of myelomonocytic cells. SUMMARY: The progress made in dissecting the functions of the Wiskott-Aldrich syndrome protein has direct implications for our understanding of the distinct clinical phenotypes (Wiskott-Aldrich syndrome/X-linked thrombocytopenia; intermittent thrombocytopenia; congenital neutropenia), for making diagnostic and prognostic decisions, and for the selection of therapeutic strategies--from conservative symptomatic treatment to curative hematopoietic stem cell transplantation, or, in the future, gene therapy.     

A case of systemic lupus erythematosus expressing intractable thrombocytopenia remedied effectively by intermittent and continuous administrations of a small amount of immune globulin

We describe a case where intermittent and continuous administrations of a small amount of immune globulin were effective in the treatment of refractory chronic immune thrombocytopenic purpura by systemic lupus erythematosus (SLE). Steroid pulse therapy and cyclophosphamide pulse therapy were considered for thrombopenia. However, the patient had compressed fracture of the lumbar vertebrae due to osteoporosis and right external malleolus ulcer with complications of infection. Therefore, high-dose intravenous immune globulin (IVIG) therapy (400 mg/kg daily for 5 consecutive days) was administered. Then, as a maintenance therapy, a small amount of 400 mg/kg for 1 day (400 mg/kg monthly) was given in an intermittent and continuous manner, which resulted in improvement of thrombocytopenia and reduction of the amount of steroid administered.     

A case of systemic lupus erythematosus expressing intractable thrombocytopenia remedied effectively by intermittent and continuous administrations of a small amount of immune globulin

Abstract

We describe a case where intermittent and continuous administrations of a small amount of immune globulin were effective in the treatment of refractory chronic immune thrombocytopenic purpura by systemic lupus erythematosus (SLE). Steroid pulse therapy and cyclophosphamide pulse therapy were considered for thrombopenia. However, the patient had compressed fracture of the lumbar vertebrae due to osteoporosis and right external malleolus ulcer with complications of infection. Therefore, high-dose intravenous immune globulin (IVIG) therapy (400?mg/kg daily for 5 consecutive days) was administered. Then, as a maintenance therapy, a small amount of 400?mg/kg for 1 day (400?mg/kg monthly) was given in an intermittent and continuous manner, which resulted in improvement of thrombocytopenia and reduction of the amount of steroid administered.     

Treatment of intravenous immunoglobulin-resistant Kawasaki disease with methotrexate

OBJECTIVE: To evaluate the effect of low-dose oral methotrexate (MTX) as treatment for patients with Kawasaki disease (KD) resistant to intravenous immunoglobulin (IVIG). METHODS: The subjects were four patients with KD, aged 8 months to 8 years old, who showed persistent disease after treatment with high-dose IVIG (2 g/kg) and aspirin (100 mg/kg). These patients were re-treated with IVIG and were also treated with IV dexamethasone (0.3 mg/kg). IV dexamethasone induced defervescence in three patients, but fever recurred upon discontinuing the steroid. One patient showed no response to either IVIG or dexamethasone. All patients were subsequently treated weekly with low-dose oral MTX [10 mg/body surface area (BSA)]. RESULTS: MTX treatment resulted in rapid defervescence, improvement in clinical symptoms, and normalization of acute-phase reactants in all patients. There was no progression of coronary artery dilatation and MTX was discontinued with no recurrence of fever. No adverse effects of MTX were observed. CONCLUSION: Low-dose oral MTX is an effective treatment for refractory KD.